A COMPLETE GUIDE TO LUNG CANCER
Copyright 2001, Howard A. Gutman
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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CHAPTER 1: WHAT IS CANCER
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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,
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.
1.1 COMMON CHARACTERSTICS OF CANCERS
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:
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:
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:
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:
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:
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.
3) The tumor cells manage to penetrate the protective barrier of another organ, called the basement membrame. Cells move into the new organ, and establish a source of blood supply for future growth. The process by which tumors establish new sources of blood supply is called angiogeneses, and a major source of cancer research is the creation of anti-angiogenesis drugs to frustrate this process.
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:
1.2 DIFFERENCES AMONG CANCERS
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.
1.2 GENES AND CHROMOSOMES
Many patients or family members will read about gene therapy and different advances in cancer research. A basic knowledge of what genes and chromosomes are will help you understand these advances and are how they can be important to you. Later chapters discusses gene therapy and treatments where scientists try to alter the messages gene send to one another.1.21 Chromosomes
Genes are part of a large structure called chromosomes in the body:An excellent book called Understanding Cancer discussed the structure of chromosomes:
Coleman, Understanding Cancer 30 (John Hopkins Press 1998).
1.22 Genes
Coleman then goes on to explain these genes:
In many instances, we can identify the location of specific genes, and there is a world-wide program to provide a genetic map of the human body.
1.23 What Do Genes Do
This is a finely-turned process. Cancer occurs when the genes are damaged, and things do not function as intended.
1.24 Cell Cycle
1.241 Why We Need to Understand Cell Cycles
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
There are 4 broad phases of the cell cycle: G1, S, G2, and M. In G1 or Gap 1, the cell synthesizes proteins which will enable it to grow. S phase genes contain a factor, S-phase promoting factor, or SPF, which helps cells go from G1 to S, or synthesis.
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.
1.3 HOW NORMAL CELLS CHANGE TO CANCER CELLS
1.31 Proto-Oncogenes and Oncogenes
Cancer cells are basically good cells gone bad and we can with some precision identify those cells which can become cancers. These are genes already involved with cell division and growth which are called proto-oncogenes
. A Mutations to a proto-oncogene alters its structure and activates it to produce an oncogene. The protein product of the oncogene is itself altered so that it can no longer be switched off by normal cellular signals and its expression directs the cell to divide@ Vile, Cancer Metastasis: From Mechanisms to Therapies 4-5 (Wiley & Sons 1995). A proto-oncogene is a normal gene which performs certain growth functions but when altered, can turn into a cancerous oncogene:Angier, Natural Obsessions 5 (Mariner Books 1999)
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.
1.4 HOW GENES ARE DAMAGED AND BECOME ONCOGENES
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:
1.42 Time for Cancer to Develop
Cancer does not develop overnight though some people will associate an cancer with some event or exposure that happened a few months before. Instead, as we explain in chapter two, most tumors are associated with a series of changes that may occur over a period of 10 to 15 years or even longer.
1.5 CANCER TERMINOLOGY
The
place where the first tumor is found on a patient is called the primary site and the cancer that initially forms, the primary cancer. Cancers retain characteristics based upon where they originate. Thus, a cancer which originated in the lung but metastasized to the breast would still be characterized as a lung cancer.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.
1.6 Reserved
1.7 CANCER AND THE IMMUNE SYSTEM
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.
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:
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.
For example, researchers have taken metastasic cells removed at surgery and then separated the lymphocytes in those cancer cells in them. Lymphocytes are components in the immune system which kill germs and foreign cells. On their own and keep by themselves in a dish, those are later capable of killing the cancer cells. Yet when they are adjacent to cancer cells in a secondary tumor inside the body, somehow they are prevented or blocked from killing those cancer cells. In other words, cancer cells as they grow and establish a metastasis can somehow... neutralize the cancer-killing abilities of the neighboring lymphocytes. @ Thus, one area of research is promoting the body= s natural defense mechanisms to eliminate these cancer cells. Buckman,
What You Really Need to Know About Cancer 17 (Johns Hopkins Press 1997).
CHAPTER 2: THE PROCESS OF METASTASIS
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2.1 METASTASIS PLAYS A CENTRAL ROLE IN LUNG CANCER TREATMENT
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.
2.2 HOW CANCER CELLS SEPARATE
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.
