TABLE OF CONTENTS

1. What is Cancer

2. Metastasis

3. The cancer process in the Lung

4. Lung Anatomy

5. Chemotherapy

5A. Chemotherapy side effects

6. Radiation

7. Surgery

8. Treatment of Non small cell cancer, stages 1 and 2

9. Treatment of Non small cell, stages 3 and 4

10. Small Cell Lung Cancer

11. Metastasis and Anti-angiogenesis treatments

12. Gene Therapy

13. Clinical Trials

14. Other experimental therapies and overseas treatment

15. Mesothelioma

16. Omitted or other forms of lung cancer

17. Health Insurance Issues

18. Long and Short.-term Survival

19. Screening and early Detection of Lung Cancer

20. Medical malpractice claims.

21. Smoking and Cancer

22. Asbestos, silica and other occupational claims

23. Racial and Gender Influences in the Cause and Treatment of Lung Cancer

24. Research Sources.

25. What Families Members Can Do to Help.

APPENDIX

1. Glossary

2. Organizations Dealing with Lung Cancer

3. Seminars and symposiums dealing with lung cancer

4. U.S. News and World Report Rating of Hospitals

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1.0 WHY PATIENTS AND THEIR FAMILIES NEED A BASIC UNDERSTANDING OF LUNG CANCER

This book is designed to provide a detailed, but understandable, review of lung cancer. Specifically,

Understanding what certain chemotherapy drugs are trying to do, and why certain side effects develop may help you to understand and deal with them.

1.02 Organizational Scheme

Chapter one begins by discussing what cancer is, how and why normal cells change to cancer cells. Chapter two discusses how tumors metastasize. Chapter three discusses lung cancer specifically, the division between small cell and non-small cell lung cancer, and the different stages and ways of categorizing cancers. By the end of chapter three, you should have a basic understanding of how your disease developed and where it stands now. Chapters four through nine discuss surgery, chemotherapy and radiation which are the primary forms of treatment, and in nine through eleven, we review treatments at different stages utilizing materials from the National Cancer Institute.

This chapter discusses what cancer is and how normal cells change to cancerous ones.

1.03 The Approach of This Book

As I worked on this book, a member of my family contracted cancer, and I realized firsthand the stress such a diagnosis entails. However, I have tried to discuss cancer in a analytical fashion, laying out the facts and science even where they may paint a difficult picture, believing that being educated can only help the patient and his family. This is designed to be a middle book, more detailed than a general book about cancer, easier to read than a medical text. My goal is to lay out the science of lung cancer in a thorough, comprehensive, but understandable fashion. We begin by discussing what cancer is.

1.04 Limits

Hopefully this book will add to your knowledge about lung cancer and help you to work with your physician. This book is not designed to provide medical advice regarding any individual= s condition; indeed treatment alternatives may depend upon a number of individual factors. Note that I am not a physician or oncologist. Cancer research is an evolving area; some areas may have changed and conclusions might be modified. This again highlights the fact that this book is not designed to treat any patient but as a resource source for you to use under the guidance of the physician you select.

1.11 Abnormal Growth

Cancers share three basic characteristics: unregulated growth, lack of differentiation, and the capacity to metastasize to neighboring tissues. Cancer is a malfunction which creates abnormal growth of cells in an area of the body:

{Cancer}manifests itself as a population of cells that have lost their normal controls of growth and differentiation and are proliferating. In the first instance, these cells, derived initially from a normal cell, form a primary tumor (literally a swelling).... {This} primary tumor comprises a population of cells which are said to be growth transformed- that is they have acquired a set of mutations to a set of genes which allow them to divide repeatedly in a way that normal cells cannot. Vile, Cancer Metastasis: From Mechanisms to Therapies 24 (Wiley & Sons 1995).

1.12 Cell Division is a Normal Process

Cell division and replacement is a normal process in the body. Cells in some parts of our body are constantly growing like fingernails and hair. Other areas are not growing bigger, but the cells within them are multiplying. Thus, while one characteristic of cancer cells is their ability to multiply, normal cells do that too:

A Cells do all kind of things, including divide into more cells: one cell can divide into two cells, each "offspring cell" can divide into two cells, and so on. Cell division occurs at various times and for various reasons: cells divide during the growth and development of the embryo and the fetus, for example, and when there is a need to repair an injury in the body, such as a scraped knee. Cells also divide in cancer- cancer occurs when they divide out of control A (2)

1.13 Why Cell Growth is Necessary

Cell growth is needed because almost all parts of the body are subjected to daily wear and tear that kills or damages cells. Growth is needed to replace or replenish cells and sometimes to perform specific functions. For example, cells in our immune system grow to kill certain germs. As a child grows to an adult and increases in size, there is clearly cell growth and duplication. Cell growth and duplication are normal and necessary functions in our body. While normal tissue enjoys a careful balance where cell growth and duplication occurs when cells die or for other specific reasons, cancerous tissue may simply grow. Unregulated growth means a tumor grows without regard to the needs of the tissue or the normal controls for that cell or gene. One text explains:

A In the first stage, a normal cell undergoes an initial genetic change which partly releases it from the normally very stringent controls imposed upon its growth potential; the daughter cells accumulate further genetic mutations which accentuate this loss of normal growth regulation, until a population of tumor cells emerge which no longer respond to normal signals preventing cell division and growth. The cells of the primary tumor are, therefore, said to be growth transformed. The genetic mutations which accumulate in these primary tumor cells are to members of two classes of cellular genes, the proto-oncogenes and the tumor suppressor genes. These genes control the ability of cells to pass through the cell cycle and, hence, their ability to divide or, alternatively to stop dividing and to undergo {differentiation] @ (1)

Cancer is generally not unique behavior of a cell, but normal behavior expressed to an extreme or in an incorrect context. Division and duplication of cells, movement of cells to damaged areas, and are all characteristics of normal cells. Even metastasis, movement of cells to other organs may occur with healing of wounds, the developement of a fetus, or attacking bacteria.

1.14 Understanding the term Unregulated Growth

To call the growth of cancer cells completely unregulated or unpredictable is somewhat inaccurate. Tumors share certain characteristics and we can to some extent predict how they will behave. Some types of tumors grow rapidly, like small cell cancer, while others grow slowly.

1.15 Classifying Tumors Based Upon Growth Characteristics

We categorize different types of lung tumors based primarily upon their growth characteristics. There are two main categories of lung cancer small cell and non-small cell. Small cell tumors grow rapidly but are susceptible to chemotherapy while non-small cell tumors grow more slowly. Chapters 3-5 explains the categorization scheme for lung cancer.

1.16 Differentiation

Normal cells are differentiated, that is constructed or organized for a specific purpose. As a cell changes, it loses some of its distinctive characteristics, i.e., its differentiation. Cancer cells are classified from well-differentiated to poorly differentiated, with the degree of differentiation one indicator of how the cell has changed. Under a microscope, a pathologist can look at the cell, determine and categorize its differentiation.

Tumor cells are labeled from well-differentiated, meaning relatively limited changes have occurred to poorly differentiated, meaning significant changes have occurred. The extent of differentiation is one factor in evaluating the status of the patient, but has not become a critical factor. Instead the extent of metastasis, or movement to other tissues, has become the chief factor in determining the status of the tumor and the treatment which will be administered.

1.17 Metastasis

Probably the most serious danger in cancer development is the tendency of cancerous cells to metastasize, that is, invade neighboring structures, and transmit the cellular malfunctions to those cells:

A Whereas a benign tumor will expand in size as a consequence of cell division, it will not invade surrounding tissues nor will it shed cells that are capable of initiating tumor foci elsewhere in the body. A malignant tumor will, however, actively invade and destroy surrounding tissue and also give rise to cells which often spread to produce foci of tumor growth at distant sites. Vile, Cancer Metastasis: From Mechanisms to Therapies 101-102. (Wiley & Sons 1995).

1.171 Analogies to Normal Cellular Behavior

Metastasis is not strange or unique behavior, but essentially cells misusing certain inherent traits. Imagine if someone= s leg suffered a serious burn or injury. The body would likely repair the leg by replenishing cells and repairing damaged sources of blood supply. With a cancer, the body believes the area is damaged, so it connects with neighboring sources of blood and nourishment to replenish the damaged area. In truth, many cancers do reflect damage to DNA, but the remedy the body creates simply spreads the cancer, rather than repair the damage.

Metastasis, the movement of cancer cells to normal organs and structures seems strange. Yet analogies to the behavior of normal cells are seen:

A It is also important to remember that expression of invasion promoter genes is not a purely pathological phenomenon seen only in cancer. Certain normal cell types demonstrate different elements of the phenotype as part of their usual functions. Thus, leukocytes resemble metastatic cells in many ways since they must leave the bone marrow and move, via the circulation to specific sites elsewhere in the body where they must penetrate to sites of infection and inflammation. Similarly, embryonic cells must move between developing tissues in a way that can be likened to tumor cell invasion.... Therefore, expression of the invasive phenotype by cancer cells should be thought of more as the activation of normal cellular programmes in an inappropriate cellular context, than as the expression of completely novel phenotypes. In this way, it may be possible to understand how and why the genes of invasion are expressed so aberrantly in tumor cells and, therefore, to generate more mechanism-based and effective treatments.@ Vile, Cancer Metastasis: From Mechanisms to Therapies 24 (Wiley & Sons 1995).

1.173 Summary of the Metastatic Process

Here is a short summary of the metastasic process:

1) Cancer cells located in an organ such as the lung manage to break down the barrier confining them to that organ. A Local invasion by tumor cells involves the activation of genetic programs which allow them to pass away from the confines of the primary tumor mass, through any surrounding tissues and eventually to reach of blood or lymph vessel.@ Vile, id.

2) The tumor cells then move to an adjoining lymph node or blood vessel, with the tumor establishing a source of blood supply in that new location.

1.174 Tumors Are Categorized Based Upon the Extent of Metastasis

Cancers are categorized based upon the extent of metastasis (as well as growth). Non small cell lung cancers (the largest type of lung cancer) are classified from stage 1 to stage 4. Stage 1 tumors are limited to a defined area in a single part of the lung. Stage 4 means the tumor has metastasized to another organ, with stages 2 and 3 assessing the extent of movement to adjoining or distant lymph nodes. Stage one cancers are usually treated with surgical removal of the tumor, while stage four metastatic tumors treated with chemotherapy.

1.175 Metastastic Cancer Cells Retain the Characteristics of the Original Organ

One writer explains:

A even though cancers enlarge, invade adjacent body parts, and travel to distant metastatic locations, they remain unchanged. The characteristics of human tumors, with rare exceptions, are fixed for the life of every tumor, regardless of where or when distant metastases of the tumor are found. In 1874, Dr. W. Moxon, an English pathologist, described rectum in liver, referring to rectal tumors that were growing in their original unchanged forms after metastasizing to the liver.... a prostrate tumor that is diagnosed early prostrate specific antigen (PSA) was detected in the blood will continue to produce PSA years later at a metastatic site.@ Dermer, The Immortal Cell 46-47 (Avery Pub. Co. 1994).

 

1.21 Cancer as a Group of Diseases

While cancers share the three traits of unregulated growth, loss of differentiation, and proposenity to metastasize, the extent of each may vary. Some cancers are highly metastatic meaning they move quickly to other parts of the body, while others move slowly over years or even decades.

Cancers are categorized using these three characteristics, the extent of growth, differentiation, and presence of metastasis. Most scientists believe that cancer is a group of related diseases with certain common characteristics, not one disease. Indeed, the factors which cause cancer vary.

1.22 Varying Causes of Different Cancers.

Diet plays a critical role in the development of colon cancer, yet it has a limited role in lung, and perhaps no role in skin cancer. Nutrition plays a role in many cancers, but does not affect others. Given that the factors which create cancers vary, not surprisingly the tumors themselves differ. Cancers behave differently depending upon their type and the organ where they originate. Cancers are also treated differently.

1.23 Differences in Behavior of Different Cancers

Cancers behave differently depending upon their type and the organ where they originate. Some cancers spread or metastasize very quickly while others are slow-moving.

1.24 Treatment

Treatment is generally organ specific, a skin cancer would be treated differently than a prostrate cancer. Indeed, since there are different types of cancer in a particular organ, treatment can vary according to type. As we see later, small cell lung cancer is treated differently than other types.

1.21 Chromosomes

There are different cell cycles which are important to understand for a number of reasons. Identifying the factors which trigger transition to various stages has been a major goal of cell cycle research and with it cancer research overall. How do we stop cancer cells from replicating. If we can inhibit the process at any of its various stages, we can provide a cure or at least a hinderance. Anti-cancer drugs are frequently directed to specific points in the cell cycle. Understanding cell cycles helps you understand how various anti-cancer drugs work.

A The cell cycles are coordinated by the expression and/or activation of regulatory proteins.@ Gupta, Overview of Cell Cycle and Apoptosis (cell death) 90, Pass, Lung Cancer Principles and Practice (2000). Factors existing outside the cell prompt the cell= s division. Medical research addresses cancer in two ways: we can try to change parts of the cell itself or factors which are influencing the cell= s behavior. Some simple cancers have been cured by identifying a specific factor which is influencing the cell= s behavior, and creating something, perhaps an antibody, to address it. Unfortunately, lung cancer involves a large group of different factors, and isolating the critical or most potent one has been difficult.

1.242 Cell Cycle Phases

Phase 2 is S or Synthesis. Here the cell replicates its DNA so it now has 2 complete sets of DNA. This allows the cell to divide into two daughter cells, each with a complete copy of DNA.

But, before the cell can do this, it needs to enter the third phase, G2:

1.25 Chemotherapy and Cell Cycle

Some chemotherapy drugs aim to address cancer at specific phases in the cell cycle.

1.31 Proto-Oncogenes and Oncogenes

A the beginnings of cancer lay not in a wholesale rewiring of the cell, but in a subtle alteration of a fistful of key genes among the human quote of DNA. Under normal circumstances, such genes play a vital, growth-related role in all or most tissues of the body. In some tissues, the genes may set up the rounds of simple division, helping skin cells to proliferate into a scab around a wound, or allowing the immune system to send out a host of antibodies to assail an invading pathogen.... Whatever their assigned tasks, the genes that scientists have designated oncogenes share a common characteristic: they are vulnerable to mutations. And once mutated, the genes contribute to the birth of a tumor. That= s why the genes are oncogenes; onco is from the Greek onkos meaning mass. Some scientists prefer to say protooncogene when referring to the healthy progenitor of a cancer gene, but most biologists rather imprecisely say oncogene for any gene that is prone to becomeing tumorrigenic. Nevertheless, it= s important to keep in mind that our cells possess oncogenes not because some nasty natureal or supernatural force place them there to keep our population in check, but because the body requires the genes to grow.@

Angier, Natural Obsessions 5 (Mariner Books 1999)

A An oncogene is a sequence of deoxyribonucleic acid (DNA) that has been altered or mutated from its original form, the proto-oncogene. Operating as a positve growth regulator, the proto-oncogene is involved in promoting the differentiation and proliferation of normal cells. A variety of proto-oncogenes are involved in different crucial steps of cell growth, and a change in the protoB oncogene= s sequence or in the amount of protein it produces can interfere with its normal role in cellular regulation. Uncontrolled cell growth, or neoplastic transformation, can ensue, ultimately resulting in the formation of a cancerous tumor.@ www brittanica.com.

It= s somewhat like an eight year old boy playing baseball in the house, a normal activity performed in the wrong context where it can do substantial harm.

1.32 How Oncogenes are Categorized

We have identified a number of proto-oncogenes and oncogenes. The term oncogene derives from the Greek term onco, meaning mass, and cancer is a mass of abnormal tissue. We know from our discussion of chromosomes that genes and oncogenes can be identified with a specific location such as chromosome 17. Oncogenes are also given specific names, which are usually three letter abbreviations such as myc, erb, or P53. Sometimes a prefix will be added such as v, for virus, indicating that the oncogene is associated with a virus, or c, indicating that the oncogene is associated with a chromosome defect.

1.33 The Two Types of Oncogenes: Growth and Tumor Suppressor Genes

There are two types of gene mutations which essentially combine to create a cancer. The first, is an abnormality of a gene involved with growth. An example is a gene that produces a protein that causes a growth-factor receptor on the cell's surface to be constantly on when in fact no growth factor is present. Thus the cell receives a constant message to divide.

The second type of gene which turns off the cell cycle and helps control cell growth is called a tumor suppressor gene. When the tumor suppressor gene malfunctions, the signal to the gene to stop duplicating is lost. Imagine a car. A car would travel when it wasn= t supposed to if the accelerator was on ( growth-factor gene) or if the brakes were not functioning, (tumor-suppressor gene).

1.34 How Do Cells Know When to Divide:

Cells divide only when they receive the proper signals from growth factors that circulate in the bloodstream or from a cell they are in direct contact with. For example, if a person loses blood, a growth factor called erythropoietin which is produced in the kidneys, circulates in the bloodstream and tells the bone marrow to manufacture more blood cells. Growth factors that come from outside the cell can transmit a message by binding to the appropriate receptor on the cell triggering a signaling system that activates a specific gene in the cell's nucleus. Other signals generated within the cell itself can use the signaling system to activate a gene.

1.41 DNA Damage

A normal gene can become damaged in different ways. A cell can become abnormal when part of a gene is lost (deleted), when part of a chromosome is rearranged and ends up in the wrong place on a chromosome (called a translocation), or when an extremely small defect occurs in the DNA, which results in an abnormal DNA blueprint and production of a defective protein. A gene may be initially defective or an outside product such as tobacco smoke may over time cause damage. In some situations, we can identify which gene has been damaged:

In Burkitt lymphoma, a malignancy of immature B cells, one characteristic feature is a chromosomal translocation about 80% of the time, a translocation between the long arms of chromosomes 8 and 14 are involved; less frequently, a translocation between the long arms of chromosomes 8 and 2 or chromosomes 8 and 22. All three translocations found in Burkitt lymphoma involve a specific position on chromosome 8 (8q24) that is occupied by the cellular proto-oncogene/oncogene, c-myc. www.cancergenetics.org.

1.42 Time for Cancer to Develop

1.52 Complete Response and Partial Response

The term complete response means elimination of the cancer, at least based upon available medical tools of measurement. It unfortunately does not preclude reappearance of the disease. The term partial response, as used by most authorities means a 50% reduction in the size of the tumor. The initial chemotherapy is called first-line chemotherapy; if the chemotherapy is needed again, that is second-line chemotherapy. Since there the cells develop some immunity to chemotherapy, there may be some different considerations with second line chemotherapy.

1.53 Lymph Nodes

There are two basic ways that cancer metastasize, that is spread to other organs. The most common route is by channels that exist in every part of the body called lymph channels. Lymph channels are a fine network of vessels that carry the liquid portion of the blood from different parts of the body. Returning to the bloodstream, the lymph is filtered through lymph nodes and returns to a large lymph vessel near the heart. Given the flow of lymph to and from the lymph nodes, we can understand why the finding of cancerous cells in the lymph nodes will be critical. If the tumor has moved to a lymph node, its potential for dissemination throughout the body increases. A tumor which is detected and removed before a lymph node becomes cancerous has a far better prognosis than one which has contaminated a nearby lymph node.

1.531 Regional and Other Lymph Nodes.

In staging the patient, that is ascertaining his status, doctors consider whether the lymph nodes are cancerous, and where the cancerous nodes are located. The spread of a tumor to a lymph node located near the tumor, or a regional node, is less serious than the spread to one further away, a contralateral node. If the lymph node is further from the tumor, that indicates a greater spread of the tumor.

1.54 Blood Vessels

A tumor may also spread through the body through a blood vessel. There are various tests to ascertain the extent of cancer in the blood however, blood vessels cannot be individually assessed as lymph nodes usually are. A surgeon will generally obtain samples or biopsies from lymph nodes to ascertain whether the nodes are cancerous. This is important because as we will see in chapter 4, the type of treatment given depends upon lymph node status.

1.55 Carcinomas and other Forms of Cancer

The most common type of cancer is a carcinoma, a cancer that arises in the cells that forms the lining of different parts of the body. Cancers in the lung, breast, prostrate, and colon are all carcinomas. Cancers that involve tissue or bone are called sarcomas. Cancers involving blood cells are known as lymphomas or leukemias. While most research is organ specific, some studies will cross organ lines. Some forms of chemotherapy for lung cancer are also used for breast or colon. Scientists are less likely to test a treatment on other types of cancer.

Because cancer cells are basically normal cells gone wrong, they are frequently not recognized by the immune system. Sometimes there is a minor type of immune reaction, but by various mechanisms, the cancer cells manage not to be affected by it.

1.71 The Argument for An Immune Reaction.

The precise role of the immune system in cancer is confusing and unclear, with some indication of an immune defense, and some of immune failure in the face of cancer.

A In support of immune surveillance, lymphocytic and mononuclear infiltrates are found in many tumors, and their presence correlates with a better prognosis in certain tumor types. Tumor-infiltrating mononuclear cells have been shown in a number of studies to lyse tumor cells in vitro. (In vitro means a test of cells in a laboratory). In addition, immunological activation markers... are unregulated or induced on tumor cells in a proportion of cancers. These observations, however, have not been universal, and provide only indirect evidence for immunological responses to tumors.

Early studies of chemically or irradiation-induced tumors in inbred mice revealed the presence of unique antigens in these tumors. Tumor cells which were transplanted from the host into a naive recipient (the term naive means that patient or animal was not previously exposed to the substance at issue)

grew progressively. On the other hand, if the tumor was transplanted into an animal which had been exposed previously to the same tumor, then the tumor was rejected.@

Vile, Cancer Metastasis: From Mechanisms to Therapies 101-102. (Wiley & Sons 1995).

1.72 How the Immune System Fails in Attacking Cancer

Vile also discusses the compelling contradictory findings:

Against an effective immune surveillance mechanism is the lack of an increase in the incidence of most common cancers in patients with immunodeficiencies or on long-term immunesuppression. Immuno-depressed individuals do show an increased incidence of lymphoid malignancies and tumors associated with oncogenic viruses, but not of the more common spontaneous tumors such as cancers of the lug, breast, or colon. Similarly, no increased incidence of tumors is seen in congenitally immunodeficient nude mice. Id. At 102.

1.73 Observations About the Immune System= s Role.

We can provide some general observations about cancer and the immune system:

1) The immune system has some role in attacking cancer cells, but it is frequently reduced or evaded entirely,

2) The efficiency of the immune system depends upon the type of cancer and its location. This reinforces the basic principle that cancer treatment is organ-specific. Indeed, the Food and Drug Association (FDA) does not approve A cancer drugs,@ but essentially approves drugs for treatments on specific types of cancers. This is why it is almost always incorrect to read an article about positive finding of a cancer drug on one organ and assume it will translate to success on another.

3) Since the immune system has the capacity to successfully attack various types of foreign bodies, research continues in terms of improving the performance of the immune system. This can entail ways of having specific cells like killer T cells activate against cancer cells, or somehow improve the body= s ability to recognize cancer as an abnormal event.

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2.11 The Importance of Understanding Metastasis

The potential for metastasis is a problem for all cancers, and in particular lung cancer. The chief cause of death in lung cancer is not the direct damage to the lung but the consequences of metastasis. Most lung tumors are detected in an advanced stage where there has been significant spread of the tumor. Thus, an understanding of how a tumor metastasizes, and ways of treating metastatic lung cancer are critical to any discussion of treatment options.

2.12 The Steps Involved in Metastasis

There are four basic steps involved with metastasis:

1) Tumor cells in an organ such as the lung must separate from each over, overcoming the usual restrictions imposed by cell adhesion and cell-contact inhibition,

2) Tumor cells come to a nearby lymph node or blood vessel enabling them to use that pathway to ultimately travel to another organ

3) The tumor encroaches into the protective covering of another organ breaking down the extracellular matrix.

4)Tumor cells create a blood supply (vascularization) by inducing capillary growth into and around the tumor- a process know as angiogenesis. An adequate blood supply is essential so that the rapidly proliferating cells can obtain nutrients and oxygenation, otherwise mass necrosis (cell death) can half the growth of the cells. Tumor cells move to another organ which can sustain its growth.

Normal cells are connected with one another. For example, cells in a person= s arm combine to help perform various tasks. However, in a cancerous tumor, one of the first steps is for cells separate from one another. A Separation of cells from the primary tumor mass must occur before long range spread can be possible. Detachment of single cells or clumps of cells may be directly related to a decreased level of cell adhesiveness in tumor populations.@ Wile, Id, at 26.

The boundary that separates one group of normal cells from the next is called the basement membrane. Under a microscope, a tumor, a group of cancer cells, can be seen be seen penetrating through the basement membrane:

Cancers can produce substances that attack constituents of the glue that binds cells together (the technical term is intercellular matrix). This matrix contains many different components, such as a substance called collagen, which gives strength to many tissues. Cancers may produce a type of substance called collagenase that attacks and breaks down the substance Cancer cells can also produce other substances such as hyaluronidase, a group of substances called protease, and probably dozens of others that allow the growing cancer cells to push through normal tissue boundaries. As a result, cancers often have a very ragged, irregular, and indistinct border- a feature that is often important in distinguishing a cancer from a nonmalignant lesion, as nonmalignant areas (such as warts, benign tumors, or cysts) have a border that is clearly visible and quite distinct.).@ Buckman, What You Really Need to Know About Cancer 14 (Johns Hopkins Press 1997).

2.31 Drugs to Combat MMP

New drugs are being designed and tested to see if they can frustrate this process of MMP. Many have worked in a laboratory where these drugs succeed in frustrating this process with cancer tissue, and sometimes animals. However, with humans, there has been difficulty in delivering the particular drug to the tumor area in sufficient quantity to be effective. A later chapter discusses the success of MMP drugs.

2.41 Tumors Cannot Grow Beyond a Certain Size Without Creating a Source of Blood Supply.

Once the tumor cells have separated, entered a nearby lymph node, and penetrated a distant or nearby organ, the final step is to link to a source of blood supply and nourishment. For simplicity, we have called this the final step; some scientists would suggest that establishment of a source of blood supply occurs first, or that there are multiple parts of the process.

The creation of a source of blood supply is essential to a tumor= s growth, and probably to its ability to sustain itself. Dr. Judah Folkman pioneered this area called angiogenesis research and a book about him explains:

no tumor could grow beyond a tiny size until it sent out a chemical message to recruit an ample blood supply. For that chemical signal to be sent out, Folkman believed, an angiogenic switch had to be flipped- a switch that turned on the tumor= s production of a growth-producing agent such as B-FGF (basic fibroblast growth factor), or VEGF (vascular endothelial growth factor), which Folkman had long referred to as TAF. It was this angiogenic switch that made nearby blood vessels sprout and grow new branches and kick-started the rapid growth of tumors. Cook, Dr. Folkman= s War Angiogenesis and the Struggle to Defeat

2.43 Anti-angiogenesis Research

There is continuing research about developing drugs to inhibit growth factors with called anti-angiogenesis drugs. A number of drugs are attempting to inhibit angiogneseis and there are over 100 clinical trials involving anti-angiogenesic drugs. Chemotherapy involves drugs used to kill cancer cells while anti-angiogeneic drugs attempt to frustrate their spread. Since the two types of drugs work differently, new research attempts to combine the two types of drugs.

One theme of cancer research in the 21^st century is combining different types of treatment, with each type reaching an optimal level of toxicity, where it attacks cancer cells but not does not unmanageable damage to other cells.

2.51 Location and Proximity

Metastasis is partly explained by geographical proximity:

In some instances, this organ preference of metastasis can be explained simply in terms of the anatomical relationship of the organ with the site of the primary tumor growth. Hence, many secondary tumors will develop in those organs which provide the first capillary bed encountered by dispersing metastatic cells, since the tumor cells may be carried as aggregates which pass into a capillary whose lumen is smaller than the clump diameter. A knowledge of the circulatory anataomical associations of the primary tumor site with other organs can typically be used to predict the seeding site of about 60% of the metastases from that tumor. Metastases from colon cancer probably occur with high frequency because the liver receives the drainage of the blood supply to the large intestine. Vile, Cancer Metastasis: From Mechanisms to Therapies10-11 (Wiley 1995) (hereinafter cited as Vile, at ).

2.52 Chemical and Cellular Attractants

In other instances, there are specific chemical or other attractants which lead cancer cells to particular parts of the body: Usually when tumors are located at a distant site which could not be predicted on the basis of circulatory anatomy, it is because the site expresses specific determinants which actively promote the growth of the metastatic cells.

We know that different structures are harder or easier to penetrate, and some areas such as brain, bone, and liver are the subject of frequent metastasis, while others such as feet are virtually never. It may be that those structures where lymph and blood are frequently transmitted have to be receptive to other cells, allowing cancer cells to enter. Using an analogy, a burglar might be able to penetrate some houses whereas others would have sufficient protection.

2.53 Soil and Seed Hypothesis

2.54 Different Types of Collagens

Scientists divide the collagens in the basement membranes into types and describe how tumors create collagenese to attack some of these protective barriers:

Tumor cell invasion requires crossing tissue compartment barriers such as basement membranes and interstitial connective tissue. Both of these barriers have various collagen types that compose the structural scaffolding upon which other matrix components {are assembled]... Ultrastructural studies of tumor cell invasion demonstrated local dissolution of basement membrane materials and suggested that tumor cells produce a distint callegonolytic enzyme to degrade basement membranes. In support of this concept, highly metastatic tumor cells, endothelial cells, and polymorphonuclear leukocytes have been found to produce a type IV collagen-specific metalloproteinase.....Type IV collagenolytic activity correlates with metastatic activity in murine tumor models. Highly aggresive human tumors, such as carcinomas, melanomas, hepatomasa, fibrosarcomas, and reticulim cell sarcomas, all have elevated levels of type IV collagense when compared with benign control cells. (1)

Thus we can theorize that bodily structures with collagen types 1-3 are less susceptible to metastasis that those with types 4 and 5.

2.61 Why Cancer Patients and their Families Need to Understand Growth Factors and Related Concepts

Some cancer patients may be asked to participate in clinical trial, experiment procedures testing new drugs after they have shown success in laboratory experiments on cells and tests with animals. Some of these clinical trials deal with methods of combating growth factors or cancer spread to other organs. Thus, an understanding of these terms and what the new drugs are attempting to do may help you to decide whether to utilize these new treatments.

The term growth factors is frequently used, sometimes with different meanings depending upon the speaker. Sometimes, growth factor is used as a term synonymous with oncogene or proto-oncogene. Thus growth factors refers to a protein, or signal which prompts improper cell growth and replication, i.e., cancer. In some instances, growth factors are used to denote certain behavior involved with angiogenesis, the establishment of sources of blood supply by tumors. To heighten precision, scientists have identified many growth factors and attempted to define their behavior, when do they prompt cell division, why, on what types of tumors to they act.

2.611 The many different growth factors and why it is difficult to find a cure.

In an ideal context, a growth factor would be identified, the reason why it acts in an abnormal fashion would be determined, a method of preventing this behavior, perhaps by administration of an outside agent would be identified, and the tumor would be cured, or at least its spread frustrated. This model has worked with other types of cancer, however, there are problems at each stage with lung. Specifically,

1) There are a number of growth factors involved with lung cancer. Determining which one is preeminent has been difficult.

2) Since there are different growth factors, it is likely that there will be different types of treatment for different types of lung cancer. However, today we divide treatments in two large categories: small cell and non-small cell. We will need to further define the cancer type and cell behavior to achieve even a partial cure.

3) Achieving a cure in the laboratory has been easier than in practice. Anti-cancer drugs like angiostatin appeared to frustrate cancer spread in the laboratory but have not done so in practice.

4) Delivering the drug to the cancer is difficult. How do we arrange so that any drug or new gene reaches the necessary areas.

Thus, the cancer researcher's task is difficult and we must be careful not to attribute too much significance to small advances in the laboratory. This is why cancer testing is a five or more step process:

Test the new agent in a laboratory on cancer cells, in vitro testing (check)

Evaluate the test on animals,

Perform initial tests to see if the new drug is tolerated by humans and does not cause significant side effects, (Phase 1 Clinical Trial)

Compare the new drug with existing treatment to determine if the new treatment achieves best results. (Phase 3 Clinical Trial)

Determine whether the new drug should be combined with other existing forms of treatment to achieve optimum efficiency, evaluating the new drug in different contexts.

Will future researchers be able to build upon our increasing knowledge, use computers to digest and analyze information more effectively and ultimately develop a cure. In the interim, the multi-faceted nature of the task means that it is difficult to develop a quick cure so that those who report extraordinary results may not be genuine.

2.62 Tumor Angiogenesis Factor- TAF and VEGF

One well-known growth factor is tumor angiogenesis factor (TAF). A The tumor secretes a substance known as tumor angiogenesis factor (TAF) which induces blood vessels to produce new capillaries that grow toward the tumor and finally connect with it.@ American Cancer Society, Informed Decisions 19 (1997). Scientists now call TAF, vascular endothelial growth factor (VEGF), indicating it creates new sources of vascular growth or blood supply, and arises in the endothelial or lining cells.

One of the chief areas of medical research is finding ways of inhibiting VEGF. One could find ways of directly stopping or reducing VEGF, or inhibiting those factors which prompt VEGF. While VEGF occupies a significant role, there are a number of other growth factors involved in the cancer process. One difficulty with combating cancer is identifying the roles of these different growth factors so that substances can be developed to attack or frustrate them.

Once a cancer has metastasized, it is more difficult to attack or cure. Let us look at some of the difficulties metastatic cancer presents.

2.71 Surgery and Metastatic Cancer

Surgery is the first consideration in treating a cancer; simply remove the cancer in an operation. However, if the cancer has spread to various parts of the body, it would be difficult to remove the entire tumor. One might know where the tumor cells are located, and even if we did, operating on many different organs would be risky and time-consuming. Many lung cancer patients are older, with breathing capacity compromised by years of smoking. For such patients, lengthy procedures would create substantial risk. That is why surgery is almost never used if the cancer has metastasized to another organ (stage 4 cancer as we discuss in a later chapter). However, if the tumor has moved to a nearby lymph node but not yet reached another organ, surgery may be recommended if the patient has good pulmonary reserve (breathing capacity).

2.72 Radiation and Metastasis

Radiation has some of the same problems as surgery. Radiation is designed to target specific areas of the body. If the cancer has spread, radiation may not completely successful in killing all the cancer cells.

2.73 Chemotherapy

First, chemotherapy generally has only the capacity to kill a certain percentage of cancer cells. Thus, as cancer cells spread and divide creating a larger number of cells, the ability of chemotherapy to completely combat it decreases. Secondly, as chemotherapy progresses, some cancer cells unfortunately develop the ability to withstand the chemotherapy, called multi-drug resistance. Sometimes, a drug will be used, substantially reduce the size of the tumor, but lose its effectiveness after a period of time. Second-line chemotherapy involves drugs used after the first group has stopped being effective.

2.74 Anti-angiogeneic Drugs

Consider an analogy. Many believe that crime is connected with a lack of education. A city decides to try a program which provides after school assistance to junior high and high school students in subjects such as english, math, and science. After one year, crime statistics have not decreased. Do we conclude that the program is ineffective. There may be other factors at work, it may take long to demonstrate a connection. Cancer researchers face similar problems trying to isolate a single factor in a clinical trial. In the laboratory, other factors can be eliminated but in trial with humans, many variables remain. This is one reason why laboratory successes in detecting gene abnormalities do not immediately translate into successful treatments.

_________________________________

Having a basic understanding of cellular behavior helps us understand the carcinogenic process. Recall an oncogene is a cellular component which stimulates or predisposes a cell to divide, and a tumor suppressor gene, the cell component which can stop or frustrate abnormal cellular division. Lung cancer is basically a two step process, activation of growth oncogenes, and deactivation of recessive tumor suppressor genes. Dr. Devita= s book, Cancer Principles and Practices of Oncology, explains the cancer process in the lung:

bronchial cells in the lung.

2. Continued exposure leads to the development of deletions and translocation in the genes. Abnormal oncogenes develop and those replicating cells are activated or developed. Other oncogenes are also activated.

3. There are other genetic changes, such as mutation of ras family, c-raf-1 and other oncogenes, some of which could involve growth factor or growth factor receptor genes. Thus, three steps occur: growth factor is produced, continued exposure leads to changes in the DNA, and finally abnormal growth factors develop.

The book, Lung Cancer by Desmond Carney describes the process of carcinogenesis, the change of normal cells to cancer cells this way:

The concept of multi step carcinogenesis, which has been well described in some human carcinomas such as carcinoma of the colon, remains much more elusive in lung cancer....

Initiation is the first step when DNA in a cell is altered so that it no longer responds normally to signals for proliferation or differentiation. This can occur over a short period of time and years before cancer develops. The second step, promotion is the expansion of the initiated cell into nodules, papillomas or polyps; progression to the third and final step is the evolution of the premalignant lesion into invasive cancer. Carney, Lung Cancer 15

(Arnold Publishing Co., Great Britain, 1995)

Here is another description of lung cancer development:

3.21 Initiator, Promoter Carcinogenic Process

Many scientists describe the cancer process as a two step process of initiation and promotion. Thus some cancer agents initiate changes in the body to alter the cells, with other agents taking these initially changed cells and transforming them into cancer cells. It is believed that since these are multiple carcinogens in cigarette smoke, it acts as both initiator and promoter. The book Lung Cancer describes the process this way:

The concept of multi step carcinogenesis, which has been well described in some human carcinomas such as carcinoma of the colon, remains much more elusive in lung cancer.... Initiation is the first

step when DNA in a cell is altered so that it no longer responds

normally to signals for proliferation or differentiation. This can occur over a short period of time and years before cancer develops. The second step, promotion is the expansion of the initiated cell into nodules, papillomas or polyps; progression to the third and final step is the evolution of the premalignant lesion into invasive cancer. Carney, Lung Cancer 15(Arnold Publishing Co. Great Britain, 1995)

3.22 The Carcinogenic Process in a Smoker

A company called Lungcheck describes the development of cancer in a smoker:

1. Columnar Cells Protect the Lung. Before you started to smoke, your air passages probably looked perfectly healthy. Tall columnar cells lining the air passages help keep the lungs clean. Some columnar cells secrete sticky mucus which coats the entire respirator tract with a protective barrier. The mucus traps the dust particles you inhale. Other columnar cells grow hair-like bristles (cilia) that sweep the mucus and trapped dirt out of the lungs and up to your throat, where you can cough it up.

2. Irritation to Columnar Cells As you start to smoke, this cleaning process begins to break down. Poisons in cigarette smoke paralyze the cilia and their sweeping motion stops. Severe irritation to the columnar cells results.

3. Production of Mucus and white Blood Cells In response to this irritation, your lung tissue produces more mucus and white blood cells in an attempt to protect itself from the poisons in cigarette smoke.

4. Columnar Cells Deteriorate and Metaplasia Develops As the irritation from smoking gets worse, patches of columnar cells begin to deteriorate and change their shape. The cilia disappear and the columnar cells transform themselves into flat, lacelike cells, a process called metaplasia.

5. The Precancerous Phase Called Dysphasia These metaplastic cells become Increasing abnormal until they reach a precancerous stage called dysplasia. Even at this stage, if you quit smoking, your lungs have a good chance to recover and heal themselves. Cancer develops after your lung suffers many years of irritation from cigarette smoke.

Lungcheck was developed to detect lung cancer or even precancerous changes at an early stage. Lungcheck is a type of sputum cytology (analysis of sputum) which has a great life-saving potential by identifying cancerous changes at an early stage, but unfortunately like most early detection tools in the lung, has limited use.

3.31 Growth and Tumor Suppressor Genes

There are again two types of gene mutations: an abnormality which causes unrestrained growth, (growth factor gene) and one which causes a tumor suppressor gene to malfunction:

3.32 Why Only Some Cigarette Smokers Get Cancer

We know that both genes are involved with the formation of cancers. This helps explain why some smokers contract cancer while others don= t. It may be that cigarette smoke causes some changes but only results in cancer when combined with an existing gene abnormality. That is why people with family histories of certain cancers are more likely to contract cancer than others. It is somewhat like destruction of buildings in a hurricane. Buildings with defects in the foundation will be damaged while others can withstand the assault.

Additionally, we know that exposure to multiple carcinogens increases the risk of cancer. Thus, people who smoke and were exposed to asbestos are more likely to contract lung cancer than people exposed to only one carcinogen. It would simplify analysis to say that smoking causes a change in a dominant gene while asbestos causes a malfunctions in a tumor suppressor gene (or vice versa). However, it appears that each carcinogen can cause changes in both types of genes:

A Various factors, including cigarette smoking, asbestos, and diet, have been reported t o correlate with the development of lung cancer. Of these factors, cigarette smoking is believed as the major carcinogen for lung cancer. Recent studies indicate that cigarette smoke carcinogens cause genetic damages at both oncogenes(K-ras) and tumor suppressor genes(p53) of lung cancer, and hence initiate and promote the development of lung cancer.@ Yano, Causative Agents for Lung Carcinogenesis, Nippon Rinsho, 2000 May, 58:5, 1017-22.

At this stage in cancer research, we are generally unable to reverse the cell abnormalities though significant progress has been made in identify them. Clinical trials for patients with advanced cancer are experimenting with various means of correcting or mitigating gene malfunctions.

3.33 Growth Oncogenes Which Contribute to Lung Cancer

We can identify specific genes involved in the developement of cancer in the lung:

Generally the genes which cause lung cancer are not peculiar to lung cancer; that is, they contribute to the carcinogenic process in other areas of the body. For example, squamous cell cancer is a common type of lung cancer and there are squamous cells in other parts of the body. We examine specific types below.

Some readers may wonder why it is necessary to discuss particular genes in a general book about lung cancer. Many clinical trials that patients and their families will want to evaluate aim to remedy particular genetic abnormalities, and a basic knowledge of this area can help you understand what a new drug is attempting to do.

3.34 K-Ras Gene

The K-Ras Gene is a gene associated with the development and spread of lung cancer. A recent study found that 13% of Taiwanese men with adenocarcinoma had K-Ras mutations but no women had these mutations. While many Taiwanese men smoke, very few women do. Thus, the study indicates that smoking contributes to the development of adenocarcinomas (a type of lung cancer,) and creates K-Ras mutations, but that other factors also contribute to the developement lung cancer.

3.341 K-Ras and VEGF

K-Ras is a proto-oncogene which means that the normal K-Ras gene performs certain functions in the body, while the mutant form contributes to cancerous behavior. The normal form is called wild-type while the abnormal form is called mutant K-Ras.

Recall that vascular endothelial growth factor (VEGF) causes the creation of new blood vessels and the spread of the tumor. One study found that abnormalities of the K-Ras Gene contributed to VEGF. A Of 14 tumors with mutant K-ras genes, 7 cases (50.0%) had high VEGF expression whereas only 39 of the 167 tumors with wild-type K-ras

3.342 K- Ras Mutations and the Early Detection of Lung Cancer

In the United States, the vast majority of lung tumors are detected late, when physical pain the patient is experiencing means that the tumor has grown and spread. Ideally, lung cancer, or cellular abnormalities presaging lung cancer, could be detected early, leading to medical intervention when it is most likely to effect a cure. Sputum cytology is a means of evaluating cells in the lung by having the patient emit a deep cough and analyzing those cells in a laboratory. A 1999 article asks whether a means of evaluating K-Ras mutations could be added to conventional sputum cytology technigues to provide a method of early detection:

3.35 Myc Photogene Family

Scientists have identified one particular gene family, the Myc gene, as associated with abnormal cellular development and cancer in various organs.

The retinoblastoma (RB) gene has a protein that appears to regulate the cell cycle. It is associated with a rare tumor of the eye. Most small cell lung cancers have absent or abnormal RB protein. Studies of individuals with abnormalities regarding RB genes showed they develop tumors at 10 times the normal rate.

3.37 The P-53 Tumor Suppressor Gene

The P-53 gene is another gene specifically associated with the development of many cancers. P-53 is a tumor suppressor gene and alteration of the gene results in it not preventing abnormal cell development. Imagine a policeman at a busy intersection. If we taped the officer's hands behind him, he would not be able to regulate traffic or stop cars. In a sense, the P-53 gene acts like a policeman regulating cell development, and cancer results partly because the P-53 gene malfunctions.

p53 protein...mediates several cellular functions: regulation of the cell division cycle, DNA repair, and programmed cell death.

DNA repair, and programmed cell death. In response to various forms of genomic DNA damage... the p53 protein can arrest the cell cycle at the G1 to S transition point, thus affording time for DNA repair and preventing duplication of a mutant cell, or alternatively, failing DNA repair, p53 protein can implement programmed cell death (apoptosis). Accordingly, p53 has been dubbed the A guardian of the genome.@ Etiology of Cancer: Carcinogenesis:http:/edcenter.med.cornell.edu./CUMC_PathNotes/Neoplasia/Neoplasia_04.html.

