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 forma