2.3 HOW TUMOR PENETRATE OTHER ORGANS AND DRUGS AND DRUGS TO INHIBIT THAT PROCESS
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:
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... 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 Prospects, Invest New Drugs 1997;15(3):175-85.2.31 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.
2.4 ANGIONGENESIS
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:
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 21st 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.
2.5 WHERE DOES METASTASIS OCCUR
2.51 Location and Proximity
Metastasis is partly explained by geographical proximity:
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
Eighty years ago, Paget proposed the A seed and soil hypothesis.@ That is, a seed (the carcinoma) will only give rise to a secondary tumor in organs that sustain its growth (the soil). That is, cancers can only successfully locate in certain organs; for others, inherent characteristics of the organ prevents or inhibits metastasis. Additionally, organs vary in their ability to resist penetration by cancer cells, A The basement membrane of different organs vary in composition and the hetrogeneity in binding of tumor cells to components of the extracellular matrix may well be another mediator in the organ preference of metastasis.@ Vile, Cancer Metastasis: From Mechanisms to Therapies 54 (1995)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:
Thus we can theorize that bodily structures with collagen types 1-3 are less susceptible to metastasis that those with types 4 and 5.
2.6 GROWTH FACTORS
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:
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.
2.7 DIFFICULT TREATING METASTATIC CANCER
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
Chemotherapy is the use of drugs to kill cancer cells.
Theoretically, chemotherapy could at least work in various ways. Drugs could interfere with the messages to travel that certain tumor cells receive to replicate or move, it could increase defenses in the basement membrane, or it could induce the body= s own defenses to attack the invading cancer cells. These drugs have been successful in reducing the size and spread of tumors, in mitigating pain, but they are not regarded as an overall cure, at least in most cases where the tumor has metastasized to another organ. Why?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
Anti-angionesis drugs are a specific type of drug to combat the process of angiogenesis. On a technical level, chemotherapy drugs are designed to kill cells while anti-angiognenic drugs try to frustrate the creation of new blood vessels. These drugs are in their infancy with numerous clinical trials attempting to find a drug which effectively stops the angiogenesis processConsider 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.
CHAPTER THREE: THE CANCER PROCESS IN THE LUNG
_________________________________
3.1 ONCOGENES AND HOW CANCER DEVELOPS
IN THE LUNG
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.
The book, Lung Cancer by Desmond Carney describes the process of carcinogenesis, the change of normal cells to cancer cells this way:
(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:
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:
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.
3.3 HOW LUNG CANCER DEVELOPS: THE ROLE OF
SPECIFIC GENES
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:
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
23.4%) had high VEGF expression.@ Konishi, The K-ras gene regulates vascular endothelial growth factor gene expression in Non-small cell Lung Cancers
, Int J Oncol 2000 Mar;16(3):501-11.3.342 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.
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.
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.
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:
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.
3.4 TREATMENT OPTIONS
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:
CHAPTER FOUR: THE STRUCTURE OF THE LUNG
AND LUNG CANCER CLASSIFICATION
________________________________________
4.1 LUNG ANATOMY
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:
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,
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:
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.
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.
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:
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.
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.
References
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.
4.3 SMALL CELL CANCER
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:
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)
4.4 CLASSIFICATION OF NON SMALL CELL LUNG CANCER BY STAGE
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:
4.412 Metastasis to Bone
Carney= s book (65-66) reviews testing for bone metastasis:
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.
4.6 CELL DIFFERENTIATION
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:
Alcase, The Lung Cancer Manual 2.4 (1998)
Pathologists and physicians classify tumors according to their state of differentiation:
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.
4.7 TREATMENT OVERVIEW
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.
4.8 DIAGNOSTIC TOOLS
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.
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.
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:
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:
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:
Virtual Hospital, Lung Ttumors: A Multidisciplinary Database, Bronchoscopy, www.vh.org.Providers/Textbooks/LungTumors/Diagnosis/Bronchoscopy/bronchosopy.htm.
The website Healthgate.com discusses what a patient
will experience during a bronchoscopy4.842 Reliability of the Bronchoscopy
Reliability seems to depend upon the location of the tumor.
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.
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.
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.
4.9 SYMPTOMS OF LUNG CANCER
There are five basic symptoms of lung cancer: cough, chest pain, fatigue, hemoptysis (or coughing up blood), dyspnea, difficulty breathing. Devita notes, A Symptoms of centrally located tumors include cough, wheezing, stridor, deep chest pain, hemoptysis, and dyspnea,@ Devita, Principles and Practice of Oncology (3rd Ed. 1989 note that later editions are available).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.