3.371 Wild and Mutant type P-53 Genes

P-53 is a protein of 53 kilodaltons and is located on chromosome 17 (p13). There are two types of P-53. First, there is normal P-53 also called wild-type P-53. This is P-53 in its normal condition, serving various tumor suppression functions outlined above. Mutant P-53 means the gene has been damaged. Not only will the gene not perform its tumor suppressor function, evidence indicates it plays a role in prompting duplication of cells.

Gemba, Immunohitochemical Detection of Mutant P53 protein in

Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31.

3.372 P53 and Small Cell Lung Cancer

A 1999 study found that 52% of small cell cancer patients had traces of P53 in bronchial specimens. Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. P53 presence was unfortunately a negative factor for these patients. A The overall response rate of patients in the p53 -positive group was significantly lower than that in the P53 negative group.@ Gemba, id.

2.373 Early Diagnosis of Lung Cancer with P-53 Testing

P-53 alterations appear to occur early in lung cancer:

If this damage to P-53 could be repaired or new P53 delivered, then cancerous behavior could theoretically be limited. This type of treatment has worked in the laboratory dealing with cancer cells:

Reintroducing a wild-type p53 gene into lung cancer cells, including bronchioalveolar lung cancer (BAC), dramatically inhibits tumor cell growth and promotes tumor cell death despite the presence of mutations in multiple other genes. Lee, Gene Therapy, 324 in Pass, Lung Cancer: Principles and Practice (2000).

3.375 Clinical Trials with P53

In a laboratory, scientists have been able to control tumor growth by introducing sufficient amounts of P-53. Clinical trials have shown modest success with humans by introducing P-53 gene retro-virus into the area of the tumor. Getting a sufficient amount in the body without creating intolerable effects continues to be the challenge.

To simplify the discussion, we divided genes into two categories, dominant or growth genes, and tumor suppressor genes. However, as the above shows, the process by which tumors grow is complex and sophisticated, with the term growth an oversimplification. The tumor suppressor genes play some role in growth while the dominant genes perform related functions.

Understanding the way in which cancer develops can help us understand why certain treatment are administered. Here are the primary forms of treatment for lung cancer:

1. Surgery The purpose of surgery is to remove the cancerous cells. With removal, the capacity to metastasize is eliminated as well as the direct impact upon the organ itself. Surgery is the preferred method of treatment, but frequently the cancer has spread so that it does not make sense to undergo the risks associated with surgery only to remove part of the tumor.

2. Radiation Radiation aims to do something similar, kill the cancer cells. Sometimes the purpose of radiation can be curative, to eliminate the cancer, alone or with other forms of treatment, or palliative, that is treatment designed to reduce pain or discomfort associated with the cancer.

3. Chemotherapy Chemotherapy is the use of certain drugs to kill cancer cells or prevent them from dividing or replicating. Today, mutlti-modal chemotherapy is the standard treatment, using a group of drugs which work in different ways to kill cancer cells or inhibit their growth and duplication.

4. Gene Therapy "The approach is to treat the disease by inserting a gene that has been lost or altered, or trying to block expression of a gene whose function is to promote uncontrolled cell growth. Gene therapy can also be used to provide a new function to cells, such as producing new proteins." Alcase, The Lung Cancer Manual 6.24 (1999) available online with the Alliance for Lung Cancer Advocacy, Support and Education.

5. Anti-AngioGenesis Drugs The principal danger of lung cancer is its spread to other organs. These drugs seek to limit and inhibit the spread of cancer through various means.

 

 

 

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4.10 The Left and Right Lungs

The lungs are two organs located in the chest or thoracic cavity. The right lung has three sections called lobes. The left lung has two lungs and is smaller because the heart takes up more room on that side of the body. A tumor= s location might be identified as right upper lobe or left lower lobe. The lung= s basic function is breathing, taking in oxygen and getting rid of carbon dioxide gas. See What is Lung Cancer, www.educ.kent.edu.

4.11 The Trachea and the Pleura

The trachea is a thin windpipe about four and a half inches long which divides into the right and left lungs. The windpipe or trachea brings air into the lungs. The lining which surrounds the lungs and helps to protect them is called the pleura, and the chest cavity is called the pleural cavity. Mesothelioma, a rare form of lung cancer, comes from asbestos entering the pleura and creating tumors in it. Pleurisy is inflammation of the pleural membrane. The pleura is divided into an outer layer called the parietal pleura and an inner layer, the visceral pleura. Between the parietal pleura and the visceral pleura is the pleural cavity which contains a lubricating fluid the body forms between the membranes to allow them to move easily on one another during breathing. On occasion, this fluid would need to be drained in a lung cancer patient. If the pleural cavity fills with air, this is called pneumothorax, and blood in the pleura is called hemothorax.

4.12 Mediastinum

The mediastinum is an area between the two lungs which contains lymph nodes. Recall that lymph nodes are part of the lymph system which helps purify the blood and remove certain byproducts. A mediastonomy is a procedure where the physician looks at the mediastinal area to detect the presence of cancer in the mediastinal lymph nodes. You will see reference to mediastinal nodes in the description of stage in assessing non-small cell lung cancer.

4.13 The bronchial tree.

The bronchial system is like a tree with the trunk the primary bronchus, branches, the bronchioles, and numerous small twigs, the alveoli. The trachea leads first to the primary bronchus in the right and left lungs. Some scientists refer to the bronchi as the larger airways. The right bronchus is more vertical, shorter and wider than the left and as a result, foreign objects that enter can lodge in it. Cancer in the right lung is slightly more common 55% versus 45% than in the left. ( Remember too that the right lung is a little larger than the left, with three lobes). Some patients have squamous cell carcinoma, which is a tumor involving squamous cells in the bronchus. The bronchi divide to form small bronchi called the secondary or lobal bronchi, which in turn continue to branch forming tertiary bronchi which divide into bronchioles. See What is Lung Cancer, www.educ.kent.edu Bronchospasm associated with asthma occurs when the muscles of the walls of the bronchioles go into spasm narrowing or closing off the air passageways and causing labored breathing.

4.14 Alveoli and breathing

Bronchioles subdivide into microscopic branches called respiratory bronchioles, and this in turn divides into microscopic alveoli where air exchange occurs. In the alveoli, carbon dioxide from the outside is converted to oxygen, and a descriptive name for alveoli is air sacs. The lungs consist of about 300 million alveoli where the primary exchange of gas and breathing functions occur. During emphysema, the walls of the alveolar are destroyed by smoking.

The author of The Chronic Bronchitis and Emphysema Handbook explains this process:

Because emphysema destroys elastic fibers in the membranous walls surrounding individual air sacs these alveoli lose their ability to recoil to their original size during expiration. Then, as an alveolus remains stretched, the rest of the membrane fibers eventually break. The wall is destroyed, meaning the air sac with its neighbor. As the process continues, alveoli become larger and fewer. It is somewhat like tearing down the interior walls in a building of multi-room apartments until each apartment is one large room. The alveoli's membrane walls- which are richly supplied with capillaries, the circulatory system's tiniest vessels- are the actual gas exchange sites. Haas, The Chronic Bronchitis and Emphysema Handbook (1990)

The process by which foreign substances destroy cells can cause different forms of disease. In some instances, the area will remain damaged as in emphysema while in others it appears the process of rebuilding and replacing cells creates cancer. A less common form of lung cancer is bronchio-alveolar, which affects the smaller alveiolar region of the lung. Since smoke and dust first come in contact with the primary bronchus, it would make sense that more cancers would occur there. However, since the advent of filtered cigaretes, smokers compensate by inhaling more deeply and cancer affecting the deeper airways are occuring more frequently.

4.16 Nodes

One of the chief dangers of cancer is that it may spread or metastasize to other organs and we discussed lymph nodes earlier. The Lung Cancer Manual by Alcase, an advocacy group for lung cancer, notes,

Because the lungs are so richly supplied with blood vessels, they serve as a convenient route for lung cancer cells to travel to other parts of the body. Most of the cancer cells that enter the bloodstream die, some survive and grow and become metastatic cancer... The lungs also have a rich supply of lymph vessels. The system of lymph vessels resembles the system of blood vessels. The purpose of the lymphatic system is to drain the clear fluid called lymph from the body tissues and bring it back into circulation.

Lymph nodes filter germs and other foreign invaders, such as cancer cells. Trapped cells can create tumorous growth in the lymph nodes causing them to swell, and an enlarged lymph node in the neck region can be an indication of lung cancer. Lung cancer usually develops in a single spot but if lymph nodes are involved, it may spread to other parts of the body. Typically the lymph nodes in the hilus (hilar lymph nodes) the place where the large airways and blood vessels enter the lung from the mediastinum (towards the center of the chest) are affected first. From there, the cancer may spread to the nodes of the mediastinum and then to the nodes in the neck and /or abdomen. If the tumor cells enter the blood stream, they may migrate (metastasize) to the liver, other section of the lung, the brain, the bones, and/or the bone marrow. Alcase, Lung Cancer Manual (1998) (at the time of this printing, the lung cancer manual was available at no cost on the Alcase website).

4.161 Staging and Measuring Lymph Node Involvement

The extent to which the lymph nodes are involved is an important consideration in determining the stage of disease, and the prognosis. Once there is lymph node involvement, surgery is unlikely to remove all the cancer. Thus, the staging systems below consider as a critical element the presence of cancer in the lymph nodes. A cancer located in the larger bronchi would typically move towards an adjacent hilar lymph node, then a mediastinal lymph node, and then to a node connected with another organ.

4.17 Sources of Pain

A tumor that grows may obstruct a bronchus, causing shortness of breath or chest pain. Thus, two of the classic non-specific symptoms of lung cancer are shortness of breath and chest pain. A non-specific symptom is one which can indicates a number of different diseases.

4.2 TYPES OF LUNG CANCER: NON-SMALL CELL

AND SMALL-CELL

Lung cancer is divided into two basic types, non-small cell and small cell. About 80% of lung cancers are non-small cell. Non-small cell lung cancer (NSCLC) combines at least three types of lung cancer: squamous cell (occasionally called epidermoid carcinoma), adenocarcinoma, and large cell carcinoma. These are classified together because their treatment and prognosis are generally similar. One textbook explains:

The remaining common histologic varieties of lung cancer- adenocarcinoma, squamous cell carcinoma, large cell carcinoma- behave as a group in a biologically similar fashion and respond similarly to therapeutic intervention. These tumors account for approximately 85% of all lung cancers. Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996).

4.21 Squamous Cell Carcinoma

Squamous cell refers first to a type of cell which lines the large bronchi, and squamous cell tumors are generally centrally located. It is generally agreed that approximately 90% of squamous cell carcinomas arise in subsegmental or larger bronchi...they have a tendency to grow centrally toward the main stem bronchus and to infiltrate the underlying bronchial cartilage, lymph nodes, and adjacent lung parenchyma. In time, this progression may lead to the formation of largenodular masses.

Epithelial tissue lines body surfaces or tissues, glands, and body cavities, and squamous cell is a type of epithelial tissue. Squamous cells line the pleural cavity and squamous cell cancer can occur outside the brochi and in other parts of the body . Thus one question is whether a squamous cancer is another part of the body will act similar to a squamous cell tumor in the lung.

4.212 The Percentage of Squamous Cell Carcinomas is Decreasing Perhaps Because Smokers are Breathing Low Tar Cigarettes More Deeply Leading to Peripheral Rather Than Central Tumors

While squamous cell remains the most prevalent form of lung cancer, its incidence is decreasing. One study found the percentage of squamous tumors in men decreased from 51.8% to 42.7%. Aisner, et. al., Comprehensive Textbook of Thoracic Oncology 251 (1996). With filtered cigarettes becoming more prevalent, smokers may be inhaling more deeply leading to the development of more peripheral adenocarcinomas rather than the central squamous cell carcinomas.

4.213 Squamous Cell Carcinomas and Early Diagnosis

with Sputum Cytology

There are important changes in squamous cells that occur long before the cancers can be seen on an x-ray. Sputum cytology is a device to detect these cancers at their earliest and most treatable stages. Sputum cytology is a test where the patient provides a deep cough and sputum, which is then analyzed in a laboratory by a pathologist. See Lungcheck.com (website by commercial entity providing detailed reports). The cytology can frequently identify early stage cancers and if sputum cytology were used more widely, many lives would be saved.

4.22 Adenocarcinoma

Adenocarcinoma is the second type of lung cancer comprising the group non-small cell lung cancer. It represents about 40% of all cancers and has become the most common lung cancer among women. It generally starts near the outer edges of the lungs, and its increasing incidence is connected with the tendency of smokers to breath the lower-tar cigarettes more deeply. It is occasionally called glandular cancer.

4.221 Adenocarcinoma, Asbestosis and Silicosis

While smoking remains the largest cause of adenocarcinoma, some scientists have seen an association with lung scars, and the term scar carcinomas has been used with adenocarcinoma. Where a foreign particle deposits in the lung, and collagen forms to encapsulate the particle, some have called this scar formation. For a detailed discussion of silica-related scar formation, See Castranova, Silica and Silica-Related Diseases (CRC Publications 1997). Asbestosis, silicosis, residuals of tuberculosis along with other scar formations have been linked to adenocarcinoma. Thus, an individual with asbestosis and adenocarcinoma, would likely have a legal claim. See Chapter 22. Some have questioned how closely adenocarcinoma should be associated with the various types of fibrosis or scaring in the lung:

For many years, adenocarcinoma was believed to develop on the basis of scar of (a) any kind. Although we do not deny the existence of scar cancer in the lung,... We have proposed the concept that central or subpleural scars in most peripheral adenocarcinomas were formed not before, but after, the development of carcinoma, and showed the mode of development of such a scar or a fibrotic focus.

4.222 Subtypes of Adenocarcinoma

There are three subtypes of adenocarcinoma:

* Acinar

* Papillary

* Bronchioalveolar

* Solid carcinoma with mucus formation

Acinar is the most common subtype.

4.223 Bronchioalveolar Carcinoma

Bronchioalveolar carcinoma is a type of adenocarcinoma which originates in the alveoli. Squamous cell carcinoma usually begins in the larger breathing areas, while adenocarcinomas originate in the smaller or peripheral airways, even occasionally at the microscopic level of the alveoli.

4.23 Large Cell Cancer

Large cell cancer constitutes about 15% of all cancers and the term large cell refers to large, masses of tissue usually displaying signs of necrosis (cell death). Since one of the characteristics of the tumor is necrosis, it can sometimes be confused with a poorly differentiated adenocarcinoma or squamous cell carcinoma. That is, the characteristic large cell tumor has experienced significant cellular changes similar to those which change a normal cell to a poorly differentiated adenocarcinoma. However, since the treatment for adenocarcinoma, squamous cell, and large cell are generally grouped together, a physician might not be overly concerned with distinguishing cell type within the group. A subtype of large cell carcinoma is giant cell.

4.231 Categorizing Large Cell

4.25 Differences Within the Non-Small Cell Lung Cancer Category

It is rare to categorize a disease based upon what it is not, but here it is accurate. Non-small cell lung cancer has these differences from small cell lung cancer:

1) it does not quickly metastasize like small cell,

2) it is not immediately responsive to chemotherapy in most cases like small cell,

With that said, there are many important differences within the non-small cell group which impact treatment and prognosis.

4.251 Greater Expression of MMP

Adenocarcinoma has a greater tendency to metastasize, compared with squamous cell. Most organs have a protective barrier called the extracellular matrix. During cancer, certain proteins called metalloproteinases or MMP help enable the tumor to penetrate these barriers. A Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes.@ Dennis, Matrix metalloproteinase inhibitors: present achievements and future prospect, Invest New Drugs 1997;15(3):175-85.

One study found that adenocarcinomas produced greater quantities of these MMP= s than squamous cell tumors possibly accounting for the greater tendency of aendocarcinomas to metastasize. A Compared with squamous cell carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, -13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression.@ Thomas, Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer, J Pathol, 2000 02, 190: 2, 150-6. Thus, we can theorize that an additional amount of MMP inhibitors, would be needed to accomplish the same result with adenocarcinomas as with squamous cell tumors.

4.252 Longer Survival with Squamous Cell

One study found, A For the 71 stage II patients with a squamous histology, a 5-year survival rate of 44% was noted as opposed to 14% for patients with a large cell or adenocarcinoma.@ (1) Given that dramatic difference in survival, one could argue that it could be erroneous to group squamous cell and adenocarcinoma patients in the same clinical trial. Using this assumption about 5 year survival, if the same drug were given to two groups of patients, one squamous and adeno, results could be interpreted to show triple the effectiveness (as measured by 5 year mortality) in the first group. Additionallly, since adenocarcinomas usually produce a greater number of MMP= s, we can theorize that higher doses of MMP inhibitors may be necessary to accomplish the same result as with squamous cell.

Thus, there are dangers in grouping these three types of cancer together, both for treatment and research. Future research may examine how the tumors act differently, allowing physicians to make more accurate judgments, and refine treatment based upon type.

1. Rodrigus, The Impact of Surgical Adjuvant Thoracic Radiation for Different Stages of Non-Small Cell Lung Cancer: The Experience of a Single Institution, Lung Cancer 23 (1999) 11-17.

4.31 Characteristics and Subclassifications

The other type of cancer group is small cell which has sub-classifications of oat cell and mixed. Small cell acts differently than non-small cell, requires different types of treatment, has its own prognosis, and therefore is separately categorized. It usually originates in large central airways and is composed of sheets of small cells. Small cell carcinoma is a tumor of neuroendocrine origin and is very aggressive, metastazing early and often. Endocrine cells are associated with growth which probably explains why small cell cancers are aggressive. Small cell carcinoma accounts for approximately 15% to 20% of all lung cancers. Small cell is a high-grade tumor meaning it reproduces and metastasizes quickly, but is also responsive to chemotherapy. 4.32 Role of Smoking and Location in Large Airways

Smoking is a clear factor in the development of small cell tumors. As with other cancers, but perhaps even more so, early detection and treatment is the key to cure.

4.33 Related Hormonal Syndromes

Small cell carcinoma can cause a number of hormonal syndromes. "The tumor cells may produce ectopic adrenocorticotropic hormone (ACTH), resulting in Cushing's syndrome, another paraneoplastic hormone syndrome that commonly occurs is the syndrome of inappropriate anti-diuretic hormone (SIADH). This is caused by secretion of ADH from the tumor.

4.34 Small Cell Staging

Small cell cancer is usually staged only as limited or extensive, depending on whether or not it has spread outside the chest. For non-small cell cancer, treatment will depend upon stage; stage 1 tumors are usually surgically resected. In contrast, chemotherapy is the standard treatment for small cell cancers, so most physicians do not use the stage 1-4 terminology for non-small cell cancer. In chapter 5, I discuss the question of how small cell cancer should be staged.

Limited stage carcinomas account for 30% of all cases. Limited stage means the small cell cancer is confined to one of the regional lymph nodes. Regional lymph nodes means lymph nodes in the area where the tumor originates. 70% of small cell carcinomas are extensive meaning at the time of diagnosis, the cancer has spread to other organs, or at least beyond the regional lymph nodes. Because extensive disease is common, patients are evaluated with head CT scan, bone scan, liver scan and bone marrow biopsy to see if any metastasis is present.

4.35 Small Cell Location and Appearance

Over 90% of small cell tumors are found in a central location and they typically grow around major bronchi.. The tumor typically extends also to lymph nodes and may invade vascular tissue which explains why many patients have metastases at the time of diagnosis

3.36 Role of Surgery in Small Cell Lung Cancer

With non-small lung cancer, surgery is the preferred option and is invariably used for early stage lung cancers, except when the patient has other significant health problems which create risks for surgery. However, a medical article discusses surgery for small cell lung cancer patients:

In the 1950's, surgical resection was still considered the preferred treatment of SCLC (small cell lung cancer) However, in a study conducted by the British Medical Research Council in the 1960's, patients were randomly assigned to receive surgery alone or radiotherapy alone; in patients with limited disease, the median survival was 199 days for those receiving surgical treatment versus 300 days for those receiving radiotherapy. One the basis of this study and the discovery of systemic chemotherapeutic agents with activity, surgical treatment for SCLC has been abandoned, and chemotherapy has been used for both limited and extensive disease.

Midthun, Chemotherapy for Advanced Lung Cancer Postgraduate Medicine, vol. 101, no. 3, March 1997.

Some observations:

1. Scientists determine the validity of certain treatment forms through epidemiological studies. The word epidemiological comes from epidemic and epidemiological studies investigate the patterns of disease, sometimes comparing the impact of disease between two group receiving different types of treatment.

2. Books like this are intended to provide a general overview, and you need to listen to your physician's advice regarding specific types of treatment, since statements in books and articles can be misinterpreted by patients unaware of subtle difference, for example, differences between non-small cell and small cell. Likewise, your physician should be familiar with recent studies and developments.

3. The National Cancer Institute agrees that surgery has limited utility in small cell lung cancer, but would not agree that surgery has been abandoned. See Chapter Four. One has to be careful of making quick conclusions based upon one or two studies, and you need to measure a study conclusions against our overall medical knowledge in an area. Perhaps a better way of assessing surgery and small cell cancer is to say that many small cell cancers have already had significant spread at the time of diagnosis. Where there has been such spread, that is movement to lymph nodes or other organs, surgical resection cannot accomplish the goal of completely removing the tumor. However, if we can be persuaded that the entire cancer can be removed, surgery might be appropriate.

4.37 Comparison among the Different Types

The book Lung Cancer categorizes the different forms of cancer as follows: In lung cancer, we know that the histological type (type of cell) is one of the most important factors, and that SCLC is most malignant of all; squamous cell carcinoma, adenocarcinoma and large cell are intermediate in terms of malignancy; while carcinoid tumor, adenoid cystic carcinoma and mucoepidermoid carcinoma (all relatively rare) are low grade malignancies. Carney, Lung Cancer (Arnold Publishing Co., Great Britain, 1995)

4.41 The American Joint Committee on Cancer (AJCC) Classification

Non-small cell lung cancer patients are classified by stage which largely determines the type of treatment which is provided. To understand your disease and treatment, you should have at least a basic understanding of the staging process. The American Joint Committee on Cancer (AJCC) uses the TNM classification. with T designating the size and location of the primary tumor, N the existence of cancerous lymph nodes, and M meaning metastasis or spread to other organs. Thus a medical chart would have a notation; classification of tumor, T1NoMo. (Tumor, size 1, no lymph node involvement, and no or 0 metastasis).

Tumors are classified from 0-4 based upon their size, ranging from a 0, tumor which cannot be seen on an x-ray but only identified microscopically, to a T4, a tumor, going beyond the lung tissue into another organ or structure. N or node specifies whether the tumor has entered into a lymph node and that node= s location in relation to the tumor. A tumor may first spread to an adjoining hilar lymph node, N1, and then to a contralateral lymph node, node further away from the main tumor. An overriding question is whether surgery can eliminate the tumor, and the higher the lymph node classification the less likely surgery will be performed. Lung surgery is major surgery carrying some significant risks. If the physician believes it is unlikely that the entire cancer can be removed, he may therefore believe that surgery should not be performed and that other forms of treatment should be used.

M designates Metastasis or spread of the tumor to other organs. If the cancer has spread to another organ, surgery again is not likely to be a viable option since the cancer cannot be entirely removed. The physician will want to accurately "stage the patient" not only to assess surgery but to gauge what type of chemotherapy or radiation is preferred. Here is the staging terminology:

PRIMARY TUMOR (T)

TX or T0: Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscope

T1: A tumor that is 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, and without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*

T2: A tumor with any of the following features of size or extent: More than 3 cm in greatest dimension Involves the main bronchus, 2 cm or more distal to the carina

Invades the visceral pleura associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T3: A tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung

T4: A tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or separate tumor nodules in the same lobe; or tumor with a malignant pleural effusion **

REGIONAL LYMPH NODES (N)

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor

N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)

N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

DISTANT METASTASIS (M)

MX: Distant metastasis cannot be assessed

M0: No distant metastasis

M1: Distant metastasis present

Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).

Sites are specified according to the following notations:

BRA = brain EYE = eye HEP = hepatic LYM = lymph nodes

MAR = bone OSS = osseous OTH = other OVR = ovary

PER = peritoneal PLE = pleura PUL = pulmonary SKI = skin

4.41 Metastasis, Types and Areas.

The most common sites of metastatic spread are the bone, brain, liver, and adrenals.

4.411 Brain Metastasis

These metastasis are discussed are Carney, Lung Cancer at page 64:

The reported incidence of asymptomatic brain metastasis varies from 2.7 to 9.6 percentand the value of screening (to detect these metastases) remains controversial. Silent intracerebral metastases occurring in isolation are well described with Adeno and large cell carcinomas. This is an uncommon presentation in patients with squamous cell carcinoma... Thus in contrast to other cell types, routine pre-operative brain scans are not indicated in those patients in whom the primary tumor is of squamous cell origin.

4.412 Metastasis to Bone

Carney= s book (65-66) reviews testing for bone metastasis:

Fifty per cent of bone material content must be lost before changes are apparent on plain radiographs.... [Thus] plain radiograph is an insensitive method of investigating localized bone pain. Radiopharmaceutical bone scans are in contrast highly sensitive though non- specific. Bone scanning is thus only indicated in those patients who have bone pain, elevated alkaline phosphatase levels, or recent exacerbation of bone pain... MRI may be useful to assess localized areas of persistent bone pain which appear normal on bone scan and plain radiographs.

4.42 The International Staging System for Lung Cancer

The International System for Staging Lung Cancer was adopted in 1997 by the American Joint Committee on Cancer and the Union International Contre le Cancer. The international staging system uses the TNM classification and then gives the patients a number, i.e., stage 1, stage 4, with the use of surgery and the patient's survival negatively related to the stage number. That is, surgery would generally be used to remove a tumor from a stage 1 patient, where it would not be employed for a stage 4 patient with metastasis since the tumor could not be completely removed

Stage I is divided into two categories by the size of the tumor; IA, T1N0M0 and IB, T2N0M0. Stage II is divided into two categories by the size of the tumor and by the nodal status; IIA, T1N1M0 and IIB, T2N1M0. T3N0 was been moved from stage IIIA in the 1986 version of the staging system to stage IIB. The other change has been to clarify the classification of multiple tumor nodules. Satellite tumor nodules in the same lobe as the primary lesion that are not lymph nodes should be classified as T4 lesions. Intrapulmonary ipsilateral metastasis in a lobe other than the lobe containing the primary lesions should be classified as an M1 lesion (stage IV).

Another type of staging is done by the AJCC. Their categorization using T, tumor size.

N, nodes, and M, metastasis is as follows:

Occult Carcinoma

TXN0M0 (T x means the tumor is sufficiently small than it cannot be seen on an x-ray).

Stage 1 T1or T2, N0,M0

Stage 2 T1, N1, M0 or T2, N1, M0 or T3, N0, M0 or T1N1M0, or T2, N1, M0

Stage 3A T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0

Stage 3B Any T-T4, N3;

Stage 4 Any TAny NM1

Here is a shorthand way of understanding the stages.

3.43 Small Cell Staging

The above classification scheme is for non-small cell carcinoma, squamous cell, adenocarcinoma, and large cell. Unlike these nonsmall cell carcinomas, small cell carcinoma is staged only as limited or extensive, depending on whether or not it has spread outside the chest. Limited stage carcinomas account for only 30% of all cases. Limited stage is confined to one hemithorax and regional lymph nodes (including mediastinal, contralateral hilar, and ipsilateral supraclavicular). Given the prevalence of metastasis, small cell patients are usually e evaluated with head CT scan, bone scan, liver scan and bone marrow biopsy to see if there has been metastasis. Some books will use the non-small cell terminology for small cell, even though the stages have different meanings for small cell tumors. For example, surgery would be the usual treatment for stage 1 non-small cell tumors, while it would still be unusual for small cell.

Scientists and physicians also classify lung cancer by its cell differentiation. Normal tissue is differentiated while cancerous tissue is haphazard, disorganized if you will. As one book explains:

When a cell grows and develops normally, it becomes more specialized to perform a particular function in life. This process is called differentiation and it results in irreversible changes in the cell's characteristics. Differentiated cells are mature cells that perform a particular function. For example, a lung cell looks and works like other lung cells. As a cell becomes more differentiated, it becomes more restricted in what it can do.... As malignant, or cancerous cell grow and divide, they become less and less differentiated. Eventually, they can nor longer perform the functions of the tissue where they originated.... The term differentiation is also used to describe how the cells of a tumor appear in comparison to normal cells. For example, tumors that are classified as "well differentiated" still contain cells that resemble normal cells of the original tissue.

Alcase, The Lung Cancer Manual 2.4 (1998)

Pathologists and physicians classify tumors according to their state of differentiation:

! Well differentiated, (a cell at its earliest stage of carcinogenesis)

! Moderately differentiated (more progression in the change to cancer cells)

! Poorly differentiated (a cell seen as clearly cancerous)

Within those categories, there may be subcategories, such as well to-moderately differentiated, or moderately to poor differentiated. Generally, the level of differentiation is a positive factor in survival with the more differentiated the cancer cell, the less chance of metastasis. One study found the DNA content of poorly differentiated adenocarcinoma significantly greater than that of well-differentiated adenocarcinoma. Carney, Lung Cancer (Little Brown 1995). Thus one can assume that the loss of differentiation is associated with increasing DNA mutations in the cell. However, stage rather than differentiation remains the primary factor in determining treatment.

4.61 The Importance of Classification

Survival as well as the nature of treatment is related to lung cancer stage as you will see in chapter four. If a tumor is relatively small, confined to a particular location without involvement of lymph nodes, or other organs, surgery- removal of the tumor would be the preferred treatment. In contrast, if the tumor had already spread to another organs, surgery would not accomplish he desired goal since parts of the cancer would remain. Let us review what these three items means before looking at the classification.

4.62 Patient Stage Related to Survival

Finally, tumor size, nodes, and metastasis are directly related to survival. Survival rates of 60-80% have been reported in TXNoMo patients. That is, patients with microscopic tumors with no lymph node involvement or metastasis. In contrast, appreciably lower survival rates apply when the cancer is much larger, lymph nodes are involved, or metastasis to other organs has occurred.

The particular types of treatment are discussed in detail in the succeeding sections. Because the materials can be somewhat technical, you need to understand the terminology

which is used in this area.

4.71 Surgical Options

Surgery is the treatment of choice for non-small cell lung cancer. Ideally, a small cancerous tumor is removed with surrounding tissue and that eliminates the cancer. This is done for smaller tumors, ideally without any lymph node involvement.

4.72 Lobectomy

The lungs are divided into lobes. There are generally three lobes on the right lung, two on the left lung. The left lung also has a cardiac notch to accommodate the shape of the heart. A lobectomy involves removal of the entire section of lobe of the lung.

4.73 Pneumonectomy

Pneumonectomy is surgical removal of the entire lung.

4.74 Wedge Resection

Wedge resection is removal of a small part of the lung. Because cancer recurrence rates were higher with wedge resection than with lobectomy in some recent studies, this treatment is not generally used.

4.81 Chest X-Ray

The most widely used diagnostic tool is the chest x-ray. It is economical and easy to use. A chest x-ray could take as little as ten minutes and cost less than $100. However, it is not a reliable method of diagnosing lung cancer. Many smaller tumors whose early detection could be critical to the patient's survival are missed with the chest x-ray.

4.811. Chest X-Ray Interpretation Problems

Radiologists are upon to make critical assessments based upon what are frequently almost imperceptible shadows. The chest contains tissues of different consistency, with air next to thick soft tissue and bone. Adequately producing an image which provides clear definition of all structures in the chest requires meticulous technique and attention to detail. The machine (film processor) used to develop the film should be working properly though up to 50% of x-ray film processors may have some deficiency.@

www.chest.x-ray.com.

While this is a most commonly performed examination, it often is done incorrectly. Studies have shown that from 20B 40% of x-rays are incorrectly interpreted. www.chest.x-ray.com. Indeed, there is a discernible difference in skill among radiologists interpreting chest x-ray films. However, even with good equipment and skilled people, the x-ray is still inaccurate.

4.822 Chest X-Ray Misses Over 75% of Stage 1 Tumors, those at the Most Treatable Stage

An important 1999 study discussed deficiencies in the chest x-ray, contrasting it with the accuracy of the CT or Cat Scan. In this study 1,000 smokers with no symptoms of disease were evaluated with CT Scan and chest x-ray. 27 of the participants were found to have lung tumors which were detected by CT Scan. However, only 7 of the 27 tumors were detected by chest x-ray! Many corporations trumpet less than 1 in 100 defects for various products and the HLA test for detecting paternity is more than 99.7% accurate. The chest x-ray in contrast was shown here to be less than 30% accurate in the patients who would benefit most by early diagnosis. Not suprisingly but quite sadly, many patients with advanced lung cancer reveal that they had a prior x-ray which failed to detect the tumor.

Stage 1 or beginning stage cancers are the most treatable. The results of the chest x-ray in this study for small, stage 1 tumors was even worse. With the Ct Scan, 23 of the 27 tumors were detected at stage 1. However, the chest-ray revealed only 4 of the 23 small, stage 1 tumors. Thus A stage 1 tumors were detected six times more frequently on low-dose CT than on radiography.@ Note, that this study was done in a clinical context at a well-known hospital. The x-ray machines were presumably working correctly and the slides interpreted by capable radiologists. Even in this context, the chest-ray performed poorly.

The study dealt with smokers with at least 10 pack year histories (pack years are computed by multiplying the number of years smoked by the number of packs in each year), who had no symptoms of cancer. Most of the persons detected turned out to have highly treatable cancers. Chest x-rays do detect some tumors, but primarily those at advanced stages which are more difficult to treat. It is a test of limited use, better than nothing, but not even 40 or 50% reliable in detecting small tumors.

Given the unreliability of the x-ray, we hope that physicians will begin using CT Scans to test those at high risk. Certainly, where an x-ray is ambiguous or displays some abnormalities, the prudent physician should order an x-ray. Misread chest x-rays are a chief source of medical malpractice claims. The prudent physician will check his equipment and have all slides read by a qualified radiologist. While that can reduce the possibility of error, it cannot eliminate the inherent limitations of the test.

4.82 Sputum Cytology

Sputum cytology is a microscopic analysis of cells from the lung. The patient does a deep cough and the liquid or sputum is analyzed by a pathologist and a report prepared. Using sputum cytology, a man named Saccamanno in a landmark study was able to detect the progression of lung cancer in a smoker. This test has the following benefits and limitations

1. The test is effective at diagnosing central squamous cell carcinomas, even at microspopic levels, imperceptible on a chest-ray and perhaps a CT Scan. Thus, it has some utility is detecting tumors at an early stage when the disease can be cured.

2. Recall that the category non-small cell lung cancer includes squamous cell cancer and adenocarcinoma. Squamous cell cancer is generally located in the larger central airways , while adenocarcinomas tend towards the smaller, peripheral airways of the lung. The nature of the test is to retrieve liquid in the lungs, and the patient is more likely to cough up liquid from the larger more central parts of the bronchial tree, than the parts of the smaller airways that produce adenocarcinoma. Thus, the test is effective at diagnosing squamous cell cancers, but less effective at detecting adenocarcinomas. While squamous cell remains the most common form of cancer, with low tar cigarette smokers inhaling more deeply, the number of adenocarcinomas in the peripheral airways is almost equal.

3. The European Cancer Institutes states, A Sputum cytological analysis is greater for squamous (93%) or small cell (89%) histotypes than for adenocarcinoma (25%) and large cell carcinoma (54%). www.sias.it/start/chap-13/chap13-2.htm

Thus, sputum cytology is a good tool for detecting some lung tumors, but not others. Used with Ct Scan, the two become a reliable method of detecting lung cancer in its early stages. The test is inexpensive, running in the $100.00 range.

4.821 Recent Advances in Detection of Lung Cancer with Sputum Cytology

Sputum cytology is an economical, non-invasive way of detecting lung cancer in its earliest and most treatable stage, with its primary drawback difficulty in detecting adenocarcinomas. However, a recent study indicated progress in refining sputum cytology to improve detection of adenocarcinoma:

Lam and colleagues developed a computer-assisted and automated image analysis method that detects aneuploidy and nuclear abnormalities in sputum samples. Between 5000 and 10,000 cells are stained with a Feulgen thionine DNA cellular stain, analyzed with a digital camera, and then screened using computer-assisted algorithms. In a series presented at the presidential symposium, Lam reported results showing that this screening technique was 70% sensitive for stage 0/1 lesions and 80% for adenocarcinomas, with a specificity of 90%. Lynch, 9^th World Conference on Lung Cancer, (2000) citing, Lam et. al, Lung Cancer Control Strategy in the New Millennium. Lung Cancer. 2000;29(Suppl 2):145.

4.83 Computerized Tomography or CT Scan

Computerized tomography or CT uses a beam that rotates around the body to produce a series of pictures taken from different angles. See www. Colorado Health Net, org./cancerlung.symptoms.html. This information is then processed by computer to produce a cross-section of a specific area. CT can reveal the existence of a tumor, and specifics about its location and size. Today, CT is the best non-surgical method of detecting lung cancer and revealing its size and status.

4.831 CT Scan to Detect the Nature and Extent of Disease.

Indeed, physicians go beyond using Ct as a device to detect cancer to using it to determine the extent of disease. CT is used to provide a picture of whether a tumor has infilitrated lymph nodes or other organs. One study found the CT to be 80% effective in determining whether there was cancer in lymph nodes:

A meta-analysis of 42 studies published between 1980 and 1988 found (using a node size greater than 1.0 cm as abnormal) a pooled sensitivity of 83%, specificity of 81% and accuracy of 81%. The 20% false negative rate is largely due to microscopic metastases to normal sized lymph nodes and the 20% false positive rate is due to enlarged nodes from pre- or coexisting inflammatory disease.@ chestx-ray.com/StaginglungCa/Lung Cancer

The Early Lung Cancer Detection survey found an even higher rate of

reliability in detecting tumors themselves.

4.84 Test Specificity and Accuracy

Let us review these terms which are frequently used with medical tests. A false negative occurs where the patient has a disease or characteristic and the test fails to detect that. Thus, the test is falsely or incorrectly negative; it should have been positive. Another word for false negative is accuracy. That is, what percentage of persons with a given disease are detected. If the CT is 80% accurate in detecting lymph node metastases, its accuracy or false negative rate is 80%.

Specificity is the number of false positives. That is, how many tests are incorrectly read as positive. For example, a person with inflamed nodes could have a CT Scan read as positive for spread of the cancer to the node.

4.85 Bronchoscopy

If Ct Scan is the most reliable non-invasive test, bronchoscopy is the most reliable minimally invasive test. While bronchoscopy should be viewed as a surgical procedure, its risks are generally minimal. The Virtual Hospital is an excellent site which describes bronchoscopy:

A Bronchoscopy is the examination of the airways under direct visualization. Bronchoscopy began with the use of a candle and a rod with a polished metal disk to visualize the osopharaynx. It has evolved into a wide variety of precision optical instruments capable of visualizing the endobronchial tree to the 5th or 6th generation....

bronchoscopy is used to obtain peripheral lung samples in the presence of lung parenchymal disease such as peripheral coin lesion(s), hilar adenopathy, or diffuse or focal parenchymal infiltrates. Finally, bronchoscopy is useful in staging lung cancer, evaluating the airways in patients with normal radiographic findings and positive sputum cytology, and evaluating the airways after thoracic trauma, or if there is a suspected airway foreign body.@

Virtual Hospital, Lung Ttumors: A Multidisciplinary Database, Bronchoscopy, www.vh.org.Providers/Textbooks/LungTumors/Diagnosis/Bronchoscopy/bronchosopy.htm.

4.851. How the Patient Feels During a Bronchoscopy

A The surgeon makes a small incision in the skin on the chest with a scalpel. The biopsy needle is inserted into the lung. You may feel a sharp, temporary pain when the biopsy needle touches the lung. A small amount of lung tissue is removed. Biopsy needle and syringe are removed. Adhesive bandage is applied to the biopsy site. Tissue is sent to the laboratory for analysis.@

4.842 Reliability of the Bronchoscopy

Reliability seems to depend upon the location of the tumor.

A Tumors may be present in three ways in the lung, as central endoscopically visible lesions, as submucosal or extrinsic lesions, and as peripheral lung lesions. The diagnostic yield and bronscospic approach to diagnose these lesions varies among these three presentations. In endobronchial visible lesions, bronchoscopy will correctly diagnose the lesion in 94% of the cases if at least 5 samples of the lesion are obtained....

By contrast, direct forceps biopsy correctly diagnoses only 27% of patients with extrinsic airway compression or with submucosal or peribronchial disease. The low yield is most likely due to the fact that the forceps biopsy does not sample tissue deep enough. Much better diagnostic results are obtained in this situation by using transbronchial needle aspiration. In this technique, a 1 cm. needle attached to a catheter is placed through the mucosa using the bronchoscopy....

The diagnostic yield for peripheral lung lesions varies widely from 30-90% using transbronchial biopsies. In this technique, the forceps are passed through the airways distal to the directly visualized sites using fluoroscopy.@ Virtual Hospital, Lung Tumors: A Multidisciplinary Database, Bronchoscopy, www.vh.org.Providers/Textbooks/LungTumors/Diagnosis/Bronchoscopy/bronchosopy.htm.

Sadly, some people have gone undiagnosed after a physician failed to detect a tumor during a bronchoscopy. The above highlights that the following:

1) Bronchoscopy is not a conclusive test. Where symptoms of lung cancer continue, and a definitive diagnosis of another disease is not made, additional diagnostic tests must be done. Our office is handling a medical malpractice claim where the physician essentially concluded treatment with a negative bronchoscopy and the patient was diagnosed with lung cancer approximately one year later. Where a patient seems to fit the profile of a lung cancer patient- significant smoking history, loss of weight, fatigue, chest pain, cough, and has other symptoms of the disease, a repeat bronchoscopy, needle biopsy, or even a thoracatomy (surgical biopsy) may be called for with a negative bronchoscopy. Timely diagnosis of lung cancer is critical.

2) Success in detecting the tumor will depend upon the tumor= s location and to some extent, the skill of the physician performing the procedure.

3) An adequate sampling is critical. Reports should clearly indicate how many samples have been taken so the extent of reliance on the bronchoscopy can be determined by other physicians.

4.85 Tools to Analyze Cancer Cells

Cancer cells may be analyzed to assess their structure and DNA.

4.851 Flow Cytometry

Flow Cytometry measures how many pairs of chromosomes the cells= s DNA contains. See American Cancer Society, Informed Decisions 136 (1997). If a cells has a normal number of chromosomes, it is diploid. If the cells have severely disrupted DNA, it is said to be aneuploid.

4.852 S-plase Faction, SPF

SPF measures the percentage of diseased cells in the synthesis phase of cell division. If the number is high, a great percentage of cells are in the S-phase and dividing rapidly, indicating the tumor is growing quickly. American Cancer Society, Informed Decisions 136 (1997). A low SPF indicates a slow-growing tumor.

Both flow cytometry and SPF show promise in providing an early indication of disease, though neither are routinely reommended for screening purposes.

4.91 The Sad Under diagnosis of Lung Cancer

As we note in a later chapter, there are potential legal claim arising from the failure of many physician to timely diagnose lung cancer. Indeed, in a country with supposedly the best medical care in the world, more people are diagnosed with advanced stage lung cancer than the more easily treatable stage 1 cancers. One would think that most lung cancers would be timely diagnosed. After all, lung cancer is the largest type of cancer for both men and women, unlike other cancers, the risk factors, smoking and exposure to dust like asbestos are easily identified,

and the time of diagnosis can make a significant difference in the patient= s prognosis. Nonetheless, we can identify four reasons why lung cancers are under diagnosed:

1) chest x-rays are a difficult tool to interpret and as noted, only tumors of at least 1 cm (centimeter) can be seen on a chest x-ray.

2) Strangely at the same time they note significant difference in patient prognosis based upon stage at diagnosis, both the American Cancer Society and the National Cancer Institute have failed to advocate programs for early detection of lung cancer. Instead unduly relying on 20 and 25 year old studies whose significance have been misinterpreted, they fail to recommend the obvious, that in addition to telling smokers not to smoke, we need to encourage them to be regularly checked for signs of a progressive disease which will afflict approximately 1 in 10.

Those reading this book who are heavy current or former smokers should be aggressive in seeking the maximum amount of testing and request that tests be performed regularly. While quitting reduces risks, and presumably stays the development of many cancers, former smokers still have an enhanced risk for the disease. Chapter four discusses the different options for patients depending upon the stage at which their cancer was diagnosed.

Cancer A cellular malignancy where loss of normal controls- results in unregulated growth, lack of differentiation, and ability to invade local tissues and metastasize.

Chest X-Ray An x-ray of the thoracic or chest area which includes the lungs. The chest x-ray will show tumors of at least 1 centimeter. Its advantage in its ease of use and low cost, disadvantage is that small tumors can be missed and others may not be shown.

Differentiation Normal cells are differentiated. As cancer progresses, cells lose their essential characteristics or differentiation. Cancer cells are categorized from well-differentiated to poorly differentiated.

Lobectomy Surgical removal of one of the lobes of the lung.

M or Metastasis M refers to metastasis in the TNM staging system, or movement of cancer from the lung to another organ.

N (or Node) N refers to lymph node in the TNM staging system.

Pneumonectomy Surgical removal of the entire lung

Sputum Cytology Analysis of lung cells by having the smoker cough. Effective at detecting very small microscopic cancers. An excellent technology not used nearly enough.

TNM Classification The American Joint Committee on Cancer (AJCC) has designated staging by the TNM classification. with T designating the size and location of the primary tumor, N standing for the existence of cancerous lymph nodes, and M meaning metastasis or spread to other organs. Thus a medical chart would have a notation; classification of tumor, T1NoMo.

T or Tumor T is the primary tumor in the TNM staging system, and is measured from 0, undetectable on an ordinary x-ray to 4 based upon its size and spread to nearby organs or structures.

5.01 A Chemo@ or Chemical Therapy

The term A Chemo@ means chemical and chemotherapy is the use of particular drugs alone or in combination to treat cancer. The term anti-cancer drugs is simpler. However, anti-cancer drug is a broad term covering a number of different types of drugs which affect cancer. Chemotherapy is generally used to identify anti-cancer drugs whose primary goal is to kill cancer cells.

The mechanisms by which chemotherapy drugs attempt to attack cancer are varied. Since the drugs perform different functions, it should make sense to use a number of different drugs simultaneously to attack cancer (so long as normal organs are not signficantly impaired ) and that is what is being done today.

Most patients are given more than one drug. The best mix of drugs or even the optimum dose is not known for lung cancer, and clinical trials continue to investigate the success of different combinations, with these trials yielding varying and sometimes contradictory results. Clinical trials generally divide patients by stage and category and it is possible that the particular type of tumor, squamous, adeno or large cell, might play a role, or the degree of differentiation in the cell, poorly differentiated to well-differentiated. Medical abstracts summarizing the results of clinical trials are available on Medline, www.healthgate.com (Medline is the world medical literuature database).

Generally, chemotherapy targets any area where cancer cells are located, in comparison to surgery and radiation which target defined areas. Chemotherapy may be used to reduce tumors, or in some cases, prevent the development of cancer in particular areas. These drugs generally destroy cancer cells by stopping them from growing or multiplying at one or more points in their life cycle. Most oncologists will recommend multi-modal chemotherapy (more than one drug), though the best mix of drugs is not known with clinical trials yielding varying results. The task is to provide a large enough dose to successfully attack the cancer while not unduly affecting the normal cells.

5.02 History of Chemotherapy

An accident in World War 2 paved the way for modern chemotherapy. A U.S. navy vessel sank in Naples, Italy. When the mustard gases it was carrying exploded, the casualties who had been exposed to the poisonous gases were examined and it was found that large number of cells in their bone marrow had disappeared and their lymphatic system had atrophied. An Army biologist began testing on animals with similar substances and found he was able to inhibit lymphoid tumors in animals. These drugs were tested on humans with Hodgkin's disease and found to temporarily inhibit tumors.

The Food and Drug Administration (FDA) regulates prescription drugs. Prescription drugs must be given with a doctor= s supervision and have FDA approval for use in the United States. FDA approval comes after review of clinical trials and other data to determine the safety and effectiveness of a particular drug. For example, in a shining moment, the FDA refused to approve Thalidomide in the early 1960's believing that adequate information about its safety had not been provided. Subsequently it was found that the drug caused serious birth defects.

5.11 FDA approval is Organ and Treatment Specific.

Cancer or chemotherapy drugs are not approved for all purposes. Instead the FDA limits their use to certain organs and sometimes in certain doses. For example, look at this FDA approval:

A FDA today approved Taxotere for treating non-small cell lung cancer that does not respond to cisplatin-based chemotherapy....

Taxotere was approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior cisplatin-based chemotherapy. Most patients with non-small cell lung cancer are found to have metastatic disease (cancer which has spread to other organs) when diagnosed, and curative treatment is not possible. Two randomized controlled clinical trials demonstrated that patients treated with Taxotere had increased survival compared to patients receiving supportive care or cancer therapy consisting of either vinorelbine or ifosfamide.@ www.fda.gov.

Note, that the approval denotes the type of cancer covered, the status of the patient, and the circumstances of use.

5.21 Chemotherapy Generally Targets Rapidly Growing Cells

Chemotherapy attacks all body cells to some extent, but targets rapidly dividing cells such as cancer cells. Its effect on other rapidly dividing cells such as hair follicles, cells lining the stomach, and red blood cells, accounts for at least some of its side effects. Chemotherapy affects the course of cancer by taking advantage of the cancer cell's penchant for constant reproduction. Almost all of the drugs used in chemotherapy suppress cancer by somehow altering the cells' DNA and thus their ability to reproduce. See Bruning, Coping with Chemotherapy (Ballantine Books 1993) (an excellent book written by a woman with breast cancer) .

5.22 What Does Cell-Cycle Specific Chemotherapy Mean

Almost all the drugs used in chemotherapy suppress cancer by altering the cells' DNA and thus their ability to replicate or reproduce. Since DNA is most vulnerable to drug interference during the reproductive phases of the life cycle, cancer cells are more likely to be affected than are the bulk of the body's normal cells, which reproduce at a much more relaxed pace. Thus, the very characteristic that makes cancer so dangerous has in some cases helped to contribute to its undoing. Indeed, some rapidly growing cancer such as small cell cancer are particularly susceptible to chemotherapy.

Chemotherapy drugs are either cell-cycle-specific (lethal to cells only during a specific reproductive phase) or "cell-cycle-nonspecific" (able to sabotage the cells no matter what phase they are in). In a sense, the inner workings of cells (cancerous and otherwise) are like gearboxes; what chemotherapy does is to throw a biochemical monkey wrench into the gearbox causing the machine to grind to a half-causing the cells to stop working, to die.

5.23 Adjuvant Therapy, Combining Chemotherapy with Other Therapy

Sometimes chemotherapy is the only therapy a patient receives. One advantage of primary chemotherapy is that because the cancer cells have not yet been exposed to anticancer drugs, they may be more vulnerable. A case of primary chemotherapy could be a patient with a severe heart problem who could not tolerate surgery and chemotherapy would be the exclusive form of treatment. The disadvantage of such chemotherapy is that the drugs must destroy a larger target, since none of the cells were removed by surgery or diminished by radiation.

Chemotherapy used in addition to surgery or radiation is called adjuvant therapy (adjuvant or in addition to). Chemotherapy is sometimes used after surgery and/or radiation therapy to help destroy any cancer cells that may remain.

5.25 Considerations Before Treatment Begins

Because chemotherapy can be harmful to certain organs, preliminary tests are conducted. For example, cells in the bone marrow frequently divide and therefore like other rapidly dividing cells are susceptible to the effects of chemotherapy. Thus, a blood test would be conducted to determine that the patient has a healthy number of red and white blood cells and platelet. Liver, kidney, and heart would normally also be checked.

5.31 Activity

The first question that must be asked is whether the drug has some favorable impact upon a particular type of cancer. If it does, the drug is A active.@ That a drug is active does not mean it will always or usually be used. Its level of activity may be less than other drugs, or its side effects could be significant. Let use assume that we have drugs A, B, C, and D.

5.32 Partial and Complete Response

There are some objective ways of categorizing activity. Most scientists call a partial response, a 50% decrease in the size of the tumor. Thus, if we have an 8 centimeter tumor, and with a particular drug, the tumor is reduced to 4 centimeters, the drug is active and the patient had a partial response.

If the tumor is completely eliminated, for example, it cannot be seen on an x-ray, that is called a complete response. A complete response must unfortunately be distinuished from a cure. Chemotherapy might temporarily eliminate a tumor, only to have it later return, or it might leave microscopic traces undiscernible by x-ray or perhaps even Ct Scan.

There are five basic types of chemotherapy drugs:

5.41 Alkylating Agents

Alkylating agents bind with DNA, preventing the cell from dividing. Cisplatin, a widely used drug is considered an alkylating agent, though it inhibits DNA by a mechanism that is different from most drugs in this category. It is cell cycle nonspecific, meaning it is not designed for any specific cycle in the cell.

5.42 Antimetabolite

Antimetabolite mimic nutrients the cells needs, tricking the cell into consuming them, so it eventually starves to death.

5.43 Plant Alkaloids

Plant alkaloids, also called vinca alkaloids are cell cycle specific. They interfere with those parts of chromosomes necessary for cell division. A Vinorelbine is now the major vinca alkaloid worth consideration. Vinorelbine is a classic antitubulin agent that arrests cell mitosis in metaphase and prevents tubulin polymerization to form microtubules. It is a cell cycle-dependent antimitotic agent.@ Pritchard, Other Chemotherapeutic Agents: Do We Need Them,@ The 2nd International Breast Cancer International Research Group Conference, medscape.com

Taxol, a popular drug, is a plant alkaloid and destroys a cancer cell= s ability to function and divide by preventing the cell from dissembling its fibrous skeleton of micro tubules. When the natural process is inhibited, the cell becomes choked with fibrous structures

5.44 Antitumor Antibiotics

These are not the same drugs used to treat bacterial infections. Rather, these drugs cause the strands of genetic material that make up DNA to uncoil, thereby preventing the cell from reproducing. An example is doxorubicin, though this type of chemotherapy has had limited use with lung cancer.

5.45 Hormones

Hormones occur naturally in the body and are involved with the normal growth process. Since some tumors may require certain hormones to grow, when the hormone is blocked, the tumor may not grow. Tamoxifen is an example of a hormone. Cuneo-Lung Cancer Study Group, M. Tonato, From Nitrogen-Mustards to cis-platinum and Beyond, www.culcase.org. The Cuneo lung cancer study group is one of the few organizations devoted solely to lung cancer and it holds an important conference on lung cancer each year.

5.51. Taxol

Taxol has been used to treat cancer for some years. It is an extract from the bark and needles of the yew tree, Taxus brevi folia. Taxol is a white powder and when prepared for use becomes a clear, colorless liquid which is given by intravenous route only. It has been used to treat the following cancers: Ovarian, Testis Metastatic breast cancer Head and neck cancer, melanoma, and lung cancer.

Taxol is most commonly used in combination with other chemotherapy drugs such as: 5-FU, Adriamycin, Vinorelbine, Cytoxan and Cisplatinum .The type and extent of a cancer will determine the method and schedule of administration of this drug. This decision is made by the medical oncologist. At present, Taxol is normally given once every three weeks.

The history of Taxol is supplied on a webpage entitled The Taxol Molecule:

Taxol was discovered at Research Triangle Institute in 1967 when Dr. Monroe E. Wall and Mansukh C. Wani isolated the compound from the Pacific Yew Tree, taxus brevi folia and noted its antitumor activity in a broad range of rodent tumors. Interest in Taxol waned for nearly a decade. ... In 1980, scientists at Albert Einstein Medical College reported that Taxol has a unique mechanisms of action, making it the prototype for a new class of chemotherapeutic drugs. Taxol bind tubulin, thereby inhibiting cell division... RTI.org. (Research Triangle Institute)

It is active as single agent therapy in non pretreated NSCLC and probably also after prior chemotherapy. Combinations with cisplatin or carboplatin have been the object of multiple phase II studies.(7). Taxol is manufactured by Bristol-Meyers Squibb. www.BMS.com.

5.511 Taxol Side effects:

While its consistent effectiveness throughout many clinical trials has made it a stable of lung cancer chemotherapy, there are side effects effects associated with Taxol. Some patiients will experience nausea or loss. I discuss some ways to deal with nausea in the next chapter. Other side effects have included: Low white blood counts, low platelet count, anemia, hair loss, soreness of the mouth, difficulty swallowing , diarrhea, nerve damage, allergic reactions, fluid retention.. Taxol is metabolized in the liver and excreted into bile and dosage may be reduced for patients with liver dysfunction or liver metastasis. Some patients have considered Gemcitabine instead of Taxol to reduce these side effects, though Gemcitabine has fewer clinical trials to confirm its efficacy. Patients should relay any side effects or problems to their oncologist.

5.52.Docetaxel

A recent press release touted the ability of Docetaxel to address non-small cell lung cancer, at least where prior chemotherapy had been unsuccessful:

A Events SA (NYSE: AVE), announced today that Taxotere* (docetaxel) for Injection Concentrate, 75 mg/m2, was cleared for marketing by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy.

Taxotere is the first chemotherapeutic agent to be approved by the FDA for the second-line treatment of advanced non-small-cell lung cancer.... We hope this new approval for Taxotere will enable physicians to extend the lives of non-small-cell lung cancer patients who previously had limited options once their disease had progressed.....

About.Com Pharmaceutical Guide Quoting December 23, 1999 Press Release by Events Co. Note that the above is a quotation from a press release, not an impartial analysis, and it is not clear whether the FDA has approved this drug for patients without prior unsuccessful chemotherapy. From the press release, it appear further clinical trials should directly compare Taxotere with other chemotherapy drugs in patients who have not undergone chemotherapy.

5.54 Tamoxifen

5.5541 Trade Name and Manufacturer

Tamoxifen is manufactured by Zeneca and has the trade name Nolvadex. It is also less commonly called Tamoxifen Citrate, Tamaxin, Tamofen,

5.5542 Mechanism of Action

Some cancer cells are estrogen sensitive, and estrogen binds to these cells and stimulates them to grow and divide. Tamoxifen is an anti-estrogen which inhibits the binding of estrogen and with it the division and growth of cancer cells. Not surprisingly, Tamoxifen has been used during the last twenty years for treatment of breast cancer. (1) Tamoxifen is also known to work through other growth factors and the immune system to provide some benefit to patients whose tumors are not estrogen sensitive. It appears to exert its anti-tumor effects by competing with estradiol for estrogen receptor protein. (2)

5.543 Classification

Tamoxifen is classified as a hormonal/biological response modifier or an antineoplastic. (2)

5.544 Potential Side Effects

5.644A Emotional Changes

Since Tamoxifen impacts a hormone which in turn interacts with mood, it can conceivably impact mood or create emotional changes

5.644B Liver Changes

Tamoxifen has been associated with changes in liver enzyme levels or other liver abnormalities. Thus, the existence of liver problems may be a contraindication

5.55 Vinorelbine

This drug is active or effective with non-small cell lung cancer and has been successfully combined with cisplatin. Vinorelbine has been investigated in 4 randomized trials and found to improve survival. The combination of vinorelbine to cisplatin has been compared in two randomized trials to vinorelbine alone with significant response rates improvement with survival increase in one (Le Chevalier, J Clin Oncol 12: 360; 1994) and not in the other (Depierre, Ann Oncol 5: 37; 1994). In the first one, the comparison was also performed with a third arm treatment made of cisplatin and vindesine, with a marginal effect on survival. It should be noted that both trials have obtained high quality score in our review (89 and 79,8%).

5.56 Gemcitabine

It is active as single therapy in non pretreated NSCLC and has been shown in phase II randomized trials to be better tolerated than the combination cisplatin-etoposide. That is, its side effects appear to be less and is generally not associated with nausea or vomiting. Gemciabine, sometimes called Gemcar has been successfully combined with cisplatin and ifosfamide in phase II studies. Results of phase III trials are pending.

5.57 Topotecan

Two studies assessing its effectiveness as single therapy in non pretreated NSCLC have shown contradictory results. Further data are required to specify the place of topotecan.

One of the presenters at the 1998 Cuneo Lung Cancer conference

summarized the status of chemotherapy for late stage lung cancer patients:

In another article presented at the 1999 conference entitled, A Activity of Drugs Recently Introduced in the Market for the Treatment of Non-Small Cell Lung Cancer, Sculier, et., al write,

5.7 MULTI-DRUG RESISTANCE

Chemotherapy works best when there are (1) small numbers of cancer cells that are (2) actively dividing. Chemotherapy is highly effective with small cell lung cancers promptly diagnosed, since this type of cancer rapidly divides. The effectiveness of chemotherapy with non-small cell lung cancer is less clear. One writer states,

In "cell kinetics" experiments it has been shown that drugs destroy a constant fraction or percentage of cells, not a constant number. So if there are 10 trillion cancer cells and 99 percent are killed, 100 billion are still left after the first treatment. After the second treatment, 1 billion cells are left, and after the third 10 million remain. The proportion of cells killed is the same, but each time a smaller number of cells is killed. The cells that are resting rather than actively reproducing escape the drugs' killing effects.

In between treatments, when it is safe, the resting cells resume production and replace the ones that have been killed. Chemotherapy under the best of conditions is a matter of taking two steps forward and one step back, and it is very difficult to make enough progress to kill off every single cell. Kinetic studies have also shown that as the cancer increases in size-the more cells it contains-the number of actively reproducing cells (the "growth fraction") decreases. The higher the number you start with, the harder and longer you have to work at getting the cell population down, because not only are there more cells to kill, there are more cells that are not vulnerable.

5.71 The Development of MDR, Multi-Drug Resistance

In addition to the fact that chemotherapy may not reach every cancer cell, unfortunately cancer cells develop resistance to certain drugs. Thus, while initially successful, chemotherapy is subsequently less effective at addressing recurrent cancer. One author suggests that PGP (P-glycoprotein) is produced which inhibits the ability of the drug to reach cancer cells, thus reducing A intracellular drug concentrations and hence reduced cytotoxicity.@ Twentyman, Mechanisms of Drug Resistance in Lung Cancer Cells, 214, in Carney, Lung Cancer (Arnold Pub. Co. 1995).

In a laboratory, Twentyman developed cancer cells which increased their resistance to doxorubicin, a chemotherapy drug.

5.72 Assessing Resistance to Chemotherapy

A contributor to the same book states,

At least three different MDR (multi-drug resistance) phenotypes exist, two of which are are relatively well defined. The best known is the so-called > classical= or P-glycoprotein- related MDR phenotypes, in which resistance is due to reduction of the intracellular drug accumulation via a 170 kDa protein pump (P-glycoprotein). Jensen, et. al., New Directions in Drug Therapy of Small Cell Carcinoma based on in vitro studies, 234, in Carney, Lung Cancer (Arnold Pub. Co. 1995).

5.73 Why Dosage and Scheduling Can Be Critical

Devita and Park in their book on cancer, discuss the reasons why dosage scheduling can be critical and is the subject of many clinical trials.

A Rapidly growing tumors tend to be most sensitive to chemotherapy. Also, damage to normal tissues at short intervals after chemotherapy or wide-field radiation is most often observed in organs such as the bone marrow or the intestine, which are renewal tissue known to contain rapidly proliferating cells. These observations suggest that rapidly proliferating cells may be more susceptible to therapy and have led to several studies of the relationship between cytotoxicity and proliferative rate.

When mammalian cells are cultured, they show a period of exponential growth when all cells are proliferating, followed by slowing of growth as cells become crowded and consume available nutrients.... Frequently this type of experiment leads to survival curves which show that rapidly proliferating cells are more sensitive to the drug. This technique and others have demonstrated that some drugs (e.g. methotrexate, cytarbine, and vinca alkaloids) exert lethal effects only against proliferating cells. Others, including anthracylines and most alkylating agents, have some activity against slowly proliferating cells but are considerably more toxic to proliferating cells. Only for alkylating drugs, including cisplatin, nitrosoureas, and bleomycin, is there little or no selectivity, and this may be cell-line dependent.

Most drugs and ionizing radiation vary in their lethal effects at different phases of the cell Because most drugs have varying toxicity for cells in different phases of the cell cycle, immediately after treatment a high proportion of surviving cells will be partially synchronized in a resistant phase. Several investigators have proposed that drug treatment might be scheduled at intervals that allow the surviving tumor cells to progress to a drug sensitive phase of the cell cycle, or, conversely, such that cells in critical normal tissues are again in a drug-resistant phase. In practice, the wide heterogeneity of cell cycle parameters makes this difficult to achieve. It has been demonstrated that therapeutic outcome is markedly dependent on scheduling interval for drug treatment of experimental tumors, but it has been difficult to predict the optimum scheduling interval from knowledge of cell kinetics. Institute. For updated information visit its website(s) at www.nci.org. Devita, et. al, Principles and Practice of Oncology (Lippincott 3d ed. 1989)

This tells us is that chemotherapy administrations should not be missed. Since the oncology staff has carefully constructed a regimen based upon its knowledge of the location of the cancer, its stage, and other dynamics, that schedule should not be disrupted. If an administration is missed, the doctor should be immediately informed.

The oncologist= s choice of drug depends on the type of cancer, location, stage, its impact on bodily functions, the patient= s general health, and his assessment of clinical trials or studies. Clinical trials are research studies that test new cancer treatments or refine existing ones. While some increase in survival times may be seen, most clinical trials do not show tremendous breakthroughs. Patients participate in clinical trials to make an important contribution to medical care and because other treatment options may be limited. To learn more about clinical trials, call the National Cancer Institute's Cancer Information Service and ask for the booklet What Are Clinical Trials All About? You also may want to ask about the videotape "Patient to Patient: Cancer Clinical Trials and You." The Cancer Information Service can be reached by dialing 1-800-4-CANCER (1-800-422-6237).

5.9 CHEMOTHERAPY ADMINISTRATION

5.91 Where is Chemotherapy Administered : Chemotherapy for lung cancer is generally administered in a phsyician= s office, a clinic or hospital's oncology department. When the patient first begins chemotherapy, a hospital stay might be needed to assess the medicine's effects.

5.92 How Often Will Chemotherapy be administrered.?

How often the therapy is administered will vary. Chemotherapy is sometimes given in on-and-off cycles that include rest periods so that the body has a chance to re-build new cells and the patient regain its strength.

5.93 Goals of Chemotherapy

Depending on the type of cancer and its stage of development, chemotherapy can be used:

* To cure cancer.

* To keep the cancer from spreading.

* To slow the cancer's growth.

* To kill cancer cells that may have spread to other parts of the body from the original tumor. To relieve symptoms that may be caused by the cancer.

* Chemotherapy also help people live more comfortably by eliminating cancer cells which cause pain, discomfort or other problems. This is called palliative care, where the goal is to help the patient better function, not cure.

5.94 Methods of Administration

One common way for the drug to be given is by mouth. This is more convenient and less costly than other methods. The disadvantage is that may be many instructions given with the drug, and the patients should follow these instructions explicitly and maintain careful records of when the drugs are taken.

Drugs may also be injected into a vein where the cancer cells appear to be circulating. Two kinds of pumps-external and internal- may be used to control the rate of delivery of chemotherapy. External pumps remain outside the body. Some are portable and allow a person to move around while the pump is in use. Other external pumps are not portable and may restrict activity. Internal pumps are placed surgically inside the body, usually right under the skin. They contain a small reservoir (storage area) that delivers the drugs into the catheter. Internal pumps allow people to go about most of their daily activities.

5.95 Does Chemotherapy Hurt

Getting chemotherapy by mouth, on the skin, or by injection generally feels the same as taking other medications by these methods. Having an IV started usually feels like drawing blood for a blood test. Some people feel a coolness or other unusual sensation in the area of the injection when the IV is started. Report such feelings to your doctor or nurse. Be sure that you also report any pain, burning, or discomfort that occurs during or after an IV treatment.

Many people have little or no trouble having the IV needle in their hand or lower arm. However, if a person has a hard time for any reason, or if it be comes difficult to insert the needle into a vein for each treatment, it may be possible to use a central venous catheter or port. This avoids repeated insertion of the needle into the vein. Central venous catheters and ports cause no pain or discomfort if they are properly placed and cared for, although a person usually is aware that they are there. It is important to report any pain or discomfort with a catheter or port to your doctor or nurse.

5.96 Use of Other Medication During Chemotherapy

Some medicines may interfere with the effects of your chemotherapy. That is why you should take a list of all your medications to your doctor before you start chemotherapy. Your list should include the name of each drug, how often you take it, the reason you take it, and the dosage. Remember to include over-the-counter drugs such as laxatives, cold pills, pain relievers, and vitamins. Your doctor will tell you if you should stop taking any of these medications before you start chemotherapy. After your treatments begin, be sure to check with your doctor before taking any new medicines or stopping the ones you already are taking.

5.97 Working During Chemotherapy

Most people are able to continue working while they are being treated with anticancer drugs. It may be possible to schedule your treatments late in the day or right before the weekend, so they interfere with work as little as possible. If your chemotherapy makes you very tired, you might want to think about adjusting your work schedule for a while. Speak with your employer about your needs and wishes at this time. You may be able to agree on a part-time schedule, or perhaps you can do some of your work at home. Under Federal and state laws, some employers may be required to allow you to work a flexible schedule to meet your treatment needs. To find out about your on-the-job protections, check with your local American Cancer Society, a social worker, or your congressional or state representative. The National Cancer Institute's publication Facing Forward: A Guide for Cancer Survivors, also has information on work-related concerns. How Will I Know If My Chemotherapy Is Working? Your doctor and nurse will use several methods to measure how well your treatments are working. You will have frequent physical exams, blood tests, scans, and x-rays. Don't hesitate to ask the doctor about the test results and what they show about your progress. While tests and exams can tell a lot about how chemotherapy is working, side effects tell very little. (Side effects-such as nausea or hair loss-occur because chemotherapy harms some normal cells as well as cancer cells.) Sometimes people think that if they don't have side effects, the drugs aren't working, or that, if they do have side effects, the drugs are working well. But side effects vary so much from person to person, and from drug to drug, that having them or not having them usually isn't a sign of whether the treatment is effective. If you do have side effects, there is a lot you can do to help relieve them. The next section of this document describes some of the most common side effects of chemotherapy and gives you some hints for coping with them.

1. Bruning, Coping with Chemotherapy (Ballantine Books 1993)

2. Devita, et. al. Principles and Practice of Oncology (1999)

_______________________________

It is important to discuss, but not overemphasize, the significance of side effects from chemotherapy. With the emergence of new drugs, medication to reduce side effects, and refinements in dose, some of the traditional side effects have been reduced. I discuss side effects generally, but only your oncologist can give you a case-specific analysis based upon, the nature of your disease and the type of chemotherapy provided.

The American Cancer Society Guide, Informed Consent (172) describes the reason for side effects:

A All the tissues and organs of the body are subject to an anticancer drug= s action, which is to destroy rapidly dividing cells or prevent them from reproducing. Cancer cells, which continuously and quickly replace themselves, are obviously targets. But some health cells that also divide rapidly, such as those in the hair follicles and lining the intestinal trace, are vulnerable to the drugs as well. Consequently, temporary hair loss and nausea are common side effects. The challenge, then, for the oncologist is to balance the cancer-destroying benefits of a particular drug or combination of drugs against their toxic effects. It is sometime quite a delicate balance, but with good emotional and physical care and support the side effects can be managed in most cases and, if not fully controlled, at least made tolerable.@ The American Cancer Society Guide, Informed Consent 172 (1997).

 

Chemotherapy causes side effects in some patients. However, it is incorrect to therefore conclude that the decision to use chemotherapy represents a tradeoff between length and quality of life. One recent study analyzes quality of life with the use of an increasingly popular chemotherapy drug for lung cancer, vinorelbine. Effects of Vinorelbine on Quality of Life and Survival of Elderly Patients with Advanced Non Small-Cell Lung Cancer, 91, No. 1 66-72 (Jan. 6, 1999)

First, the study found that vinorelbine extended life among the stage 3b and 4 patients with advanced lung cancer. Survival rates at 6 months and .12 months were 55% and 32% in the chemotherapy treated group versus 41% and 14% in the group receiving best available care without chemotherapy. Indeed, the trial had to be stopped because physicians were increasingly reluctant to assign patients to the control group whose mortality rate was demonstrably higher. There is increasingly little debate that chemotherapy extends life even among advanced lung cancer patients, at 3b and 4. In the vinorelbine chemotherapy group, there was one patient with a complete remission and 14 partial responses of 50% or more reduction in tumor volume (of approximately 76 in the group). There should be little question that chemotherapy has proven to be effective even with patients whose cancer has metastasized to lymph nodes or other organs. Chemotherapy will extend life in many cases, and in a few it had the capacity to serve as a cure. Based upon this study and some others, the only realistic question is what type of chemotherapy should be prescribed.

Equally important to cancer patients were the findings of quality of life. Quality of life or (Qol) can be statistically measured using a questionnaire given to patients in the clinical trial, and comparing results in the group receiving chemotherapy and the one given best supportive care. Vinorelbine-treated patients scored better on quality of life, and the study found a reduction in cancer-related symptoms such as pain and dyspnea, loss of breath. This would presumably correlate with the reduction in the size of the tumor in many cases. The study did find an increase in certain chemo-related side effects. Constipation was observed in three patients, heart arrhythmias in two, loss of hair- alopecia in three, and other side effects in approximately five. Thus there is a sad tradeoff between chemo-related side effects and those of the disease itself, but most would prefer the chemotherapy and the prospect of extending life with the drug. The study concludes, A we obtained a survival advantage that was not at the expense of a worse Qol (quality of life). It should be noted that while these results may be representative, they remain to be duplicated, since quality of life has generally not be the focus of studies of chemotherapy and lung cancer. Likewise, the results of other chemotherapy drugs such as cisplatin could be conceivably different.

5.2A NAUSEA, VOMITING, AND THE USE OF ANTI-EMETIC DRUGS

Some anticancer drugs cause nausea and vomiting because they affect parts of the brain that control vomiting and/or irritate the stomach lining. The severity of these symptoms depends on several factors, including the chemotherapeutic agent(s) used, dose, schedule, and the patient's reaction. Management of nausea and vomiting caused by chemotherapy is an important part of care for cancer patients when it does occur. Although patients usually receive antiemetic drugs that help control nausea and vomiting, there is no single best approach to reducing these symptoms in all patients. Doctors must tailor antiemetic therapy to meet each individual's needs, taking into account the type of anticancer drugs being administered; the patient's general condition, age, and related factors; and, of course, the extent to which the antiemetic is helpful. Note, however, that our ability to combat nausea has improved, and do not assume that side effects encountered by a patients 10 years ago will occur with the same severity today.

5.21 Mainstream Anti-emetic Drugs

The informative book, A Guide to Chemotherapy states, "Sedative/hypnotics such as Valium and almane have been used to reduce nausea in patients. Many oncologists are prescribing Ativan, an antinausea medication that also acts as an antidepressant and sleeping pill.@

5.22 Marijuana and Nausea

There has been some interest in the use of marijuana to treat a number of medical problems, including chemotherapy-induced nausea and vomiting in cancer patients. Two forms of marijuana have been used: compounds related to the active chemical constituent of marijuana taken by mouth and marijuana cigarettes. Dronabinol (Marinol), a synthetic form of the active marijuana constituent delta-9-tetrahydrocannabinol (THC), is available by prescription for use as an antiemetic. The U.S. Food and Drug Administration has approved its use for treatment of nausea and vomiting associated with cancer chemotherapy in patients who have not responded to the standard antiemetic drugs.

NCI scientists feel that antiemetic drugs or combinations of antiemetic drugs have been shown to be more useful than synthetic THC as "first-line therapy" for nausea and vomiting caused by anticancer drugs. Examples include drugs called serotonin antagonists, including ondansetron (Zofran) and granisetron (Kytril), used alone or combined with dexamethasone (a steroid hormone); metoclopramide (Reglan) combined with diphenhydramine and dexamethasone; high doses of methylprednisolone (a steroid hormone) combined with droperidol (Inapsine); and prochlorperazine (Compazine). Continued research with other agents and combinations of these agents is under way to determine their usefulness in controlling chemotherapy-induced nausea and vomiting. However, NCI scientists believe that synthetic THC may be useful for some cancer patients who have chemotherapy-induced nausea and vomiting that cannot be controlled by other antiemetic agents. The expected side effects of this compound must be weighed against the possible benefits. Dronabinol often causes a "high" (loss of control or sensation of unreality), which is associated with its effectiveness; however, this sensation may be unpleasant for some individuals. The informative book, A Guide to Chemotherapy deals specifically with the side effects of chemotherapy and discusses them generally, though not specifically with reference to chemotherapy drugs for lung cancer. "Sedative/hypnotics such as Valium and Dalmane have been used to reduce nausea in patients. Many oncologist are prescribing Ativan, an antinausea medication that also acts as an antidepressant and sleeping pill."

5.3A CHEMOTHERAPY AND INFECTION

Chemotherapy may increase the risk of infection:

Chemotherapy and extensive radiotherapy often interfere with t he formation and maturation of blood cells (hematopoeises)... According to a Gallup poll of chemotherapy patients,nearly half had their treatment postponed at least once because their white counts were alarmingly low. White cells safeguard us again infection, partiuclarly the neutrophils, which make up 60 percent of all white cells. Their job is to intercept and destroy bacteria. A person is said to be mildly neutropenic when her absolute neutrophil count (ANC) is between 2,000 and 1,000. The ANC is determined by multiplying the percentage of neutrophils by the total white-blood-cell count. Oncologists will generally continue chemotherapy so long as the number says in the 500-1000 range, which is considered moderate netrupenia....

5.31A Ways to Reduce Infection

Some general precautions against infection:

C Wash your hands frequently. Be sure to clean under your nails and between your fingers. Take a warm bath or shower each day and wash between folds of skin. Germs may locate inside the groin, between a woman= s breasts- anywherte than skin touches skin and is not exposed to air.

C Stay anyone from anyone with a cold or disease. Do not share drinking glasses, washclothes or other items which may carry germs.

C When you are done preparing food- particularly meat, poultry, and eggs, disinfect countertops and cutting boards.

C Avoid small groceries and check food expiration dates. Avoid food leftover for more than a day. Check that your refridgerator and freezer are working properly.

C Cook fresh vegetables. Avoid raw foods like shellfish or sushi.

There are many sources of support you can draw on. Here are some of the most important:

* Doctors and nurses. If you have questions or worries about your cancer treatment, talk with members of your health care team. Some doctors may be easily to speak with about side effects, while others may be more distant and clinical. Try to find a knowledgeable and sympathetic person at your hospital or phsyician= s office so you can discuss issues of side effects or other questions.

* Counseling professionals. There are different kinds of counselors who can help you express, understand, and cope with the emotions cancer treatment can cause. Depending on your preferences and needs, you might want to talk with a psychiatrist, psychologist, or social worker.

* Religious Groups Your priest, minister, or rabbi is best qualified to talk about the difficult questions you may experience during treatment. It is perfectly appropriate to reach out to your clergyman even if you have not attended services.

* Friends and family members. Talking with friends or family members can help you feel a lot better. Often, they can comfort and reassure you in ways that no one else can. You may find, though, that you'll need to help them help you. At a time when you might expect that others will rush to your aid, you may have to make the first move.

Some people do not understand cancer, and may withdraw from you because they're afraid of your illness. Others may worry that they will upset you by saying "the wrong thing." You can help relieve these fears by being open in talking with others about your illness, your treatment, your needs, and your feelings. By talking openly, you can correct mistaken ideas about cancer. You can also let people know that there's no single "right" thing to say, so long as their caring comes through loud and clear. Once people know they can talk with you honestly, they may be more willing and able to open up and lend their support. The National Cancer Institute's booklet Taking Time offers useful advice to help cancer patients and their families and friends communicate with one another.

* Support groups. Support groups are made up of people who are going through the same kinds of experiences as you. Many people with cancer find they can share thoughts and feelings with group members that they don't feel comfortable sharing with anyone else. Support groups also can serve as an important source of practical information about living with cancer. Support can also be found in one-to-one programs that put you in touch with another person very similar to you in terms of age, sex, type of cancer, and so forth. In some programs, this person comes to visit you. In others, a "hotline" puts you in touch with someone you can talk with on the telephone. Sources for information about support programs include your hospital's social work department, the local office of your American Cancer Society, and the National Cancer Institute's Cancer Information Service. (See Resources.)

There are a variety of sources of assistance available on the Internet. One is a group which shares their experience by way of posting to a news group. For those unfamiliar with the Internet, these are groups devoted to specific subjects, on American Online, simply use the key word newsgroup. Individuals can post a question or comment on a prior posting with the posts divided by topic. For some, it is easier to talk about sensitive topics on computer in the anonymity of your own home. The occasional disadvantage is that misinformation could be communicated. However, by and large, people find these news groups to be a useful way of acquiring information and communicating your feelings.

Here are some tips to help yourself while you are getting chemotherapy from the National Cancer Institute:

* Try to keep your treatment goals in mind. This will help you keep a positive attitude on days when the going gets rough. Remember that eating well is very important. Your body needs food to rebuild tissues and regain strength.

* Keep a journal or diary while you're in treatment. A record of your activities and thoughts can help you understand the feelings you have as you go through treatment, and highlight questions you need to ask your doctor or nurse. You also can use your journal to record the steps you take to cope with side effects and how well those steps work. That way, you'll know which methods worked best for you in case you have the same side effects again.

* Set realistic goals and don't be too hard on yourself. You may not have as much energy as usual, so try to get as much rest as you can, let the "small stuff" slide, and only do the things that are most important to you.

* Ask your doctor or nurse about a safe and practical exercise program. Using your body can help you feel better about yourself, help you get rid of tension or anger, and build your appetite.

You can use a number of methods to cope with the stresses of cancer and its treatment. Here are some techniques recommended by the National Cancer Institute.

A Muscle tension and release. Lie down in a quiet room. Take a slow, deep breath. As you breathe in, tense a particular muscle or group of muscles. For example, you can squeeze your eyes shut, frown, clench your teeth, make a fist, or stiffen your arms or legs. Hold your breath and keep your muscles tense for a second or two. Then breathe out, release the tension, and let your body relax completely. Repeat the process with another muscle or muscle group.

You also can try a variation of this method, called "progressive relaxation." Start with the toes of one foot and, working upward, progressively tense and relax all the muscles of one leg. Next, do the same with the other leg. Then tense and relax the rest of the muscle groups in your body, including those in your scalp. Remember to hold your breath while tensing your muscles and to breathe out when releasing the tension.

* Rhythmic breathing. Get into a comfortable position and relax all your muscles. If you keep your eyes open, focus on a distant object. If you close your eyes, imagine a peaceful scene or simply clear your mind and focus on your breathing. Breathe in and out slowly and comfortably through your nose. If you like, you can keep the rhythm steady by saying to yourself, "In, one two; Out, one two." Feel yourself relax and go limp each time you breathe out.

You can do this technique for just a few seconds or for up to 10 minutes. End your rhythmic breathing by counting slowly and silently to three.

* Biofeedback. With training in biofeedback, you can help control body functions such as heart rate, blood pressure, and muscle tension. A machine will sense when your body shows signs of tension and will let you know in some way such as making a sound or flashing a light. The machine will also give you feedback when you relax your body. Eventually, you will be able to control your relaxation responses without having to depend on feedback from the machine. Your doctor or nurse can refer you to some one trained in teaching biofeedback.

* Imagery. Imagery is a way of daydreaming that uses all your senses. It usually is done with your eyes closed. To begin, breathe slowly and feel yourself relax. Imagine a ball of healing energy- perhaps a white light-forming somewhere in your body. When you can "see" the ball of energy, imagine that as you breathe in you can blow the ball to any part of the body where you feel pain, tension, or discomfort such as nausea. When you breathe out, picture the air moving the ball away from your body, taking with it any painful or uncomfortable feelings. (Be sure to breathe naturally; don't blow.) Continue to picture the ball moving toward you and away from you each time you breathe in and out. You may see the ball getting bigger and bigger as it takes away more and more tension and discomfort. To end the imagery, count slowly to three, breathe in deeply, open your eyes, and say to yourself, "I feel alert and relaxed." .

* Visualization. Visualization is a method that is similar to imagery. With visualization, you create an inner picture that represents your fight against cancer. Some people getting chemotherapy use images of rockets blasting away their cancer cells or of knights in armor battling their cancer cells. Others create an image of their white blood cells or their drugs attacking the cancer cells.

Visualization and imagery may help relieve stress and increase your sense of self-control. But it is very important to remember that they cannot take the place of the medical care your doctor prescribes to treat your cancer.

* Hypnosis. Hypnosis puts you in a trance-like state that can help reduce discomfort and anxiety. You can be hypnotized by a qualified person, or you can learn how to hypnotize yourself. If you are interested in learning more, ask your doctor or nurse to refer you to someone trained in the technique.

* Distraction. You use distraction any time an activity takes your mind off your worries or discomforts. Try watching TV, listening to the radio, reading, going to the movies, or working with your hands by doing needlework or puzzles, building models, or painting. You may be surprised how comfortably the time passes.@

Anorexia, the loss of appetite or desire to eat, is the most common symptom in cancer patients that may occur early in the disease or later as the cancer grows and spreads. Cachexia is a wasting condition in which the patient has weakness and a marked and progressive loss of body weight, fat, and muscle. Anorexia and cachexia frequently occur together, but cachexia may occur in patients who are eating an adequate diet but have malabsorption of nutrients. A Tumor cells deprive normal cells of nutrients. Meanwhile the body is expending extra energy as it heals from the effects of cancer surgery, radiotherapy, or chemotherapy . In order to sustain vital functions, the body retrieves nutrients stored in fatty tissue. Once all available fat has been broken down for fuel, it sets to work on muscle. Of all nutrients, protein is the one most essential for building muscle, bone, skin, and bood cells. If the body= s cells consume more protein than you take in, muscle mass rapidly wastes away, causing the emaciated look often associated with cancer.@ Teelley & Bashe, The Complete Cancer Survival Guide (Doubleday 2000). Maintenance of body weight and adequate nutritional status can help patients feel and look better, and maintain or improve their performance status. Teely recommends the following:

COMPLETE PROTEINS canned tuman, skinless turkey, steak, whitemeat chicken, whole milk, hard-boiled effs, nuts, wheat germ.

NUTRIONAL SUPPLMENTS with your oncologist= s approval

LIGHT EXERCISE To stimulate your appetite,

The author of that book, a cancer patient himself, recommends foods dense in high-quality protein. such as meat, chicken, fish, egs, and dairy products. Some patients may not easily tolerate these foods, and you will need to structure a diet which provides the necessary nutrients without creating nausea.

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Here is an explanation of radiation:

A Radiation therapy (RT) is the use of focused high energy electromagnetic waves (photons) or electrons to treat cancerY . These beams strike and transfer varying amounts of energy to carbon, nitrogen, and hydrogen atoms in or near the DNA chains in the nucleus of cells thereby producing breaks, deletions, or cross linkages in the DNA chains, some of which are lethal to the cell. A few cells may die within minutes after being hit, but after sustaining lethal damage most cells survive until they attempt to go through mitosis and cell division. Cells are most sensitive to RT when they are in mitosis or shortly after cell division. Tissues in which a high proportion of cells are actively multiplying tend to be more sensitive to high energy photons than are tissues where most cells divide relatively infrequently.