DEFINITIONSCancer 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.
CHAPTER FIVE: CHEMOTHERAPY
_________________________________5.0 WHAT IS CHEMOTHERAPY
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.
5.1 THE FDA APPROVAL PROCESS
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:
Note, that the approval denotes the type of cancer covered, the status of the patient, and the circumstances of use.
5.2 HOW DOES CHEMOTHERAPY WORK
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.
5.3 CHEMOTHERAPY TERMINOLOGY
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.
5.4 CLASSIFYING CHEMOTHERAPY
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.
5.5 PARTICULAR DRUGS
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:
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:
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
Any form of chemotherapy drug should be carefully monitored by the oncologist for potential side effects. According to one source speaking about the use of Tamoxifen for breast cancer, A adverse reactions to Tamoxifen citrate are relatively mild and
rarely severe enough to require discontinuation of treatment.@ (2)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.
5.6 THE ERA OF MULTI-MODAL OR COMBINATION CHEMOTHERAPY
From a search for the magic bullet or cure, has come a recognition that success is most likely to come from a combination of drugs, each of which has an incremental impact on cancer. While combining four drugs with 20% response rate will unfortunately not lead to an 80% response, it will yield success beyond that of any one drug. One article explains the considerations in multi-modal chemotherapy:One of the presenters at the 1998 Cuneo Lung Cancer conference
summarized the status of chemotherapy for late stage lung cancer patients:
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.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,
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.
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.
5.8 HOW DRUGS ARE SELECTED
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.
FOOTNOTES
1. Bruning, Coping with Chemotherapy (Ballantine Books 1993)
2. Devita, et. al. Principles and Practice of Oncology (1999)
CHAPTER FIVEA: CHEMOTHERAPY SIDE EFFECTS
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5.0A MEDICAL REASONS FOR SIDE EFFECTS
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:
5.1AIN ADDITION TO LENGTHENING LIFE, CHEMOTHERAPY MAY IMPROVE QUALITY OF LIFE BY REDUCING THE SYMPTOMS OF THE DISEASE.
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:
5.31A Ways to Reduce Infection
Some general precautions against infection:
5.4A CHEMOTHERAPY AND YOUR EMOTIONS
Any observer must express tremendous admiration for the typical patient. Chemotherapy can bring major changes to a person's life. It can affect overall health, threaten a sense of well-being, disrupt day-to-day schedules, and put a strain on personal relationships. No wonder, then, that many people feel tearful, anxious, angry, or depressed at some point during their chemotherapy. These emotions are perfectly normal and understandable, but they also can be disturbing. Fortunately, there are ways to cope with these emotional "side effects," just as there are ways to cope with the physical side effects of chemotherapy. (Some time after this was written, my wife contracted a form of cancer, not of the lung. However, I realized that is far easier to talk about calmness and relaxation as an
outlooker, than as a patient or family member).5.5 SOURCES OF SUPPORT
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.)
On-line Support
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.
5.6 RELIEVING STRESS
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.@
5.7A LOSS OF WEIGHT, ANOREXIA AND CACHEXIA
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.
CHAPTER SIX: RADIATION
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6.1 WHAT IS RADIATION THERAPY
Here is an explanation of radiation:
6.2 BENEFITS OF RADIATION
6.21 Radiation and Small Cell Cancer
6.3 TYPES OF RADIATION
The primary type of radiation used for lung cancer is external beam radiation which directs radiation from a machine to the area of the tumor. Another type of radiation used with other cancers is brachytherapy, used more frequently with other types of tumors, in which a radioactive source is placed inside the body in the area of the tumor.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:
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
6.4 HOW RADIATION IS PERFORMED
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).
6.5 SIDE EFFECTS
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.
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.
6.6 RADIATION FOLLOWING SURGERY
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.
CHAPTER SEVEN: SURGERY AND DIAGNOSTIC PROCEDURES
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7.1 SURGICAL DIAGNOSTIC PROCEDURES
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.
7.2 TYPES OF SURGERY
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:
Http://health.yahoo.com
7.3 VIDEO-ASSISTED THROASCOPIC SURGERY
Benefits
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.