By giving daily doses of RT large enough to kill a high proportion of the rapidly dividing cancer cells while killing only a small proportion of the more slowly dividing normal tissue cells in the area, a malignant tumor can be eradicated. The factors which determine whether or not a cancer can be eradicated by radiation therapy include the sensitivity of the tumor to RT, the volume of tumor cells to be eradicated and the tolerance of the most radiation sensitive vital tissues in the area. This latter factor is influenced by how effectively these structures can be shielded from the irradiation received by the tumor and whether the vital tissues can be sacrificed without mortality. Thus, RT is most effective when the volume of tumor cells to be treated is small, i.e. microscopic deposits of tumor cells left behind after the visible part of a tumor has been surgically excised, or when the tumor can be given a high dose of high energy photons or electrons without destroying the function of the vital structures in the areaY

6.21 Radiation and Small Cell Cancer

6.31 Hyperfractionated Radiotherapy

Hyper fractionated radiotherapy is a new form of radiation which has been used in other areas. One study showed beneficial results but increased side effects:

A Patients were randomly allocated in a 3:2 ratio to CHART (Continuous hyperfractionated accelerated radiotherapy) or conventional radiotherapyY . {In the Chart group]there was a 24% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2-year survival of 9% from 20% to 29% (p = 0.004, 95% CI 0.63-0.92). Subgroup analyses (predefined) suggest that the largest benefit occurred in patients with squamous cell carcinomas (82% of the cases), in whom there was a 34% reduction in the relative risk of death (an absolute improvement at 2 years of 14% from 19% to 33%). During the first 3 months, severe dysphagia occurred more often in the CHART group than in the group on conventional radiotherapy (19 vs 3%). Otherwise, there were no important differences in short-term or long-term morbidityY . CHART compared with conventional radiotherapy gave a significant improvement in survival of patients with NSCLC.@ Saunders, Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee [see comments] Lancet 1997 Jul 19;350(9072):161-5 6.311 Cost Issues with Hyperfractioned Radiotherapy

Some HMO may balk at the cost of this type of radiation even if there is some research showing its effectiness. See Coyle, Costs of conventional radical radiotherapy versus continuous hyperfractionated accelerated radiotherapy (CHART) Clin Oncol (R Coll Radiol) 1997;9(5):313-21 However, Chart is not an unusual or strange therapy, it has been used with other forms of cancer, and there are clinical findings indicating its effectiveness with lung cancer. Thus, it should be a decision of the physician and patient as to its use. I suspect that confronted with a vigorous well-documented presentation, most HMO= s would provide reimbursement for this treatment, even if they initiatially rejected its use, and did not approve its use for lung cancer on a routine basis. We seem to have limited side effects with radiation but also limited curative powers. The obvious question becomes can does be increased to kill more cancer cells without causing substantial destruction of normal tissue or disproportionate side effects: McGuire, 73.6 Gy and Beyond: Hyperfractionated, Accelerated Radiotherapy for Non-Small-Cell Lung Cancer. J Clin Oncol 2001 Feb 1;19(3):705-711

6.41 Personnel Involved

There are different medical professionals involved with radiation as follows:

Radiation Oncologist a physician specializing in treating cancer with radiation. He makes many of the decisions as to the type and frequency of radiation.

Radiation Physicist an expert in medical physics trained in planning radiation treatment. He helps determine the treatment plan and the specific of the radiation.

Dosimetrist, a technician who also plans and calculates the dosage of radiation and how it will be administered, sometimes with a computer program.

Radiation Technologist A specially trained technician who operates the radiation equipment. A nurse trained in radiation therapy may help patients deal with any side effects. See American Cancer Society, Informed Decisions 1997).

Generally there are not significant, long-lasting side effects, and one of the goals of radiation and why it requires skill is to attack the tumor without damaging normal tissue . Radiation therapy does not hurt, though some people experience a sensation of warmth or tingling. While chemotherapy kills some normal cells as well as tumorous cells, the goal of radiation is kill only cancerous cells. While one injecting a drug into the bloodstream cannot control its effect, however, when directing radiation one can, and there are fewer side effects associated with radiation than chemotherapy.

6.51 Tiredness

Tiredness and lethargy are associated with radiation, though the precise cause is not known. . According to the American Cancer Society Guide, A fatigue is likely to begin early and increase using the course of treatment, peaking between the third and fifth weeks.... Why the body reacts to radiation in this way isn= t exactly understood, though there are a number of plausible explanations. It may be that the healing process drains the body= s energy. Another reason may be the buildup of toxic wastes resulting from cell destruction. An increase in the body= s metabolism may play a role, too. Furthermore, daily trips to a radiation center disrupt the normal activities of life.@ American Cancer Society, Informed Decisions (1997).

9.52 Poor Appetite

It may be that changes in some cells affect hunger signals or the stress of illness reduces appetite.

9.53 Skin Problems

Skin in the radiation area may undergo temporary changes such as redness, dryness, or itchiness.

9.54 Addressing Side Effects

With any side effects, the physician and nurse should be informed. Doctors vary, with radiation we can have skilled physicians with limited empathy for the patient. Consider cancer support groups and speak with groups like the American Cancer Society. You should consult with your oncologist before making any changes since that could affect treatment in some way.

There is debate about the benefits of radiation following surgery. One study found a slightly elevated mortality in patients who had undergone radiation after surgery, though investigations in this area are ongoing and we can expect clinical trials.

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7.11 Types of Biopsies

A biopsy is usually the first surgical procedure a patient will undergo. It involves taking a piece of tissue and having it analyzed by a pathologist to determine its cellular makeup. A biopsy can determine whether the cells taken are cancerous and sometimes determine the level of differentiation in the tissue. The excellent website called Oncolink reviews the different types of biopsies.. These include aspiration biopsy, needle biopsy, excisional biopsy, and incisional biopsy. The approach used depends on the type of tumor suspected, its size, location, and characteristics of growth...

Aspiration Aspiration of cells and tissue fragments through a needle that has been guided to a suspected malignant tissue. Cytological analysis can provide a tentative diagnosis. Since the tumor can be missed, only a positive test is diagnostically significant.

Needle Obtaining a core of tissue through a specially designed needle introduced into suspected malignant tissue. Sufficient for the diagnosis of most tumors. Differentiating benign or reparative lesions from malignancies is often difficult with soft tissue and bony sarcomas. Since the tumor can be missed, only a positive test is diagnostically significant.

Incisional Removal of a small wedge of tissue from a larger tumor mass. Preferred method for diagnosing soft tissue and bony sarcomas.

Excisional Excision of the entire suspected tumor tissue. Procedure of choice for small, accessible tumors when they can be done without compromising the ultimate procedure.@ http://oncolink.upenn.edu

7.12 Other Diagnostic Procedures

A mediastinoscopy is a diagnostic procedure to test whether mediastinal lymph nodes are positive. For example, if multiple nodes are positive, surgery might not be recommended because it would not eliminate the cancer and open chest surgery could involve significant risk. The procedure involves inserting a crop through a small incision in the neck or check into the mediastinum where the nodes in that areas are viewed and tested. A thorascopy is a limited surgical procedure that allows the lining of the chest wall and the lungs to be examined for tumor. A thorascopy is inserted through a small incision in the chest wall. These procedures are diagnostic, they do not attempt to cure the cancer, but determine its existence and extent.

7.21 When is Surgery Performed

Surgery is the preferred form of treatment for stage 1 patients, and is assessed with many stage 2 and stage 3A patients. Surgery is generally not performed upon stage 3B and Stage 4 patients. Ideally, surgery results in the removal of the entire tumor and that result becomes less possible as the tumor spreads and invades other structures. The ideal of cure and eliminating the tumor occurs in approximately 50% to 60% of stage 1 patients.

Where the patient has other significant health problems, surgery may not be recommended, for example, for an 84 year old man with significant heart problems. Surgery removes the lung tumor and surrounding tissue. If the patient has severe breathing problems, he may lack sufficient pulmonary reserve to permit surgery.

7.22 Lobectomy and pneumonectomy

There are two basic types of surgery to remove a lung tumor, lobectomy and pneumonectomy Lobectomy is surgical removal of one of the lobes of the lung. Less intrusive procedures like a wedge resection, removal of part of the lobe have been tried, but cancer reoccurred in greater percentages so they are not generally used. A bilbectomy is the removal of two lung lobes. A pneumonectomy is the removal of the entire lung, and would be used where the cancer may involve substantial portions of the lung. Thoracotomy is the general name for surgery to examine the lung and remove cancerous portions. Yahoo has a good brief explanation:

A thoracotomy is a surgical procedure to open the chest and repair or remove lung tissue

While the patient is deep asleep and pain-free (general anesthesia), an incision is made between the ribs to expose the lung. The chest cavity will be examined and diseased lung tissue will be removed (All or portions of relevant lymph nodes will be removed and undergo pathology testing to see if they are cancerous) A drainage tube is inserted to drain air, fluid and blood out of the chest cavity and the ribs and skin are closed. Hospital stay is usually 7 to 10 days. Deep breathing is important to help prevent pneumonia, infection and re-expand the lung. The chest tube remains in place until the lung has fully re-expanded. Pain is managed with medications. The patient recovers fully in 1-3 months after the operation.

Http://health.yahoo.com

In recent years, surgeons have utilized modern technology in surgery, particularly the television camera. Laparoscopic surgery, use of a laparoscopy together with a television camera has now been used for a number of years in many gall bladder removals and certain gynecological procedures. Recently, some have begun using this type of television aided surgery in lung procedures. The advantages of the camera-aided procedures are as follows: by using and moving a camera during surgery, much smaller incisions can be used. For example, with laparascopic gall bladder removal, four small incisions are used instead of the large one with traditional surgery. Thus, there is an appreciably smaller scar and shorter recovery period. With this video-assisted lung surgeries, it may not be necessary to break a rib to enter the area where the lung is located, as is done with standard surgery. Thus, we have a less intrusive surgery, reduced pain, smaller scar, and quicker recovery time.

Using our knowledge of laparoscopic procedures, we can suggest the following drawbacks with video-assisted thorascopic surgery. In nine out of ten procedures, the result is a quicker, less intrusive surgery, with a smaller scar and quicker recovery. However, using these new procedures requires significant skill and there is a high learning curve. There is less, or at least different, visibility with a video-assisted procedure; the surgeon now relies on a television camera. Thus if there are anatomical anomalies or other problems, the surgeon could be hindered by his lack of direct visibility. If a serious problem arises, the procedure will have to converted to an open or traditional procedure, creating a small amount of added risk.

We can identify two potential problems. First, a surgeon inexperienced with this type of procedure will present greater risks. With such a procedure, you want a surgeon highly experienced with this procedure, at a hospital which it is also routinely done. Secondly, given the reduced or at least different visibility and the need to convert the procedure if problems arise, use may be limited for patients with other significant health problems.

We have included U.S. News and World Report= s excellent rating system for cancer centers. With experience and specialization, we can expect that care at these top hospitals will be better.

7.41 Private Nurses and Problems at Night

Care in ICU (intensive care units) following surgery is usually excellent, and care during days at most hospitals are usually good also. Where there is a difference tends to be at night. Few nurses and staff wish to work at night, and with limited budgets, there are frequent staffing problems at many hospitals which will not be apparent to the average patient or his family. Consider hiring a nurse or health care aid to assist in monitoring the patient during the night when problems are least likely to be detected. Unfortunately, insurance is unlikely to cover this type of expenses. Alternatively, consider having a family member sleep over or remain in the room if possible to assist the patient.

8.01 The Author= s Approach

Chapter 4, 5, and 6 include detailed material from the National Cancer Institute (NCI) website. The National Cancer Institute is a government funded agency which compiles information and oversees various studies. It is a conservative and authoritative source.

The material from NCI is generally thorough and authoritative; however, it frequently is difficult reading. My goal is to take material designed for medical professionals, organize, explain and abbreviate it so that it can be understood by the average patient or family member. To do this, I have done several things. First, each chapter begins with a brief summary. This will highlight the issues which you will be examining. Secondly, for some individual topics, I have provided a summary after each section, to give a less technical overview of what is said. Thirdly, where the material became overly technical, I have removed some portions to facilitate the reading while hopefully maintaining the important material. Fourthly, while NCI is authoritative, their views are not the only ones, though they usually provide a good start. Therefore, at the end of some sections, I have provided excerpts from articles and presentations or even my own views.

Even with these steps, the material can still be challenging, though I believe a good knowledge of this will be important for the patient or family member seeking to understand the nature of treatment and any options presented. Try to read each section, consult the definitions at the end of the book, and have a medical dictionary on hand. If you become confused about different stages, review the discusssion of different stages in chapter 2. This chapter presumes you are familiar with the TNM staging system, and NCI will uses terms like T1 or T2 indicating the size and location of the primary tumor. If you are able to digest the information here, you may be able to reduce the general information which takes up time in doctor-patient conferences, better understand your condition and the treatment which is proposed, and be able to ask your physician knowledgeable questions about treatment procedures and alternatives

8.02 Treatment Overview

Since the use of surgery, type of treatment, chemotherapy and radiation depends upon stage, the chapter is divided that way. Surgery is the major potential curative option for early diagnosed patients with smaller tumors and no lymph node involvement or metastasis. For others, radiation and chemotherapy provides varying results delineated below.

The book, Lung Cancer by Carney (Arnold Pub. Co., Great Britain, 1995) provides a summary of treatment options at different stages

! A Stage 1 (T1 N 0 MO or T2 N0 M0) These patients have T1 or T2 carcinomas but no metastasis to lymph nodes or distant organs. They are candidates for curative resection (surgical removal of the tumor) with a very favorable prognosis.

! Stage 2 (T1 N1 M0 or T2 N1 M0) These patients have T1 or T2 carcinomas but also have pulmonary node metastasis (N1). Hilar lymphanopathy may require pneumonectomy (removal of the lung) for curative resection, and as a result, some patients with poor pulmonary reserve may not be candidates for surgery.

! Stage 3a (T3 N0 M0, T3 N1 M0 or T1-3 N2 Mo) These patients have locally advanced disease with hilar or ipsilateral mediastinal nodal metastasis, but a select few may be suitable for surgical resection. Prognosis is poor with 5 year survival less than 20 percent.

! Stage 4 (T1-4 N1-3 M1) These patients have distant metastasis and have the worst overall prognosis. Surgery is of no proven benefit, but radiotherapy or chemotherapy may provide palliative relief. A Carney, Lung Cancer (Arnold Pub. Co., Great Britain, 1995)

Today, it appears that chemotherapy is clearly beneficial even in stage 3 and 4 patients. It extends life, reduces the ill effects of the cancer, and in a minority of cases can provide a cure.

8.2 OCCULT NON-SMALL CELL LUNG CANCER (Stage 0)

TX, N0, M0

An occult cancer is a microscopic tumor which cannot be seen on a chest x-ray. Tumors discovered in this fashion are very early stage and curable by surgery.

8.21 Why Most Occult Tumors are Squamous Cell

One text states, A 90% of occult lung cancers are squamous carcinomas, and 10% are either adenocarcinomas or large cell carcinomas.@ Martini, et. al. Treatment of Stage 1 and II Disease 339 in Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996). Squamous cell tumors are usually in the main bronchus. Sputum cytology is gathering sputum from a cough. These small central tumors can sometimes be detected during an analysis of cells from a cough while deeper tumors in the smaller airways are not so easily found. The 90% figure means that of early cancers diagnosed, 90% are squamous cell, not that 90% of all tumors are squamous cell.

Diagnostic tools like sputum cytology need to be used more often, so we can treat certain lung cancer in its early stage when treatment is most effective. Since sputum cytology is less effective at revealing adenocarcinomas, it is not an all-inclusive diagnostic tool. Nonetheless with a cost of less than $100.00 per administration and date of detection critical, it needs to be utilized more frequently.

Tis, N0, M0

Stage 0 non-small cell lung cancer (NSCLC) is the same as carcinoma in situ of the lung. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, there is a high incidence of second primary cancers, many of which are unresectable.

Phototherapy has been described as an alternative to surgical resection in carefully selected patients. [1-3] This investigational treatment seems to be most effective for very early central tumors that extend less than 1 centimeter within the bronchus.[2] Efficacy of this treatment modality in the management of early NSCLC remains to be proven.

Treatment options:

1. Surgical resection using the least extensive technique possible (segmentectomy or wedge resection) to preserve maximum normal pulmonary tissue since these patients are at high risk for second lung cancers.

2. Endoscopic photodynamic therapy.[2,3]

8.22 Author= s Note on Photodynamic Therapy

A recent article discusses photodynamic therapy and its use with Stage 0 patients:

Photodynamic therapy uses a photosensitizing agent, which becomes activated when exposed to light of the appropriate wavelength (1) and produces toxic oxygen radicals, resulting in cell death....Tissue penetrations is limited to a few millimeters in this method. This fact and the relatively low power prohibit complete eradication of large obstructing airway lesions. However, successful eradication of superficial (penetration less than 5 millimeters) bronchial wall tumors has been demonstrated. Superficial tumors are usually squamous cell carcinomas that are radiographically occult. They are often detected through cytological examination of sputum.

Surgical resection remains the best treatment for early-stage lung cancer. However, photodynamic therapy may be considered for some operable cancers, for cancers that are inoperable because of high surgical risk or limited pulmonary function or because they are multicentric, and for cancer in patient who refuse surgery. To be a candidate for photodynamic therapy, a patients must have a superficial stage 1 lesion (I/e. no evidence of nodal metastasis) that has a surface area estimated to be less than 3cm.Midthun, Endobronchial Techniques in Lung Cancer, Options for Nonsurgical Care. Vol. 101, No. 3, March 1997 Postgraduate Medicine

Note that this photodynamic surgery is generally an option only for those patients who cannot tolerate surgery. For example, if an 84 year old man with previous heart problems and poor health were diagnosed with in-situ lung cancer, photodynamic therapy could be used. For others, given the overall good results achieved through surgery, that is the preferred form of treatment.

1. Omitted

2. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early-stage lung cancer. Journal of Clinical Oncology 11(10): 1852-1857, 1993.

3. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102(5): 1319-1322, 1992.

9.30 Surgery is the Preferred Option leading to Excellent Five Year Survival Prospects

Surgery, specifically a lobectomy- removal of the affected lobe of the lung and surrounding tissue, is the preferred option. Stage 1 patients have an excellent prognosis, ranging from 55% to 85% five year survival, depending upon the study. One writer found that 80% of stage 1 operated patients never had another lung tumor. Why don= t we operate on all stage 1 patients?

9.31 Surgery and Pulmonary Reserve

The main consideration in surgery is whether the patient has sufficient pulmonary reserve. That is, can his pulmonary or respiratory system tolerate the removal of substantial parts of a lung. Surgery involves removal of not only the tumor, but some surrounding tissue. For the average person, removal of a part of one lung would not present significant problems. However if a patient= s lungs have not only cancer but other disease such as emphysema, a physician may decide against surgery. Pulmonary function tests assess the patient= s breathing capacity in various contexts.

8.32 Wedge Resection Surgery Instead of Lobectomy Is Recommended Only for Stage 1 Patients with Impaired Pulmonary Function

NCI states, A Patients with impaired pulmonary function may be considered for segmental or wedge resection of the primary tumor; the Lung Cancer Study Group has conducted a randomized study (LCSG-821) to compare lobectomy with limited resection for patients with stage I cancer of the lung. The results of this study show a reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision but no significant difference in overall survival.[2] Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3] A survival advantage was noted with lobectomy for patients with tumors greater than 3 centimeters, but not for those with tumors smaller than 3 centimeters. However, the rate of local/regional recurrence was significantly less after lobectomy, regardless of primary tumor size. Another study of stage I patients showed that those treated with wedge or segment resections had a local recurrence rate of 50% (31 of 62) despite having undergone complete resections.[4] Exercise testing may aid in the selection of patients with impaired pulmonary function who can tolerate lung resection.[5] The availability of video-assisted thoracoscopic wedge resection permits limited resections in patients with poor pulmonary function who are not usually considered candidates for lobectomy.[6]@

8.33 Radiation is Used for Stage 1 Patients with Poor Pulmonary Reserve

NCI states, A Patients with stage I disease for whom surgery is deemed inappropriate may be considered for radiation therapy with curative intent. In one report of patients older than 70 years of age who had resectable lesions smaller than 4 centimeters but who were medically inoperable or who refused surgery, survival at 5 years following radiation therapy with curative intent was comparable to a historical control group of patients of similar age resected with curative intent. In the two largest retrospective radiation therapy series, inoperable patients treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%. Both series found that patients with T1, N0 tumors had better outcomes, with 5-year survival rates of 60% and 32% in this subgroup..... Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator.

Treatment options:

1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.

2. Radiation therapy with curative intent (for potentially resectable patients who have medical contraindications to surgery).

3. Clinical trials of adjuvant chemotherapy following resection...

5. Endoscopic photodynamic therapy (under clinical evaluation in highly selected T1, N0, M0 patients).

4.33 Post-Operative Radiation for Stage 1 Tumors.

A 1999 article in the respected journal Lung Cancer states, A There is no place for routine postoperative thoracic radiotherapy after complete resection of a stage 1 tumour@ Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17.

8.31 Surgery as the Preferred Option for Stage 2 Non-Small Cell Patients

NCI states, A Surgery is the treatment of choice for patients with stage II non-small cell lung cancer (NSCLC). Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age-related, but up to 5%-8% with pneumonectomy or 3%-5% with lobectomy can be expected.

8.32 Radiation for Patients for Whom Surgery is Not Recommended

NCI states, A Patients with stage II disease for whom surgery is not recommended but with sufficient pulmonary reserve may be considered for radiation therapy with curative intent.[1] Among patients with excellent performance status, up to a 20% 3-year survival rate may be expected if a course of radiation therapy with curative intent can be completed. In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC treated with definitive radiation therapy achieved a 5-year overall survival rate of 10%; however, the 44 patients with T1 tumors achieved an actuarial disease-free survival rate of 60%. This retrospective study also suggested that improved disease-free survival was obtained with radiation therapy doses greater than 6,000 cGy....

8.33 Surgery and Chemotherapy and/or Radiation for Stage 2 Non Small Cell Patients

Recall that stage 2 means that the tumor has penetrating adjoining lymph nodes. Thus the potential for dissemination of the cancer is greater and the chance that surgery can remove the entire tumor less. Thus, combining surgery with some type of post-surgical treatment for eradicating any remaining tumor cells makes logical sense. However, precisely what should be done and what benefits can be realized continues to be debated.

One site discusses the potential benefits of adding radiation to surgery: A Although surgery is the cornerstone for treating stage II disease, the addition of postoperative adjuvant radiation and chemotherapy may be more effective in this patient population. Postoperative radiation therapy decreases the rate of local relapse, especially in patients with squamous cell NSCLC, but long-term survival is not improved.

With lymph node involvement at stage 2, the possibility of recurrence or metastasis increases. One may reason that in addition to radiating the area of the tumor to kill any cancer cells missed at surgery, why not add chemotherapy to attack any cells in that or other areas. While the approach carries with it some logic, clinical studies have not shown success, and many if not most physicians would reason that patients should not be required to deal with chemotherapy treatment if definite benefits are not shown. Here are results from one study.

Others have reached similar conclusions, A Chemotherapy used alone or in combination with radiation therapy postoperatively resulted in prolonged time to disease progression and a modest improvement in survival. However, long-term survival was not affected. The precise role of adjuvant chemotherapy and/or radiation therapy in patients with stage II NSCLC remains to be determined. Investigators are also exploring the use of preoperative and postoperative paclitaxel and carboplatin chemotherapy in patients with stages Ib, IIa, IIb, and IIIa NSCLC.@ www.uspharmacist.com current Treatment of Non-Small Cell Lung Cancer, (US Pharmacist Continuing Education).@

Note that these studies deal only with prophlactic chemotherapy, that is chemotherapy designed to deal with the possibility of additional cancer cells remaining. Where a recurrence is detected, the patient= s stage would change, and chemotherapy would likely be administered as part of standard treatment.

Prophylactic chemotherapy is not standard treatment for stage 2 non small cell patients, though some patients may be interested in clinical trials assessing post-operative chemotherapy.

9.34 Survival Rates for Stage 2 Non Small Cell Patients

A 1999 article in the journal Lung Cancer states, A For the 98 patients with postoperative lobar or hilar node metastases, overall survival rates at 3 and 5 years of 45.2 and 37.3% were found. Fifteen (15.3% showed a local failure within the radiation field as a first failure relapse. Distant metastases as first failure were noted in 38 patients (39%) with 12/38 brain metastases.... At 5 years, a local progression free survival rate of 79% and a distant metastasis free survival rate of 52% was noted. @ Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17.

8.341 Survival Rate Differences Between Adenocarcinoma and Squamous Cell

The above article states, A For the 71 stage II patients with a squamous histology, a 5-year survival rate of 44% was noted as opposed to 14% for patients with a large cell or adenocarcinoma. Although the local failure was not different (the term local failure meaning reappearance of the tumor in the area of radiation or where the tumor was removed) 17% for squamous, 11% for non-squamous, the non-squamous group failed more often at distant sites. From the 27 patients, 18 developed metastases as a first failure with 8/27 (30%) brain metastases. For the squamous group, 20/71 (28%

developed distant metastases, with 5/71 brain (metastases).@ Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17. It can be concluded that adenocarcinoma is a quick moving tumor than squamous cell. Significant different like these may lead physicians and scientists to make distinctions in treatment within the non-small cell category. Today, for the most part, squamous cell, adenocarcinoma and large cell tumors are treated alike.

___________________________________________________

Stage III lung cancer originally included patients with locally advanced disease, without distant metastases. In 1986, the International Staging System for Lung Cancer further divided this group into two subgroups C IIIA and IIIB.⁴ These subgroups attempted to separate patients with tumors that were potentially resectable (stage IIIA) from patients with tumors clearly beyond the scope of surgical extirpation (stage IIIB). Stage IIIA originally included tumors of any size within the lung with limited extension of the primary site to the pericardium, mediastinal pleura or fat, or chest wall and without lymph node metastases or with lymph node metastases confined to the ipsilateral mediastinal lymph nodes. Experience has demonstrated that patients with this classification form a very heterogeneous group, with a long-term survival following surgical resection that ranges from 10 to 50%. Consequently,this classification has recently been modified. www.chestnet.org/education/pccu/vol12/lesson18.html

One of the main difference between stage 3 A and B non small cancer is that surgery is part of 3A treatment. Surgery in stage 1 patients is designed to remove all of the tumor. In stage 3A while that may not be the goal, it is at least to remove enough tumor to make the risks of surgery and reduction of lung capacity make sense. In stage 3B where the tumor has extended beyond the immediate area into the mediastinum and adjoining structures, it is felt tha the risk does not make sense. Since one group with different treatment plans is confusing, the division into 3A and 3B. Note that within each category are tumors with different characteristics, but the intra-category treatments are essentially the same.

9.11 TNM Grouping and Stage 3

The grouping using the TNM (tumor, node, metastatsis) is now, Stage IIIA T1-3, N2, MOT3, N1, MO, Stage IIIB T4, Any N, MO Any T, N3, MO.

A pharmaceutical site provides a good overview of Stage 3 A treatment:

A Historically, patients with stage III NSCLC (locally advanced disease) were managed with radiation therapy, but long-term survival was poor (5%B 10%). The development of active chemotherapy regimens for NSCLC has led to the use of combined modality therapy for the management of stage III disease. Surgery and radiation are effective at controlling local disease, while chemotherapy works to control distant metastatic disease. Any two of these modalities or all three could be combined to treat stage III disease. However, patients with stage IIIb disease are generally not candidates for surgical resection and will most commonly receive combination chemotherapy, plus or minus radiation therapy.

Numerous trials comparing combined chemotherapy/radiation to radiation alone have been conducted in patients with stage III NSCLC. The chemotherapy regimens and radiation schedules have varied greatly among the studies, and conflicting results have emerged.... When two different meta-analyses were conducted with the data from all of the published randomized trials comparing chemotherapy/radiation with radiation alone, a small improvement in survival was reported for combined modality therapy. All of these studies utilized the older generation of chemotherapy regimens (cisplatin or cisplatin-based) in combination with radiotherapy. The improved activity of the newer combination chemotherapy regimens used in stage IV disease could lead to improved results when combined with radiation for the treatment of stage III disease. www.uspharmacist.com

9.22 Chemotherapy Before Surgery or NeoAdjuvant Surgery

Chemotherapy and radiation are also, with research continuing as to what combination of these three forms of treatment will achieve the best results. Recall that Stage III A tumors involve either large T2 or 3 tumors orsituations of significant lymph node involvement. Many physicians believe in chemotherapy before surgery:

Neoadjuvant chemotherapy with or without radiation therapy followed by surgery is another combined modality treatment for stage III (primarily stage IIIa) disease that is under investigation. Neoadjuvant chemotherapy is administered to patients with bulky disease prior to surgery in an attempt to decrease tumor size and increase surgical resectability. Two randomized studies have {favorably} compared chemotherapy followed by surgery with surgery alone.@ Current Treatment of Non-Small Cell Lung Cancer, U.S. Pharmacist continuing Education.

A recent article discusses the purposes of neoadjuvant chemotherapy:

9.11 T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0

9.121 Immunotherapy

No consistent benefit from any form of immunotherapy has been demonstrated thus far in the treatment of NSCLC.

Treatment options:

1. Surgery alone in highly selected cases.[20-22]

2. Chemotherapy combined with other modalities.[4-6,12,17-19]

3. Surgery with postoperative radiation therapy.[13,15]

4. Radiation therapy alone.[1,2]

Superior sulcus tumor (T3, N0 or N1, M0)

9.4 STAGE IIIB NON-SMALL CELL LUNG CANCER

Chemotherapy is the primary treatment for Stage 3B and Stage 4 non small

For patients concerned about chemotherapy side effects, this may become a valid alternative, though scientists may disagree about whether it achieves precisely the same results. There are difficult issues of medical choice which might ultimately have to be made by the patient= s themselves. Is a slightly longer projected life-span worth additional side effects. Chemotherapy presents the problem of killing cancer cells, while preserving normal cells and bodily functions. How do we eliminate the rapidly dividing cells we call cancer, but preserve the other rapidly dividing cells necessary for different life functions.

6. A review of some chemotherapy studies and drugs is included in the appendix.

NCI states, A Patients with stage IIIb non-small cell lung cancer (NSCLC) do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on sites of tumor involvement and performance status. Most patients with excellent performance status should be considered for combined modality therapy. However, patients with malignant pleural effusion are rarely candidates for radiation therapy, and should generally be treated similarly to stage IV patients (see separate section of this summary on treatment of stage IV disease). Many randomized studies of unresectable patients with stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and chest irradiation is associated with improved survival compared to treatment with radiation therapy alone.[1-5] A meta-analysis of patient data from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death compared with radiation therapy alone.[6]

Patients with stage IIIb disease with poor performance status are candidates for chest irradiation to palliate pulmonary symptoms (e.g., cough, shortness of breath, or local chest pain). No consistent benefit from any form of immunotherapy has been demonstrated thus far.@

Chemotherapy is the primary form of treatment and serves to extend life and sometimes reduce cancer-related symptomology. While there is near agreement that chemotherapy is beneficial, the exact form of chemotherapy which should be used remains unclear, though the combination of Taxol and Carboplatin is becoming the standard treatment. Carboplatin, vinorelbine, taxol, gemcitabine and other forms of chemotherapy have displayed benefits, but the optimal mix of drugs remains unclear since clinical trials have reached varying results.

Some have suggested that the nonsmall cell cancer category is too large and encompasses forms of lung cancer which might respond slightly differently to forms of chemotherapy. For example, some studies have shown that squamous cell cancer metasatizes slower than adenocarcinoma so the prognosis for squamous cell patients is a little better. Thus, if we tried the same drug in two clinical trials of non-small cell patients at the same stage but with different proportions of patients with adenocarcinoma, we could expect different results with the same drug. Perhaps future studies and evaluation will consider the percentage of adenocarcinoma patients in assessing results.

The National Cancer Institute states,

A Cisplatin-containing and carboplatin-containing combination chemotherapy regimens produce objective response rates (including a few complete responses) that are higher than those achieved with single-agent chemotherapy. Although toxic effects may vary, outcome is similar with most cisplatin-containing regimens; a randomized trial comparing five cisplatin-containing regimens showed no significant difference in response, duration of response, or survival.[1] Patients with good performance status and a limited number of sites of distant metastases have superior response and survival when given chemotherapy when compared to other patients.[2] A prospective randomized comparison of vinorelbine plus cisplatin versus vindesine plus cisplatin versus single agent vinorelbine has reported improved response rate (30%) and median survival (40 weeks) with the vinorelbine plus cisplatin regimen.[3] Two small phase II studies reported that paclitaxel (Taxol) has single-agent activity in stage IV patients, with response rates in the range of 21%- 24%.[4,5] Reports of paclitaxel combinations have shown relatively high response rates, significant 1 year survival, and palliation of lung cancer symptoms.[6] With the paclitaxel plus carboplatin regimen, response rates have been in the range of 27%-53% with 1-year survival rates of 32%-54%.[6,7] The combination of cisplatin and paclitaxel was shown to have a higher response rate than the combination of cisplatin and etoposide.[8] Additional clinical studies should better define the role of these newer combination chemotherapy regimens in the treatment of advanced non-small cell lung cancer.[8] Meta-analyses have shown that chemotherapy produces modest benefits in short-term survival compared to supportive care alone in patients with inoperable stages IIIb and IV disease.[9-11]

Although these results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced non-small cell lung cancer (NSCLC), efficacy of current programs is such that no specific regimen can be regarded as standard therapy. Appropriate patients should be encouraged to participate in clinical trials. Outside of a clinical trial setting, chemotherapy should be given only to patients with good performance status and evaluable tumor lesions who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC such as tracheal, esophageal, or bronchial compression, bone or brain metastases, pain, vocal cord paralysis, hemoptysis, or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[12] Such therapeutic intervention may be critical in the prolongation of an acceptable lifestyle in an otherwise functional patient. In the rare patient with synchronous presentation of a resectable primary tumor in the lung and a single brain metastasis, surgical resection of the solitary brain lesion is indicated with resection of the primary tumor and appropriate postoperative chemotherapy and/or irradiation of the primary tumor site and with postoperative whole-brain irradiation delivered in daily fractions of 180-200 cGy to avoid long-term toxic effects to normal brain tissue. In asymptomatic patients kept under close observation, treatment may often be appropriately deferred until symptoms or signs of progressive tumor develop.@

In some circumstances, the non-small cell patient will have a tumor seemingly unresponsive to chemotherapy. What should be done?

9.81 Change of Chemotherapy Regimen

As noted, there are various types of anti-cancer drugs, with no consensus of what is best, and even in what amount. If one type of chemotherapy is not successful in reducing the size of a tumor, the patient should consider a change. While we may find that some types of tumors are chemo-resistant or develop that characteristic, it may also be that some drugs work better on particular types of tumors. The term non-small cell cancer comprises squamous cell, large cell, and adenocarcinoma. It could be that certain drugs work better on certain types of non-small cell cancer, those in certain locations, or with certain cellular characteristics (poorly differentiated versus moderately differentiated). There is at least as much about lung cancer that we don= t as we do, despite millions in research. Thus, it is certainly reasonable to switch physicians, hospitals, or chemotherapy regimens where what was being done is not successful.

5.82 Experimental Programs and Clinical Trials

We deal with experimental treatments and clinical trials in later chapters. However, it is perfectly appropriate for the stage 4 patient, particularly those whose tumors have not responded to chemotherapy, to consider new forms of treatment. This area is rapidly evolving with numerous drugs being tried, some with limited success. At the time of evaluation, which will likely be some period after publication, the patient and his physician must survey the literature, consider the location of clinical trials, and choose among various treatments. We can provide a brief overview here based upon some of the information available at the time this is written. Before looking at specific drugs, here are some of the considerations to evaluate.

9.82 Anti-AngioGenesis Drugs

Angiogenesis drugs attempt to hinder the establishment of new sources of blood supply by metastatic tumors. These drugs are still experimental but the patient whose tumors has not been combatted by chemotherapy may wish to consider them. No anti-angionenic drugs has been determined by the FDA to be effective in treating non-small cell lung cancer, though clinical trials continue.

9.821 Erissa

Erissa has shown promising results in some earliest clinical trials, though these results have not reached formal FDA approval.

9.831 Interferon

Interferon has shown some promise in the treatment of advanced

non-smallcell cancer.

9.84 Hospice.

If most physicians and patients believe in maintaining a positive attitude and hope for cure, there are others who believe that all lives must inevitably come to an end and that sometime, all medical science does is prolong the patient= s agony. Whether chemotherapy has this result is debatable since some studies show that chemotherapy increases quality of life by mitigating the harmful effects of the tumor. Some patients may decide that maintaining a peaceful and dignified end, free of medical unnecessary medical intervention is the preferred course. Where an older patient has stage 4 metastatic lung cancer, where has not responded to chemotherapy, such a decision cannot be regarded as wholly unreasonable. The decisions are difficult, but perhaps the patient= s well-considered wishes must be respected in such a situation. Hospices provide end of life care, frequently doing this far better than a hospital or other facility.

9.85 Experimental Drugs

A final alternative where existing chemotherapy or other treatments have not achieved positive results is to consider certain drugs awaiting FDA approval. Because these drugs are experimental, they are generally administered in a clinical trial. However, a patient may not wish to enter a clinical trial or may be ineligible for certain ones because of his physical status and the advanced stage of disease. There are several lawful ways to obtain a drug in clinical trials:

A If the eligibility criteria in a study protocol are not suitable for a particular patient, it may still be possible to be treated according to the study protocol special exception (sometimes called compassionate exemption). ... Another alternative is for a physician to file a single patient or emergency directly with the FDA. www.FDA.gov.

10.01 Small Cell Cancer Spreads and Metastasizes Quickly

Small cell is a quick-moving cancer, rapidly spreading to lymph nodes and other organs. A Characterized by rapid cell division, SCLC long-term survival rates are low because patients usually have widespread disease at the time of diagnosis... Metastases usually involve the bone (35% of the cases), liver (25% of the cases) and either the brain, central nervous system, lymph nodes, subcutaneous tissue, or pleura (10% of cases).@ www.cancer.mednet.cula.edu/CancerJournal/htm/small.html.

We will first look at an NCI overview of small cell and then address specific issues. NCI states, A Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2-4 months. Compared with other types of lung cancer, small cell carcinoma has a greater tendency to be widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation.

Because of the propensity for distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, generally cannot produce long-term survival.[1] With incorporation of current chemotherapy regimens into the treatment program, however, survival is unequivocally prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. Furthermore, about 10% of the total population of patients remain free of disease over two years from the start of therapy, the time period during which most relapses occur. However, even these patients are at risk of dying from lung cancer (both small and non-small cell types). The overall survival at 5 years is 5%-10%.

At the time of diagnosis, approximately 40% of patients with small cell carcinoma will have tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited stage disease, and most 2-year disease-free survivors come from this group. In limited stage disease, median survival of 16-24 months with current forms of treatment can reasonably be expected. A small proportion of patients with limited stage disease may benefit from surgery with or without adjuvant chemotherapy; these patients have an even better prognosis. Patients with tumor that has spread beyond the supraclavicular areas are said to have extensive stage disease and have a worse prognosis than patients with limited stage. Median survival of 6-12 months is reported with currently available therapy, but long-term disease-free survival is rare.

The pretreatment prognostic factors which consistently predict for prolonged survival include good performance status, female gender, and limited stage disease.[3,9,10] Patients with involvement of the central nervous system or liver at the time of diagnosis have a significantly worse outcome.[3,9-11] In general, patients who are confined to bed tolerate aggressive forms of treatment poorly, have increased morbidity, and rarely attain 2-year disease-free survival. However, patients with poor performance status can often derive significant palliative benefit and prolongation of survival from treatment.

Regardless of stage, the current prognosis for patients with small cell lung cancer is unsatisfactory even though considerable improvements in diagnosis and therapy have been made over the past 10-15 years. Therefore, all patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis.@

Exactly how small cell should be staged is somewhat controversial, with two different approaches representing to some extent different approaches to treatment. Recall that non-small cell cancer is divided into four stages (five if we count 3A and 3B) based on the involvement of lymph nodes and other organs.

In contrast, most United States physicians divide small cell into but two categories: limited and extensive. Our National Cancer Institute explains, A Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.@ [1]

Non small cell is divided into stages because the determination of whether to perform surgery depends upon stage. If surgery is not generally recommended for small cell patients a four stage demarcation is unnecessary. One text states, A The biologic nature of small cell lung cancer causes dissemination to regional lymph nodes and/or distant metastatic sites in more than 90% of patients at the time of initial presentation.@ Small cell cancers are a quick moving or high-grade cancer which double and metastasize quickly.

10.11 Countries Which Use Four Step Staging for Small Cell

A Japanese article discusses surgery and employs the four step staging of non small cell cancer. Indeed, given the difficult prognosis of small cell patients, the use of surgery must be considered The two step staging system contains an implicit bias against surgery, since surgical decisions need to utilize accurate information about tumor status that the simple two stage analysis does not provide.

In the United States, chemotherapy is the primary form of treatment for small cell lung cancer. Initial results are usually promising but the cancer frequently returns, and second line chemotherapy has less success. A text on lung cancer explains:

A (Chemotherapy) regimens will result in response rates of 85-95% in limited disease and 65-85 percent in extensive disease patients. Complete responses, prerequisite for potential cure, can be achieved in about 50 per cent limited disease patients and in about a quarter of extensive disease patients. Depending on the addition of radiotherapy, in limited disease patients about a third will have disease-free survival in excess of 2 years.@ Chemotherapy of Small Cell Lung Cancer, 157, in Carney, Lung Cancer (Arnold Publ Co. 1995)

10.22 Recurrence and Drug Resistance

While the initial success of chemotherapy for small cell cancer is indeed promising, the propensity for recurrence and difficulties combating that are troubling. In 1991, one doctor wrote, A Chemotherapy is the main treatment modality for small cell lung cancer. The disease is highly chemoresponsive and around 50 per cent of patients receive complete response. In the great majority of these, however, the disease recurs within a few months and is progressively chemoresistant.@ Twentyman, Mechanism of Drug Resistance in Lung Cancer Cells, included in Carney, Lung Cancer (Arnold Publ. Co. 1995). A A primary cause of treatment failure in SCLC (Small Cell Lung Cancer) is the emergence of drug-resistant cell clones during chemotherapy.@ Chemotherapy of Small Cell Lung Cancer, 158 in Carney, Lung Cancer (Arnold Publ. Co. 1995).

10.25 Cellular Classification

The current classification of subtypes of small cell lung cancer are:[1]

* small cell carcinoma

* mixed small cell/large cell carcinoma

* combined small cell carcinoma (small cell lung cancer combined with neoplastic squamous and/or glandular components)

A Staging procedures are important in distinguishing patients who have disease limited to their thorax from those who have distant metastases. Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated for response. Also, the choice of treatment is usually influenced by stage, particularly when chest irradiation or surgical excision is added to chemotherapy for patients with limited stage disease. Staging procedures commonly used to document distant metastases include bone marrow examination, computed tomographic or magnetic resonance imaging scans of the brain, computerized tomographic scans of the chest and the abdomen, and radio nuclide bone scans.

Because occult or overt metastatic disease is present at diagnosis in most patients, survival is usually not affected by small differences in the amount of locoregional tumor involvement. Therefore, the detailed TNM staging system developed for lung cancer by the American Joint Committee on Cancer (AJCC) is not commonly employed in patients with small cell carcinoma. This international staging system is outlined in detail in the PDQ summary on non- small cell lung cancer. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small cell lung cancer patients.[1]

10.33 Limited stage

Limited stage small cell lung cancer means tumor confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, which can be encompassed within a "tolerable" radiation therapy port. There is no universally accepted definition of this term, and patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from limited stage by various groups.

10.34 Extensive stage

Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above. Patients with distant metastases (M1) are always considered to have extensive stage disease.[1,2]

Even if we assume that at least 90% of small cell patients have advanced disease, that leaves a critical 10% with timely diagnosed tumors confined to part of a single lung. That subgroup has a excellent prognosis perhaps almost equivalent to stage 1 non-small cell patients. One text states, A Shields analysis of patients with small cell carcinomas in the VASOG trials also demonstrated the importance of TNM (tumor, node, metastasis) staging for tumors of this cell type. Sixty percent of patients with T1, No, Mo tumors were alive at 5 years, whereas there were almost no 5-year survivors among the patients who presented either with T2--3 tumors or with mediastinal lymph node involvement. Patients with T1 tumors with only hilar or bronchopulmonary nodes involved had an intermediate survival of approximately 30%. In fact, these survival results are similar to those of patients who have undergone complete surgical resection for non-small cell lung cancer of equivalent stage.@ Aisner, et. al., Comprehensive Textbook of Thoracic Oncology 441 (Williams & Wilkins 1996).

10.42 Excellent Japanese Results with Surgery and Stage 1 and 2 Small Cell Patients

A Japanese study found good results with surgery for small cell patients. The author concluded that surgery played a substantial role in long survival for limited stage small cell lung cancer. A The 4 year survival rate of the patients in stage I was 50%, and that of those in stage II and IIIA was 50% and 37.5%.@ The authors boldly conclude, A Surgical resection for limited SCLC should be recommended in patients with stage I, II and T3NoMo or T3N1Mo disease. Ohkubo, Surgical Analysis for Small Cell Lung Cancer of the Lung , Kyobu Geka 1999 Dec; 52 (13) 1061-6. (abstract available on medline, go to healthgate.com and search for small cell lung cancer surgery). Aisner concludes, A Although there was general acceptance by the 1970's that surgical resection was inappropriate for the majority of patients with small cell lung cancer, the observations of Shields and his colleagues suggested that there might be a subpopulation of patients with small cell cancers for whom a surgical approach could be considered.@ Id. at 441. The notion that small cell treatment is comparable to non-small cell treatment would be rejected by most physicians and investigators. However, at least at early stage 1, there are signficant similarities and the same favorable prognosis. In many areas surgery is not performed upon small cell patients, even in earlier stages. The small cell patient will want to carefully review his options and assure himself that decisions are made or recommended by oncologists and surgeons of the highest caliber. If surgeon is a realistic option, this highlights the need for early detection. As I discuss later in the book, neither the American Cancer Society nor the National Cancer Institute recommend screening as a means to assure timely diagnosis and improved long term survival.

10.43 Chemotherapy and Radiation for Limited Stage Patients

A It is useful to identify patients with limited- stage disease as several randomized controlled trials employing combined modality therapy (chemotherapy and thoracic irradiation in this group have demonstrated survival advantage over treatment with chemotherapy alone.@ Richardson & Ihde, Staging of Small Cell Cancer 114, in Carney, Lung Cancer (Arnold Publ Co. 1995).

NCI states A In patients with small cell lung cancer, combination chemotherapy produces results that are clearly superior to single-agent treatment, and moderately intensive doses of drugs are superior to doses that produce only minimal or mild hematologic toxicity. Current programs yield overall objective response rates of 65%-90% and complete response rates of 45%-75%. Because of the frequent presence of occult metastatic disease, chemotherapy is the cornerstone of treatment of limited stage small cell lung cancer. Combinations containing two or more drugs are needed for maximal effect.

Mature results of prospective randomized trials suggest that combined modality therapy produces a modest but significant improvement in survival compared with chemotherapy alone. Two meta-analyses showed an improvement in 3-year survival rates of about 5% for those receiving chemotherapy and radiation therapy compared to those receiving chemotherapy alone. Most of the benefit occurred in patients less than 65 years of age. Combined modality treatment is associated with increased morbidity and, in some trials, increased treatment-related mortality from pulmonary and hematologic toxic effects; proper administration requires close collaboration between medical and radiation oncologist.ve effect for combined modality therapy employed thoracic irradiation early in the course of treatment, concurrently with chemotherapy.

6.53 Particular Chemotherapy Drugs Used

10.54 Chemotherapy and Radiation

Reddy also suggests that combining chemotherapy with radiation improves results:

Reddy, id at 1.

NCI states, A As in limited stage small cell carcinoma, chemotherapy should be given as multiple agents in doses associated with at least moderate toxicity in order to produce the best results in extensive stage disease. Doses and schedules used in current programs yield overall response rates of 70%-85% and complete response rates of 20%-30% in extensive stage disease. Since overt disseminated disease is present, combination chemotherapy is the cornerstone of treatment of this stage of small cell lung cancer. Combinations containing two or more drugs are needed for maximal benefit.

The relative effectiveness of many 2- to 4-drug combination programs appears similar, and there are a large number of potential combinations. Therefore, a representative selection of regimens that have been found to be effective by at least two independent groups has been provided. Some physicians have administered two of these or other regimens in alternating sequences, but there is no proof that this strategy yields substantial survival improvement.[1-3] Optimal duration of chemotherapy is not clearly defined, but there is no obvious improvement in survival when the duration of drug administration exceeds 6 months.[4,5] There is no clear evidence from reported data that maintenance chemotherapy will improve survival duration.[6-9]

Combination chemotherapy plus chest irradiation does not appear to improve survival compared with chemotherapy alone in extensive stage small cell lung cancer. However, radiation therapy plays an extremely important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases...

Patients with small cell lung cancer treated with chemotherapy with or without chest irradiation who have achieved a complete remission can be considered for administration of prophylactic cranial irradiation (PCI). Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system metastases within 2-3 years after starting treatment.[11,12] The majority of these patients relapse only in their brain and nearly all of those who relapse in their central nervous system die of their cranial metastases.[12-14] The risk of developing central nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 2400 cGy.[12] Retrospective studies have shown that long-term survivors of small cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment.[15-17] However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated.[12] In addition, the majority of patients with small cell lung cancer have neuropsychological abnormalities present before the start of cranial irradiation and have no detectable decline in their neurological status up to 2 years after the start of their cranial irradiation.[18] Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the start of treatment.[15-17] Therefore, additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Many more patients with extensive stage small cell carcinoma have greatly impaired performance status at the time of diagnosis when compared to patients with limited stage disease. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients,[19-22] However, prospective randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent or low-dose regimens.[21-23]

Treatment options:

Standard:

1. Combination chemotherapy with one of the following regimens with or without PCI given to patients with complete responses:

The following regimens produce similar survival outcomes:

CAV: cyclophosphamide + doxorubicin + vincristine [24,25]

CAE: cyclophosphamide + doxorubicin + etoposide [26]

EP or EC: etoposide + cisplatin or carboplatin [27,28]

ICE: ifosfamide + carboplatin + etoposide [29]

2. Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases.

3. Identification of effective new agents is difficult in patients who have previously been treated with standard chemotherapy because response rates to agents, even of known efficacy, are known to be lower than in previously untreated patients. This situation led to the suggestion that patients with extensive disease who are medically stable be treated with new agents under evaluation, with provisions for early change to standard combination therapy if there is no response.[34] Such a strategy has been shown to be feasible, with survival comparable to survival with initial standard therapy, as long as the patients with extensive disease are carefully chosen.[35-37] A variety of other strategies have been proposed, depending on the activity of the new agent in other tumors, in preclinical small cell lung cancer models, or the activity of drug analogs.[38] Active single agents undergoing further evaluation include paclitaxel and topotecan.[39,40]

Under clinical evaluation:

10.72 Recurrent Small Cell Lung Cancer

The prognosis for small cell lung carcinoma that has progressed despite chemotherapy is poor. NCI states, These patients should be considered for palliative therapy or clinical trials. Patients who are primarily resistant to chemotherapy and those who have received multiple chemotherapy regimens rarely respond to additional treatment. However, patients who have initially responded and relapsed more than 6 months following initial treatment are more likely to respond to additional chemotherapy. While no single chemotherapy regimen should be considered standard, those that have shown activity as second line treatment include oral etoposide, etoposide/cisplatin, cyclophosphamide/doxorubicin/vincristine (CAV), lomustine/methotrexate, and topotecan.[1-8]

Patients with central nervous system recurrences can often obtain palliation of symptoms with radiation therapy and/or additional chemotherapy. The majority of patients treated with radiation therapy obtain objective responses and improvement following radiation therapy.[12] A retrospective review showed that 43% of patients treated with additional chemotherapy at the time of CNS relapse respond to second-line chemotherapy.[13]

Treatment options:

1. Palliative radiation therapy.[11]

2. Salvage chemotherapy can provide some palliative benefit for patients previously sensitive to standard chemotherapy.[2,4-8]

3. Local palliation with endobronchial laser therapy, endobronchial stents, and/or brachytherapy.[9,10]

4. Clinical trials of phase I or phase II drugs. Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with recurrent small cell lung cancer.

Author's Note This chapter is based upon public material supplied by the National Cancer Institute. For updated information visit its website(s) at www.nci.org

A well-known author on lung cancer notes the prevalence of metastasis to the brain with small cell lung cancer and suggests pre-diagnosis radiation to reduce the effects of metastasis. His letter in the August 12, 1999 issue of the New England Journal of Medicine entitled Prophylactic Cranial Irradiation and Small-Cell Lung Cancer says the following:

A Small-cell lung cancer, the type of lung cancer most strongly associated with tobacco exposure, accounts for 20 to 25 percent of all cases of lung cancer (approximately 45,000 new cases per year in the United States). The majority of patients are treated with combination chemotherapy (etoposide and cisplatin) for four to six months, with or without concurrent thoracic irradiation. The median survival for patients who are not treated is only 6 to 12 weeks, whereas for patients treated with combination chemotherapy, the median survival is 10 to 12 months. For patients with extensive disease (disease extending beyond one hemithorax or beyond regional lymph nodes) who are treated with combination chemotherapy, the median survival is only seven to nine months. (1)

Limited disease (disease confined to the lung) accounts for 30 to 40 percent of all newly diagnosed cases of small-cell lung cancer. It is now treated with combination chemotherapy and thoracic irradiation of the site of the primary tumor. With this approach, the median survival is 18 months, and up to 25 percent of patients survive for more than 2 years. The use of combination chemotherapy and concurrent thoracic irradiation of the site of the primary tumor in these patients is based on the results of meta-analyses that revealed that chemotherapy plus thoracic irradiation improved the overall two- or three-year rate of survival by 5.4 percent, as compared with chemotherapy alone. (2,3) More recent studies aimed at defining the best method of combining chemotherapy with thoracic irradiation have indicated that twice-daily thoracic irradiation given concurrently with chemotherapy results in two- and five-year survival rates of 44 percent and 22 percent, respectively. (4) These results confirm the importance of both thoracic irradiation and chemotherapy in the treatment of patients with limited small-cell lung cancer.

A major cause of morbidity and mortality in patients with small-cell lung cancer is brain metastasis, which in most patients results in multiple tumors. At the time of initial diagnosis, brain metastases can be detected in up to 10 percent of patients, and 1 to 2 percent of these patients have metastases only in the brain. However, among patients who complete chemotherapy, an additional 30 to 70 percent subsequently have clinically apparent brain metastases, and even more have such metastases at autopsy. (5) Moreover, among patients who have a complete remission with chemotherapy, approximately 15 percent have brain metastases as the initial or sole manifestation of recurrence. As the length of survival after diagnosis increases, the risk of metastases to the brain increases. Thus, as chemotherapy with concurrent thoracic irradiation becomes more effective for patients with limited small-cell lung cancer, the frequency of brain metastases later in the course of the disease may continue to rise.

For many years, prophylactic cranial irradiation has been used in patients with small-cell lung cancer in the belief that the treatment of microscopic or subclinical metastases would prevent or delay the onset of symptomatic brain metastases, but its efficacy for this purpose has been uncertain. Those who advocate prophylactic cranial irradiation point out that it is a safe way to reduce the overall incidence of brain metastases, even if only a small number of patients benefit. (6,7) Others argue against routine prophylactic cranial irradiation. They point out that the brain is rarely the sole site of recurrence, that radiation can be neurotoxic, and that radiation therapy does not prolong survival. (8,9) In this issue of the Journal, Auperin et al. report the results of a detailed meta-analysis of the efficacy of prophylactic cranial irradiation in 987 patients (847 patients with limited disease and 140 patients with extensive disease) who took part in seven trials and who had complete remission with chemotherapy, with or without thoracic irradiation. (10) Prophylactic cranial irradiation was associated with an absolute decrease of 25.3 percent in the cumulative incidence of brain metastasis at three years, from 58.6 percent in the control group to 33.3 percent in the treatment group. More important, prophylactic cranial irradiation was also associated with an absolute increase in overall survival of 5.4 percent at three years, from 15.3 percent in the control group to 20.7 percent in the treatment group. Prophylactic cranial irradiation was beneficial in patients with either limited or extensive disease. As previously reported in the two largest trials included in the meta-analysis, in which neuropsychological tests were performed on most but not all patients before, during, and after treatment, neurocognitive impairment was often detected at diagnosis, but no deterioration was found after prophylactic cranial irradiation. (6,7)

Can we now conclude that prophylactic cranial irradiation should become standard treatment for all patients with small-cell lung cancer who are in complete remission? I think so. This study confirms that there is a small absolute survival advantage for patients who receive prophylactic cranial irradiation. Even though this advantage is small, it is important: early studies of thoracic irradiation in patients with limited-stage small-cell lung cancer revealed no significant trend toward improved survival, but when large numbers of patients were studied, the small absolute survival benefit associated with thoracic irradiation was identified. (2,3) Today, for almost all patients with limited small-cell lung cancer, thoracic irradiation is an integral part of therapy.

We still do not know how best to integrate prophylactic cranial irradiation with chemotherapy in patients with small-cell lung cancer. The optimal dose of radiation, volume of tissue to be irradiated, and duration and timing of prophylactic cranial irradiation have not been determined. Also, questions remain regarding the safety and long-term neuropsychological consequences of prophylactic cranial irradiation. The study found a significant survival benefit, but it should be noted that four of the trials included in the meta-analysis had fewer than 100 patients, which suggests that there may have been some selection bias.

On the basis of the data presented, it is now reasonable to include prophylactic cranial irradiation as part of the treatment of patients with limited small-cell lung cancer who are in complete remission (usually evident after three or four cycles of chemotherapy) and of patients with extensive disease who have isolated metastases and are in complete remission. To minimize the risk of neurologic damage, prophylactic cranial irradiation should not be administered concurrently with chemotherapy or to elderly patients. As treatment of the primary tumor in patients with small-cell lung cancer improves, brain metastases are likely to become an increasingly frequent manifestation of treatment failure. Thus, studies are needed to define the optimal dose and fractionation schedule for prophylactic cranial irradiation and to determine how best to integrate this therapy with chemotherapy and thoracic irradiation. D. Carney, Prophylactic Cranial Irradiation and Small-Cell Lung Cancer, The New England Journal of Medicine Vol. 341, No. 7 (August 12, 1999)

How do we know if a particular form of treatment works? Self-reporting by doctors, hospitals or pharmaceutical companies could be subject to exaggeration or at least inaccuracy. Instead, what is needed is a scientific method of assessing the reliability of certain treatments and comparing them with what is used today. Clinical trials are designed to test new drugs, compare them with existing treatments, and determine if they provide better results, fewer side effects, or other benefits. Before a drug can be approved for use by the FDA, clinical trials must show it has some type of demonstrable positive effect.

There are three stages in clinical trials. The stages are progressive, stage one, being a basic test to see if a drug has some effect and to establish the maximum amount which can be given without substantial side effects, stage two, to evaluate the drug and assess its success, usually based upon the maximum allowable does established in stage one, and stage 3, measuring the drug against conventional treatments being used, to see if it provides better or at least comparable benefits.

In addition to seeing if the drug has some impact, in stage one, the study authors try to define a maximum dose, that is, what amount of the drug can be prescribed without significant side effects. Using Interleukin, we may administer the drug in various doses to see what is the maximum amount which can be tolerated without substantial side effects. Note that a clinical trial can be stopped or modified if a clear pattern emerges. For example, if people given large amounts of Interleukin suffer severe effects, we may decide to reduce the amount to prevent injury. Likewise, if it becomes clear that certain doses of the drug are providing clearly beneficial results, we may change the design so that all patients receive the benefit from the drug. Typically, however, the results are not clear, and conclusions about the drug are made after a phase of the study is completed. Here is how the American Cancer Society describes stage one:

A During a phase I trial-the initial investigation of a treatment= s safety and effectiveness in humans- a promising new therapy is tested to learn if it is worthy of further investigation. In the case of a new drug, this is when researchers learn about its effects by gradually increasing the dosage in a step-wise fashion and carefully analyzing the response among the participants. These are preliminary trials in which the researchers learn, for example, how well the drug is absorbed by the body, how much of it reaches the blood stream, and how it is metabolized and eliminated from the body.@ American Cancer Society, Informed Decisions 230 (1997)

11.31 Stage One is Not Designed to Assess the Success of a Drug

While we want to see if a drug works in stage one, defining the extent of tumor reduction is not really our purpose. A phase 1 trial might administer a drug in different dosages with response rates depending on the dosage. We would not measure the success or failure at stage one. If we have five different dosages used at stage 1, it is difficult to tell whether the drug works. If we have 18 participants in a stage 1 trial given three different doses of a new drug and in the group given the maximum there are two persons with partial responses, it is somewhat misleading to conclude that the drug has a 33% response rate at its maximum dose. Most scientists would instead call the results in phase 1 A promising@ and proceed to realistically assess the drug at phase 2.

11.32 A Stage One Protocol

Here is an example of a description of a phase 1 clinical trial:

Objectives

I. Determine the maximum tolerated dose (MTD) and the principal toxicities of irinotecan and gemcitabine in patients with surgically unresectable or metastatic solid tumors.

II. Determine if the principal toxicities and MTD of this combination regimen are affected by drug sequencing in this patient population.

III. Determine the potential for gemcitabine to alter the pharmacokinetic characteristics when administered with irinotecan in these patients.

IV. Describe the influence effected by varying the administration sequence of this combination regimen in this patient population.

V. Obtain preliminary data regarding efficacy of this combination regimen in these patients.

--Disease Characteristics--

Histologically confirmed metastatic or surgically unresectable solid tumor, having received the following maximum number of prior therapies for advanced disease:

Bladder cancer - no more than 1 prior therapy

Breast cancer - no more than 2 prior therapies...

Lung cancer - no more than 1 prior therapy

(this clinical trial deals with different forms of cancer, others may be restricted to lung cancer, or even to a particular stage and type of lung cancer)

Bidimensionally measurable disease outside a previously irradiated field at least 2 cm x 2 cmNo known bone metastases...

Chemotherapy:

No prior irinotecan, topotecan, or gemcitabine, Prior adjuvant chemotherapy allowed, if at least 1 year between last dose of adjuvant chemotherapy and recurrence of cancer

The study seeks to test two chemotherapy drugs which have shown some prior success in reducing the size of tumors and what is experimental is apparently a unique combination of the two being tested. The study involves a number of different cancers. Patients with some but not extensive chemotherapy are permitted.

11.33 Participation in Phase 1 Tests

Some scientists would say that it is overly simplistic to say that phase 3 tests are the safest, phase 2 second, and phase 1 the least safe. What we can say is that by phase 3, a drug has been initially tested for maximum allowable dose, shown some promise in stage 2 in reducing tumors without creating significant side effects, and is now measured against standard treatment in stage 3. No such track record is present for drugs used to phase 1 and they are at least to some extent, an unknown quantity. We are probably unsure of the drug= s efficacy, at the least we do not know the appropriate dose that should be administered.

Thus, most physicians would advise caution before entering a phase I trial. While it may be initially appealing to participate in a trial involving an innovative new treatment, the practical reality is that too much remains to be done at stage 1. Only those patients with a poor prognosis who have been told that conventional treatment is unlikely to do any good and who are ineligible for stage 2 and 3 trials would want to participate in a stage 1 assessment. One can note that in a stage 1 trial, the patient will frequently get excellent care and attention from physicians intimately acquainted with the particular disease.

The American Cancer Society describes stage two trials this way, A Once researchers confirm the possible value of a drug (or other treatment) and determine the safe dosage and other specifics of administering it, they focus on how effective it is people with one (a particular form of) cancer.... to gather information about how well people are responding, researchers may measure the size of tumors for shrinkage.... The study may also involve monitoring the patient= s blood for substances called tumor markers that often indicate whether their cancers are growing or shrinking.@ American Cancer Society, Informed Decisions 230 (1997)

If good results are shown in stage 2, we are now ready for stage 3. We will compare the new drug with the standard treatment used, with patients randomly assigned to either group. Thus, if Interleukin works at stages one and two, we compare its success in a phase 3 trial against, for example, a cisplatin based chemotherapy. Obviously if it is no better than existing treatments, there is no reason for its usage. For example, Gemcitabine may not show significantly better response rates than Cisplatin, but its diminished side effects merit its FDA approval.

The stages are progressive, stage one, being a basic test to see if a drug has some effect and to establish the maximum dosage without , if it does appear to work, stage two is designed to refine the dose and assess side-effects, and finally, stage three, measuring the drug against conventional treatments being used. Once a drug shows positive results in stage 3 it is generally ready to be marketed.

Here is a description of a phase 2 clinical trial:

A In a prior Cancer and Leukemia Group B (CALGB) Phase II trial of patients with advanced, previously untreated mesothelioma, diyhdro-5-azactidine (DHAC) demonstrated a 17% response rate, including 1 complete response, with only mild myelosuppression. This Phase II study (CALGB 9031) was conducted to determine the effectiveness of and toxicities that would result from adding cisplatin to DHAC administered to the same patient population. Overall, 5 objective responses were observed in 29 evaluated patients (objective response rate, 17%.... The major toxicity noted was significant chest/pericardial pain,... (s)ignificant leukopenia was observed in 29% of the patients. The addition of cisplatin to DHAC did not increase the response rate over that observed with DHAC alone in patients with mesothelioma; however, it did increase toxicity, especially leukopenia. This combination is not recommended for further studies involving mesothelioma patients.@ Samuels, et. al, Di-hydro-5-azacytidine and Cisplatin in the Treatment of Malignant Mesothelioma: a phase II study by the Cancer and Leukemia Group B, Cancer, 1998 Apr, 82:9, 1578-84. Let us review the results from this trial:

1) We can infer that there was a phase I clinical trial involving DHAC where the drug was shown to diminish tumor size (partial response) without unwarranted side effects. A phase II trial followed which showed a modest 17% response rate for use of DHAC, and in the trial various doses of DHAC were likely tried.

2) Most physicians use multi-modal chemotherapy, administering various types of anti-cancer drugs to attack the disease in different ways. Cisplatin is a well-known chemotherapy drug which has been shown to have demonstrated ability to reduce tumor size in many trials involving non-small cell lung cancer. Its efficacy in attacking mesothelioma, a rare type of lung cancer, is not known. In this phase II trial, Cisplatin was combined with DHAC, in the hope of improving response rates without creating additional side effects. If the study were successful, a phase III trial would occur, comparing DHAC and Cisplatin against the standard treatment being used, with patients randomly assigned to either group.

3) This Phase 2 trial was not successful. The response rate did not improve upon existing forms of treatment while the rate of side effects did, and the authors concluded that this combination did not warrant further investigation.

4) This appears to be part of an on-going study. The study authors will now have to determine whether the 17% response rate using DHAC alone merits a phase III trial. If other chemotherapy drugs show a response rate of more than 17%, then the drug would presumably not be FDA approved. The study authors may decide to combine DHAC with another drug, or take other action to improve the response rate. These changes would be evaluated in additional phase I or II trials and if successful, compared against the prevailing form of treatment in phase III.

Assume that interleukin showed promise in stage 1 with a maximum dosage being determined, in stage 2 there were good results with that dosage, the drug is now ready for stage 3 comparison testing. In stage 3, the drug will be compared with conventional methods of treatment.

11.41 Patients are Divided by type of Cancer and Stage

To accurately assess a form of treatment, the participants must be restricted to those with a particular form of disease at a particular stage. Thus non-small cell and small cell trials would almost always be done separately, and usually trials would be restricted to stage. Thus our hypothetical trial could be called, Assessment of the Effect of Interleukin with Chemotherapy versus Chemotherapy Alone in Stage 3 B non-small cell lung cancer patients. Since the study authors, (sometimes with a pharmaceutical company= s assistance) are interested in demonstrating a positive result, they will frequently restrict participation to those in otherwise good health. Thus, a clinical protocol, the summary of how and what will be done, may restrict the trial, and prohibit those with other health problems from participating.

If the stage 3 trial shows a positive result, then other trials might be conducted to confirm the results and meet FDA requirements before allowing the product to be marketed tot he public. Sometimes clinical trials will display inconsistent or contradictory results, which is why a series of trial is more reliable than one. For example, an increase in survival in a 20 person clinical trial might be due to one patient doing very well for reasons which could be unrelated to the particular drug tested. A meta-analysis is combining the results of many tests to reach particular conclusions

Where there is effective available conventional treatment, it makes sense for the patient to get it, rather than be randomly assigned a form of treatment which may or not be effective. That is why participants in clinical trials are generally limited to those for whom conventional treatment has not been proven effective. Thus, stage 3B and stage 4 lung cancer patients are eligible for clinical trials, because conventional treatment is not usually curative.

American Cancer Society, Informed Decisions 230 (1997).

Control group refers to the people in a clinical trial receiving the standard treatment, and not the experimental treatment. Randomization means the participants are randomly assigned to either an experimental or a control group. In a double-blind study, neither the physicians nor the participant= s know which treatments are administered to whom until the study is completed. This is done to prevent some types of conscious or unconscious bias. In a blind study, the patients are not told whether they are receiving the experimental treatment, but the doctors are informed.

11.71 Placebos are Rarely Used in Cancer Clinical Trials

Cancer clinical trials typically do not use placebos unlike other trials for the following reason. These clinical trials typically test a new cancer drug or formulation in phases one and two and measure it against standard treatment in stage 3. The primary measuring point is likely to be tumor reduction and there is usually no place in this framework for the absence of treatment, i.e., a placebo.

significant results,

! Treatment can sometimes occur in a distant medical center, rather than a local hospital,

For advanced stage patients, clinical trials are clearly an option, but must be discussed with the treating oncologist.

11.81 Eligibility and Conflicts.

The creators of the clinical trial seek first and foremost to establish that their drug works which is determined by looking at statistics of how the drug performs during the trial. For example, if existing chemotherapy drugs have a 25% partial response, a successful trial would show a 30% reduction. Thus, it is in the interest of the study creators to pick those patients who are most likely to fare well. If we know that those patients were severe existing health problems or generally less likely to respond to new drugs, then the study creators may want to exclude them from the trial. (Note that in a stage 3 trial at least theoretically that would not matter, because we selecting two equivalent groups.). Many trials exclude patients with prior unsuccessful chemotherapy, and those with severe health problems. It is conceivable that some of these people could benefit or at least might want to participate.

12.0 THE DIFFERENT STEPS IN METASTASIS

Metastasis remains the most serious danger of lung cancer. While considerable progress has been made in understanding cancer, that has not translated to success in treating metastatic cancer.

12.21 What is Angiogenesis

Angiogenesis is the disturbing ability of cancer cells to form new sources of blood supply to facilitate their expansion into other organs. In 1998, the National Cancer Institute provided this summary:

Angiogenesis means the formation of new blood vessels. Angiogenesis is a process controlled by certain chemicals produced in the body. These chemicals stimulate cells to repair damaged blood vessels or form new ones. Other chemicals, called angiogenesis inhibitors, signal the process to stop. Angiogenesis plays an important role in the growth and spread of cancer. New blood vessels "feed" the cancer cells with oxygen and nutrients, allowing these cells to grow, invade nearby tissue, spread to other parts of the body, and form new colonies of cancer cells.

Because cancer cannot grow or spread without the formation of new blood vessels, scientists are trying to find ways to stop angiogenesis. They are studying natural and synthetic angiogenesis inhibitors, also called anti-angiogenesis agents, in the hope that these chemicals will prevent the growth of cancer by blocking the formation of new blood vessels. In animal studies, angiogenesis inhibitors have successfully stopped the formation of new blood vessels, causing the cancer to shrink and die. http//cancernet.nci.nih.gov/

12.22 Angiogenesis can be a Normal Part of Body Regeneration

Angiogenesis occurs in healthy individuals, and is part of normal body functions:

12.23 Size and AngioGenesis

The Lycos website dealing with lung cancer discusses tumor size and anngiogenesis:

compounds called angiogenesis inhibitors. These are drugs that block

angiogenesis, the development of new blood vessels. Solid tumors

cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters)

without inducing the formation of new blood vessels to supply the

nutritional needs of the tumor. By blocking the development of new

blood vessels, researchers are hoping to cut off the tumor's supply

of oxygen and nutrients, and therefore its continued growth and

spread to other parts of the body

The National Cancer Institute and its participants have been gracious in placing their research on the Internet. In proceedings from an NCI conference, a speaker explains the angiogenesis process.

Thus, if this process can be eliminated, or even delayed, the prospect for long-term survival would dramatically increase. Squamous cell and adenocarcinoma are two types of non-small cell lung cancer. Squamous cell tumors frequently have areas of necrosis, or cell death. Statistically, squamous cell patients seem to survive longer than those with adenocarinoma. Thus we can survive that adenocarcinomas may produce chemicals, protein reaction to create angiogenesis more effectively than squamous cell tumors, enabling the adeno tumors to spread.

12.31 Proximity to Nearby Organs and Blood Vessels

Metastasis is partly explained by geographical proximity:

In some instances, this organ preference of metastasis can be explained simply in terms of the anatomical relationship of the organ with the site of the primary tumor growth. Hence, many secondary tumors will develop in those organs which provide the first capillary bed encountered by dispersing metastatic cells, since the tumor cells may be carried as aggregates which pass into a capillary whose lumen is smaller than the clump diamater. A knowledge of the circulatory anataomical associations of the primary tumor site with other organs can typically be used to predict the seeding site of about 60% of the metastases from that tumor. Metastases from colon cancer probably occur with high frequency because the liver receives the drainage of the blood supply to the large intestine. Vile, Cancer Metastasis: From Mechanisms to Therapies10-11 (Wiley 1995) (hereinafter cited as Vile, at ).

12.32 Cellular Connections

In other instances, there are specific chemical or other attractants which lead cancer cells to particular parts of the body: Usually when metasases seed at a site which could not be predicted on the basis of circulatory anatomy, it is because the site expresses specific determinants which actively promote the growth of the metastatic cells, thereby providing a favorable soil....

12.41 Highly Metastatic Cancers and the Immune Response

Tumors vary in their ability to circumvent individual organ= s immune defenses. Vile states:

A Tumor cells must evade the immune response to achieve successful growth and metastases Target organ-associated natural mechanisms are important in the late stage of cancer progression and metastasis formation. A number of reports have shown that some metastatic cell line are more resistant to host immunity... For example the highly metastatic RAW117-H10 lymphoma cell line is more resistant to the cytotoxic activity of spleen-derived mice natural killer (NK) cells than the poorly metastatic parental RAW117-P cell line. Resident Kupffer cells in the liver also show heterogenity in their tumer-killing ability....Poorly understood mechanisms of heterogeneity in the susceptibility of tumors to organ immunity may contribute to the organ preference of metastasis.@ Vile at 60.

Thus, the ability of a tumor to metastasize depends upon its cellular type and the ability of the host cells to recognize it as an invader, and successfully attack the intruding cell.

The Lycos website dealing with lung cancer discusses clinical trials with anti-angiogenesis drugs:

About 20 angiogenesis inhibitors are currently being tested in human

trials. Most are in early phase I or II clinical (human) studies.

Three are in phase III testing and the results for one are expected

by the end of 1999. (See list of Angiogenesis Inhibitors in Clinical

Trials.) Phase I/II trials include a limited number of people to

determine the safety, dosage, effectiveness, and side effects of a

drug. In phase III trials, hundreds of people around the country are

assigned at random to receive either the new treatment or the

standard treatment.

In normal tissue, new blood vessels are formed during tissue growth

and repair, and the development of the fetus during pregnancy. In

cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels,

are the source of new blood vessels and have a remarkable ability to

divide and migrate. The creation of new blood vessels occurs by a

series of sequential steps. An endothelial cell forming the wall of

an existing small blood vessel (capillary) becomes activated,

secretes enzymes that degrade the extracellular matrix (the

surrounding tissue), invades the matrix, and begins dividing.

Eventually, strings of new endothelial cells organize into hollow

tubes, creating new networks of blood vessels that make tissue

growth and repair possible.

12.51 Endothelial Cell Growth

The Lycos site, then discusses this cell growth:

Most of the time endothelial cells lie dormant. But when needed,

short bursts of blood vessel growth occur in localized parts of

tissues. New capillary growth is tightly controlled by a finely

tuned balance between factors that activate endothelial cell growth

and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and

movement, including angiogenin, epidermal growth factor, estrogen, fibroblast growth factors (acidic and basic), interleukin 8,

prostaglandin E1 and E2, tumor necrosis factor-, vascular

endothelial growth factor (VEGF), and granulocyte colony-stimulating

factor. Some of the known inhibitors of angiogenesis include

angiostatin, endostatin, interferons, interleukin 1 ( and), interleukin 12, retinoic acid, and tissue inhibitor of metalloproteinase-1 and

-2. (TIMP-1 and -2).@ Lycos

12.52 Growth Factors

At a critical point in the growth of a tumor, the tumor sends out

signals to the nearby endothelial cells to activate new blood vessel

growth. Two endothelial growth factors, VEGF and basic fibroblast

growth factor (bFGF), are expressed by many tumors and seem to be

important in sustaining tumor growth. Angiogenesis is also related

to metastasis. It is generally true that tumors with higher densities of

blood vessels are more likely to metastasize and are correlated with

poorer clinical outcomes. Also, the shedding of cells from the primary

tumor begins only after the tumor has a full network of blood vessels. In addition,both angiogenesis and metastasis require matrix

metalloproteinases, enzymes that break down the surrounding tissue

(the extracellular matrix), during blood vessel and tumor invasion.

Strategies

Of the anti-angiogenesis drugs now in clinical trials, some were

designed to target specific molecules involved in new blood vessel

formation. For others, the exact mechanism of the drug is not known, but it has been shown to be anti-angiogenic by specific laboratory tests (in the test tube or in animals). In general, four strategies are being used by investigators to design anti-angiogenesis agents:

Block the factors that stimulate the formation of blood vessels

Use natural inhibitors of angiogenesis

Block molecules that allow newly forming blood vessels to invade

surrounding tissue

Incapacitate newly dividing endothelial cells

Several differences between standard chemotherapy and

anti-angiogenesis therapy result from the fact that angiogenesis

inhibitors target dividing endothelial cells rather than tumor

cells. Anti-angiogenic drugs are not likely to cause bone marrow

suppression, gastrointestinal symptoms, or hair loss -- symptoms

characteristic of standard chemotherapy treatments. Also, since

anti-angiogenic drugs may not necessarily kill tumors, but rather

hold them in check indefinitely, the endpoint of early clinical

trials may be different than for standard therapies. Rather than

looking only for tumor response, it may be appropriate to evaluate

increases in survival and/or time to disease progression.

Drug resistance is a major problem with chemotherapy agents. This is because most cancer cells are genetically unstable, are more one

to mutations and are therefore likely to produce drug resistant

cells. Since angiogenic drugs target normal endothelial cells which

are not genetically unstable, drug resistance may not develop. So

far, resistance has not been a major problem in long-term animal studies or in clinical trials. Finally, anti-angiogenic therapy may prove useful in combination with therapy directly aimed at tumor cells. Because each therapy is aimed at a different cellular target, the hope is that the combination will prove more effective. Early trials are under way. For further information about clinical trials, refer to the National

Cancer Institute's website: http://cancertrials.nci.nih.gov.@

13.22 Drugs Used for Angiogenesis

Set forth below is a chart from the National Institute of Health of angiogenesis drugs and their status as of July, 1998. The chart discusses angiogenesis generally, and does not deal specifically with lung cancer.

12.51 Practical Difficulties with Anti-Angiogenesis Drugs

Teicher discusses some of the theoretical problems with these drugs and the important of timing in the drug administration in animal studies:

We then looked at the antiangiogenic combination, starting therapy very early in the life of the tumor on day 4, when the tumor is just a seed and beginning to explode in its angiogenic activity. We are starting the angiogenic agent combination 3 days later on day 7, when the tumor is actually a fairly well-established nodule. The cytotoxic chemotherapy was administered on days 7-11. So we learned a lesson that cancer researchers learn again and again, and that is the tumor burden is very important. If we started the antiangiogenic therapy early on day 4 and treated at days 4-11 or 4-18, we obtained the greatest enhancement in tumor growth delay, but even if we had to limit the antiangiogenic therapy to the same 5-day period that we gave the cytotoxic therapy, we still had tumor growth delay of 29 days, which was better than cytotoxic chemotherapy alone.

It was only when we administered the antiangiogenic therapy for the full 2-week period of days 4-18, which is really the full exponential growth phase of this tumor, that we obtained the greatest tumor response and with this therapeutic regimen. Forty to fifty percent of the animals were cured of the Lewis lung carcinoma. Cancer Therapy www.conference-cast.com/webtie/sots/lung/transcripts/teichertran.htm

12.53 Matrix metalloproteinases Inhibitors

Instead of trying to kill the cancer cells, one could try to prevent metastasis or spread to other organs. Recall that cancer cells metastasize because they do not have an enclosing shell and acquire the ability to penetrate the shells or basement membranes of normal cells. Matrix metalloproteinases (MMP) such as collagenase, help break down the extracellular matrix which protects other bodily structures. Some drugs are used to inhibit MMP, and thereby to prevent tissue matrix break. We can review some of the recent information about these drugs. However, none have been shown to have proven, clear anti-cancer fighting properties in laboratory experiments and clinical studies. All have a theoretical basis for believing they could be used which are described below.

Experimental data indicate that angiogenesis is crucial for growth and persistence of solid tumor and of their metastases. Another agent to display anti-angiogenesis properties is suramin . Although suramin has shown, at least in vitro (in cells), to inhibit lung cancer growth (7), clinical studies in NSCLC have yielded negative results. Angiostatin, a component of plasminogen and endostatin, inhibits metastasis by inducing a balance between metastatic and primary tumor cells defined as "dormancy". Both agents are capable of inhibiting tumor growth in vivo in animal models. Although tumors re-grow when anti-angiogenic treatment is discontinued, experimental tumors, remain sensitive to a second cycle of treatment with the same agent. Different from conventional chemotherapeutic agents, no drug-resistance was observed even after multiple repeated cycles of antiangiogenic therapy (9). These agents hold considerable promise for the treatment of a number of tumor types including NSCLC. Other drugs which, in preclinical models, have been found to be angiogenesis inhibitors and that are currently entering clinical trials include TNP-470 (a synthetic fumagillin derivative), thalidomide, vitamin and squalamine.

13.21 National Cancer Institute Discussion of Anti-AngioGenesis

References

Paget, Distribution of Secondary Growths in Cancer of the Breast, 1889, Lancet 571-73

Vile, Cancer Metastasis: From Mechanisms to Therapies (Wiley & Sons 1995)

A Excitement has grown about a fourth approach, one that stimulates the body= s own immune system to recognize, attack, and destroy cancer cells. It= s called biological therapy or biotherapy, because the agents are made from living body cells. Biological therapy began with the discovery of immunization more than 200 years ago. In modern times, research has centered on isolating specific cells of the immune system and their chemical products and manipulating them in the laboratory to target their activity and control their effects.@ Informed Decisions, p. 192.

A Introducing genetic material can directly inhibit tumor growth by replacing a damaged tumor-suppresor gene, decreasing the expression of activated or overexpressed dominant oncogenes, or by introduction of an enzymatic activity that confers sensitivity to an otherwise nontoxic drug.@ Lee, et. al., Gene Therapy 323, in Pass, Lung Cancer Principles and Practice (Lippincott 2000).

Here are some of the problems researchers have encountered.

13.21 Getting Access to All the Tumor Cells

A In all of these studies, it has been difficult to deliver recombinant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which may be of limited clinical benefit.A Lee, et. al., Gene Therapy 325, in Pass, Lung Cancer Principles and Practice (Lippincott 2000).

13.22 Side Effects

Anti-angiogenesis gene therapy attempts to frustrate the creation of new blood vessels or the use of existing channels by tumor cells. Recall that angiognesis is in other contexts a normal process used for wound healing and other functions which this therapy may frustrate.

13.31 T Cells and Lymphocytes

The most important cells of the immune system are the white blood cells known as lymphocytes. There are two main types of lymphocytes, T cells and B cells. T cells get their name from the fact that they multiply and mature inside the thymus gland in the chest. T cells include the following:

C Killer T cells destroy the invader directly.

C Lymphokine-producing T cells release proteins called lymphokins, such as the interferons and interleukin 2, which speed up the activity of the immune system,

C Helper T cells boost the activity of B cells.

C Suppressor T cells slow down the immune response to keep the system from attacking normal cells.

C Memory T cells keep a record of the invader encountered, so the next time the body is exposed there will be an efficient response.

As you can see, there are various types of T cells. Probably the most important are killer T cells, and much investigation has focused upon activating these killer T cells.

13.32 Interferons

Interferons are proteins secreted by immune cells that A interfere@ with a virus= s ability to reproduce and proliferate. In the laboratory, low concentrations of interferon help boost the power of natural killer T cells. With some tumors, interferons can help inhibit the development of the blood vessels that tumors need to metastasize and grow, the process called angiogenesis. Thus, interferon is being investigated for use as an anti-angiogenesis. There are three main types and 17 subtypes of interferon.

Anti-growth factor therapy can be accomplished through two different strategies. One is to hamper the binding of growth factor to their receptors. The other is to interfere with the signal that occurs after the growth factor has bound to its receptor. See Ardizoni, Drug Therapy of Non-Small Cell Lung Cancer: News from the Lab, Cuneo Lung Cancer Conference. Ardizoni explains,

This latter strategy is achieved by inhibiting signal transduction

molecules such as tyrosine kinase (PTK) and protein kinase C (PKC). The rationale is that the inhibition of deregulated cellular signaling pathways in malignant cells at the level of PKC or PTK, where multiple mitogenic signals converge, should lead to the inhibition of tumor growth. PKC inhibitors, in addition to reducing tumor growth, are also able to sensitize cancer cells to cytotoxic agents by reverting the MDR phenotype. A series of new drugs with anti-PTK or anti-PKC properties have been recently developed and are close to entering clinical trials in a number tumor types including lung cancer (10). Another enzyme involved in signal transduction which has been targeted for anticancer drug development is farnesyl transferase. Farnesylation is necessary for the association of ras proteins to the cell membrane and therefore for their transforming activity. A number of compounds which are able to interact with Farnesylation of H-ras and K-ras proteins have been developed.... Experiments in human tumor xenograft, including A-549 lung cancer

xenografts, have shown almost 90% growth inhibition. Some of these agents are presently undergoing phase I clinical evaluation in a number of tumor types including NSCLC.@

13.36 Distinguishing Active and Passive Immunotherapy

Immunotherapy is therapy designed to trigger an immune response. Nonspecific immunotherapy is designed to trigger some type of general immune response activating a wide range of immune cells. For example, the immune response to tuberculosis also assists in fighting certain types of cancer.

A Certain cancer cells contain antigens that appear foreign to your immune system. In some cases, it is possible to remove cancer cells, analyze them in the lab, and identify their antigens. Theoretically, once the antigens are know, a treatment can be designed that stimulates a specific immune response against them. This is called specific active immunotherapy. Results of this approach have been disappointing.@ American Cancer Society, Informed Decisions (1999)

13.41 Role of the P-53 Gene

P-53 is a tumor suppressor gene. Recall that cancer results from activation of growth proto-oncogenes and inhibition of tumor-suppressor genes such as P-53. Its role is critical:

13.45 P53 and Small Cell Lung Cancer

A 1999 study found that 52% of the patient had traces of P53 in bronchial specimens. Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. P53 presence was unfortunately a negative factor for these patients. A The overall response rate of patients

If this damage to P-53 could be repaired, then tumor spread could be limited and perhaps P-53 could again perform its function of preventing cell duplication. This type of treatment has worked in the laboratory dealing with cancer cells:

Reintroducing a wild-type p53 gene into lung cancer cells, including bronchioalveolar lung cancer (BAC), dramatically inhibits tumor cell growth and promotes tumor cell death despite the presence of mutations in multiple other genes. Lee, Gene Therapy, 324 in Pass, Lung Cancer: Prinicples and Practice (2000).

A In NSCLC it was initially shown that introduction of a vector containing the wt-53 (wild type) into cell lines, which {had} either a deletion or a missense mutation in p53, markedly reduced cell proliferation and tumorigenecity.@ Fredericksen, Gene Therapy for Lung Cancer, Lung Cancer, Vol. 23 (3) (1999) pp. 191-207.

13.48 Clinical Trials and Other Research on Humans

13.48.1 Presence of P53 Correlated with Survival

Some limited, promising results have been seen in P-53 clinical trials.

Here is one description: A In the protocol, tumor regression was observed in three out of seven patients. In two patients, postreatment biopsies taken 4 weeks after injection with the retrovirus (P53 wild type) showed no evidence of viable tumor.@ However, the patients involved in the trial died, with the inhibition of the tumor apparently too late. Fredericksen, Gene Therapy for Lung Cancer, Lung Cancer, Vol. 23 (3) (1999) pp. 191-207.

13.461 Problems and Hurdles to Successful Treatment

It is difficult to repair the gene, the solution being studied is transferring another P-53 gene to the cancer area. Lee writes:

The complexities of the three-dimensional structure of the p53 tumor-suppresor gene product and the radical changes in this structure induced by a single point mutation makes it extremely difficult to restore its function with pharmaceuticals. Thus, the basic concept of tumor suppressor gene therapy utilizing p53 is to reintroduce a functionally active copy of the defeicte genes in the cancer cell by direct gene transfer to directly induce cell death by apotosis. Lee, id at 324.

Getting enough P-53 to the tumor to have significant results is difficult:

A In all of these studies, it has been difficult to deliver reconbitant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which may be of limited real clinical benefit.@ Lee, at 324.