Potential Problems
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.
| RELEVANT FACTORS |
IDEAL PROFILE |
PROBLEM PROFILE |
|
DR.= S EXPERTISE |
Extensive experience, over 100 surgeries of this exact type performed. |
Limited experience (note that this will not be quickly revealed) |
|
HOSPITAL |
Excellent hospital with years of experience performing this particular type |
New to hospital, nurses and others learning how it works |
|
GENERAL HEALTH |
Excellent health other than the cancer |
Existing health problems such as COPD chronic obstructive pulmonary disorder or heart problems, Present additional risks |
|
STATUS OF THE TUMOR |
Small stage 1 tumor |
Stage 1b, 2, or 3, more complicated surgery. |
7.4 HOSPITAL STAYS
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.
CHAPTER EIGHT: NON-SMALL CELL LUNG CANCER-
STAGES 1 AND 2
_________________________________
8.0 OVERVIEW
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
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]
A recent article discusses photodynamic therapy and its use with Stage 0 patients:
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.
References:
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.
8.3 STAGE I NON-SMALL CELL LUNG CANCER
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
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.
8.3 STAGE II NON-SMALL CELL LUNG CANCER
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.
9.4 CHEMOTHERAPY ADDED TO RADIATION FOR STAGE 2 PATIENTS, A CONTINUING AREA OF CONTROVERSY
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.
| Median Survival Time |
39 |
38 months |
|
Recurrance Rate |
53 |
56% |
|
Recurrence Time |
30.4 |
26.1 months |
A presentation at the 2000 World Conference on Lung Cancer summarizes the results: A This large, well-conducted, multicenter study suggests no clinical advantage at all for adding chemotherapy to radiation therapy in the management of resectable lung cancer. While newer chemotherapy agents are available, it is not clear that these drugs would change the fundamental outcome compared with the widely used platinum-based regimen used in this study. It is fair to say that the use of chemotherapy in the adjuvant setting of stage 2 or 3A NSCLC remains investigational; however, to date, these data are not encouraging.@ Burstein, Adjuvant Chemotherapy for Lung Cancer: Still No Benefit
, World Conference on Lung Cancer (2000), www.medscape.com, referencing, Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311:899-909.Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med. 2000;343:1217-1222.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.
CHAPTER 9: NON-SMALL CELL LUNG CANCER-
STAGES 3 AND 4
___________________________________________________
9.1 STAGE 3 IS DIVIDED INTO 3A AND 3B
One website explains how stage 3 non-small cancer came to be subdivided into two categories: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.
9.2. CHEMOTHERAPY, RADIATION AND SURGERY ARE THE STANDARD TREATMENT WITH THE BEST MIX OF THE THREE STILL UNDER INVESTIGATION
A pharmaceutical site provides a good overview of Stage 3 A treatment:
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:
A recent article discusses the purposes of neoadjuvant chemotherapy:
Rosell,
Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial Lung Cancer, Vol. 26 (1) (1999) pp. 7 - 149.11 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
cell lung cancer. We can note the following
: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.
9.32 Stage 3 B Patients Managed Best by Chemotherapy and Radiation
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.@
9.4 STAGE IV NON-SMALL CELL LUNG CANCER
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.@
9.8 SECOND-LINE CHEMOTHERAPY AND OTHER OPTIONS FOR STAGE FOUR PATIENTS
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.
| Clinical Trial Stage |
We have clinical trials stages 1, 2, and 3, and generally the higher the number, the greater chance of success. |
|
Location |
Is the treatment located near you. Obviously going to a distant hospital can create stress for the patient and family. |
|
Reported Success and Objectivity of the Reporter |
Is there published literature indicating some success. If there are reports of initial success in clinical trials, are these evaluations from impartial third parties. |
|
Reputation of the Hospital |
Is the trial done by an excellent hospital or cancer center unlikely to stake its reputation on a questionable form of treatment. |
|
Your Oncologist= s Opinion |
Based upon the evaluation of your condition, does your oncologist recommend participation in this trial or protocol. |
|
Eligibility |
Some clinical trials are limited to patients with no prior chemotherapy or those without certain medical problems. (Remember the clinical trial authors generally want to create conditions for success). |
|
Plausibility |
Ultimately you have to make a decision of whether this particular experimental treatment will be successful. |
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.
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:
CHAPTER TEN: SMALL CELL LUNG CANCER
_________________
10.0 AUTHOR= S OVERVIEW AND SOURCES
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.@
10.1 SMALL CELL STAGING
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.