 

 

 

 

 

Cancer overall is a serious disease, with lung cancer particularly serious. Why? First, we can say generally that the existence of cancer in the lung itself is usually not a cause of death. Instead, it is the tendency of cancer to metastasize, going through lymph nodes or blood vessels to other organs which generally causes death. The seriousness of a cancer is directly related to its propensity to metastasize. Thus, prostrate cancer usually has a good survival rate because the cancer does not easily move from the prostrate; whereas, pancreatic cancer has a high mortality because the pancreas secretes hormones which are spread throughout the body. Likewise, lung cancer, with a network of lymph nodes and blood vessels going to and from the lung does have an unfortunate tendency to metastasize.

Survival with lung cancer is linked to stage which is connected with the tendency to metastasize. A stage one patient with a surgically resected tumor will generally do well, and we have five year survival rates ranging from 55% to 75%. One Japanese study found survival rates approaching 80% for stage one and stage 0 lung cancers. (microscopic tumors only visible on cellular examination). Ideally, when a stage one cancer is surgically resected, there is no more cancer, and nothing to metastasize. Many of the 30-40% of stage 1 patients who have future problems were not really stage 1 patients at all; that is, there were cancer cells within the lymph nodes which could not be seen though available diagnostic tools.

As the cancer progresses, the chance of metastasis increases and the probability of long-term survival decreases. There is a direct relationship between stage and long term survival. Let us look at excerpts from American Cancer Society research with all cancers:

This chart is based on cases diagnosed from 1986-1993, www.bioscience.org, American Cancer Society Surveillance Research, 1998. Survival rates today are higher, because these statistics are based on cases 7-14 years old. While the absolute numbers will be higher, the basic trend will remain constant. Where we have a stage 4 patient whose cancer has already reached another organ, the prognosis is dim., but not hopeless. With a stage 4 patient, the cancer has already spread, and the physician has the task of preventing further spread and arresting the cancer through chemotherapy, as well as treating the symptoms in the lung and the other organ.

Estimations of survival time generally represent a statistical assessment, not an assessment of a particular patient. We know on an aggregate basis that because stage 3 and 4 patients larger cancer with a greater tendency to metastasis that their probability of survival is decreased. However, in most cases, the doctor cannot venture an entirely accurate prediction as to a particular patient. Thus, if there is a 5 year survival rate for stage 3 patients, the oncologist usually cannot tell whether our patient will be the lucky one for whom chemotherapy will work successfully.

14.2 PREDICTIONS ARE ACCURATE ON AN AGGREGATE, NOT INDIVIDUAL BASIS

Within a statistical group are people who live longer and shorter, and the doctor usually has no accurate way of determining the patient's precise period of survival. People with advanced state 4 cancer do have remissions, albeit a small number. The term six months, frequently used, is a somewhat arbitrary number, accurately taking into account the uncertainty of prediction. Some doctors do not like to provide predictions, believing that they could in some way frustrate recovery by decreasing a patient= s will to live, and that the patient may misinterpret an opinion as fact. When a doctor interprets a pathology slide as squamous cell carcinoma, that is a fact, or something very close to it, when he ventures an estimates on survival time, that is really an opinion, albeit an educated opinion.

14.21 Examples of Issues with Small Cell Lung Cancer

For example, some estimate that 50% of patients with small cell lung cancer have a complete response to chemotherapy, meaning the tumor disappears. Sadly, the cancer generally reappears. However, the physician cannot accurate predict when or if the cancer will reappear, though he can utilize established diagnostic tools to assess the current status of the cancer.

The primary factor in assessing survival is cancer stage. Many questions relating to treatment and status of particular cancers are discussed in chapter 4 (nonsmall cell) and chapter 5, small cell. The Lung Cancer Manual provides five year survival estimates as follows:

! stage IA 60% to 67% (that is, 60 to 67% of people diagnosed stage 1A NSCLC are alive five years after being diagnosed,

! stage 1B 36% to 71%

! stage 2A 34% to 55%

! stage 2B 24% to 39%

! stage 3A 13% to 23%

! stage 3B about 5%

! stage 4 about 1%

Alcase, The Lung Cancer Manual 6.2 (1999) (as of the date of this publication available only on-line but at no cost on the Alcase website) With respect to small-cell cancer, the median survival time for patients with limited SCLC is 14 to 30 months. From 10% to 25^% of people diagnosed with limited stage SCLC live five years. With treatment, the median survival time for patients with extensive disease is 8 to 14 months. Only 1% and 5% of people diagnosed with extensive-stage SCLC live five years or more.@ Alcase, The Lung Cancer Manual 7.2 (1999).

An informative website on lung cancer presents these survival statistics based upon patients for patients eligible for surgery:

Adapted from www.cancer.about.com. Note that the statistics represent the subgroup who is eligible for surgery, with surgery for stage 3 patients still a matter of debate.

14.31 Since Survival is Directly Related to Stage at Diagnosis, We Need to Create Early Detection Programs

The fact that survival is so directly related to stage is a strong argument for early detection programs. Such programs would increase the number of patients diagnosed with early stage cancers and thereby increase survival. As noted, there is no established program for early detection of lung cancer in the United States. The American Cancer Society and the National Cancer Institute have only recommended against smoking; they have failed to establish programs to enable smokers to have their disease diagnosed in early and treatable stages. In contrast, the lesser-known lung cancer advocacy group Alcase, authors of the Manual cited above, have strongly urged the creation of early detection systems.

14.32 Limits to Predicting Survival Bases on Stage

The information above is helpful is assessing long-term survival, but there are a number of variable not noted. For example, performance status, the type of lung and overall health of the patient, is an important factor. As noted, we cannot provide an accurate prediction in individual cases. We look at survival issues at stage 1 and 4 below.

14.33 Stage 1 Tumors

Stage 1 tumors have five year survival rates of 50% to 70%. The Stage 1 survival rate is improved when the tumor can be surgically removed. Stage 0, or tumors known by cellular analysis but which cannot be seen on an x-ray or bronchoscope, have an even better prognosis of 70 to 80%. Thus anyone with a stage 0 or 1 tumor which has been surgically removed has an excellent prognosis. Indeed, as a society, we need to work harder to diagnose lung cancer at earlier stages.

One treatise reports on the favorable experience of stage 1 patients:

A Results were reported recently with surgical treatment of 598 patients with stage 1 tumors. The male to female ratio was 1.9 to 1 and the median age was 62 years. The primary tumor was located in the upper lobe in 67% of the patients, in the middle or lower lobes in 30%, and in the main bronchus in 3% The histology was squamous carcinoma in 233 patients and nonsquamous carcinoma in 365 (adenocarcinoma, 253; Bronchoalveolar in 98; large cell carcinoma, 14).

The overall 5- and 10 year survival rates (Kaplan-Meier were 75% and 67%, respectively (Fig 14.2). Patients with T1 tumors fared better than those with T2 tumors. Survival in patients in T1 tumors was 82% at 5 years and 74% at 10 years, compared with 68% at 5 years and 60% at 10 years for those with T2 tumors.@ Martini, Treatment of Stage 1 and 2 Disease, 340 in Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996).

14.34 Stage 3 Tumors

Stage 3 patients are frequently studied in clinical trials. One study A calculated three year survival rates at 35% for stage 3A patients and 26% for stage 3B patients.@ Impact of Preoperative Biomodality Induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.@ J. Clin Oncol 1999 Apr, 17 (4) 1185.

14.35 Stage 4

Stage 4 tumors, tumors involving metastasis to other organs have a dim prognosis. There are periodic reports of cures and long-term survival, statistically, we seem unable to develop adequate chemotherapy and radiation regimens to attack and permanently cure metastatic cancer. For many stage 4 lung cancer victims, treatment is palliative designed to reduce pain, extend life for a period, or limit the spread of the tumor. Within stage 4, it appears prognosis is most adverse where there are metastasis to the bone marrow, liver or brain) whereas the prognostic impact of spread to pleura, skin or peripheral nodes, or the presence of an abnormal bone can have less impact on mortality.

Many of the clinical studies involve stage 4 patients. There we know that there is an approximate rate of response to chemotherapy of 25%, with some recent reports indicating higher success rates, and with success defined as a partial or complete response. Thus, at least one in 4 patients overall will enjoy some favorable response with chemotherapy. However, the cancer cells develop some immunity or tolerance to the chemotherapy and second line or second round chemotherapy is usually less successful than the first. In short, a complete cure is possible, and can be hoped with current modes of treatment, which have the capacity to eradicate cancer and have done so in a few cases. Statistically chemotherapy with stage 4 patients usually does not effect an overall cure, though it does improve the patient= s condition.

14.41 Performance Status

One frequently used for assessing activity the level of activity in a patient for various purposes is called performance status. Activity is related on a scale of 0 (normal) to 4 (bedridden). Survival levels have been correlated with a patient= s performance status. For specific articles, and recent developments, go to Medline, the world medical database, at www.healthgate.com. In a later chapter, different research tools on-line and from different libraries are discussed.

Most cancers are named after the part of the body where the cancer first starts. See American Cancer Society Webpage (Malignant Mesothelioma- Overview). This type of cancer begins in the tissue that surrounds different organs inside the body. This tissue, called mesothelium, protects organs by making a special fluid that allows the organs to move. Mesothelium surrounds the lungs, stomach, and heart, and tumors can begin in any of these areas. Three quarters of mesothelial tumors begin in the pleura of the lungs, with the remainder in the peritoneum (stomach), and a small number in the heart.

15.11 Why a Rare Cancer is So Intensively Studied

Mesothelioma is a rare cancer which has attracted much attention because it is related to exposure to asbestos. From a scientific perspective, the disease can be studied to understand how a cancer develops in relation to a specific causative agent. Thus there are animal studies to trace the development of mesothelioma when asbestos is administered in large amounts.

15.12 The Nature of Mesothelioma and Why Surgery is Difficult

The ideal treatment for lung cancer is surgical resection of the tumor which can eliminate the prospect of metastasis (transfer of the cancerous cells to other organs) and removes the tumor from the lung. Five year survival rates of between 50% and 80% have been reported in early stage one patients with other forms of lung cancer. However surgery has been difficult to perform with mesothelioma because it is a group of tumors.

15.13 Mesothelioma Develops in the Pleura

Unlike other cancers where a single tumor develops in the large or small breathing pathways, with mesothelioma, a group of tumors develops in the pleura. A more accurate term for mesothelioma is diffuse malignant mesothelioma.

The disease is described at page 757 of the Comprehensive Textbook of Thoracic Oncology:

A Mesothelioma of the pleura is characterized by local growth and invasion of contiguous structures and by relatively late spread to distant organs. Recent studies provide evidence that pleural mesothelioma begins in the parietal lawyer and subsequently spreads to involve the visceral pleura. Pleural effusion (fluid in the pleura of the lung) usually is present.... Proliferation of mesothelioma cells and accompanying stromal elements form firm, gray nodules that subsequently coalesce [and] the pleura gradually thickens."

The nature of the disease unfortunately makes it difficult to treat. The consistent lesson is that when tumors can be surgically removed, the patient enjoys a good prognosis. However, with mesothelioma, since there can be a group of tumors spread throughout the pleura, surgery has been difficult to perform, though there is some literature which discussed it as an option.

15.14 Smoking Does Not Appear to Be A Cause of the Disease

While most lung cancer is associated with smoking, that appears to play no role in mesothelioma. Studies do not indicate a clear increased risk with smoking and the tumors do not develop in the breathing areas of the lung.

15.15 The Role of Latency

When initially questioned, some patients may indicate that they do not recall recent exposure to asbestos. However, mesothelioma appears to have a long latency period, or period to develop, and heavy asbestos exposure has been traced 20 and 30 years before the patient developed the disease. It appears a heavy exposure, but possibly of short duration, may create the conditions for the disease, and that it is a cancer which develops and spreads slowly.

15.2 DIAGNOSTIC TOOLS

Your doctor may look inside your chest cavity with a special instrument called a thoracoscope. A cut will be made through your chest wall and the thoracoscope will be put into the chest between two ribs. This test, called thoracoscopy, is usually done in the hospital. Before the test, a local anesthetic is given.

The physician may also look inside your abdomen (peritoneoscopy) with a special tool called a peritoneoscope. The peritoneoscope is put into an opening made in the abdomen to ascertain the existence of peritoneal mesothelioma. This test is also usually done in the hospital with a local anesthetic. Biopsies are usually done during the thoracoscopy or peritoneoscopy.

Mesothelioma uses a different staging system called the Butchert system using stages one through four to designate the extent of spread of mesothelioma:

! Stage I: The cancer is found in the lining of the chest cavity near the lung and heart or in the diaphragm or the lung.

Advanced malignant mesothelioma

! Stage II: The cancer has spread beyond the lining of the chest to lymph nodes in the chest.

! Stage III: Cancer has spread into the chest wall, center of the chest, heart, through the diaphragm, or abdominal lining, and in some cases into nearby lymph nodes.

! Stage IV: Cancer has spread to distant organs or tissues.

15.32 Types of Mesothelioma

15.33 Distinguishing Mesothelioma from Adenocarcinoma

In some cases, mesothelioma is not easily distinguished from adenocarcinoma, a type of non-small cell lung cancer discussed in chapter 2. "Well-differentiated tumors have a tubulopappilary growth pattern that may be indistinguishable from an adenocarcinoma. A Canadian panel disagreed on the diagnosis of mesothelioma in 30% of the cases. Some suggest that immunohistochemistry can help distinguish the two diseases and provide better information for treatment and prognosis Here are some figures based on chapter nine, Pathology of Malignant Mesothelioma, in the book, Asbestos and Malignancy.

Test Adenocarcinoma Mesothelioma

Periodic Acid Schiff diastases Negative 50% are positive

Hyaluronidase alkene blue One third positive

Negative

Mucicarmine Negative 50% are positive

CEA (Carcinoembyonic antigen) 10% of cases, positive 90% of cases

Keratin proteins

15.31. Pathological Differences Between Adenocarcinoma and Mesothelioma

Antman in her book on asbestos diseases including mesothelioma comments:

A the microvilli are the most dramatic aspect of a mesotheliomas ultrastructure. The microvilli not only appear very long, but they are extensively branched with secondary and tertiary branching points. Using the length to diameter ratio (LDR) one is able to compare mesotheliomas with adenocarcinomas with respect to the character of their microvilli ... [and] mesotheliomas have significantly longer [ones] than adenocarcinomas.@ Warhold, Electron Microsophy in the Diagnosis of Mesothelioma 209 in Antman, Asbestos-Related Malignancy (Grune & Stratton 1987) . Electron Micro sophy is an ultra-sensitive microscope useful in making difficult distinctions in tissue.

15.4 TREATMENT OVERVIEW

The following is excerpted from the National Cancer Institute webpage on mesothelioma.

A Treatment depends upon the disease spread, your age, and your general health. You may receive treatment that is considered standard based on its effectiveness in a number of patients in past studies, or you may choose to go into a clinical trial. Not all patients are cured with standard therapy and some standard treatments may have more side effects than are desired. For these reasons, clinical trials are designed to find better ways to treat cancer patients and are based on the most up-to-date information. Clinical trials are going on in many parts of the country for many patients with malignant mesothelioma. If you want more information, call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237); TTY at 1-800-332-8615.

LOCALIZED MALIGNANT MESOTHELIOMA (STAGE I)

If the cancer is only in one place in the chest or abdomen, your treatment will probably be surgery to remove part of the pleura and some of the tissue around it. If the cancer is found in a larger part of the pleura, your treatment may be one of the following:

1. Surgery to remove the pleura and the tissue near it to relieve symptoms, with or without radiation therapy after surgery.

2. Surgery to remove sections of the pleura, the lung, part of the diaphragm, and part of the lining around the heart.

3. External beam radiation therapy to relieve symptoms.

4. A clinical trial of surgery followed by chemotherapy given inside your chest.

5. A clinical trial of surgery, radiation therapy, and/or chemotherapy.

ADVANCED MALIGNANT MESOTHELIOMA (STAGES II, III, AND IV)

Your treatment may be one of the following:

1. Draining of fluid in the chest or abdomen (thoracentesis or paracentesis) to reduce discomfort. Drugs also may be put into the chest or abdomen to prevent further collection of fluid.

2. Surgery to relieve symptoms.

3. Radiation therapy to relieve symptoms.

4. Chemotherapy.

5. A clinical trial of surgery, radiation therapy, and chemotherapy.

6. Chemotherapy given in the chest or abdomen.

RECURRENT MALIGNANT MESOTHELIOMA

Your treatment depends on many factors, including where the cancer came back and what treatment you received before. Clinical trials are testing new treatments.@

15.4 THE ROLE OF SURGERY IN TREATING MESOTHELIOMA

Because surgery has not been a viable alternative in many cases, the prognosis for mesothelioma like other advanced forms of lung cancer has been poor. However, a recent article study provided some encouraging news. A group of 183 patients underwent extra pleural pneumonectomy (removal of a large portion of the lung) followed by chemotherapy and radiation. There were seven deaths associated with the surgery and survival rates as follows:

A Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months (Univariate analysis identified 3 prognostic variables associated with improved survival and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell types (52% 2 year survival, 21% 5 year survival, negative resection margins, and extrapleural nodes without metastasis....31 patients with 3 positive variables had the best survival (68% 2 year survival, 46% 5 year survival, median 51 months." Sugarbaker, et. al., Resection Margins, extra pleural nodal status, and cell type determine postoperative long term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 cases. J. Thoracic Cardiovascular Surgery 1999, Jan, 117:1, 54,65.

Some conclusions can be drawn from this important study:

* Aggressive treatment seems to help prolong life with mesothelioma, though initial surgery does carry significant risks,

* Some of the same considerations with other forms of lung cancer apply to mesothelioma. Early diagnosis and the absence of metasasis to other organs improves the chance of long-term survival.

*Good resection margins indicates the cancer has been resected with room to prove and contribute to a favorable prognosis.

* While not explicitly stated in the study, it can be inferred that choice of hospital is important. Boston Hospital where the study was conducted is an excellent hospital, and the mesothelioma patient should choose a facility with specific experience treating mesothelioma.

Scientists have also debated what areas should be removed during surgery with no clear consensus arising.

References

Sugarbaker, et. al., Resection Margins, Extra pleural nodal status, and Cell type determine Postoperative Long term survival in Trimodality therapy of Malignant pleural mesothelioma: Results in 183 cases. J. Thoracic Cardiovascular Surgery 1999, Jan, 117:1, 54,65.

Roberts, Surgical Treatment of Mesothelioma: Pleurectomy. Chest, Dec. 116:, Suppl, 446S-449S.

15.5 CHEMOTHERAPY AND MESOTHELIOMA

Generally, chemotherapy has shown limited results with mesothelioma, though the form, type, and administration of different forms of chemotherapy remain to be investigated through clinical

trials. A 1998 review states:

A To our knowledge, no chemotherapeutic regimen has emerged as a standard of care. A review of the literature reveals that small activity against this disease has been shown by t he anthracyclines, platinum compounds, and alkyllating agents, whereas higher activity has been reported with the antimetabolites. Dose-escalated chemotherapeutics regimens may offer an advantage, whereas combination chemotherapy has not shown any benefit over single-agent therapy. Favorable responses have been reported with the administration of intrapleural biological response modifiers. Further trials and the investigation of new agents in the treatment of this disease are necessary. Ryan & Vogelzang, A Review of Chemotherapy trials for Malignant Mesothelioma, Chest, 1998, Jan. 113:1, Supp. 66s-73s.@

Another article discussed the effectiveness of chemotherapy:

Malignant pleural mesothelioma (MPM) is an uncommon malignancy characterized by a rapid clinical course. Few patients are possible candidates for radical surgery. According to most reviews, radiotherapy has a limited role in the treatment of MPM. The role of chemotherapy in the management of pleural mesothelioma still remains uncertain. The available data indicate that although 10-20% of patients are known to achieve on objective response to a number of chemotherapeutic agents, the impact on survival appears limited and improvement in the quality of life remains uncertain. The results of combination chemotherapy are comparable to those of single-agent chemotherapy and no major difference is detectable among the various combinations. Prospective phase II trials are recommended for the identification of new active treatments while large-scale randomized phase III trials are needed to identify the best available treatment. In addition, new standard criteria for eligibility and response assessment are required. Ardizzoni, Systemic Drug Therapy of Malignant Pleural Mesothelioma, Monaldi Arch Chest Dis, 1998 Apr, 53:2, 236-40.

15.51 Cisplatin combinations

Cisplatin is a widely used chemotherapy drug which has demonstrated effectiveness with non-small cell lung cancer. Clinical trials are using cisplatin together with other drugs or forms of gene or immuno-therapy to fight mesothelioma.

15.511 Cisplatin and Irinotecan

A Japanese clinical trial combined Cisplatin with Irinotecan. The abstract states:

A The purpose of this study was to assess the efficacy and toxicity of a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients with malignant pleural mesothelioma.... METHODS: Fifteen previously untreated patients with malignant pleural mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2 on Days 1, 8, and 15) administered intravenously and followed by a 1-week rest period... RESULTS: All patients were evaluable for response and toxicity. Four partial responses (response rate of 26.7%) with a median response duration of 25.9 weeks and 2 regressions of evaluable disease (overall response rate of 40%) were observed.@ Nakano, Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile. Cancer, 1999, Jun, 85:11, 2375-84. Note the term response rate usually is defined as reduction in tumor size by at least 50%.

15.512 Cisplatin and Interferon Immunotherapy

Immunotherapy and gene therapy are frequently used to fight mesothelioma. In a phase 1 study of 13 patients with mesothelioma, four patients had a partial response, and one a complete response. A phase 1 trial is designed to determine tolerable doses as well as assess response. Some anemia and renal or kidney problems were noted from the therapy, but overall the study showed promise with phase 2 trials expected. Porohit, Weekly systemic Combination of Cisplatin and Interferon Alpha 2a in Diffuse Malignant Pleural Mesothelioma, Lung Cancer, 1998, Nov. 22.:2, 119-25.

15.513 Cisplatin and Multi-Drug Regimens

Here are the results from a recent French study combining Cisplatin with Etoposide and 5-fluourouracil, a drug combination previously used with other forms of lung cancer:

The authors conducted a Phase II trial in which two drugs (etoposide and 5-fluorouracil) were added to the Cancer and Leukemia Group B cisplatin-mitomycin regimen in an effort to define a more effective chemotherapy. METHODS: Forty-five patients with confirmed Stage II malignant pleural mesothelioma were prospectively enrolled in the study. Thirty-one patients received cisplatin 60 mg/m2 on Day 1, 5-fluorouracil 600 mg on Days 1-4, folinic acid 100 mg/m2 on Days 1-4, mitomycin C 10 mg/m2 on Day 3, and etoposide 100 mg/m2 i.v. on Days 1-3, with prophylactic hematopoietic growth factors.... Histology included epithelial (in 33 cases), sarcomatous (in 6), mixed (in 3), and unspecified type (in 3).

RESULTS: Two hundred eleven cycles were administered. Treatment was well tolerated and the major toxicity was hematologic: anemia in 30% of cases, neutropenia in 24%, and 2 probable cases of mitomycin-induced pneumonitis. The objective response rate was 38% (17 of 45 were partial responses), and the median response duration was 12 months. The median survival time was 16 months. There were no differences in response or survival between the 31 patients treated with growth factors and the 14 patients treated without them. Survival was slightly better for responders than for nonresponders who had stable disease or progression (20 vs. 10 months, P < 0.05). CONCLUSIONS: This four-drug combination was effective, with a notably high response rate, acceptable toxicity, and good adherence to protocol doses. The impact on survival was limited.@

15.52 Gemcitibine

Gemcitibine is well-known chemotherapy drug used to treat lung cancer. Its side effects are limited compared with cisplatin making Gemcitibine an attractive drug if it works. One case report, (review of treatment of a single patient states), A The patient benefited of a dramatic regression of disease with symptomatic improvement during chemotherapy with gemcitabine. Serum CA-125 values declined consensually to tumor regression. The duration of response was 12 months. The activity of gemcitabine in malignant mesothelioma has been already confirmed in phase II studies. Data are also available suggesting that better results can be obtained combining this agent with cisplatin, and a multicenter phase II study is now exploring the activity of this combiantion Amodio, Gemcitabine in peritoneal mesothelioma: a case report] Clin Ter, 1998 Nov, 149:6, 447-51

The results of one recent study were less encouraging, showing only a 7% response rate to the drug.

15.53 Carboplatin and Interferon

A recent study combined carboplatin (a platinum based chemotherapy drug with success in non-small cell cancer) with interferon, but only a 7% response rate was shown. O= Reilly, Phase II trial of interferon alpha-2a and carboplatin in patients with advanced malignant mesothelioma. Cancer Invest, 1999, 17:3, 195-200. A patient or his family must investigate the negative as well as positive finding to make a judgment about which treatment to take.

15.53 Chemotherapy Conclusion

Initial and phase 2 clinical trials are showing some favorable results which should give mesothelioma patients some hope. There are clearly documented cases of remission and tumor reduction. However, no one approach has shown such consistent success that is should be regarded as the standard treatment. Mesothelioma patients should carefully consider clinical trials at well-known hospitals or treatment centers since many of these new forms of treatment offer the best hope and the physicians have expertise in treating this rare form of cancer. The choice of which clinical trial to enter will be a difficult one. Gene and imuno therapy are showing more promise than conventional chemotherapy, and the patient may want to consider gene therapy with or with chemotherapy.

15.61 Interleukin 2 and Interferon

Interferon has had some significant beneficial effect in treating mesothelioma. Interferons are proteins secreted by immune cells that A interfere@ with a virus= s ability to reproduce and proliferate. In the laboratory, low concentrations of interferon help boost the power of natural killer T cells. With some tumors, interferons can help inhibit the development of the blood vessels that tumors need to metastasize and grow, a process called angiogenesis. There are three main types and 17 subtypes of interferon. In a French phase II study, over 50% of the participants showed some tumor reduction from Interferon :

BACKGROUND: The prognosis associated with malignant pleural mesothelioma (MPM) is poor in spite of surgery, radiotherapy, photodynamic therapy, or chemotherapy. Therefore, new therapeutic strategies, including intrapleural immunotherapy, are being investigated. Several clinical studies have demonstrated objective antitumoral responses to intrapleural interleukin-2 (IL-2) administration in the treatment of malignant pleurisy. The maximum tolerated dose, 24 x 10(6) IU/m2/day for 5 days, was determined in a Phase I study. Based on these results, a Phase II study was conducted, in which intrapleural IL-2 (21 x 10(6) IU/m2/day for 5 days) was given to patients with MPM. METHODS: Patients with histologically documented MPM were evaluated for response 36 days after treatment by computed tomography scan and thoracoscopy with biopsies. Toxicity was recorded and graded according to World Health Organization criteria.... RESULTS: Twenty-two patients entered this study. Of the 22 cases of MPM, 19 were epithelial, 2 were mixed, and 1 was fibrosarcomatous. Three patients had Stage IA disease, 1 had Stage IB, 16 had Stage II, 1 had Stage III, and 1 had Stage IV (Butchart classification). All patients received their planned treatment. No dose reduction or interruption occurred. There were 11 partial responses and 1 complete response. Stable disease occurred in 3 patients and disease progression in 7 patients. The overall median survival time was 18 months; the median survival time of responders differed significantly from that of nonresponders (28 months vs. 8 months, P < 0.01). The 24- and 36-month survival rates for responders were 58% and 41%, respectively. CONCLUSIONS: These results confirm that intrapleural administration of IL-2 is well tolerated and has antitumor activity in patients with MPM. The authors recommend a dose of 21 x 10(6) IU/m2/day for 5 days. However, determination of the schedule of IL-2 and its superiority to conventional treatment in a Phase III study has yet to be accomplished. Astoul, Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: a Phase II study Cancer 1098 Nov, 83:10, 2099-104

A Turkish study found moderately favorable results, a response rate of 24% combining Interferon with Cisplatin. Metintas, Cisplatin, Mitomycin, and Interferon-alpha2a combination chemoimmunotherapy in the treatment of diffuse malignant pleural mesothelioma. Chest, 1999 Aug, 116:2, 391-8 STUDY

OBJECTIVE: To investigate the therapeutic activity and toxicity of combination chemoimmunotherapy with cisplatin, mitomycin, and interferon (IFN)-alpha2a, by comparing the responses in a group of patients with diffuse malignant pleural mesothelioma (DMPM) to the responses in a control group of DMPM patients given supportive care alone. DESIGN: Patients with histopathologically confirmed DMPM were evaluated for treatment with chemoimmunotherapy... Forty-three patients with DMPM received chemoimmunotherapy until the end of the survey; 19 patients were given supportive therapy alone after refusing chemoimmunotherapy. INTERVENTIONS: Drugs were administered according to the following schedule: IV cisplatin, 30 mg/m2 qd on days 1 and 2; IV mitomycin, 8 mg/m2 on day 1; and subcutaneous IFN-alpha2a, 4.5 million IU twice weekly.... A total of 10 objective responses (ORs) in 43 patients (23%) were assessed, including 2 complete responses (5%), 4 partial responses, and 4 regressions. Seventeen patients had stable disease, and 16 patients had progression. The median survival time was 11.5 months for the 43 patients who received chemoimmunotherapy and 7.0 months for the 19 patients who received supportive therapy alone. The difference in survival times between the chemoimmunotherapy and supportive therapy groups was not significant. However, the median survival time for the patients who had OR was 21.3 months, which is significantly longer than that of the patients who received supportive care alone and that of patients with progressive disease (6 months). The toxicities associated with the treatment schedule of this study were, for the most part, tolerable. CONCLUSIONS: The drug combination used in this study is moderately effective and well tolerated in patients with DMPM, especially in those who responded to the treatment.

15.611 Why Interferon Works

A recent study explains how Interleukin works on laboratory animals.

A Malignant mesothelioma (MM) is a solid tumor of the mesothelium for which there is no curative treatment. MM appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immunomodulatory cytokines with antitumor effects is interleukin (IL)-12. We have previously shown in a murine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response. The nature and accessibility of MM tumors means that they are suitable candidates for direct cytokine and gene-transfer therapeutic approaches. In mixing experiments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells producing IL-12 represented more than 50-80% of the inoculum.... This study shows that paracrine secretion of IL-12, generated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM. Caminschi, Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12. Am J Respir Cell Mol Biol, 1999 Sep, 21:3, 347-56

15.611 Negative Studies with Interferon

Not all studies have been favorable. A study at New York= s renowned Sloan Kettering Cancer Center reported, A The combination of low-dose interferon alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. Although toxicity was mild, carboplatin and low-dose interferon, given at this dose and schedule, cannot be recommended for this patient group.@ .OReilly, A phase II trial of Interferon Alpha-2a and Carboplatin in patients with Advanced Malignant Mesothelioma. Cancer Invest, 1999, 17:3, 195-200. Perhaps the lesson is that low doses of Interferon are unlikely to effect favorable results, and the dosage must be compared with the more favorable studies. Signficant side effects have been reported with Interferon so defining the maximum tolerable dose is no easy task.

15.64Treatment Outside the United States

For reasons not entirely clear, a number of French studies have dealt with mesothelioma, a relatively rare tumor. With most areas of medicine, the patient will want a physician with expertise and experience with his particular form of disease. A recent French study dealing with gene therapy showed promise, and patients may want to consult one of the physicians experienced with mesothelioma. Note that this is a typical situation where most medical insurers will be reluctant to pay increased costs associated with treatment overseas, taking the position that. treatment at a contracting hospital is sufficient.

15.65 Conclusion

Initial and phase 2 clinical trials are showing some favorable results which should give mesothelioma patients some hope. There are clearly documented cases of remission and tumor reduction. However, no one approach has shown such consistent success that is should be regarded as the standard treatment. Mesothelioma patients should carefully consider clinical trials at well-known hospitals or treatment centers since many of these new forms of treatment offer the best hope and the physicians have expertise in treating this rare form of cancer. The choice of which clinical trial to enter will be a difficult one.

15.61 Mesothelioma Generally Comes from Exposure to Asbestos.

There is extensive and overwhelming evidence that mesothelioma primarily comes from exposure to asbestos. (Note, the author of this book is an attorney who represents mesothelioma plaintiffs in claims against asbestos companies) Although the risks of asbestos exposure were known throughout the last 40 years, many forms of asbestos came with little or no warnings. Asbestos manufacturers failed to utilize basic precautions to make their product safety such as encapsulating the asbestos so it would not become airborne, recommending uses that not expose workers to dust, suggesting bi-annual pulmonary examinations, and utilizing substitute products which did not cause cancer. Workers especially those in the United States have received substantial compensation for asbestos-related mesothelioma. The largest producer/manufacturer of asbestos, Johns Manville developed a claims facility which has provided over one billion dollars in compensation to victims of mesothelioma and other asbestos diseases. Individuals with mesothelioma are welcome to contact the author about compensation to which they may be entitled.

15.7 ASBESTOS LEGAL CLAIMS

The asbestos products that most companies manufactured or distributed failed to carry appropriate warnings. Documents have been uncovered showing that corporations knew of the dangers of asbestos but failed to disclose or concealed them. The Sumner-Simpson correspondence was a series of letters in the 1930's and 40's where Johns Manville and Raybestos-Manhatten corporate executives discussed and concealed the dangers of asbestos. Because the products were dangerous, not properly labelled and caused serious injuries, many victims of asbestos diseases, particularly mesothelioma have obtained substantial compensation.

15.73 Jobs Where Asbestos Was Used

Unfortunately even brief exposure to asbestos may cause mesothelioma. These jobs have customarily involved the use of asbestos:

! Insulators and pipefitters

! Brake mechanics,

! Janitors and roofers,

! And many others since asbestos was universally used for insulation, heat prevention and other purposes).

15.74 Statute of Limitations Issues

Mesothelioma typically develops from 20-30 years after the date of first exposure. Obviously if the statute of limitations were two years from the date of exposure, virtually every claim would be time-barred. Instead most states use a discovery rule, finding that the statute of limitations begins two years or some other period after the date the patient knew or had reason to know of a claim. In some cases, the court will conclude that period when the patient is first diagnosed with the disease Most patients with mesothelioma will be entitled to some form of compensation, frequently a significant amount, any anyone interested in filing a claim should consult an attorney.

The Johns Manville Claims Facility allows claimants from other countries to submit claims for asbestos-related mesothelioma. If an American company made an asbestos product which caused a disease overseas, frequently a claim can be presented in the United States.

Antman, Asbestos-Related Malignancy 201 (Grune & Stratton 1989)

National Cancer Institute website, Malignant Mesothelioma

_______________________________________

16.01 Inapplicability of this Chapter

This chapter deals with certain uncommon or rare tumors. Most readers need not review the chapter and it may confuse matters. Every patient should understand the basics of his disease including stage, type of cancer, and the nature of treatment.

16.1 CARCINOID TUMORS

Carcinoid is by far the most prevalent of the less common pulmonary tumors (1). It has a considerably better prognosis than other forms of lung cancer, because it is typically slow growing and can frequently be fully resected at surgery. Most observers, but not all, think that the cell of origin is the neuroendocrine cell of the tracheobronchial tree. In this sense it is thought by some to represent a more benign counterpart of small cell cancer, despite the fact that it is not related to cigarette smoking.

16.11 Anatomy

Neuro-endocrine cells of the lungs help control air flow and blood flow in the lungs and play a role to control growth of other type types of lung cells. Neuroendocrine cells may detected decreased or increased carbon dioxide in the air we breath and release chemical messages to adjust these changes. People who live at high altitudes have an increased number of lung neuroendocrine cells, apparently because there is less oxygen in the air. Lung neuroendocrine cells undergo changes causing them to grow excessively and create tumors. Like other tumors, growth is normal, but somehow chemical messages are encoded improperly causing the cell to grow excessively ultimately resulting in tumors. American Cancer Society, The Lung Carcinoid Tumor Resource

Center (online at www.cancer.org).

16.12 Growth and Prognosis

Most carcinoid tumors grow slowly and do not quickly metastasize. Therefore their prognosis is good.

16.13 Size

The carcinoid tumor is typically between .5 centimeter, under one fourth of an inch and two centimeters, over three fourths of an inch.

16.14 Cause

The causes of carcinoid tumors are generally unknown. It is not been shown to be related to smoking or for that matter, exposure to chemicals or dusts in the workplace or environment. Some tumorlets have developed in smaller airways where there was been scar tissue. Thus, one could reason that there is an association between asbestosis or silicosis in these locations (scar formation due to silica or asbestos exposure) where this type of scar tissue accompanies a carcinoid tumor.

16.2 SUBCATEGORIES OF CARCINOID TUMORS

The Comprehensive Textbook of Thoracic Oncology 127 (1996) states:

"There are two clinical and histologic varieties of this tumor, the so-called typical carcinoid, which is slow-growing and metastasizes very late, and the less common atypical form, which is considerably more aggressive with a higher incidence of metastatic disease and histologically increased mitotic activity. " Classification is also done by location, central tumors form in the large airways near the center of the lung; peripheral tumors form in the smaller airways towards the edges of the lung.

1. Aisner, et. al. Comprehensive Textbook of Thoracic Oncology 126 (1996),

2. American Cancer Society, The Lung Carcinoid Tumor Resource

Center, www.2cancer.org.cancerinfo/main

CHAPTER SEVENTEEN: SCREENING AND EARLY DETECTION OF LUNG CANCER

Sadly, most lung cancers are diagnosed late, when the cancer has infiltrated significant organs and created pain, difficult breathing, and other symptoms. A Unfortunately, by the time a sign, symptom, or visible nodule appears, dissemination to regional or distant lymph nodes or distant extra nodal sites usually has occurred.@ Devita, Cancer Principles and Practice of Oncology, 607 (3d Ed. 1989)

Given the many and varied ways in which we are investigating lung cancer treatment in the United States, one would expect an impressive program of early detection, since that can be the best treatment- an ounce of prevention is clearly worth a pound of cure. Stage 1 cancers do very well, and are usually cured through surgery, it is at best a battle to cure or at least stem the spread of advanced cancer. One could assume that early detection programs would compliment anti-smoking programs, reinforcing the potential hazards of the tobacco. That assumption would be wrong. We do not in this country routinely check smokers for signs of lung cancer, nor is there any organized program to detect lung cancer at earliest and most treatable stages. Thus, well over 60% of lung cancers are diagnosed late, when the cancers are at advanced stages, have spread to lymph nodes or other organs and medical science is least able to treat them.

17.12 The Dramatic Difference in Long-Term Survival by Stage is a Compelling Reason for an Early Detection Program

Five year survival rates are over 60% for stage one cancers, less than one tenth that amount for stage two and three cancers, and even lower for stage 4 patients. For many cancers, early detection programs are difficult since we do not know who is at risk; for lung cancer we know that smoking causes at least 85% of the cancers and occupational exposures a good 10% more. For some cancers, the number of people involved is small to justify widespread screening. Lung cancer is the number one cause of cancer death and the number two cause of death overall, involving at least 150,000 people each year.

17.13 Comparison with Early Diagnostic Programs for Other Cancers.

There is no program of screening high-risk smokers for lung cancer. One of nine women contract breast cancer, and yearly mammograms for women over 40 helps detect breast cancer in its earliest and treatable stages. PSA tests for prostrate cancer help create an over 95% survival rate by insuring that prostrate cancer is diagnosed in its earliest and most treatable stages. Pap smears for woman are now part of exams for many women and also help provide timely detection of cervical cancer.

While approximately one in ten men and women who smoke will contract lung cancer there is no program of early diagnosis in the United States With that said why don't we institute a program for early diagnosis. Indeed, lung cancer kills more women each year that breast and cervical cancer combined each of which have sensible early detection programs in place to improve survival and qualify of life. Preoccupied with telling smokers not to smoke, a laudable if difficult goal, we have ignored the equally important point of getting those at risk diagnosed at early and treatable stages.

17.2 WHY THERE IS NO PROGRAM OF EARLY DETECTION IN THE UNITED STATES

The explanations for a lack of early detection are neither persuasive nor well-reasoned, though they merit examination. Basically the merit of any form of treatment must be established through testing. We learned in tenth grade biology that a hypothesis can be formed, but it must be confirmed through an actual experiment. In this case, the experiment is some type of examination of how two groups do, one with the treatment and the other without- in this case, with and without screening.

According to the National Cancer Institute, early detection programs have not established a significant improvement in patient survival; therefore it cannot be implemented as a reliable for of treatment. Here is a summary:

A In the Johns Hopkins and Memorial Sloan Kettering Studies, patients in the screened group received chest radiographs annually and sputum cytology every 4 months, whereas the control group received only an annual chest radiograph. In the Mayo Clinic study, the screened group received a chest x-ray and sputum cytology every 4 months, where the control group received the standard Mayo advice of the time, consisting of an annual chest radiograph and annual sputum cytology, but without reminders to comply after the first visit... The conclusion from all three trials,; however, was that screening with chest radiography and sputum cytology was of no benefit in reducing lung cancer mortality. Despite lower stage at presentation, increased resectability, and an apparently higher 5 year survival rate in lung cancer patients in the screened group (35% in the screened group versus 15% for the control group), the cumulative lung cancer mortality and over survival were the same for both screened and control populations in all three trials." Aisner, et. at., Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996)

Based on these studies, researchers have reached the dubious conclusion that screening does not save lives or is not merited. Let us examine the errors which have probably cost so many lives during the last twenty years.

17.31 The critical positive findings of the study have been ignored.

In the Mayo Clinic study, the five year survival was higher in the intensively screened group. More important, both groups, had appreciably higher survival rates than the general unscreened population. That is because, both groups were essentially screened, one group receiving chest x-rays and sputum cytology, and another instructions to see their physicians for an annual checkup and have a chest x-ray performed there. As one observer explains:

Thus, a reasonable interpretation of the study was that screening or annual chest -x-rays reduces mortality, with the only issue determining the optimum combination. Instead, some commentators concluded that screening did not save lives, a finding directly contrary to the study= s findings regarding the screened group which received chest -rays and sputum cytology and the other group which was directed towards annual chest x-rays. This demonstrates a strange and distrubing phenomenon regarding screening- all findings are interpeteted with an eye or strong pre-disposition to disregard or reject screening.

17.32 Medical Date Concerning Survival Statistics Were Ignored.

If we know that screening resulted in getting patients diagnosed at an earlier stage, and survival is related to stage, screening works. The Lung Cancer Manual provides five year survival estimates as follows:

! stage IA 60% to 67%

! stage 1B 36% to 71%

! stage 2A 34% to 55%

! stage 2B 24% to 39%

! stage 3A 13% to 23%

! stage 3B about 5%

! stage 4 about 1%

Thus, having patients diagnosed earlier, according to accepted medical science, leads to increased and longer survival. Indeed, five year survival was higher in the screened group.

17.33 The Difficulties of Performing a Clinical Trial with Healthy People If we have two groups of cancer patients, both in poor health, we can ethically create a study to try one type an experimental treatment on one group and compare it with the currently accepted mode of treatment. We cannot tell people at risk not to be seen by a doctor. That is one reason there was a small difference between the two groups, because the study authors could not create conditions which would deliberately endanger the control group.

17.331 An Example of the Same Type of Specious Reasoning

When children between the ages of 4 and 8 are hit by cars, they suffer serious injury. However, there is no study showing that holding a child= s arm while crossing the street saves lives or reduces injuries. A clinical trial is run at which one group holds the child= s hand while crossing, and the other checks for cars and tells the child to be careful and look both ways. Results were similar for both groups, therefore, it cannot be concluded that holding a child= s hand while crossing the street has any proven benefit. That conclusion is clearly erroneous because precautions in both groups lead to safety.

17.34 The difference in treatment between screened and un-screened may not have been tremendously significant in the Mayo Clinic study.

In the Mayo Clinic study, one group received bi-annual screening with the other instructed to consult a physician each year, who might provide the same tests as the screened group. Thus, Not a significant difference. The problem is that it is difficult to develop an effective, yet ethical clinical trial. To illustrate the difference, we could have one group of heavy smokers given bi-yearly sputum cytology and chest x-rays while the other group is told not to undergo these tests for a five year period. While that would likely demonstrate that screening saves lives, it would be unethical and put the control group at risk.

17.25 Limits of X-Ray Screening

Even as we recognize that x-rays can extend lives by detecting lung cancer before it become symptomatic, we must also recognize its limitations. In a study discussed below, chest x-rays were only able to detect 7 of 27 stage 1 tumors which were visible on Ct Scan. Henschke. Et. al., Early Lung Cancer Action Project: Overall Design and Findings from Baseline Screening, Lancet (1999 ) Chest- x-rays were ineffective at detecting the smaller, highly curable tumors. Thus, while it is clear that x-rays provide an important function in detecting lung cancer, its utility is limited, and its reliability in detecting small tumors questionable. Recent attention has focused on developed a more effective and sensitive method of detecting lung cancer.