10.2 CHEMOTHERAPY AS THE PRIMARY FORM OF TREATMENT IN THE U.S.
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:
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).
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)
Electron microscopy, which can detect neuroendocrine granules, may help to differentiate between small cell and non-small cell cancers. Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is small cell lung cancer, which has a poor prognosis. At the other extreme are bronchial carcinoid, with an excellent prognosis after surgical excision. Between these extremes is an unusual entity called well-differentiated neuroendocrine carcinoma of the lung.[4] It has been referred to as malignant carcinoid, metastasizing bronchial adenoma, pleomorphic carcinoid, non-benign carcinoid tumor, and atypical carcinoid. Like small cell lung cancer, it occurs primarily in cigarette smokers, but it metastasizes less frequently. The 5-year survival rate is greater than 50% in some series, and surgical cure appears possible in most stage I patients. Careful diagnosis is important, however, since the differential pathologic diagnosis from small cell lung cancer may be difficult.
10.32 NCI StagingA 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]
10.4 LIMITED STAGE SMALL CELL LUNG CANCER
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
As with non-small cell, definiing combinations of drugs, maximum doses, and other variables, is a continuing process with sometimes conflicting results. By the time this is printed, there may be clinical trials which provide new information. At the end of 2000, at a conference, on research wrote,
A Although clinical trials have failed to show superiority of 1 chemotherapeutic regimen over another, the original combination regimens of cyclophosphamide/doxorubicin-based chemotherapy has been replaced by combination cisplatin/etoposide-based regimens.@ Reddy, Small Cell Lung Cancer: Improving Outcomes, Presentation, American Society for Therapeutic Radiology and Oncology 42nd Annual Meeting, 2000, excerpted on www.medscape.com.10.54 Chemotherapy and Radiation
Reddy also suggests that combining chemotherapy with radiation improves results:
Reddy, id at 1.
6.7 EXTENSIVE STAGE SMALL CELL LUNG CANCERNCI 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:
Areas of active clinical evaluation in extensive stage small cell lung cancer include evaluation of new drug regimens, dose intensity, alternative drug schedules, and high-dose chemotherapy. A meta-analysis of long-term outcomes in extensive stage disease did not show consistent evidence for improved response rates or survival for more intense chemotherapy regimens.[41][Level of evidence: 1iiA]
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
10.9 PROPHYLACTIC CRANIAL RADIATION
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)
CHAPTER ELEVEN: CLINICAL TRIALS
_________________________________11.1 WHAT IS A CLINICAL TRIAL
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.
11.2 DIFFERENT STAGES OF A CLINICAL TRIALThere 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.
11.3 STAGE ONE TESTS
Stage one
is the first step to see if a particular drug or other form of therapy works, and to define a maximum allowable dosage assuming it does. For example, if interleukin has been successful with some forms of cancer, a phase one trial could be used to see if it works by reducing the size of lung tumors. Individuals entering the study would be prescribed interleukin, measurements would be made, and the study authors would attempt to ascertain whether the drug positively impacts patients.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:
Phase I Study of Irinotecan and Gemcitabine in Patients With Unresectable or Metastatic Solid Tumors
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.
Protocol Entry Criteria
--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.
11.3 STAGE 2 TESTS
Stage two clinical trials test treatments shown to have promise in stage 1. With hopefully a decent sample size, we now administer the maximum dose and see how the drug performs. In particular with lung cancer, we will assess partial response rate, usually defined as reduction of tumor size by one half, complete response, elimination of the tumor on x-ray or Ct Scan, and survival rate. For example, let us assume that for a drug to be used to treat non-small cell cancer, it should show at least a 20% response rate, that is, at least 20% of the patients= tumors show at least a partial response, without significant side effects, at least as compared with other forms of chemotherapy .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:
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.
11.4 STAGE THREE
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
11.5 SOURCES OF INFORMATION ABOUT PENDING CLINICAL TRIALS
An excellent book is Finn, Cancer Clinical Trials (O= Reilly 1999). To learn about pending clinical trials, go on the Internet to the National Cancer Institute (NCI) site: http://CancerTrials.nci.nih.gov/. You may also call the National Cancer Institute's Cancer Information Service and ask for the booklet What Are Clinical Trials All About, or view 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).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.
11.6 CLINICAL TRIAL TERMINOLOGYProtocol
is the written outline of a clinical trial. The patients receives an informed consent document which will provide an abbreviated description, but you can request and obtain the protocol itself. Standard treatment refers to the therapy that is accepted by the medical community and has FDA approval. For example, the forms of treatment set forth in chapters four and five are generally the standard treatments. Placebo is a harmless substance given to members of the control group when the study is attempting to evaluate the benefit of adding a new drug to current treatment.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.
11.8 CONSIDERATIONS IN ENTERING CLINICAL TRIALS
Occasionally, you will see clinical trials for patients for whom conventual treatment works. There is one clinical trial attempting to assess the efficacy of sampling some lymph nodes versus all lymph nodes in surgical resection. Participation in such clinical trials seems to make little sense from the patient= s perspective. Instead, a clinical trial makes sense when available treatment appears may not to be sufficient. Here are some of the advantages and disadvantages of clinical trials:ADVANTAGES
DISADVANTAGES
significant results,
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.
CHAPTER 12: ANTI-ANGIOGENESIS DRUGS
_________________________________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.
12.1 THE BEST SOLUTION TO METASTASIS: EARLY DETECTION
Since medical science has been largely ineffective in treating metastatic cancer, the best solution is early detection. Surgically removing the tumor at an early stage usually eliminates the need to address the consequences of a tumor that has spread. Sadly, despite recognizing the difficulties in treating metastatic disease, neither the National Cancer Institute nor the American Cancer Society recommend programs for early detection and diagnosis of lung cancer.12.2 ANGIOGENESIS
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:
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:
A
One promising avenue of cancer research is the study of a group ofcompounds 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.
12.3 WHERE IS METASTASIS LIKELY TO OCCUR
12.31 Proximity to Nearby Organs and Blood Vessels
Metastasis is partly explained by geographical proximity:
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....
12.4 METASTASIS AND THE IMMUNE RESPONSE
12.41 Highly Metastatic Cancers and the Immune Response
Tumors vary in their ability to circumvent individual organ= s immune defenses. Vile states:
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.
12.5 ANTI-ANGIOGENESIS DRUGS
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.
Background
In normal tissue, new blood vessels are formed during tissue growth
and repair, and the development of the fetus during pregnancy. In
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
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
-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
poorer clinical outcomes. Also, the shedding of cells from the primary
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
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
Standard Chemotherapy Versus Angiogenesis Inhibitors
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.
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
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.
|
ANTI-ANGIONGENESIS RESEARCH- Drugs that prevent new blood vessels from invading surrounding tissue: DRUG COMPANY NAME PHASE MECHANISM OF ACTION
|
|||
| Marimastat |
British Biotech Annapolis, Md. |
Phase III |
Synthetic inhibitor of matrixmetalloproteinases (MMPs) |
|
Bay 12-9566 |
Bayer West Haven, Conn. |
Phase III |
Synthetic MMP inhibitor |
|
AG3340 |
Agouron LaJolla, Calif. |
Phase III |
Synthetic MMP inhibitor |
|
CGS27023A |
Novartis East Hanover, N.J. |
Phase I |
Synthetic MMP inhibitor |
|
COL-3 |
Collagenex Pharmaceuticals Newtown, Pa. |
Phase I |
Antibiotic derivative that inhibits MMPs |
|
Vitaxin |
Ixsys, Inc. LaJolla, Calif. |
Phase I |
Antibody to integrin, present on endothelial cell surface |
|
Natural inhibitors of angiogenesis: |
|||
|
Platelet factor-4 |
Repligen Cambridge, Mass. |
Phase II |
Inhibits endothelial cell growth |
|
Interleukin-12 |
Genetics Institute Cambridge, Mass. |
Phase I/II |
Inhibits endothelial cell growth |
|
Drugs that block factors that stimulate the formation of blood vessels: |
|||
|
RhuMabVEGF |
Genentech South San Francisco, Calif. |
Phase II/III |
Monoclonal antibody to vascular endothelial growth factor (VEGF) |
|
SU5416 |
Sugen, Inc. Redwood City, Calif. |
Phase I |
Molecule that blocks VEGF receptor signaling |
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:
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)
CHAPTER THIRTEEN: GENE THERAPIES
_______________________________________________13.0 GENE THERAPY REMAINS EXPERIMENTAL FOR LUNG CANCER
Surgery, radiation, and chemotherapy are the primary forms of treatment for lung cancer. While surgery has been successful with stage 1 tumors, chemotherapy has had limited success with stage 4 metastatic tumors. Therefore, research continues into finding new methods of tumor control and eradication. Gene therapy is a broad category of treatment which attempts to improve immune responses, correct gene abnormalities, and otherwise address the gene malfunctions which are cancer. The American Cancer Society Book, Informed Decisions says this: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).