A recent study screened present and former smokers using a special type of CT Scan. The results were excellent, with many lives saved by early detection of tumors and prompt surgery. While the long-term prognosis for many patients is not good, patients whose tumors were timely detected are doing well. Alcase, the American cancer advocacy group, has suggested Ct screening for heavy smokers and former smokers. With clinical proof, we hope that now major cancer organizations like the American Cancer Society and the National Cancer Institute will finally recommend screen and save thousands of lives.

17.31 The Interrelationship between CT Scans and Smoking Cessation

Many smokers wait to diagnosis to quit. A test which alerts them to the substantial dangers of smoking with respect to their own lungs may prompt many smokers to quit- A An unanticipated benefit of the screening was that many of the enrolees quit or decreased smoking after enrollment, and stated that hte review of their CT images with the Elcap radiologys, had prompted the change and provided the necessary focus for maintenance of their non-smoking behavior.@ www.health.state.mn.us/htacctdr.htm Helical Computed Tomography (CT) for Lung Cancer Screening for Asymptomatic Patients,@

17.32 Other Studies Finding CT Scan to be Effective in Diagnosing Lung Cancer

A Japanese study confirms the Cornell findings:

Another Japanese study concluded:

A Small peripheral lung cancers can be detected by spiral or helical computed tomography (CT). We applied mobile spiral CT as the first step in further examination (or secondary screening) for lung cancer. We detected 86 lung cancers per 100,000 persons without spiral CT, and 102 patients with spiral CT. Using the latter method, the resection rate and the rate of early-stage lung cancer increased significantly from 48.6% to 67.3%... Good results were obtained with mobile CT, especially in women. The mean tumor size of lung cancer detectable with CT was 7 mm smaller than that detected by the previous method.... Overall 787 lung cancers per 100,000 persons were detected using spiral CT for primary screening (1,039 lung cancers/100,000 in men)@ Kusonoki, Diagnosis of small peripheral lung cancers using spiral computed tomography lung cancer screening,.@ Nippon Geka Gakkai Zasshi 1999 Nov;100(11):705-11

One commentator stated:

Chest Surg Clin N Am 2000 Nov;10(4):729-36

17.41 Only radiologists should be Interpreting Chest X-Rays

One critical problem is the misinterpretation of x-rays, and it is relatively common for an old x-ray of a patient to be examined and traces of a tumor found, indicating that precious time was lost. Given the critical need for prompt detection, qualified professionals need to be examining films but that is not what is occurring today. Frequently, internists and pulmonologists with limitations on their ability to interpret x-ray slides are doing the readings, and tumors are missed. Frequently, there is little documentation of the result, and no report issued, in contrast to a radiologist who invariably prepares a written report. Whether to insure that the patient receives the maximum amount of accuracy in the reading of x-rays, or to avoid medical malpractice claims, all slides of at least heavy smokers at risk for lung cancer should be interpreted by radiologists.

17.42 Better Follow up

Along with a misinterpreted chest x-ray frequently comes a lack of follow-up. The following basic principles should govern:

1) Lung cancer should be a differential diagnosis for a smoker with any symptomology of lung cancer such as chest pain, fatigue, shortness of breath, or loss of weight.

2) Ct Scans should be taken whenever there is an abnormal chest x-ray. X-rays are too imperfect a tool to make a critical life judgment.

3) Available non-intrusive tests must be used where the CT Scans show an abnormality.

We cannot take the chance of a tumor spreading simply because a CT Scan is unclear. Thorascopy and mediastinomy, while involving some minimal risk, make sense where positive Ct Scans indicate a substantial possibility of lung cancer. Basically, there is a ladder of tests and additional tests should be ordered unless the possibility of disease is conclusively eliminated. Here is a summary:

PATIENT STATUS TESTS TO BE CONSIDERED

Physicians may disagree on the precise order and individual considerations can change this general order. However, the point should be that with a heavy smoker, diagnostic tests should be ordered until the diagnosis of lung cancer is excluded.

When health maintenance organizations were created, there was a theory that would emphasize prevention as well as cure. That has not proven to be the case. Many HMO= s resist early detection and screening.

HMO= s may reason that tests should be taken only where there is a demonstrated need. From the patient= s perspective, all necessary tests should be taken where there is a possibility of this disease, since the consequence of delay may be a difference of life and death, or at least the time of survival. Doctors are caught in the middle. However, smokers and their families need to be far more vigilant in demanding follow up in situations where the disease is a possibility. Again, it is not smoking that causes lung cancer death; it is smoking combined with a delay in diagnosis.

Consider the following:

! Create an effective anti-smoking program in your schools which vividly explains the consequences of smoking. Have cancer patients come to schools to explain the consequences of their illness, and the pain they experience. Too many anti-smoking programs are boring recitals of numbers, figures, and medical terminology. Explain to students that the consequence of smoking can be pronounced suffering and even death at ages as young as 40, that about 1 in 10 smokers will contract lung cancer, and that we have no clear cure for advanced stage lung cancer, which is when most people are diagnosed.

! Write to the American Cancer Society and the National Cancer Institute and suggest that they institute early detection program. Tell people about the recent study showing that CT Scans can detect cancer at early stages. Help save the lives of your friends and neighbors.

! Tell smokers not only of the importance of quitting but of the need for CT Scans, chest-x-rays, sputum cytology and other diagnostic tools,

! Ask your family physician and your HMO of they have early detection programs in place for high risk such as smokers, those exposed to heavy amounts of dust, and people with family histories of lung cancer.

! Contact ALCASE, and other lung cancer advocacy groups to lobby for more effective detection.

17.71 Conference Statements

Some groups and conferences have recommended Ct screening or provided language almost to that effect. The Third International Conference of Screening stated:

The importance of this recommendation should not be overestimated. The group convened where the Cornell-Weil study had been conducted, so their objectivity and influence can be questioned.

17.60 Screening in Japan

Japan has wisely decided to implement a policy of early detection and screening.

17.61 Irish Medical Journal Editorial

A All heavy smokers of 30 or more pack-years should have spirometry for the identification of airflow obstruction.⁷ The prevalence of lung cancer is approximately 2% in this high risk population.⁹ In addition, heavy smokers with airflow obstruction should have annual chest x-rays or CT scans in addition to sputum cytology. Bronchoscopy, staging, and surgical resection should be done in patients who are good surgical candidates. All patients so identified should enter a lung cancer registry. The costs of diagnosis and treatment should be recorded. These costs and outcomes should be compared with an equal number of cancer victims who are identified today by usual care, which is most commonly by the presence of symptoms such as: bone pain, pleural effusion, hemoptysis, or by accident when standard x-rays are done for other purposes. Such an approach will establish the cost-effectiveness of lung cancer as it now exists in Ireland. Editoria, Lung Cancer Detection: A New Challenge for Irish Medicine, Irish Medical Journal, February 2001, 94 num. 2.

17.61 The Importance of the American Cancer Society

The American Cancer Society (ACS) is the most important cancer group in the United States. Among other roles, they help set standards for cancer treatment and prevention. If the American Cancer Society recommended a program of early detection, most hospitals, physicians, and HMO= s would follow that recommendation, and thousands of lives would be saved or extended. 17.612 Modification of the American Cancer Society Position

There has been some movement by the ACS to consider screening. A Canadian physician first quotes then analyzes their position :

So, the American Cancer Society now expresses the stance of wholesale agnosticism only, still not knowing any available type of screening for lung cancer on any type of screening to have been, or even now to be, at all effective in preventing death from this disease (through early intervention); and further, were the American Cancer Society to come upon positive "trial" (RCT) results on effectiveness, it would take this qualitative evidence to be a sufficient basis to recommend for screening, without regard to any specifics C C in sharp contrast to the analytic, quantitative, cost-effectiveness outlook described above, which is specific to particular types of screening and screening. Direct evidence, even if only qualitative and only subjectively (mis)interpreted,⁸ rules the "evidence-based situation," stifling reason C C as in Evidence-based Medicine practiced in place of reason-and-knowledge-based medicine.@

1. Lung cancer is the largest cause of cancer death in the United States for both men and women, with 170,000 people dying each year,

2. At stage 1, the treatment is generally easy and straightforward, a surgical resection. However, the more the cancer spreads, the harder the disease is to treat and cure. Thus, early detection is critical.

3. Unlikely other diseases whose cause is unknown, we know that smoking is the primary risk factor. Thus, it is easy to identify those persons primarily at risk.

4. The American Cancer Society contributes to the setting of standards in cancer treatment in the United States. Thus, if the organization advocated early detection, many hospitals and physicians would follow.

5. Telling people not to smoke, while important, is not a program of early detection. Along with anti-smoking programs, we must develop early detection programs. Indeed, it is the combination of smoking and delayed detection which is the most frequent cause of death for lung cancer.

6. Other countries are employing programs of early detection. Japan has a program which identified smokers with cancer at early staging leading to five year survival rates about 75% in one study.

7. A recent study in New York found excellent results with early detection and CT Scan.

8. Groups like Alcase, the leading non-profit group devoted to Lung Cancer, are recommending early detection programs. Early detection was recommended at the Cuneo World Lung Cancer conference in Italy in 1998.

9. Please help, what you do, or choose not to do, can make a tremendous difference in the lives of cancer patients and their families.

You may get a form letter back or an invitation to participate in the chapter. Follow-up, be aggressive. While the ACS is an excellent organization which has helped many people, it clearly lags behind in this important area.

Thus, the patient who suspects cancer or notices some of its symptoms should be extremely vigilant in obtaining treatment and requesting diagnostic tests. The reasons for the poor state of diagnosis are several:

1) the current standard of care does not require any diagnostic tests for high risk smokers,

2) the American Cancer Society has devoted its attention to anti-smoking campaigns without recognizing that both smoking and delayed diagnosis are the reasons for lung cancer mortality,

3) there is an implicit belief that smokers cause their own illness,

4) the symptoms of lung cancer are diffuse with symptoms like shortness of breath, chest pain, and fatigue present in many smokers without disease, and

5) finally, virtually none of the some 100 billion dollar smoking settlement is being used for programs to improve the detection and diagnosis of lung cancer. Groups like Alcase, Alliance against Lung Cancer are trying to improve survival and change the above.

A At Memorial Sloan-Ketering Cancer Center, nearly one third of all patients seen with lung Nearly all have an excellent performance status at presentation. They also have a favorable prognosis if treated surgically. Many are asymptomatic. They include patients who participate in lung cancer screening programs, individuals who receive a routine chest roentgenogram (x-ray) as part of a premployment medical clearance, and patients undergoing cardiorespiratory assessment as part of readmission screening for elective surgery.@ Aisner, Comprehensive Textbook of Thoracic Oncology. (Williams & Wilkins 1996)

We can identify at least five reasons why lung cancer is not promptly diagnosed (in approximate order of their importance):

1) There is no established screening tool for lung cancer. The optimal time to diagnose cancer is before it has spread and created pain, shortness of breath, or other symptoms. We do not do this in the United States. While many good doctors arrange for some type of screening for patients at high risk, there is no requirement that they do so, and some physicians especially in poorer areas do not. Sadly, the National Cancer Institute and the American Cancer Society, while recognizing that early diagnosis is critical to long-term survival, have failed to recommend a screening program. At least with respect to lung cancer, HMO= s have not encouraged physicians to use available tools to diagnose the disease early, though one could argue that the medical costs associated with chemotherapy would be reduced as well as saving many lives.

2) Most smokers do not want to be confronted or reminded about the consequences of tobacco, and do not arrange for yearly medical examination.

3) Chest x-rays have inherent limitations, and even good doctors concerned about cancer rarely go beyond the chest x-ray as an initial evaluative tool. Wider use of sputum cytology (analysis of cells) and Ct Scan would accomplish a great deal in diagnosing disease at an early stage. Where x-rays show a spot, there is frequently insufficient follow-up. Saying we= ll check if there are any changes in the chest x-ray in three months or six months can be a life-threatening delay: again aggressive and prompt use of available diagnostic tools is critical.

4) Many of the symptoms of lung cancer are non- specific and indicative of a variety of pulmonary conditions normally associated with smoking. A smokers may have had periodic shortness of breath, cough and chest pain, and neither he nor his physician grasped that it might indicate cancer, since he had these symptoms previously, like many smokers. Some of the symptoms of lung cancer could be mistaken for emphysema or bronchitis.

17.22 The Intelligent Patient With a Smoking, Occupational, or Family History Creating an Enhanced Risk Should Be Vigilant In Requesting Diagnostic Tests

As noted, there are good, but underutilized diagnostic tools for lung cancer. Chest x-rays, while imperfect, will reveal tumors of at least 1 centimeter, and sputum cytology can reveal many microscopic tumors and is particularly effective at revealing early squamous cell tumors. Neither of these tools is routinely used or recommended for asymptomatic smokers. Thus, it is incumbent upon the patient in a high-risk category to be vigilant in requesting diagnostic tests. Many good internists do recommend yearly chest x-rays for their patients who are at least, and a few do suggest sputum cytology. The most accurate and comprehensive test is the CT Scan, with the major lung cancer advocacy group in the United States (Alcase) suggesting regular screening to promote early detection. Ct Scan is expensive and few physicians will routinely recommend it and many HMO= s would resist paying for its cost.

17.1 SYMPTOMS OF LUNG CANCER

The primary symptoms of lung cancer are chest pain, dyspnea, loss of breath, fatigue, loss of weight. A Lung cancer should be suspected in any smoker with new or worsening respiratory symptoms including haemoptysis (spitting up blood), or indication of systemic illness such as loss of energy, appetite, or weight. These symptoms are non-specific, that is, they could indicate a number of diseases which is why lung cancer is difficult to diagnose. Here is an outline from Devita= s leading text, Cancer, Principles and Practice Of Oncology:

Cough

Hemoptysis (spitting up blood)

Wheeze and stridor

Dyspnea (shortness of breath or difficulty breathing)

Pneumonitis from obstruction (fever, productive cough)

Pain from pleural or chest wall involvement

Cough

Dyspnea on a restrictive basis

Lung Abscess syndrome

Tracheal obstruction

Devita, Cancer Principles and Practice of Oncology, 607 (3d Ed. 1989). Small cell cancer has similar symptomology: A The main symptoms of SCLC are similar to those of other lung cancers and include cough, hemoptysis, chest pain, obstructive dyspnea, or signs secondary to pneumonitis. Uncommon but more specific to SCLC are the manifestations of paraneoplastic syndromes such as Cushing= s or Eaton-Lambert or inappropriate secretion of antidiuretic hormone.@ Comprehensive Textbook of Thoracic Oncology 459 (Williams & Wilkins 1996).

Here is a similar summary:

A In later stages, lung cancer my give one or more of the following symptoms:

Cough - people who smoke and already have a chronic smoker's cough often report a change in the nature of the cough. Bloody cough (hemoptysis) is a major warning sign and should never be ignored. Wheezing/Shortness of Breath - smokers may already have emphysema which may cause wheezing and shortness of breath. However, a tumor which causes blockage of a breathing passage may bring these symptoms on more acutely. Pneumonia Symptoms - such as fever with phlegm-producing couch which does not clear with antibiotic treatment may be an indication of a lung cancer. Fatigue - and loss of endurance with routine activities may be a consequence of lung cancer. Pain - in the chest may be caused by lung cancer which has spread into the lining of the lung or chest wall; pain in the back or ribs may be indicative of cancer which has spread to bones. Hoarseness - may be a sign of lung cancer which has affected the recurrent laryngeal nerve (the nerve which controls the movement of the vocal cords). Weight Loss - for reasons which are not well understood, lung cancer, especially in advanced stages, may cause a person to lose weight. Headache and Other Neurologic Signs - may be caused by cancer which has spread to the brain and nervous system. www.infolane.com/pamp/lungcncr/lungcncr.html, Care Sheet for Lung Cancer.

The physician= s job is not easy; virtually all of these nonspecific syndromes can indicate another disease, and many are already a part of the smoker= s life. Shortness of breath, loss of breathing capacity, and perhaps periodic chest discomfort are the usual lot of the smoker. The difficulty of promptly diagnosing cancer based upon the patient= s complaints alone, and the critical importance of that task, are again reasons for testing all smokers and aggressive use of available diagnostic tools.

_________________________________

18.11 Defining Experimental Treatment

In some sense, chemotherapy is experimental treatment; with the precise mix of chemotherapy drugs still the subject of much investigation and on-going clinical trials. Different oncologists can recommend varying mixes of anti-cancer drugs. An oncologist could rely on certain studies which found the chemotherapy drug Vinorelbine to be effective, while another would recommend different forms of chemotherapy. Thus, there is a fair amount of choice and discretion for the oncologist and probably the patient. However, we I use A experimental@ in this chapter, I speak of the various remedies discussed on the Internet, which are not a part of mainstream cancer care in the United States.

18.12 The Rationale Behind Experimental Treatment.

Certainly those who can be capably treated by conventional therapy should do exactly that. There are impressive five year survival rates for stage one localized cancer, and it would be sad and foolhardy for a patient to jettison treatments with a proven effectiveness for those which are at best speculative. The only area where alternative treatments could be given any consideration would be those such as advanced or stage 4 lung cancer where conventional medical science has not succeeded in creating a cure in most cases. Even there we must be careful, we have initial response rates of about 25% percent for certain advanced cancers, with a significant percentage of relapse. Thus while cure is not probable, there are a statistically signficant number of patients who will benefit from and have their lives extended from conventional treatment, and a certain percentage, albeit small, who will be cured.

Sadly there are those who pray about the seriously ill and those families desperately seeking life-saving treatment. We should note the following words of caution:

1. Many alternative practitioners, especially those are not U.S. physicians, have little or no regulation or way of verifying their claims of success. Someone could say, for example, a combination of tree bark and vitamin c, taken in quadruple doses, will kill the carcinogens which comprise cancer, and we would have no way of verifying the claim. For established medical science, one would want to see a published study reported in a medical journal, which not only chronicles favorable findings, but explains the methodology of the study so that it can reviewed and examined. Medline, the world medical database, (www.healthgate.com) contains over a half a million articles, many dealing with treatments for cancer, and the intelligent patient will want to rely on medical science, rather than the unverifiable, and self-serving claims of certain clinics and facilities.

2. Some alternative practitioners will suggest that the "medical establishment,@ presented as some type of monolithic profit-making entity is preventing discovery and dissemination of life-saving treatment. Words like these are frequently echoed- Of course, the FDA has not approved our treatment. Don't you understand that we present a threat to the pharmaceutical companies who earn millions from cancer; that cancer is a multi-billion dollar industry and our treatment threatens their wealth and influence and that is why it has been suppressed.

3. Brash and arrogant statements are used to justify expensive and questionable treatments. While life is undoubtedly precious, those with cancer must be careful about risking their life savings for unproven and unsubstantiated cures.

There is a saying in medicine-first do no harm. Thus your first task in assessing alternative treatment is exactly that. Substituting an alternative treatment for the proven benefits of chemotherapy is life-threatening; on the other hand, supplementing existing therapy with a nutritional or other plan which your oncologist approves should do no harm and might conceivably help.

Experimental treatments vary in their medical basis from a drug which many believe is effective in treating the disease but which has not been accepted by the FDA to an obscure drug or process touted by a little known organization. Consider the following in assessing experimental treatments:

! Does your own doctor approve of, or at least not strongly condemn the proposed treatment. Biofeedback and other treatment fall in this category.

! What is the medical basis for the drug or treatment. Has it been shown to provide beneficial results in lung cancer patients. For example, if product A has been shown to help stage 1 and 2 patients, but not have a proven efficacy with stage 3 and 4, it could still make some sense.

! Has the product been shown to have beneficial results with cancer generally, even if it efficacy has not been shown with respect to this organ.

! Does the logical basis for the treatment make sense. For example, if beta carotene has been shown to reduce the incidence of cancer, one could argue that it might have some positive impact upon the creation of new cancer cells. Thus, adopting a diet for example, rich in beta carotene could make some sense.

18.5 AN EXAMPLE OF EXPERIMENTAL THERAPY SHARK CARTILAGE

18.51 Shark Cartilage, Clinical Trials

Recent reports have found shark cartilage ineffective in dealing with lung cancer notwithstanding claims in two books by a proponent whose book is titled Sharks Don= t Get Cancer. An article entitled, Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer, reporting results at the M.D. Anderson Cancer Center states,

Patients with cancer and chronic inflammatory disorders

have used shark cartilage (SC) preparations for many years.

Preclinical studies that support their beneficial effects are

scanty, and reports of clinical trials have been anecdotal.

The proposed mechanisms of antitumor action include direct or indirect inhibition of angiogenesis (the building of new sources of blood supply as a part of metastasis). Because of the emerging use of SC as an alternative to conventional cancer therapy, this trial was launched to evaluate the safety and efficacy of SC....

Sixty adult patients with advanced previously treated cancer (breast cancer, 16 patients; colorectal, 16 patients; lung,

4 patients; prostate, eight patients; non-Hodgkin lymphoma, three

patients; brain, one patient; and unknown primary tumor, two

patients) were enrolled. Eligibility criteria included confirmation of diagnosis, resistance to conventional therapy, objective measurable disease, life expectancy of 12 weeks or

greater, Eastern Cooperative Oncology Group (ECOG) performance

status of 0 to 2, no recent or concomitant anticancer therapy, no

prior SC, and informed consent. Patients underwent evaluation of

the extent of disease, quality-of-life score (Functional

Assessment of Cancer Therapy-General [FACT-G] scale), and

hematologic, biochemical, and selected immune function studies at

baseline and after 6 and 12 weeks of SC therapy. The dose of SC was 1 g/kg daily orally in three divided doses. Standard criteria

were used to evaluate adverse events and response.

RESULTS: Ten of 60 patients were lost to follow-up(LTFU) or refused further treatment (RFT) before the 6-week evaluation and were not assessable for toxicity and response . Three patients with stable disease at 6 weeks were LTFU or RFT thereafter. Of the 47 fully assessable patients, five were taken off study because of

gastrointestinal toxicity or intolerance to SC. Progressive

disease (PD) at 6 or 12 weeks occurred in 22 and five patients,

respectively. Five patients died of PD while undergoing SC therapy. No complete (CRs) or partial responses (PRs) were noted. Median time to tumor progression in the entire study population was 7+/-9.7 weeks (mean, 11.4 weeks; range, 3.7 to 45.7 weeks). Ten (20%) of 50 assessable patients, or 16.7% of the 60 intent-to-treat patients, had stable disease (SD) for 12 weeks or more. The median time to tumor progression was 27 weeks, the mean was 28.8+/-9.9 weeks, and the range was 18.6 to 45.7 weeks. In this subset, FACT-G scores improved in four patients, were unchanged in four patients, and declined in two patients. Twenty-one adverse events (grade 1, eight events; grade 2, seven events; and grade 3, six events) were recorded, 14 of which were gastroenterologic (nausea, vomiting, constipation). CONCLUSION: Under the specific conditions of this study, SC as a single agent was inactive in patients with advanced-stage cancer and had no salutary effect on quality of life. The 16.7% rate of SD was similar to results in patients with advanced cancer treated with supportive care alone. J Clin Oncol, 1998 Nov, 16:11, 3649-55.

18.52 Experimental Studies on Animals

Another recent article entitled, The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma, Acta Oncol, 1998, 37:5, 441-5 states,

This study was designed to investigate the potential of shark

cartilage extracts to inhibit the growth and metastatic spread of

a murine solid tumor. The SCCVII carcinoma, implanted in the

right rear foot of C3H mice, was used. Following tumor

implantation, two different commercially available extracts of

shark cartilage (Sharkilage and MIA Shark Powder) were dissolved

in water and orally administered to the mice.... and repeated on a

daily basis for up to 25 days post-implantation of the primary

tumor. Compared to non-drug-treated animals, daily administration

of the shark cartilage extracts did not show any adverse toxicity

(as measured by changes in body weight and lethality). More

importantly, none of the shark cartilage doses tested had any

retarding effect on the growth of the primary tumor, nor did they

inhibit the development of metastases seen in the lungs of the

tumor-bearing mice at autopsy. In conclusion, our results offer

no support for the proposed use of shark cartilage extracts as an

anti-cancer therapy.

It appears that the chemicals in shark-cartilage may have some properties associated with the ability to fight cancer. Pugliese & Jordan, Some Biological Actions of Alkylglycerols from Shark Liver Oil. J Altern Complement Med, 1998 Spr, 4:1, 87-99 However, that is far cry from the product being effective as a form of treatment. Until competent studies show shark cartilage produces tangible results in lung cancer, almost all physicians will recommend those forms of chemotherapy whose effectiveness has been shown, even though they have not accomplished an overall cure for most patients with advanced lung cancer.

18.7 ALTERNATIVE THERAPIES TO CONSIDER

18.71 Alternative Therapy to Consider: Surgery for Stage 1-3 Small Cell Patients

The traditional position is that surgery is not a realistic option for small cell patients, because the cancer has generally spread at the time of diagnosis. However, the alternative therapy of surgery for small cell patients should be considered and meets our criteria as follows:

! The theory is supported by lung cancer clinical trials. A Recent Japanese study found 4 year survival of stage 1 small cell patients of 50% and stage 2 and 3A survival of 50% and 37.5%. These survival figures significantly exceed U.S. figures for conventional treatment. See Ohkubo, Surgical Analysis for Small Cell Lung Cancer of the Lung, Kyobu Geka, 1999 Dec, 52 (13): 1061-6.

! The theory makes logical sense. We know that excising the tumor in non-small cell has significantly improved survival rates, so a reasonably hypothesis is that similar results are possible with small cell.

The United States has many of the best hospitals in the world, and there is little evidence that treatment elsewhere would be better. In particular, there is virtually no evidence that treatment in Mexico would improve survival and programs which jettison chemotherapy for natural foods, nutrition therapy, or laetrile may actually cause some harm. For those convinced that United States hospitals do not provide needed care, I would consider Japan. Some of the most forward-looking material comes from Japan, and is supported by clinical studies and reports in recognized scientific journals. For example, the above discussion by Ohkubo about surgery for small cell patients has solid scientific support and another article found 75-80% five year survival of squamous cell patients through cancer screening also is documented in a recognized journal. (The success is based upon screening high risk smokers and detecting cancers at very early stages, something not done in the United States).

another country, go to a leading cancer center there, not an expensive and obscure facility which touts conspiracy theories and unusual treatments.

Who else but a lawyer would think about legal claims and compensation when people may be dying. And why threaten the very doctors and hospitals who are trying to help the patients by interposing an atmosphere of distrust, at the very time when they are trying to work together to help him or her. In an already overly litigious society, isn't there at least one time when the focus should be on health and healing, not lawsuits and money.

Initially we note that this is a personal decision. Any of the reasons above, along with the desire to focus on getting well are sufficient cause to jettison the possibility of compensation or revenge against a possibly culpable physician. However, there are legitimate reasons why perhaps more of these cases should be brought. Over half of lung cancers are diagnosed when the patients have significant symptomology indicating advanced cancer. Some could have been saved had they been diagnosed earlier and we need to do a better job of diagnosing lung cancer in the United States. If the notion of saving people has not done the trick, perhaps the threat of legal claims may induce physicians to look at high-risk groups and do the necessary diagnostic work. We can acknowledge that the physician is caught between two conflicting pressures, HMO= s who demand that each test be medically justified, and patients who may sue if they perceive a mistake. While we can sympathize with the physician= s plight, we can say that the goal of saving lives is more important and that if claims bring the medical community closer to seeing matters from the patient= s perspective they have accomplished an important goal. Perhaps such suits will accomplish the goal of establishing that certain diagnostic tests should be performed as a matter of course with high-risk smokers, and eliminate the uncertainty that exposes patients to unnecessary risks and physicians to legal liability. Having a health care system where the number 1 cancer and the second largest cause of death is diagnosed too late is 60% to 70% of cases is not satisfactory.

Failure to diagnose lung cancer claims generally involves three basic scenarios:

1. Failure to take a chest x-ray when the patients complaints and prior smoking history indicated the test was warranted,

2. Inaccurate interpretations of the chest x-ray- a difficult diagnostic tool. We can understand missing or misinterpreting that small shadow indicating a coin-sized tumor, but that failure can cost a life.

3. Failing to follow up with CT Scan or other more accurate diagnostic tools when a pulmonary problem was seen. Seeing an ambiguous shadow, a physician might assume it to be emphysema in a smoker and suggest follow-up in six months, not realizing the need for an immediate and accurate diagnosis to stop the spread of the disease.

19.311 Failure to Take an X-ray

We start with the proposition that no physician is required to take an x-ray as part of a yearly or periodic physical, notwithstanding the patient= s smoking history. However, in many cases, the patient will complain of some symptoms indicative of lung cancer such as chest pain, shortness of breath, fatigue, or loss of weight Where the patient= s smoking history and symptomology indicate the possibility of a tumor, it may be a breach of the standard of care for the physician to fail to take or follow up with appropriate diagnostic tests.

Some legal terms to know. Standard of care is that degree of care that a reasonably competent physician would exercise in the same circumstances. The physician is not required to be the best in his area of specialization; he is required to what the average or reasonably competent physician would have done. A breach or violation of the standard of care is negligence. Another somewhat more acerbic word for negligence is malpractice.

While it is clear that screening is not required, what exactly is can be a matter of opinion or even surmise. For example, with some complaint of chest pain, is a chest x-ray required, how about fatigue. It is possible in this area for physicians to reach differing conclusions.

19.312 Misinterpretation of a Chest X-ray

This type of claim is somewhat clearer. In some instances, an internist may fail to contact a radiologist to review an x-ray, and upon viewing the films, we see that a small spot was missed or misinterpreted. Given the difficulty of reading chest x-rays, no physician should take upon the task of reading one on his own, at least for an individual within a high-risk group. Some physicians would argue that reading chest x-rays is a matter of interpretation that involves not only the x-ray itself, but the patient= s background and complaints, and is an art as much as a science. They would argue that a physician should not be sued for his exercise of discretion and judgment. Nonetheless, most attorneys would consider a missed x-ray a solid case.

19.313 Failure to Perform Follow-up Tests

Some attorneys may take cases on a pure contingency basis even deferring payment for costs while others will want the clients to pay for such costs initially. Since that may involve substantial amounts, check with your attorney regarding same.

19.33 Considerations for the Patient

Here are some things you may wish to consider in evaluating whether to pursue a claim:

! What is your relationship to the physician, do you believe he did his best notwithstanding the adverse result,

! How will that affect your treatment. Will you become preoccupied with a claim or feel that you are taking action to right a wrong,

! Do you see a need to change physician's perspectives in favor of early detection and screening programs,

! Will you be required to pay any money initially,

! Is a significant verdict or settlement likely, will that help pay for any needed treatment or help support your family,

As an attorney who handles failure to diagnose claims for patients, I may have a bias or perspective in favor of these claims which should be noted.

Since some within the medical community may have the opportunity to read this, let me offer some suggestions as to how to avoid claims.

A well-documented and informative study by medical insurers found that radiologists are the chief defendants in medical malpractice cases. The reasons are clear. The x-rays is an imprecise test and many patients had x-rays taken long before the cancer was diagnosed. In many cases, a spot or shadow can be seen which at least retrospectively shows the films were not properly read. Since the gap between x-ray and eventual diagnosis may be a number of years, there is a reasonable inference that the patient= s opportunity for long-term survival was adversely affected by the diagnostic error.

Here are the results of one study:

Eighteen radiologists failed to detect 27 potentially resectable bronchogenic carcinomas revealed retrospectively on serial chest radiographs... Six consultant radiologists, who were biased by knowledge that the cases were of missed bronchogenic carcinoma, were individually shown the radiographs in 22 of the cases. Each consultant missed a mean of 26% (5.8 +/- 1.7) of the lesions. At least one of the six consultants missed the lesion in 16 (73%) of the cases. Radiology 1992 Jan;182(1):115-22 .

While some tumors are relatively clear, in many instances, trying to devine the difference between pulmonary fibrosis or pneumonia and a small tumor can be difficult.

Even the average radiologist cannot be right all the time, he can take steps to reduce the consequence of possible errors. Our office had a case of an appendicitis which was not diagnosed in the emergency room. Our consulting physician explained that the error was not the failure to diagnose the disease, but the failure to get adequate follow-up when the cause of severe stomach pain could not be determined. Where there are ambiguities in x-rays, better follow-up is needed, especially even the consequences of delay. One article stated:

19.52 What Follow-up is Needed.

First, where ambiguities are seen on an x-ray, there should be a clear bias toward recommending further testing. This increases the possibility of early diagnosis, as well as limiting the individual radiologist= s potential liability. If a tumor is misinterpreted as probable scarring from pneumonia, but the radioloigist recommends a follow-up CT Scan to make the determination, he has probably elminated liability notwithstanding the error. Given the large percentage of lung cancer patients whose disease is diagnosed too late, we need to emphasize more frequent use of the available tools to detect the disease. One radiologist routinely adds to his reports, follow-up with additional test is recommended if the results are inconsistent with other physican and diagnostic findings. While the language is self-protective, it emphasizes the need for continuing inquiry until the cause of disease is clearly identified.

The radiologist may make a life and death determination. He should do that with as much information as possible. The radiologist may want to contact the referring physician. One article states:

A Double reading of radiographs increases the likelihood of detecting pulmonary disease and, accordingly, physicians have an obligation to view the radiographic examinations performed on their patients, either with the radiologist or independently. It is also essential that the radiologist be proved with the clinical findings before he interprets the radiographs, a practice which will result in significant improvement in the accuracy of radiologic reports.@ Prim Care 1976 Mar;3(1):107-36

19.53 Referral for CT Scan

There also need to be a recognition of the inaccuracy of the chest-ray compared with the CT Scan. Using a chest-xray to make or support a diagnosis is a questionable endeavor, as a recent article explained:

Thus, chest x-ray failed to detect a number of tumors greater than 20 millimeters. More significantly, if failed in detecting smaller, surgically removable tumors, when timely diagnosis could do the most good. Perhaps, a radiologist cannot recommend a CT Scan in every cases referred to him. However, he must recognize that this is a highly imprecise test at best, and using it to base determinations may well cost the patient his life. Where there are smokers, or some type of positive finding on x-ray, Ct Scan should be recommended.

Both physicians and patients would benefit from a clear standard regarding diagnostic testing. Today, most patients are diagnosed late, after their cancers have spread, presenting serious questions about long-term survival. Since many of these patients saw physicians before they were diagnosed, we live in a litigious society and the patient= s health may have been comprosmised by the delay, inevitably claims will be brought. Compensating the patient and/or his family does not solve the basic problem.

Ultiamtely it would reduce claims and benefit physicians were a clear standard enunciated. Thus, if the American Cancer Society determined that CT Scans were warranted for patient with a heavy smoking history, say 30 pack years (packs per day smoked x years smoked), that would establish a benchmark. Doctors could presceibe Ct Scans for such persons at risk, and a clear demarcation would reduce the incidence of claims.

1. Hamer, Medical malpractice in diagnostic radiology: claims, compensation and patient injury,Radiology, 1987 Jul;164(1):263-6

Under American law, two parties can agree to pay for a service or enter into any other contract. Under extreme circumstance, an agreement can be said to be so unfair as to be unconscionable, or be unenforceable because it involves illegal conduct or conduct which offends public policy. However, in most contract cases including those involving health insurance, the court's task is to determine what was intended, first by looking at the written agreement. A It is the duty of the courts to enforce an insurance policy as it is written, and the courts are not at liberty to rewrite policies of insurance to provide coverage where no coverage was intended. Likewise, we are not at liberty to rewrite an insurance policy simply because we do not favor its terms or because its provisions produce harsh results. In the absence of fraud, overreaching or unconscionability, the courts must give effect to an insurance policy if its language is clear and its intent certain. A Black v. Aetna Ins.. Co., 909 S.W.2d 1, 3 (Tenn. App. 1995

Thus, the first task for any patient or family member is to assemble the relevant papers and to review what the health care agreement provides. The chief areas of dispute are as follow

1) is the treatment medically necessary and therefore should the health care provider be required to pay for it,

2) may the patient choose a hospital or physician,

The health care policy typically states that the provider will reimburse for what is medically necessary.

20.21 Consider and Evaluate what the HMO says, though you do not have to accept It

In many cases, HMO's act unreasonably and for their own financial interests. Sometimes however, a patient may fail to understand medicine or the nature of the HMO. Initially, the HMO does not have to refer you to the physician or hospital that you would like or prefer. The very nature of the HMO is to achieve cost savings through negotiation and centralization of certain tasks. Thus, if the HMO has retained qualified hospital A to provide certain treatment, you may not simply opt for hospital B because you like it better, (or you may be called upon to pay additional costs for B) . You do have a right to select a hospital, or more accurately participate in the selection process, if the particular physician or hospital is not as well-equipped to perform a task as your own. Thus you would need to demonstrate their selection's lack of, at least lesser qualification as compared with your choice.

20.22 Some examples, Defining what is Medically Necessary

Let us look at three examples of HMO problems, noting that the approach to each will be different:

1)John Smith has stage 4 lung cancer. The doctor has prescribed an FDA approved medication to relieve pain which while effective is very expensive. The HMO has delayed for several days providing the appropriate approvals.

2) After being given a negative prognosis from the treating oncologist, the Smith family decides that the approach which has the best chance of cure is an innovative approach being taken by a physician located in Los Cacos, Mexico. There are reports on the Internet and in some newspapers of success though the procedure is not FDA approved.

3) United States physician have experimented with a bone marrow transplant for terminal lung cancer patients. The FDA has allowed the procedure for limited use. The HMO refused to provide payment for the procedure.

The HMO= s delay in 1 is clearly wrong and unlawful; its refusal to approve 2 is clearly correct and lawful, and it is probably wrong in 3. Regarding 1, there have been reports of HMO= s delaying pain medication for cancer patients, figuring the cost is substantial while the long term benefits are minimal. However, no patient should suffer. If you have a family member in that situation, you should contact the HMO orally, follow up with a supervisor, send a letter, send a letter by express mail, contact an attorney, have him file a complaint, file a complaint with the insurance board of your state, have the attorney seek an injunction for the care. If your family member is in pain and you even suspect delay for financial reasons, do all these steps quickly, hopefully within 72 hours. Let them know you are looking at a substantial lawsuit if proper treatment is not provided.

In 2 there is little you can do, no HMO will (or perhaps should) approve an unusual procedure in a foreign land. If you decide on that course, you will be responsible for your own costs. Regarding 3, the approach may be similar to 1 with an exception. In 1, the HMO was simply delaying; here, the HMO= s position has some validity because the procedure is experimental. You can and should push the HMO, but if you go to court, you will need to gather medical studies and other information to establish that this course is the medically appropriate one.

Assuming the HMO is acting unreasonably, as a lawyer, one sees a somewhat strange phenomenon in how people approach the legal system. You may see a client send four letters and file a formal complaint over damage to a $121.00 dress. In a divorce, two combatants may spend hours arguing over the disposition of a piece of furniture or a lamp. Yet sometimes people with real concerns, and family members of those with cancer are strangely passive. Certainly, if you believe a particular type of treatment is necessary, you should be aggressive in demanding . . Documents your concerns in a letter.

20.31 Make Sure that Necessary Papers Have, In Fact, Been Submitted by Your Physician

Assuming you believe the HMO is at fault, a letter to them should outline the following:

1) the treatment which is needed, and has been rejected,

2) the medical justification for the treatment, attaching your physician letter of explanation, and any medical studies or other data you have located,

3) a statement that the plan member will suffer severe and irreparable physical injury as a result of the delay in treatment, and noting that such injury may have already occurred because of the HMO's delay,

4) noting that you are contacting an attorney to institute legal action as a result of the HMO's willful and deliberate disregard of the patient's health and well-being, and expect to institute legal action against the responsible individuals as well as the plan itself.

Consider placing particular responsibility upon the particular person who rejected the treatment. You should fight, and in most cases you will win. From an health insurer's point of view, they may want to limit certain types of health care costs, but will alter their position if the possibility of legal or other exposure exists. There have been several large verdicts against HMO's.

If an HMO fails to authorize treatment which you believe is medically justified, you could write to the following:

1) the HMO case manager,

2) his or her supervisor,

3) the state insurance commission who deals with health care issues,

4) the central office of the health insurer,

5) members of the board of directors of the HMO,

6) your local newspaper or radio station.

7) state assemblyman or representative,

8) an Internet website dealing with this issue,

Generally form letters and copies receive less attention than the original. If you want action, address your correspondence to each of the above. Letters should be direct but brief. No letter should be longer than a page, but do include some brief documentation supporting your position.

If an HMO refuses to authorize necessary treatment, you can contact an attorney to file a lawsuit. A lawsuit or claim is initiated by filing a complaint with the court which identified the litigants, what the defendant has done wrong and why, and how the plaintiff has or will be injured by that wrong. While it is preferable to have an attorney representing you, set forth below is a form of complaint designed for use by an individual representing himself.

ROBERT PATIENT SUPERIOR COURT OF NEW JERSEY

ESSEX COUNTY - LAW DIVISION

Plaintiff

vs Civil Action

INSURANCE COMPANY, COMPLAINT AND JURY DEMAND

Docket No.

Defendant

COUNT ONE (BREACH OF CONTRACT)

1. Plaintiff resides at 43 Spring Street, Maplewood, New Jersey. Defendant is a health maintenance organization licensed by the State of New Jersey, with offices at 40 Broad Street, Newark, New Jersey.

2. Under a contract with the Defendant, Plaintiff is entitled to medical and hospital treatment with the costs of such services to be paid by the HMO.

3. Plaintiff has lung cancer. Only July 23, 1999, Plaintiff's physician recommended hospitalization to provide relief from pain associated with plaintiff's cancer. Such recommendation was reasonable and necessary for treatment of Plaintiff's condition.

4. Defendant HMO has failed to approve reimbursement to the appropriate medical and hospital providers for such treatment despite oral and written requests from Plaintiff and his physician.

5. As a result, Plaintiff has been denied medically necessary treatment. More particularly, as a result, Plaintiff has suffered substantial pain and his medical condition has deteriorated as a result of the defendant HMO'S willful and deliberate refusal to perform its contractual obligations.

6. Plaintiff believes and therefore alleges, that defendant has constructed procedures to deprive plaintiff and others of the medical treatment to which they are entitled for the purpose of reducing its costs. Furthermore, Defendant HMO has concealed and misstated its reasons for denying treatment to delay and frustrate Plaintiff and his physicians from arranging for required medical services. The above conduct violates the terms of the Plaintiff's insurance contract, insurance statutes and other applicable law.

WHEREAS, Plaintiff demands judgment against Defendant for compensation damages, punitive damages, and injunction requiring Defendant to perform its contract and restraining it from further violating applicable insurance claims.

JURY DEMAND

Plaintiff requests a trial by jury.

Dated: July 5, 2000 ___________________________________

Robert Patient

20.71 Comment on the Form Complaint

This is based on New Jersey practice; practices vary from state to state. Generally, what a complaint does is explain who the Plaintiff and Defendant are where they are located, what the Defendant did wrong, how the Plaintiff was injured by the Defendant's acts, and what Plaintiff is seeking.

File the complaint with the court with the necessary filing fee, get a docket number or a copy of the complaint marked "filed", and serve that complaint on the Defendant. You can ask a local process-server or subpoena service to serve or hand deliver the complaint to the HMO.

You may wish to send the accompanying Letter to the Defendant

Enclosed please find a copy of the complaint which I have filed with the Superior Court. I confirm that as of this date, you have not authorized the treatment which I need. If this changes, please immediately call me and my physicians. If you have any questions regarding this Complaint, you may call me directly at 973-467-8040 though I may be retaining counsel shortly.

___________________________________

Exposure to dangerous dusts in the workplace is the second leading cause of lung cancer after smoking. These dusts include silica in its many and varied forms, asbestos, and other carcinogens. Because the cellular changes comprising cancer occur slowly, exposures to dusts of ten and 20 years before may be key in the legal assessment of a claim, and make many victims unaware of their right to compensation.

There are two basic claims, a worker's compensation claim which is usually covered by the employer worker's compensation insurance, and a claim against the manufacturer of dusts or chemicals to which the employee can demonstrate exposure. Many courts require proof that the exposure was regular and proximate.

21.31 Asbestos and Silica Negligence and Product Liability Claims

We have two types of claims: negligence and products liability. Negligence is the failure to that care which a prudent person would have used in similar circumstances. In asbestos claims, the plaintiff argues that there was ample evidence of the dangers of asbestos which were disregarded by the manufacturer and/or distributor of the product. The manufacturer should have placed appropriate warnings, suggested regular pulmonary examinations, encapsulated the asbestos so that it would not become airborne, reduced the concentration of asbestos, or utilized available substitutes. A products liability claims suggests that the product was unsafe and is therefore responsible for any resultant injuries. Silicosis was known as a serious disease from the early 30's, and manufacturers failed to provide warnings, recommend wet methods to reduce dust, use inorganic silica instead of the more toxic crystalline silica, and recommend bi-yearly medical testing.

"The word asbestos refers to a group of naturally occurring mineral silicates. Although different in chemical composition and physical properties, they share characteristics of heat and chemical resistance. Asbestos has been used for multiple purposes including textiles, asbestos cement, thermal insulation, building materials, and friction products such as brake linings. There have been hundreds of commercial applications of asbestos since the expansion of this industry began in the late 1800's." Aisner, et. al., Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996).

Asbestos is associated with lung cancer, and with asbestosis, a particular type of lung disease involving a reducing in breathing capacity. These occupations may have had significant exposure to asbestos and other dusts:

! Pipefitters, steam fitters, insulators, and boilermakers

! Construction, carpenters, plumbers, sheet metal workers,

! Maintenance men, custodians, steam fitters,

! Brake mechanics.

These are the considerations a lawyer world use in evaluating a claim:

* Was there substantial exposure to asbestos. For example, an insulator removing asbestos, or a brake mechanic would have substantial exposure; in contrast someone with minor bystander exposure has a tough time arguing asbestos was a causative factor in the disease,

* Is there accompanying asbestosis or other asbestos disease such as pleural plagues, indicating asbestos fibers penetrated the lung

* Was the plaintiff a heavy smoker so that smoking can be regarded as the causative agent,

* Have there been other claims regarding the particular worksite,

* Does any pathology of the lung tissue indicate the presence of asbestos fibers.

If you are considering such a claim, you should consult a qualified attorney to evaluate it.

The author of this book handles such claims in New Jersey as do other attorneys.

Low fruit and vegetable intake has been associated with lung cancer. European Consensus Statement on Lung Cancer: Risk Factors and Prevention Cancer J. Clin 1998, 48, 167. However, advanced intake of products like Beta-Carotene have not been demonstrated to inhibit or hinder tumors which have already developed.

We know that many smokers never contract lung cancer, even after heavy exposure. It is clear that a combination of genetic malfunctions must occur for lung cancer to occur, which explains why there is a latency, or time-gap, between the first time of exposure to a carcinogenc and the date a cancer is diagnosed. A family history indicating some type of gene malfunction may predispose an individual to lung cancer. Those with such a history should particularly avoid smoking and occupational exposures, as well as arrange for frequent screenings.

_______________________________

Hopefully this book has provided substantial information about lung cancer. Here are some ways to proceed to obtain further information. You generally should proceed in the following manner in reading and research:

1) Read a general text on cancer such as American Cancer Society, Informed Decisions (1997) (Some other good books are listed below). If you are comfortable that you understand the material in that book (or this one), go to step two. Otherwise, re-read the book until you find that you have a solid understanding of the basic precepts and terminology used in discussing cancer. Keep a medical dictionary with you if you have questions.

2) Go to a specialized medical text on cancer such as Devita, Principles and Practice of Oncology. Or read articles in a medical journal such as Lung Cancer.

3) Go online to Medline (www.healthgate.com) or Oncolink and run a search on the specific type of cancer, treatment question, or other issue.

4) Try to do as much of 1-4 as possible, and then review the results with your physician. The goal is not to impress him with your knowledge or contradict his recommendations based on a short research session. Instead like the student who has diligently studies the homework, by doing so, you can better take advantage of his knowledge and ask intelligent questions that reflect your acquaintance with the subject matter.

There are a number of excellent books on lung cancer. Medical books are available for purchase from the publishers or sometimes from an online bookseller such as Amazon. Most of the books should be available for review at a medical library

1. Buchman, What You Really Need to Know About Cancer (Johns Hopkins Press ) an excellent overview of the cancer process, but not specifically devoted to lung cancer. Read this first, and then try to specialized medical books.

2. Coleman, Understanding Cancer (Johns Hopkins Press, 1997) an excellent book which explains medical terms in easy to understand language. Read this book, and What you Really need to Know about Cancer, and try the specialized medical books.

3. American Cancer Society Informed Decisions, The Complete Book of Cancer Diagnosis, Treatment, and Recovery (Viking Press 1997)

SPECIALIZED MEDICAL BOOKS ON LUNG CANCER

1. Lung Cancer Manual, by Alcase, available on-line as of this date.

2. Lung Cancer by Lippincott Medical Publishers, an excellent, but detailed examination of lung cancer, designed for medical professionals

3. Aisner, Comprehensive Textbook of Thoracic Oncology (Lippincott, 1996) A book designed for medical professionals, but tremendously useful and detailed

4. Devita, Cancer, Principles and Practice of Oncology ( The leading source of cancer overall, designed for physicians, this comprehensive text covers everything you would need to know, but the reading is not always easy.

5. Carney, Lung Cancer (1995), published in Great Britain, and distributed in the United States by Little Brown & Co.

Information is also available on-line, through the Internet. The premier search device for information about lung cancer and other medical subjects is Medline. The service is free and available on the Internet. A number of different companies offer free Medline courtesy of the National Library of Medicine including www.healthgate.com. Medline is the search engine to use for specific information about a new form of treatment or a particular area of medicine. Medline will give a list of medical abstracts of articles from the last 20 years. Here is the description of Medline furnished by the National Library of Medicine.

! Medline is the National Library of Medicine's (NLM) premier bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and the preclinical sciences.

! It contains bibliographic citations (e.g., authors, title, and journal reference) and author abstracts from over 3,900 biomedical journals published in the United States and 70 foreign countries during the current four years and contains over 9 million records dating back to 1966.

! Has worldwide coverage, but 88% of the citations in current MEDLINE are to English-language sources and 76% have English abstracts.

! Contains the citations that appear in Index Medicus, as well as the citations of "special list" journals. Special list journals include those indexed for the Index to Dental Literature and the International Nursing Index. Citations for MEDLINE are created by the National Library of Medicine, International MEDLARS partners, and cooperating professional organizations.

! An English abstract, if published with the article, is included in MEDLINE.

! Approximately 33,000 new citations are added each month (about 7,300 weekly; 350,000 - 400,000 yearly).

22.31 Medline Subject Headings and MeSH Vocabulary

The MeSH Vocabulary is the biomedical subject headings, subheadings, and supplementary chemical terms used in indexing and searching MEDLINE as well as many other databases in the MEDLARS system. Indexers always use the most specific MeSH term(s) available to describe the subject content of an article.

Lonesome Doc(r) - Obtaining the Full Text of a Medical Article Online

The Lonesome Doc feature of PubMed and Internet Grateful Med allows you to place an order electronically for the full-text of articles you select from the references retrieved in your searches. Delivery is made available by a medical library in your region with which you set up an agreement for this service; a local charge may apply. "

22.33 Sample MEDLINE Record

Here is what a sample Medline record dealing with heart disease would look like.

TITLE: Screening for cardiac disease in patients having noncardiac surgery [comment] [see comments]

AUTHOR: Fleisher LA; Eagle KA

AUTHOR AFFILIATION: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

SOURCE: Ann Intern Med 1996 Apr 15;124(8):767-72

CITATION IDS: PMID: 8633839 UI: 96213860

COMMENT: Comment on: Ann Intern Med 1996 Apr 15;124(8):763-6

ABSTRACT: The preoperative evaluation of the cardiac patient

having noncardiac surgery offers an opportunity to identify occult and further define known cardiovascular disease to modify both perioperative and long-term care.

The baseline probability of cardiovascular disease should initially be assessed using clinical variables and identifying unstable symptoms, including unstable

Noninvasive testing is best done in selected patients who are at moderate clinical risk. Otherwise, testing loses its predictive value because of a high incidence of false-negative and false-positive results. Quantitative imaging can also be used to identify those patients in whom coronary angiography is indicated. The value of coronary revascularization before noncardiac surgery has not been studied in a randomized prospective manner, but several cohort studies have suggested that patients who survive coronary artery bypass grafting have decreased risk during subsequent noncardiac surgery. Given the potential short-term increase in morbidity from two surgical

procedures, it is prudent to reserve coronary revascularization before noncardiac surgery for those patients in whom it is associated with improved long-term survival. If coronary

revascularization is reserved for these patients, then the overall evaluation should prove cost- effective from the perspective of both perioperative and long-term cardiovascular care.

MAIN MESH

HEADINGS: Coronary Disease/complications, Surgical Procedures, Operative

ADDITIONAL

MESH HEADINGS: Heart Function Tests

Human Postoperative complications/prevention & control

Preoperative Care, Risk Factors

Support, Non-U.S. Gov.

PUBLICATION

TYPES: COMMENT

JOURNAL ARTICLE

REVIEW

REVIEW, TUTORIAL

22.21 Oncolink

Another good source of information on-line is Oncolink, a cancer database operated by the University of Pennsylvania.

22.3 Support and Information Groups on the Internet

There is an excellent group on line where people exchange experiences about cancer and you may request information from other lung cancer survivors and persons with similar diseases. See alt.support cancer. Participants discuss treatment, family and psychological issues. America Online calls these groups news groups while the term usenet groups is occasionally used by other search devices.

You can obtain relevant medical articles through your Medline search. However, you may wish to order or review the many medical journals which deal with cancer. Recognize that some of the material may be technical, but you have the opportunity to obtain detailed information on critical issues at your local medical or hospital library. The International Association for the Study of Lung Cancer prepares a journal called lung cancer which is published by Elsevier Publishing Co. There are other journals which deal generally with lung cancer.

American Journal of Respiratory and Critical Care Medicine (from the American Thoracic Society

Annals of Thoracic (chest) Surgery-

CA Cancer Journal for Clinicians (published by the American Cancer Society) A peer-reviewed journal for physicians. An article which is peer-reviewed generally will have greater credibility and impact than one which is not.

Cancer (also published by the American Cancer Society) (published detailed information about cancer cause and treatments).

Cancer Control, Journal of the Moffit Cancer Center

22.51 International Association for the Study of Lung Cancer (IASLC)

22.52 ALCASE

A group called Alcase, (Alliance Against Lung Cancer) has been active in promoting early detection programs, and increasing funding for lung cancer. They have excellent materials and are accessible on the web.

Below is a list of sites available online. Since Webaddresses sometimes change, we have not attempted to list them; instead simply type in these keywords onto a directory like Yahoo and you should be able to locate the site and related information. .

UNITED STATES ORGANIZATIONS DEVOTED TO LUNG CANCER

1. Alliance for Lung Cancer Advocacy, Support, and Education (ALCASE) - is the leading lung cancer advocacy group. Started by lung cancer survivor Peggy McCarthy, the organization is a vigorous advocate for early detection of lung cancer and prepared an including an excellent lung cancer manual, available online at www.alcase.com

WORLD ORGANIZATIONS AND SITES DEVOTED TO LUNG CANCER

In 1983, a group of chest physicians decided to devote their professional interest to the study of lung cancer. The group, who later became known as "Cuneo Lung Cancer Study Group," is still active at the "A. Carle Hospital of Chest Diseases", in the city of Cuneo, Italy. The "A. Carle" hospital, currently named "S. Croce and Carle" hospital, was then designated as Hospital of National Importance, and serves the whole Cuneo Province as 2^nd Referral Institution. Among the prime acts of the Group, the creation of a clinical database for patients with carcinoma of the lung.

Its website, www.culcasg.org. contains the complete text of recent studies from the group, presentations at its annual conference, and other important information. It was one of the first groups to seriously discuss, some say advocate, programs for early detection of lung cancer.

1998 world lung cancer conference.

European Lung Cancer Working Party

contains presentations from the September, 1999 conference, recent about

recent developments in chemotherapy, and comparison of the effectiveness

of different chemotherapy drugs.

OncoLink - Lung Cancer

The excellent cancer database oncolink which contains over 100,000 pages,

sources, and materials.

CancerLit: Thoracic Cancers (National Cancer Institute) On-line abstracts

for health professionals. Sorted by month and year for Small Cell lung

Cancer, Mesothelioma,

Medline: The world medical databases containing over 500,000 articles about cancer and other subjects.

UNITED STATES HOSPITAL WEBPAGES

Lung Cancer Information from Memorial Sloan-Kettering Information about different types of cancers from one of the United States' leading cancer centers

Roswell Park Cancer Institute - cancer, breast, ovarian, bone, prostate, lung, lymphoma, pediatric cancer, skin cancer, colon/rectal, cancer treatment and diagnosis, research, education.

Lung Tumors: A Multi disciplinary Database - multimedia textbook illustrating the diagnosis and treatment of lung cancer.

Lung Cancer Online - information and resources for patients and families.

Lung Cancer Information Center - contains information for health professionals and patients on diagnosis, staging and treatment of various forms of lung cancer.

Lung Tumors: A Multidisciplinary Database Lung Tumors Database from The Virtual Hospital, material on pathology.

American Lung Association

Cuneo Lung Cancer Study Group - Studio e la Ricerca Clinica contro il

PDQ Clinical Trials List: Non-small cell lung cancer (CancerNet, USA)

Information for Health Professionals

SCREENING AND EARLY DETECTION PROGRAMS

Lung Check Inc. A commercial laboratory specializing in early lung cancer detection and prevention. The site contains excellent information about lung cancer screening and early detection programs. Lungcheck provides an inexpensive but effective way for smokers and others at risk to detect lung cancer in its early and treatable stages.

SMOKING PREVENTION ISSUES

Cigarette Advertising and Children - Information sheet (Cancer Society of New Zealand) . Summary of how children are affected by cigarette advertising.

Early Age at Smoking Initiation and Tobacco Carcinogen DNA Damage in the

Lung (Wiencke JK, Thurston SW, Kelsey KT, et al. Journal of the National

Cancer Institute, Vol. 91, 614-619, 1999)

Great American Smoke Out (American Cancer Society)

Lung Cancer and Cigarette Smoking Web Page by Frederic W. Grannis Jr. M.D.

Thoracic surgeon at leading California hospital discusses f diagnosing

and treating lung cancer.

Office on Smoking and Health - Tobacco Information and Prevention

Sourcepage (Center for Disease Control, USA) Extensive cigarettes links.

Parenting Smoke free Children (Cancer Society)

Parts of the attached were excerpted from the University of New Castle page,

Guide to Cancer. To go to that informative webpage, University of New Castle

To obtain an updated list of lung cancer links, and simply link to the sites on-line, go to the author= s website, www lungcancerclaims.com

_________________________________

There are contrasting views about the importance of a particular hospital. One book notes, "There are no studies that compare the quality of chemotherapy treatments across the board between cancer centers and local facilities. But there was a reassuring study that compared the results of the Eastern Cooperative Oncology Group consisting of university hospitals or major treatment centers with 100 affiliates consisting of small community hospitals and private-practice groups of physicians. The study involved ninety-seven randomized trials and 4,506 patients. The authors of the report of the study, published in May 6, 1982, issue of the New England Journal of Medicine, wrote that "over a wide spectrum of studies and sites, the survival, response, toxicity, and data quality were the same in affiliates as in major treatment centers."

However, another study found that mortality rates in some forms of cancer surgery were related to the surgeons experience with that particular type of surgery.

However, U.S. News and World Report along with other groups evaluate hospitals. Given the complexity of cancer treatment, it is reasonable to assume there will be some difference based upon the physician and hospital's skill, training, and experience. The ratings are included in the index. Some comments.

23.11 Leading Hospitals

The two highest ranked hospitals were M.D. Anderson in Texas and Sloan Kettering in New York City. Other highly-ranked hospitals included the Mayo Clinic in Minnesota.

CHAPTER 24 SMOKING CESSATION PROGRAMS

One might conclude that a discussion about smoking is superfluous in a book about lung cancer, since the readers or their families have already contracted the disease. However, it would be important even for this group to quit smoking. The same disease process which created the initial tumor could theoretically create further tumors with further exposure to carcinogenic smoke. Surgery cannot be performed if breathing function is severely impaired and smoking has the capacity to further damage the lung even where it does not create tumors.

Further, since smoking plays such a central role in lung cancer, one must discuss smoking and prevention to discuss the disease. Discussing lung cancer requires a discussion of its chief cause. Indeed, some with lung cancer will be the most vigorous advocates of educational programs, and will want to teach others how to avoid what they have endured.

"Smoking is a chronic condition that affects more than 46 million Americans. People who smoke are at risk of heart disease, cancer, and other smoking-related illnesses that cost more than $50 billion annually to treat, and an additional $47 billion in indirect costs from lost time at work and disability.

Smoking is the single greatest preventable cause of death and illness in the United States. An estimated 420,000 people die every year from smoking-related illnesses. Studies show that over 70 percent of adult smokers would like to quit, but only half of them have ever been urged to quit by their health care provider. Smoking only with delayed diagnosis is the chief cause of lung cancer.@

24.11 The Increase in Lung Cancer Among Women

Between 1973 and 1995, lung cancer incidence in US women rose by 126% while incidence rates in men rose by only 0.9%. During this period, incidence rates for small cell carcinoma of the lung (SCLC) increased by over 160%, faster than other histologic types in women and 8 times faster than the increase for SCLC in men. Lung cancer now accounts for one of every eight new cancers in women and one of every five lung cancers is SCLC. Small cell carcinoma is diagnosed most frequently in heavy smokers and rarely in non-smokers. Osann, Small cell lung cancer in women: Risk associated with Smoking, Prior Respiratory Disease, and Occupation Lung Cancer, Vol. 28 (1) (2000) pp. 1 - 10

 

24.12 Particular Risk Factors Associated with Smoking

24.12 Types of Cancer and Smoking

Quitting smoking dramatically decreases one= s odds of getting lung cancer.

with the risk decreasing over time. A Cigarette smoking is strongly associated with risk for small cell carcinoma. Odds ratios are nine times higher for current smokers than former smokers A Osann, Small cell lung cancer in women: Risk associated with Smoking, Prior Respiratory Disease, and Occupation Lung Cancer, Vol. 28 (1) (2000) pp. 1 - 10

A In the 1990 study we were able to assess the effects of prolonged cessation among those who had smoked cigarettes for many years. Although efforts to change from cigarettes to other types of tobacco, or from smoking substantial numbers of cigarettes to smoking smaller numbers, seemed to confer only limited benefit stopping smoking confers substantial benefit.... Even people who stop smoking at 50 or 60 years of age avoid most of their subsequent risk of developing lung cancer, and that those who stop at 30 years of age avoid more than 90% of the risk attributable to tobacco of those who continue to smoke. In the United Kingdom widespread cessation has roughly halved the number of cases of lung cancer that would now be occurring, as by 1990 it had already almost halved the number that would have occurred in the study.@

Smoking, Smoking Cessation, and Lung Cancer in the UK since 1950: Combination of National Statistics with two case-control studies, BMJ 2000;321:323-329 ( 5 August)

However, it will probably never be the same risk of a nonsmoker. The numerous genetic changes that result in lung occur over a period of roughly 15 years. Stopping smoking may eliminate some DNA damage which may contribute to lung cancer; in other circumstances the carcinogenic process may be already in place. In the Cornell study of early detection, a substantial number of lesions and pulmonary abnormalities were associated with former smokers. Thus, former smokers continue to have substantial risks of contracting lung cancer, and systems of early detection must concentrate on them as well as smokers.

24.31 The Question of Reduced Tar Cigarettes

We can concretely say that quitting smoking substantially reduces, but does not eliminate lung cancer risk. The question of whether risk is similarly reduced by low tar cigarettes is more difficult. The advent of low tar cigarettes has brought with it an increase in the number of adenocarcinomas, non small cell cancers which generally arise in the peripheral lung areas. One sensible theory is that low tar smokers breath the smoke more deeply, allowing the carcinogen is reach the smaller pathways of the lung.

Adenocarcinomas are generally more dangerous than squamous cell tumors, since the adeno tumors seem to metastasize more quickly with clinical trials showing a poorer prognosis for patients with adenocarcinoma. Thus, it may be that low tar cigarettes are having a minimal impact. Certainly most researchers would strongly recommend that the patient quit rather than change brand or type.

A numberof articles, books, tapes, and other materials have been compiled dealing with smoking. Below, utilizing some of these materials, and my own views, I have put forth a program for reducing the incidence of smoking.

Lung cancer from smoking is been the largest avoidable cause of death in the United States. Lung cancer is responsible for the largest number of cancer death in the United States, and is responsible for more deaths among women than breast and cervical cancer combined. Substantial numbers of young people continue to become addicted to smoking. Thus, our starting point must be to recognize that however well-intentioned we have been, our efforts to severely limit smoking have generally been a failure.

2. School Anti-Smoking Programs Should Candidly and Accurately Describe the Hazards of Smoking

The danger is not overly frightening a potential smoker but not adequately conveying the serious risks inherent in this habit. We need to spend less time worrying about the sensibilities of teenagers and more time starkly informing them of the hazards of smoking. Anti-smoking programs should include the elements listed below even though, or perhaps precisely because, they may scare some people.

It is sad to see someone terminally ill discuss the hazards of smoking, but it is necessary and important to vividly explain what can occur. No lawyer in a personal injury case would rely only on impersonal records; he would want to personalize the injury and give a jury a vivid sense of its impact. Whether the patient is speaking first hand, by videotape or other means, having patients will throat cancer, lung cancer, chronic obstructive pulmonary disease, and other ailments speak is a critical element of any presentation.

4. Include Slides and Pictures Vividly Showing the Hazards of Smoking

Whether it be a diseased lung, x-ray of a smoker, or the photograph of a family, pictures speak louder than words.

While medical advances continue, metastatic lung cancer continues is a difficulty disease to confront. Speakers should briefly describe how cancer metastasizes and our current difficulties in curing disease once that has occured.

6. Include Statistics

Some presentations include only statistics, but discussing life expectancies, the difficulties of complete cure, rates of mortality among smokers and other facts can impress the perspective smoker with the hazards of this habit.

Beyond telling people not to smoke, a presentation should discuss the methods of quitting, and how they have worked including the difficulty of quitting.

A The smoking cessation guideline challenges clinicians-physicians and other health care providers-to aggressively motivate and help their patients who smoke to quit. The guideline makes specific recommendations about how clinicians can identify smokers, repeatedly encourage them to quit, and offer treatments that have been proven to work.

The guideline found three treatment elements were particularly effective, used either alone or together, in helping smokers quit. They are:

! Nicotine replacement therapy-either the prescribed nicotine patch or nicotine gum, which doubles the rate of successfully quitting. [Nicotine gum has been approved for over-the-counter (OTC) use by the FDA. The nicotine patch was approved for OTC use by the FDA in July 1996.]

! Social support-encouragement and support from the clinician.

! Skills training/problem solving-practical advice and techniques from the clinician that help people adapt to life as a non-smoker.

! Individual or group counseling programs are also helpful. The guideline panel found a direct relationship between the intensity of treatment and the likelihood for success. The guideline recommends that counseling programs, if chosen, be delivered over 4 to 7 sessions (20 to 30 minutes in length), for at least 2 weeks, but preferably for 8 weeks.

No conclusions were drawn about the effectiveness of the following

treatments:

* Acupuncture or hypnosis. There was insufficient evidence to support the effectiveness of either of these therapies.

* Clonidine, antidepressants, and anxiolytics/benzodiazepines. Lack of data and/or faulty studies offered little support for their use.

The guideline panel made no recommendations regarding the use of nicotine nasal sprays and nicotine inhalers. There were limited data on these products. At the time of the panel's deliberations, the products were not licensed for prescription in the United States. [As the guideline went to press, the FDA approved the prescription use of nicotine nasal spray.]

* Identify smokers. Ask every patient at every visit if they smoke.

* Implement a tobacco-user identification system in every clinic.

* Record smoking status as a vital sign.

* Encourage smokers to quit.

* Ask smokers about their desire to quit and reinforce their intentions.

* Give motivational messages to those who aren't ready to quit.

* Help motivated smokers set a quit date.

* Prescribe nicotine replacement therapy.

* Offer specific, practical advice about how to deal with life as a non-smoker, particularly how to handle situations or emotional states that may cause relapse.

* Encourage relapsed smokers to try to quit again.

Note again that these recommendations are excerpted from a National Cancer Institute page on smoking generally, and not directed specifically towards lung cancer patients. You should speak with your physician regarding a program to quite smoking. However, while substances like nicotine are routinely used by people trying to quit smoking, no smoker should use it without a doctor's permission since it may impact certain forms of treatment.

* Talk with your doctor. Discuss nicotine replacement therapy and strategies to deal with wanting to smoke again. Do everything you can to maximize the chances for success.

* Be committed. Make sure you're ready to work hard to quit

* Set a quit date. Don't try to "taper off."

* Build on past mistakes. If you've tried to quit before, think about what helped and what hurt.

* Enlist support. Tell your family and friends you're quitting. Create a network you can turn to for help.

* Learn how to avoid or cope with situations and behavior that make you want to smoke.

Health care systems face the daily challenge of balancing quality of care and costs for every patient. Health care administrators, insurers (including managed care plans), and purchasers, can play a vital role in tackling the leading preventable cause of illness and death-smoking.

The purpose of this guide is to provide tools to make smoking cessation a priority in your organization. You can help eliminate the roadblocks to developing standard procedures for assessment and treatment of tobacco use in every health care setting. The most successful smoking cessation programs are supported by institutional policies. They incorporate reimbursement practices, clinical and systems procedures, incentives for providers, and clinician education. Supporting institution-wide smoking cessation programs can yield both short- and long-term cost savings for patients.

* Americans spend an estimated $50 billion annually on direct medical care for smoking-related illnesses. Lost productivity and forfeited earnings due to smoking-related disability account for another $47 billion per year.

* The average cost per smoker for effective cessation treatment is $165.61.

* Smoking cessation interventions are less costly than other routine medical interventions such as treatment of mild to moderate high blood pressure or high cholesterol and preventive medical practices such as periodic mammography.

* Smoking cessation interventions can save on costs by reducing health risks and complications for infants and young children.

24.81 Strategies

Following are five strategies that have been demonstrated to be effective in helping health care providers identify and treat tobacco users....

Screening systems that systematically identify and document smoking status result in higher rates of smoking cessation interventions by clinicians and in higher quit rates among patients who smoke. This approach increases the probability that tobacco use is consistently assessed and documented. Studies show that smoking cessation interventions involving minimal contact with health care providers-physicians, nurses, social workers, counselors, and others-even in sessions lasting as few as 3 minutes, are more effective at increasing cessation rates than no contact at all. Intensive interventions are more effective and should be used when resources permit. Health care report cards such as the Health Plan Employer Data and Information Set (HEDIS) are now mandating that managed care organizations include information documenting delivery of effective smoking cessation services.

Action

Implement an office-wide system that ensures that, for every patient, tobacco-use status is queried and documented.

Office system change: Expand vital signs data to include tobacco use (see sample diagram below).

Frequency of utilization Whenever health care staff collect the traditional vital signs data, they should query and document tobacco use

Strategy 2. Provide education, resources, and feedback to promote provider intervention

Smoking cessation interventions delivered by multiple types of health care providers (e.g., nurses, dentists, psychologists, social workers) markedly increase cessation rates compared with interventions where no provider intervenes (e.g., self-administered interventions). Results are consistent across diverse provider groups, with no clear advantage to any single provider type. To encourage provider interventions, health care administrators, insurers, and purchasers should provide both training and incentives, such as reimbursement for clinicians (see strategy 5). It is important to dedicate staff both to provide smoking cessation treatment and to assess the delivery of this treatment in staff performance evaluations.

National data suggest that, in a given visit with a clinician, most smokers are not advised to quit smoking and are not assisted with cessation. Factors that contribute to this problem include failure to (a) include smoking assessment and cessation in the performance expectations of clinicians and (b) provide clinicians with an environment that supports systematic intervention with smokers. Without supportive systems, policies, and environmental prompts, the individual clinician cannot be counted on to assess and treat tobacco use reliably.

Action

* Health care systems should ensure that clinicians have the knowledge and training to treat smoking, that clinicians and patients have cessation resources, and that clinicians are given feedback about their cessation practices.

* Clinical sites should communicate to staff the importance of intervening with smokers and should designate one staff person (e.g., nurse, medical assistant, or other clinician) to coordinate and deliver smoking cessation treatments.

Strategies for Implementation

Educate: On a regular basis, offer lectures/seminars/in-services with CME and other credit for smoking cessation treatment.

Resources: Have patient self-help materials, as well as nicotine replacement "starter kits," readily available in every exam room.

Provide feedback: Drawing on data from chart audits, electronic medical records, or computerized patient databases, evaluate the degree to which clinicians are identifying, documenting, and treating patients who smoke, and provide feedback to clinicians about their level of intervention.

Communicate to each staff member (e.g., nurse, medical assistant, or other clinician) his or her responsibilities in the delivery of smoking cessation services.

Designate a smoking cessation treatment coordinator for every clinical site.

Delineate the responsibilities of the smoking cessation coordinator, including instructing patients on the effective use of cessation treatments (e.g., nicotine replacement therapy, telephone calls to and from prospective quitters, and scheduled follow-up visits, especially in the immediate post-quit period).

Strategy 3. Promote hospital policies that support and provide smoking cessation services

Evidence

Implementing inpatient smoking cessation programs increases the rate at which hospitalized patients successfully quit. It is vital that hospitalized patients attempt to quit smoking because smoking may interfere with their recovery. Hospitalized patients may be particularly motivated to make a quit attempt for two reasons. First, the illness that resulted in their hospitalization may have been caused or exacerbated by smoking. Second, the hospital's smoke-free environment may enhance their motivation to quit. In addition, systematic, institutionalized mechanisms to identify exsmokers is a necessary first step in delivering relapse prevention messages. Furthermore, all clinicians have an important role as nonsmoking models for their patients.

Action Provide smoking cessation inpatient consultation services to all smokers admitted to a hospital and to all health care personnel who smoke.

Implement a system to identify and document the tobacco-use status of all hospitalized patients.Offer cessation treatment to all hospitalized patients who use tobacco. Identifya clinician(s) to deliver smoking cessation inpatient consultation services for every hospital. Reimburse providers for smoking cessation inpatient consultation services. Expand hospital formularies to include effective smoking cessation pharmaco-therapy such as the nicotine patch and nicotine gum. Ensure compliance with JCAHO regulations mandating that all sections of the hospital be entirely smoke free. Educate all hospital staff regarding nicotine withdrawal, including effective treatments such as nicotine replacement therapy and counseling.

Strategy 4. Include smoking cessation treatments as paid services in all health benefits packages

Evidence

Smoking cessation treatments (both pharmacotherapy and counseling) are not consistently provided as paid services for subscribers of health insurance packages. The level of coverage is particularly surprising given that studies show that physician counseling against smoking is at least as cost-effective as several other preventive medical practices, including the treatment of mild or moderate hypertension or high cholesterol.

26.11 Summary of the Recent NCI Study

Investigators at the National Cancer Institute in Bethesda, Md., have published the first study that analyzes the gender differences in precancerous changes in smokers' lung tissue. This study, in the Journal of the National Cancer Institute, finds that women develop a different pattern of bronchial changes than men do; that airflow obstruction, a common means to assess those at risk of lung cancer, does not seem to be valid, especially for women; and that lung damage due to smoking persists for many years and probably for life. See Journal of National Cancer Institute, April 21, 1999. More men and women die from lung cancer than from any other type of cancer. This year an estimated 171,600 new cases of lung cancer will be diagnosed, and 158,000 people will die from this disease. Approximately 50 percent of lung cancer occurs in former smokers.

Women are more susceptible to the harmful effects of tobacco-related carcinogens -- the odds ratios for major types of lung cancer are consistently higher in women than in men at every level of exposure to cigarette smoke. Furthermore, this gender difference cannot be explained by differences in baseline exposure, smoking history or body size; it is likely due to women's higher susceptibility to tobacco carcinogens.

"Cancer is the result of a complex multi step process," said Gazdar, associate director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research. "We are actively trying to develop methods of early detection and chemoprevention -- ways to chemically reverse precancerous lesions and block cancer development -- for those at high risk." The scientists found that men had a significantly higher incidence of precancerous lesions in the large central airways than women. They also found that fewer women than men had high-grade preinvasive lesions. Because women develop more cancers in the peripheral (outer) parts of the lung than men do, Gazdar and co-workers presume that women smokers are selectively damaging these parts of the lung, while smoking damage in men targets the larger, more centrally located airways. The general lesson from this study is that methods of lung-cancer screening in high risk populations must take gender into consideration, and perhaps, different screening procedures and criteria will have to be used for men and for women.

25.12 Japanese Study Finds Increasing Incidence of Adenocarcinoma Among Women and Younger Lung Cancer Patients

A Japanese study was recently completed on 790 cases of lung cancer to review the characteristics and survival rates of lung cancer patients under and over the age of 50. The study analyzed data on patients at the Tochigi Cancer Center Hospital. Jpn J Cancer Res, 1999 May, 90:5, 490-5

Of the 790 patients, 77 (9.7%) were under the age of 50 at diagnosis. The percentage of women in the younger patient group was significantly higher than that in the older patient group (39.0% vs. 27.5%; P = 0.034). Thus we have an increasing incidence of women smokers with adenocarcinoma. Tumor histology revealed a significant preponderance of adenocarcinomas (60 patients, 77.9%) and a paucity of squamous cell carcinomas (8 patients, 10.4%) in the younger age group

25.21 The Rate of Lung Cancer in the Afro-American community

While one is reluctant to ascribe racist motives, studies indicate the following:

! The percentage of blacks contracting lung cancer is higher percentage wide than whites. This is probably due to higher exposure rates to dangerous dusts such as silica and asbestos in different occupations, higher rates of smoking, residence in cities with poorer air quality and vehicle emissions, and other risk factors,

! Blacks are unfortunately diagnosed at later stages and have higher mortality rates than whites.

! Blacks are less likely to have surgery performed, which is generally the most successful medical alternative

25.22 Racial and Economic Issues

An article entitled, A The economics of surviving cancer@ contains some disturbing findings:

Disadvantaged Americans are far more likely to die of the most treatable form of lung cancer than average - not because of poor health habits, but because they don't receive the proper treatment for their malignancy. Health care delivery expert Howard P. Greenwald has analyzed more than 5,000 cases of stage-1 non-small-cell lung cancer - attempting to explain why cancer mortality rates are higher among racial minorities and the socially disadvantaged than among higher-income Americans and whites.

His findings are detailed in "Uneven Odds: Explaining High Cancer Death Rates Among Minorities and the Poor," a paper presented March 28 at an American Cancer Society conference in New Orleans....

Greenwald found that surgery may have saved the lives of nearly one in three patients whose cancer was detected early enough for surgery. But the poorest patients were about a third less likely to receive surgery than the richest patients. Fifty percent of the patients in the bottom 10 percent of income levels received surgical treatment, whereas 72 percent of patients in the top 10 percent of income levels received it.

The mortality rates were even more dramatic. Greenwald found that the poorest patients were only half as likely as the richest patients to survive. Only 22 percent of the poorest lived at least five years after diagnosis, compared to 45 percent among the richest patients. As a subset of the study group, African-American patients carried an additional burden. According to Greenwald, they had a one-in-four chance of surviving, compared to a one-in-three chance among white Americans. While 61 percent of whites received surgery, only 51 percent of African Americans did. "In the form of lung cancer studied, lack of appropriate care seems to have contributed strongly to excess mortality among the disadvantaged," Greenwald said. "It explains about 50 percent of the excess mortality in poor people and all of the excess mortality in African Americans...." Southern California Chronicle, www.usc.edu

Greenwald has written extensively about socio-economic factors and cancer. He is the author of Who Survives Cancer (1992) and Social Problems in Cancer Control (1980).

25.23 What Should Be Done

Afro-Americans need to take a more assertive role in their treatment, assess the quality of their hospitals and physicians, and assure themselves that they are receiving the best treatment. Given the extent of risk from lung cancer and its consequences, there needs to be an effective screening program, particularly for Afro- Americans. The message of this book is repeated- lung cancer at early stages is very treatable, the problems occur when the cancer is permitted to spread .

A recent article was titled, Is there a genetic basis for lung cancer susceptibility? Recent Results Cancer Res, 1999, 151:, 3-12

The author states,

The study tells us that while tobacco is the primary risk factor, family history plays an important but subsidiary role. Those with a family history of lung cancer may have less of a capacity to repair smoking related DNA damage, therefore leading to increased incident of lung cancer.

______________________________________________________

I used the term terminally ill because it is a phrase which many people use. However, it is nondescriptive and inaccurate. It can describe a variety of stages of lung cancer, lumping together patients with different prognoses. When speaking about a patient, it is far more accurate to use the TNM staging system and to discuss the specific stage of disease.

Thus, not only does the phrase terminally ill frequently group patients with different stages of disease, it presupposes a degree of predictive accuracy which does not exist. If only 15% of patients with disease at a particular stage will survive 3 years, a particular patient may live longer.

Family and close friends can play a vital role in helping a cancer patient. Here are some things you can do for a family member with lung cancer:

Alcase is the national lung cancer support group. Find out about support options, learn about new treatment developments, and learn from others how to deal with the disease.

Some patients will want to fully understand their disease and obtaining information about it is helpful in dealing with it. Most however, they would rather not spend their time thinking about metastasis and disease process. For this group, the family member who can studiously but quietly obtain information about treatment alternatives can provide a great help. For many, simply saying your doctor recommends this particular form of chemotherapy, my research shows he is very well-qualified and this is the best choice, is sufficient.

One support group put together this list of A 25 PRACTICAL TIPS TO HELP THOSE FACING A SERIOUS ILLNESS:@

1) Don't avoid me. Be the friend...the loved one you've always

been.

2) Touch me. A simple squeeze of my hand can tell me you still

care.

3) Call me to tell me you're bringing my favorite dish and

what time you are coming. Bring food in disposable containers,

so I won't worry about returns.

4) Take care of my children for me. I need a little time to be

alone with my loved one. My children may also need a little

vacation away from my illness.

5) Weep with me when I weep. Laugh with me when I laugh. Don't

be afraid to share this with me.

6) Take time out for a pleasure trip, but know my limitations.

7) Call for my shopping list and make a "special" delivery to

my home.

8) Call me before you visit, but don't be afraid to visit. I

need you. I am lonely

9) Help my family. I am sick, but they may be suffering. Offer

to come stay with me to give my loved ones a break. Invite

them out. Take them places.

10) Help me celebrate holidays (and life) by decorating my

hospital room or home or bringing me tiny gifts of flowers or

other natural treasures.

11) Be creative! Bring me a book of thoughts, taped music, a

poster for my wall, cookies to share with my family

and.friends...an old friend who hasn't come to visit me.

12) Let's talk about it. Maybe I need to talk about my

illness. Find out by asking me : "Do you feel like talking

about it?"

13) Don't always feel we have to talk. We can sit silently

together.

14) Can you take me or my children somewhere I may need

transportation to a treatment....to the store...to a doctor.

15) Help me feel good about my looks. Tell me I look good,

considering my illness.

16) Please include me in a decision. I've been robbed of so

many things. Please don't deny me a chance to make decisions

in my family...in my life.

17) Talk to me of the future. Tomorrow, next week, next year.

Hope is so important to me.

18) Bring me a positive attitude. It's catching!

19) What's in the news? Magazines, photos, newspapers, verbal

reports, keep me from feeling the world is passing me by.

20) Could you help me with some cleaning? During my illness,

my family and I still face: dirty clothes, dirty dishes, dirty

house.

21) Water my flowers.

22) Just send a card to say "I care."

23) Pray for me and share your faith with me.

24) Tell me what you would like to do for me and, when I

agree, please do it!

25) Tell me about support groups Iike Make Today Count,

Cancerwise, and American Cancer Society so I can share with

others. From the brochure "25 Tips to Help Those Facing a Serious

Illness" from Saint Anthony's Hospital's Make Today Count.

Accuracy This term is used with a medical test, for example, a method to detect cancer. A test= s specificity refers to the percentage of patients whose cancers are accurately seen. Assume that a test is given to 100 people, of whom 10 have lung cancer. If the test detects 8 of the 10 with lung cancer, it has a specificity of 80%.

The test might also incorrectly indicate that some people had cancer, when in fact they did not have the disease. For example, an x-ray could show a shadow which might be incorrectly interpreted as a tumor. This would be a false negative. Accuracy usually refers to the percentage of false negatives. Assume that the test misinterprets that 2 people have cancer when in fact they do not. That would be an accuracy rate of 98%, meaning that 2 of 100 were false negatives.

Adjuvant therapy Adjuvant means in addition to. Adjuvant therapy typically refers to chemotherapy given after surgery. Neo-adjuvant therapy refers to chemotherapy given before surgery.

and metastasize to other organs.

Anti-angiogenesis A drug which inhibits the ability of cancer cells to form or connect to blood vessels.

Apostastasis Cell death. Scientists study this phenomenon to try to determine what conditions cancer cells die.

Cancer A cellular malignancy where loss of normal controls- results in unregulated growth, lack of differentiation, and ability to invade local tissues and metastasize.

Cell-cycle-specific, A form of chemotherapy lethal to cells only during a specific phase.

Chest X-Ray An x-ray of the thoracic or chest area which includes the lungs. The chest x-ray will show tumors of at least 1 centimeter. Its advantage in its ease of use and low cost, disadvantage is that small tumors can be missed and others may not be shown.

Control group People in a clinical trial receiving the standard treatment, and not the experimental treatment.

Differentiation Normal cells are differentiated. As cancer progresses, cells lose their essential characteristics or differentiation. Cancer cells are categorized from well-differentiated to poorly differentiated.

Hemothorax When the pleural cavity fills with blood.

Lobectomy Surgical removal of one of the lobes of the lung.

Lymphocytes White blood cells, the body= s mechanism to fight cancer, a type of lymphocyte is the T cell

M or Metastasis M refers to metastasis in the TNM staging system, or movement of cancer from the lung to another organ.

Matrix metalloproteinases refers to particular substances in cancer cells

(MMP) which help break down the protective barriers which protects other bodily structures. Some drugs have been developed to inhibit MMP

Neo-adjuvant therapy Adjuvant means in addition to. Adjuvant therapy is chemotherapy given after surgery. A recent refinement is to give chemotherapy in some situations before surgery, which is called neo-adjuvant therapyo

NSLC A frequently used abbreviation for non-small cell lung cancer.

N (or Node) N refers to lymph node in the TNM staging system.

P-53 One of the most important tumor supressor genes. Abnormalities in P-53 are found in many cancers, including small and non-small cell cancer. One type of gene therapy seeks to inject normal or wild-type to restore tumor suppresion activity.

P-53 (mutant type) This is P-53 which has been damaged and mutated, and is found in many tumors. Not only will the gene not perform its tumor suppressor function, evidence indicates it plays a role in prompting duplication of cells or cancerous activity.

P-53 (wild-type) This is P-53 in its normal condition, serving various tumor suppression functions.

Palliative Treatment designed to relieve pain or discomfort rather than achieve a cure.

Pneumonectomy Surgical removal of the entire lung

Pneumothorax If the pleural cavity fills with air, this is called pneumothorax.

Pleura A thin membrane encasing each lung.

SLC A frequently used abbreviation for small cell lung cancer. Various

types of cancer are classified as small cell or non-small cell. Types of cancers within each category share similar characteristics in terms of tumor growth and metastasis.

Sputum Cytology Analysis of lung cells by having the smoker cough. Effective at detecting very small microscopic cancers. An excellent technology not used nearly enough.

Specificity The percentage of cancers accurately seen by a test. If ten people have tumors, and a test detects 8 of those, its specificity is 80%. Put another way, the rate of false positives is 20%.

Tumor angiogenesis factor(TAF) Tumor cells need a blood supply to bring them fresh nutrients and carry away wastes. The process by which a tumor links up with the bloodstream is called angiogeneses. It is believed that the tumor secretes a substance known as or (TAF) which induces blood vessels to produce new capillaries that grow toward the tumor and finally connect with it.@

TNM Classification Tumor classification. with T designating the size and location of the primary tumor, N standing for the existence of cancerous lymph nodes, and M meaning metastasis or spread to other organs. Thus a medical chart would have a notation; classification of tumor, T1NoMo, meaning a small tumor which has not invaded lymph nodes or metastasized.

T or Tumor T is the primary tumor in the TNM staging system, and is measured from 0, undetectable on an ordinary x-ray to 4 based upon its size and spread to nearby organs or structures. T Cell A type of white blood cells which activates to fight cancer. Also called killer cells.

Name of Drug Type Side Effects Status

Name of Drug Type Side Effects Status