We can say broadly that chemotherapy attempts to eliminate cancer cells, while gene therapy attempts to correct gene malfunction, though there is a significant overlap or question of definition. While gene or biological therapy has shown some success in treating other types of cancer, its use has been limited with lung.
13.2 OBSTACLES IN GENE THERAPY
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.
13.3 TYPES OF DRUGS INVOLVED WITH GENE THERAPY
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:
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.
Drugs like Interferon may be effective with certain types or forms of cancer, but not others. For example, the FDA has found that interferon has a proven benefit in treating a certain form of leukemia, and with other forms of cancer. It is not routinely used for lung cancer, though there may be clinical trials (see chapter 18 for discussion of clinical trials) testing in use with lung cancer. Generally, drugs are approved for specific types of cancer, thus interferon may be routinely used for leukemia, but be classified as experimental for lung cancer, with use for lung cancer limited to clinical trials where there is close supervision and consent forms noting various risks.
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
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)
13.4 P-53 GENE THERAPY
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:
13.42 Wild and Mutant type P-53 Genes
P-53 is a protein of 53 kilodaltons. It 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:
13.44 With What Cancers is P-53 Damage Associated
P-53 damage occurs in approximately 50% of the following cancers: breast colon, stomach, bladder, and non-small cell lung cancer. A In non-small cell lung cancer (NSCLC), most series report that 50% to 60% of tumors have identifiable mutations.@ Szak, P53 in Pass, Lung Cancer: Principles and Practice (2000).
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
in the p53 -positive group was significantly lower than that in the P53 negative group.@ Gemba, id. However, P53 does not seem to be correlated with other factors such as stage of disease.
In another study, bronchial specimens from lung cancer patients @ were used for detection of p53 gene mutation.... 15 of 25 (60%) specimens were found to be positive. In 10 small cell lung cancer specimens, 7 were positive; in 15 non-small lung cancer specimens, 8 were positive. Clinical analysis showed no correlation between positivity and the patients' clinical data such as age, sex, smoking habit, stage of tumor at the time of diagnosis.@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:
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
A Presence of p53 antibodies in sera before of during/after radiation therapy can predict increased survival in patients with non-small cell lung cancer.@
P53 auto-antibodies in non-small cell lung cancer patients can predict increased life expectancy after Radiotherapy,@ Anticancer Res 1998 May-Jun;18(3B):1999-2002.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:
Getting enough P-53 to the tumor to have significant results is difficult:
CHAPTER 14: LONG AND SHORT-TERM SURVIVAL
_________________________________14.0 SURVIVAL AND THE SIGNIFICANCE OF METASTASIS
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:
| TYPE OF CANCER |
ALL STAGES |
LOCAL |
REGIONAL |
DISTANT |
|
Breast |
84% |
97% |
76% |
21% |
|
Cervix |
69 |
91 |
49 |
9 |
|
Lung |
14 |
49 |
18 |
2 |
|
Pancreas |
4 |
15 |
5 |
2 |
|
Prostrate |
89 |
100 |
94 |
31 |
|
|
|
|
|
|
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.
14.1 WHAT TYPES OF SURVIVAL ASSESSMENTS PHYSICIANS CUSTOMARILY MAKE
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.
14.3 STAGE
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:
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:
|
Stage |
TNM (Tumor Node Metastasis Staging) |
5 Year Survival |
|
1a |
T1N0Mo |
67% |
|
1b |
T2N0Mo |
57% |
|
2a |
T1N1Mo |
55% |
|
2B |
T2N1Mo;, T3NoMo |
39% |
|
3a |
T3N1Mo;T1-3N2Mo |
23% |
|
3b |
any T,N3, MO; T4,any N, Mo |
<5%, |
|
4 (Surgery not performed) |
any T, any N, M1, |
<5%, |
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.
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:
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.
14.4 OTHER PROGNOSTIC FACTORS
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.
CHAPTER FIFTEEN: MESOTHELIOMA
_________________________________15.1 OVERVIEW
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:
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.
15.21 StagingMesothelioma uses a different staging system called the Butchert system using stages one through four to designate the extent of spread of mesothelioma: