LUNG CANCER AND MESOTHELIOMA

NOTE, Spacing and format will vary from the published version.   Please order the book from xlibris.com or amazon.com at a cost of approximately $21.25. (pricing may vary slightly).

Copyright 2005 Howard A. Gutman (Revised Edition)

All rights reserved. However, it is anticipated that permission to reprint portions of this book for education or non-profit purposes will be provided without charge. This book is intended to provide general information and is not intended to provide individual medical advice. For advice regarding your medical condition, please consult with your physician. Comments or suggestions about the book are welcome and may be sent to howian@aol.com. For information about new treatments or developments, consult our newsletter at www.lungcancerbookandnewsletter.com

This book is dedicated to my father-in-law Frank Paden who had lung cancer and demonstrates that a man= s smoking history bears no relationship to his contribution to society, importance to his family, and value as a person.

I begin by discussing what cancer is and how the orderly process of cell reproduction goes awry. The first part of the book provides the groundwork for the remainder, with a discussion of cancer terminology, cell cycles, genes and lung cancer anatomy. These topics will help you understand the medicine behind your treatments. Each chapter is designed to be independent, and your first step might be to review the material on your type of cancer, such as stage 4 non-small cell lung cancer.

The middle chapters discuss different types of treatment, surgery, radiation, chemotherapy, gene therapy, their benefits and risks, and when they are utilized. Adding some background about cell structure and treatments, I then review non-small cell lung cancer devoting a chapter to each stage.

A cautionary note. I am not a doctor and in any event you should never base your treatment on information in a book. Lung cancer research is rapidly changing, protocols evolve, and physicians design treatments based upon your age, condition, and medical history. The book helps to provide the background to help you discuss treatments with your oncologist. Instead of asking basic questions about the disease, I hope you can focus your discussions on the specifics of your treatment.

The third part of the book discusses public policy, legal, and insurance questions associated with lung cancer. Should there be screening for smokers, when are doctors responsible if tumors are not timely diagnosed, what types of treatments are covered by insurance, and how should we improve treatment. While smoking continues to be the primary risk factor, diet, and occupational carcinogens like asbestos are discussed.

Keep a medical dictionary nearby and feel free to reread a chapter and keep other medical references nearby. I spent well over 2,500 hours writing this book, don= t expect to completely understand some difficult topics in far less time.

Cautionary Note

Again this book is intended to be a general reference, not advice regarding specific treatment. No warranty is made as to the accuracy, completeness, or applicability of any of the material herein to a specific patient. The author is not a physician and all medical advice should be obtained from your physician

TABLE OF CONTENTS

CHAPTER 2: CANCER TERMINOLOGY 36 2.1 TREATMENT TERMINOLOGY 36

AND TREATMENT 44

REFERENCES 64

LUNG CANCER 78

LUNG CANCER TREATMENT 82

DRUGS TO INHIBIT THAT PROCESS 83

WHO WOULD BENEFIT FROM CHEMOTHERAPY 221

REFERENCES 375

TO COMPENSATION 376

REFERENCES 378

LUNG CANCER 391

LIST OF COMPREHENSIVE CANCER CARE CENTERS 422

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

1.01 Approach

As I worked on this book, a member of my family contracted cancer, and I realized firsthand the stress that diagnosis entails. Nonetheless, I have tried to discuss lung cancer in an 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.

1.02 Limits

Some caveats. This book is not designed to provide medical advice regarding any individual= s condition, and treatment alternatives may depend upon a number of individual factors. Cancer research is an evolving area, and some areas may have changed from the date of publication. There may be new studies and older ones may be reevaluated. Again, my goal is not to provide medical advice and you should make treatment determinations with the advice and guidance of your physician. My goal is to provide some basic information about lung cancer to make those consultations as meaningful and informative as possible.

1.11 Abnormal Growth

Cancer is a group of related diseases characterized by uncontrolled multiplication and disorganized growth of affected cells. Cancer is a significant disruption of the normal, orderly and regulated cycle of cell replication and division in the body. Cancers share three basic characteristics: unregulated growth, lack of cell differentiation, and the capacity to metastasize to neighboring tissues:

1.12 Cell Division and Multiplication as 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. in other areas, cells divide to replace dead or damaged cells, such as in the skin or the intestinal tract. While one characteristic of cancer cells is their propensity to divide and multiply, normal cells do that too:

1.13 Why Cell Division is Necessary

Cell division occurs for various reasons in the normal person. First, many parts of the body are subjected to daily wear and tear that kills or damages cells, and cell division is the body= s method of replacing these dead or damaged cells. Secondly cells may divide in order to perform certain tasks. When a germ enters our body, cells in the immune system divide and increase in number to kill the germ. Thirdly, cell division helps the body grow. Cell division is required for a child to increase in physical size and grow into adulthood.

Whether to replace old cells, perform specific functions, or help the body grow, cell division is usually a necessary and orderly process. Cell division is tightly regulated; with the cells signaled to divide only to perform specified functions. Normal tissue exists in a careful regulated balance of cellular division and cellular death. In contrast, cancerous tissue grows out of balance, resulting in an excess of cellular division.

Unregulated growth means a tumor grows without regard to the needs of the tissue or the normal controls for that cell or gene:

Cancer is generally not unique behavior in 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, are each characteristics of normal cells. Even metastasis, movement of cells to other organs may occur with healing of wounds, the development of a fetus, or attacking bacteria.

1.14 Unregulated Growth

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

Physicians classify tumors primarily upon their capacity to grow and move to other organs (metastasis). There are two main categories of lung cancer: small cell (sclc) and non-small cell (nsclc). Small cell tumors grow rapidly but are susceptible to chemotherapy while non-small cell tumors grow more slowly. I will later explain the categorization scheme for lung cancer.

1.16 Differentiation

Not only do cells divide to replace damaged or dead cells, they also develop to assume their final form and function in the body, a process called differentiation. Normal cells are differentiated, that is constructed or organized for a specific purpose. When a cell changes from a normal to cancerous one, the cell often loses some or all of its ability to form normally functioning tissue structures. 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.

1.161 Well-Differentiated and Poorly Differentiated Cells

Well-differentiated means relatively limited changes are seen in the cell. A well-differentiated cancer cell may assume an appearance that is somewhat similar to its original tissue, and even display some normal functions. Poorly differentiated means the original structure and function is almost entirely absent. The extent of differentiation of the cancer cell is somewhat correlated with the aggressiveness of the tumor; poorly differentiated tumors tend to be far more aggressive than well-differentiated tumors. While the extent of differentiation is one factor in evaluating the status of the patient, it 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, the movement of cancer cells to normal organs and structures seems strange. However, the processes associated with metastasis are not unique to cancer cells and the ability of cells to travel to different areas of the body is a normal and necessary process to maintain health. For example, circulating white blood cells must be able to exit the blood through the capillaries and enter infected tissues in response to the injury. During early development of an embryo, cells that become the embryo= s placenta must be able to invade the mother= s womb to allow the developing embryo to attach and grow. Healing of a cut requires the movement of different types of cells to cover the wound and re-form skin and blood vessels. Each of these processes is tightly controlled such that the invasion is limited in time and space.

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. Comparisons to the behavior of normal cells can be made:

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 metastasised 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.

1.2 DIFFERENCES AMONG CANCERS

1.21 Cancer as a Group of Diseases

Cancers share the three traits of unregulated growth, loss of differentiation, and propensity to metastasize, though the extent of each trait 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. Most scientists believe that cancer is a group of related diseases with common characteristics, not a single disease. While cancers share certain characteristics there are significant differences among different cancers. Some skin cancers may be relatively harmless in their early stages, while others may be more serious especially in advanced stages.

1.22 Causes of Cancer

The causes of cancers vary. Diet plays a critical role in the development of colon cancer, but 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 resulting tumors themselves vary. Cancers behave differently depending upon their type and the organ where they originate.

1.23 Differences in Behavior of Different Cancers by Organ

The behavior of cancers depends primarily upon their type and the organ where they originate. Some cancers spread or metastasize very quickly while others are slow-moving. For example, pancreatic cancer is a very serious form of cancer, while some forms of skin cancer are relatively innocuous.

1.24 Treatment is Organ-specific

Treatment is generally by organ; a skin cancer is treated differently than a prostate tumor. Clinical trials which test a particular drug may be limited to tumors in a particular organ, or at least results will be categorized by organ. Lung cancer is a solid tumor, unlike, for example, leukemia. There are some common traits among solid tumors and some of the same drugs are used for various types of solid tumors. Some drugs used for colon and breast cancer are used for lung.

1.25 Differences within the Same Organ

Since there can be different types of cancer in a particular organ, treatment within a particular organ can vary. As we see later, small cell lung cancer is treated differently than non-small cell.

One writer explains:

Cancer is treated differently than non-small cell lung cancer. This book is about lung cancer, or more specifically tumors which originate in the lung. Thus, we may discuss metastasis to other organs, which will still be treated as lung cancer in most respects.

1.4 HOW NORMAL CELLS CHANGE TO CANCER CELLS

1.41 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, (1) 4-5

A proto-oncogene is a normal gene which performs certain growth functions but when altered, can turn into a cancerous oncogene:

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.

1.42 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. Genes and oncogenes can first be identified by 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.

At a basic level, two types of gene mutations 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):

Griffith= s description gives us more insight into the carcinogenic process. It is not one growth gene and one tumor suppressor gene which combine to create cancer. Instead there are multiple growth genes, multiple tumor suppressor genes, and a system of cellular communication which malfunctions, part of which we understand and a part we do not. Targeting the particular offending gene to develop a cure, particularly with lung cancer, has been difficult.

1.44 How Do Cells Know When to Divide?

Cells divide or perform other functions in response to signals or stimuli from other cells. A Cells sense signals from both the outside environment and other cells and, in response, they regulate protein expression and function:

What types of signals does a cell receive:

Communication at the cellular level is called signal transduction. Cancer is really a signal transduction disease, in the sense that signals to replicate and perform other functions go awry, and cells are prompted to improperly replicate:

1.5 GROWTH FACTORS AND RECEPTORS

1.51 A More Sophisticated Model of Cancer Development

The simplest model of cancer is a proto-oncogene creating growth, and a tumor-suppressor gene failing to stop it. Were cancer creation that simple, scientists might be able to isolate either gene and develop a vaccine or treatment. Indeed, scientists have come close to identifying the source of some simple cancers such as particular forms of leukemia and certain childhood tumors.

Unfortunately with lung cancer, the model is more complex, with an interrelationship of many different cells signaling one another; part of which we do not fully understand. A Our current state of knowledge of tumor suppressors shows a picture of complex interactions between multiple suppressor genes with oncogenes to generate the malignant state.@ Devita (12)

As an analogy, consider juvenile crime. We know that lack of education, family instability, educational difficulties, and gang affiliation are all connected with crime. However, we do not fully understand the relationship between each component in terms of causation, which factor is most important, which causes which, and where intervention would be most successful. There are many parts to cancer, particularly lung cancer, which has made the task of inhibiting cell duplication difficult. (In comparison, with a few tumors, we have been able to isolate the cancer-causing gene). Even today with 40 years of research, the most effective treatment for lung cancer is simply removal of the tumor in its early stages, a treatment which has been known for at least the last 50 years.

1.52 Growth Factors and Receptors

Another model of replication is the growth factor and receptor. A growth factor connects with a receptor on a cell to start a process of cell reproduction, something like putting a screw in a nut. Newer forms of cancer gene therapy seek to interfere with this process. The epidermal growth factor connects with its receptor as part of the lung cancer process. The new drug Iressa is an epidermal growth factor receptor inhibitor. That is, it attempts to prevent the epidermal growth factor from coming in contact with its receptor. Interestingly, the drug seems to have success with some patients but not with others. Thus, there appear to be different characteristics of lung cancers and perhaps different pathways among patients with the same disease. A Several signaling pathways@ appear to be affected by the epidermal growth factor. Welch (13)

1.6 HOW GENES ARE DAMAGED AND BECOME ONCOGENES

1.61 Types of DNA Damage

A normal gene can be damaged in a variety of ways. Part of the gene can be lost (deletion), or a gene could be rearranged and ends up in the incorrect location (translocation). A gene may initially be defective or an outside product can cause damage. For some diseases, we can identify the genes which are damaged:

1.62 How Throat Cancer Occurs

Let us look at a model explaining the development of throat cancer:

While one instance of damage to the cell will usually not impair its form or function, the cell can be destabilized such that it becomes more susceptible to future damage. This is termed A genetic instability@ .

For example, the inactivation of certain DNA repair genes, may allow the buildup of genetic mistakes with each succeeding round of cell division. Inactivation of a tumor suppressor, may allow propagation of an occasional DNA copying mistake to the next cell division. Each event builds on itself.

1.64 Apoptosis

The body has a inherent protection against the development of cancer- apoptosis, or programmed cell death. Certain cells detect abnormalities and trigger cell death. This carefully regulated system prevents many cells with abnormalities from developing or dividing.

1.65 Time for Cancer to Develop

Since cancer requires the abnormal development of a growth factor, probably multiple defects in tumor suppressor genes, and the failure of the apoptosis system of cell death, we can surmise that cancer would take years if not decades to develop. Cancer increases with age, and most tumors are associated with a series of changes that occur over a period of 10 to 15 years or even longer.

1.66 Initiation Promotion Hypothesis

Many scientists see cancer development in different stages:

Greenwald suggests we stop seeing cancer as a defined event, for example the diagnosis of cancer. Instead, we would look to identify genetic damage and attempt to cure or correct it before it develops into a tumor. Some scientists call this chemoprevention using biomarkers to tell us which genes or cells have been damaged. A Acceptable biomarkers for cancer must be reliable (repeatable), highly sensitive and specific, quantitative, readily obtained by non-invasive methods, part of the causal pathway for disease, capable of being modulated by the chemopreventive agent, and have high predictive value for clinical disease.@ Greenwald (13). With the concept of biomarkers, we could identify damage in a smoker before a tumor has developed. Accepting the concept of biomarkers has been much easier than reaching agreement on a specific biomarker. Researchers in clinical trials are now taking various measurements to determine what changes confirm or presage the development and spread of disease.

1.7 HOW CANCER SPREADS

There are two basic ways that cancers 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 infiltrated a nearby lymph node.

1.71 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, indicating a greater spread of the tumor. A surgeon will generally obtain samples or biopsies from lymph nodes to ascertain the status of lymph nodes, and treatment will depend upon that assessment.

1.72 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.

Following the format of many scientific journals, each reference is given a number. Most of the articles cited can be located in a medical library. Almost all the articles have abstracts, a short summary identifying the study= s findings and conclusions, and these abstracts can be reviewed online on Medline.

Medline is the worldwide medical library compiled by the National Library of Science, a part of the National Institute of Health. A National Library of Medicine's search service provides access to over 10 million citations in Medline, PreMedline, and other related databases. For most journals, there is a charge to obtain the entire text, usually 10-15$ per article.

2.1 TREATMENT TERMINOLOGY

2.11 Primary Site

The organ where the cancer originates is called the primary site. 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 and treated as a lung cancer. A lung tumor which metastasized to the bone would be called a lung cancer with metastasis, not bone cancer.

Clinical trials measure a drug= s impact in a number of ways to obtain information about the disease and its interaction with the drug. When you review the results of a clinical trial, you can usually check complete response, partial responses, and disease stabilization or time of disease progression.

2.21 Complete Response

Complete response is the elimination of any evidence of cancer, as seen from a particular test, such as an X-ray or CT Scan. A complete response is unfortunately not always a cure. There may be microscopic cancerous cells which cannot be detected by the Ct Scan or x-ray and cancer can reappear. Nonetheless the percentage of complete responses is an important indicator of the effectiveness of a treatment.

2.22 Partial Response

Partial response, as used by most authorities means a 50% reduction in the size of the tumor. Scientists differ as to whether partial or complete responses are more important. Drug A may generate a larger number of partial responses but fewer complete ones than drug B. Exactly what should be the appropriate measurement continues to be an area for debate.

2.23 Disease Stabilization

Besides responses, scientists are increasingly examining the concept of disease stabilization. That is, a drug is successful in preventing spread of a tumor even though it does not effect a reduction in tumor size. Some of the newer methods of gene therapy seem to be most successful at disease stabilization.

The opposite of disease stabilization is disease progression, or time to progression which can also be measured. See 11 (arguing that time to disease progression is the most important indicator of a drug= s effectiveness).

2.24 Cellular Measurements

While disease response is the most obvious measurement of a drug= s effectiveness, there are others. Scientists may wish to measure levels of different proteins and see if a drug is having an effect in that way. For example, if we have a drug which targets the epidermal growth factor associated with lung cancer, we could test levels before and after the drug was used. Sometimes, levels may be reduced, but that does not translate into improved survival. In that event, we try to determine whether the protein tested was really that important, whether reduction in protein levels are only important at certain stages of disease, or whether the reduction did not reach the level to impact survival. The difficulty with lung cancer is that there are many proteins and receptors involved with the disease and it is difficult to assess the relative importance of each. Sometimes we call these measurements endpoints.

2.25 Side Effects

Studies will also identify and classify side effects. Chemotherapy attacks dividing cells, so normal as well as cancerous cells can be affected. Scientists may refer to the number or extent of side effects as A tolerable@ . While the side effects could be significant, they were not life-threatening nor substantially interfered with body functioning, side effects are generally measured objectively in clinical trials.

Quality of life can be viewed subjectively, comprising various perceptions of pain and discomfort, or objectively. Even though treatments may cause side effects, their impact can be less than the disease itself, with many studies reporting higher quality of life with treatment. Sometimes the purpose of treatment is to improve quality of life. Where treatment is given primarily to relieve pain or improve quality of life, it is called palliative treatment.

2.26 Maximum Tolerated Dose

How do you provide the maximum strength dose of a drug to attack a tumor yet prevent intolerable side effects? Scientists will determine a maximum tolerated dose through clinical trials. That is, what is the maximum amount that can be administered without intolerable side effects.

A similar concept is the maximum effective dose. Most chemotherapy drugs increase in effectiveness with the amount of the dose. In essence, there is no maximum effective dose, the drug= s effectiveness increases with dose with only side effects limiting how much can be prescribed. Other drugs may have limits and reach a plateau of effectiveness.

This plateau can be helpful in constructing a cure. Imagine that drug A shows some success in stabilizing disease at a maximum effective dose of 750 milligrams per day with minor side effects. We could combine the drug with another drug and increase our cancer-fighting power without creating substantial side effects.

In clinical trials, the researcher attempts to determine the effectiveness of new drugs and determine their maximum effective doses. The oncologist does something similar, measuring patient response and side effects to provide maximum fighting power without unacceptable side effects.

2.31 Five Year Survival

Survival is generally measured in years, with five year survival being the most common measurement. For patients with advanced disease, one year survival may be a benchmark, with seriously ill patients sometimes evaluated as to months of post-treatment survival.

2.32 Overall and Disease-Specific Mortality

Scientists keep track of mortality in two ways. First, they determine how many patients were lost from a disease or its consequences. Secondly, they may look at overall mortality, the number of patients who died regardless of cause. At first glance, we might be interested only in disease-specific mortality; after all, the fact that some patients may die of other causes would appear irrelevant.

However, overall mortality can present some tough questions. For example, in a clinical trial, one group receives a new form of chemotherapy, while the other receives the standard treatment. Assume that the group receiving the new treatment has a higher partial response rate, (patients whose tumors are reduced by at least half). However, the treatment group also has a higher overall mortality rate. It may be chance or the new treatment may be impacting other organs in some way. However, the drug would probably not receive FDA approval if its use involved an increased overall mortality.

This illustrates one problem cancer researchers face. The results are not always logical or predictable and may vary based on chance, characteristics of the study group, or unknown factors.

The most common type of cancer is a carcinoma, a cancer that arises in the cells that form the lining of different parts of the body. Cancers in the lung, breast, prostate, and colon are all carcinomas. Cancers that involve tissue or bone are called sarcomas. Cancers involving blood cells are known as lymphomas or leukemias.

2.41 Treatment

The FDA approves drugs by organ, such as a drug for treatment of lung cancer. While most research is organ specific, studies can cross organ lines. New drugs may be tested on different solid tumors such as breast, colon, and lung, and the drugs may ultimately be used for more than one organ. The results will still be categorized by organ.

2.42 Endpoints for Approval

The FDA issues an approval finding that a drug serves a specific need. In the past, that usually meant the drug provided a higher rate of cure than existing drugs. Today, scientists realize that standard can be too demanding or restrictive, and use a variety of endpoints to evaluate a drug. Thus, if drug B provides fewer side effects than existing treatments, it can be approved. Scientists are struggling to determine whether approvals should be granted if tumor size is diminished or stabilized, or other impact shown, when the effect upon survival is unclear.

2.43 Off-Label Prescriptions

The FDA provides an approval for a specific use, for example, second line chemotherapy for stage 4 patients. Many physicians will restrict the use of the drug to that purpose but, on occasion, a doctor will prescribe a drug, off-label, that is for another use. That is permitted, but if untoward results occur, a doctor could face liability, since some would argue the standard of care is set forth in the FDA approval.

2.5 EPIDEMIOLOGY

Epidemiology comes from the root epidemic, and is the study of patterns of disease. An epidemiologist would investigate what groups contract lung cancer, and make conclusions based upon these patterns. For example, epidemiologists noticed that people who smoked and people who worked with asbestos had substantially higher rates of lung cancer.

2.51 Determining What are Significant Findings

What changes are sufficiently significant that we can attribute causation? Some changes are simply due to chance or differences between groups studied. Assume a study where we study the impact of wives telling their husbands to have a good day on overall health. There are 100 people in each group, one group receiving the greeting and one not and assume that in the group getting the greeting 6 people contract heart disease, while in the group without the greeting 5 do. It would be incorrect to say that the greeting caused heart disease even though there is a slightly increased incidence in the study group.

2.52 The 2-1 Guide in Ascribing Causation or Connection

Some scientists use a 2-1 ratio as a guide to attribute causation. If while investigating a new drug, we find that twice as many people using the drug had complete responses, we can say the drug had an impact. In a trial the group receiving the treatment is called the study group while the group receiving standard treatment is called the control group.

2.53 Determining the Impact of a New Drug

What studies are important and should be given weight? Here are some of the considerations researchers use:

2.54 Medline Searches for the Effectiveness of New Drugs.

Assume you read of a new drug and wanted to evaluate its effectiveness. Unfortunately, many news articles are misleading, and may trumpet a new drug though its only effectiveness was shown in a single cell study. With the Internet, many patients and family members are becoming their own researchers.

Using search terms associated with the new drug, you would first go on the Medline database, medscape.com and other portals. You would review cell studies, animal studies, and human clinical trials using the criteria set forth above. Are there human clinical trials showing a substantial impact, mile one? Do cell and animal studies display a significant relationship? You can assemble the published results of studies and, using these criteria, try to make an intelligent determination.

2.6 FORMS OF TREATMENT

The four basic forms of treatment for lung cancer are surgery, chemotherapy, radiation, and gene therapy. Surgery is the ideal treatment with the goal to remove the tumor and surrounding tissue which is or may be cancerous. It is essentially the only treatment that can be completely curative, with survival rates for stage 1 patients in the 65-75% range. Less frequently, surgery is used to remove a significant part, but not all of a tumor.

Radiation is a method of targeting cancer cells in a particular area and using a beam to create a complex process of cell death. In patients with advanced disease, radiation can reduce the tumor and related pain and discomfort, palliative treatment. For advanced cancer patients, radiation is not designed to be a cure. For early stage patients who are ineligible for surgery, radiation is sometimes used with the goal of eradicating smaller tumors.

Chemotherapy is the use of different drugs to fight cancer. The drugs are injected into the blood stream and inhibit the division of cells throughout the body. That is why chemotherapy has side effects, some normal functions are associated with cell division such as hair growth.

Gene therapy is the attempt to identify specific genes which contribute to tumor formation or spread and use specific drugs to target them. A monoclonal antibody, is the use of a specific drug targeted to a single (monoclonal) antibody. The goal of therapies like monoclonal antibodies is to target specific proteins involved in the cell-duplication process, short-circuit the protein, and thereby inhibit the cancer process without affecting normal cells. The difficulty is not only developing an antibody which can successfully come in contact with specific proteins, but determining which proteins are most important in the cancer process.

2.71 How Cancer Treatments are Developed

The development of cures or partial cures for cancer involves these steps:

2.72 Do Treatments Arise by Design?

Treatments can be developed deliberately or inadvertently. Scientists may notice the positive effect of a particular cell characteristic or interaction, and go about creating a cure based upon its characteristics.

Treatments may be accidental. In the early 60's, some babies were born with birth defects after their mothers took thalidomide, which inhibited the development of new cells and sources of blood supply, necessary for fetal development. To prevent metastasis, the spread of cancer, it is useful to curtail the creation of new sources of blood supply for the tumor. Thus, scientists are investigating the use of thalidomide for patients with advanced cancer.

The first step is to test a proposed new cure on cells in a laboratory. A Cell culture is complicated by the tendency of isolated cells to "dedifferentiate" in culture, taking on the qualities of unspecialized cells instead of keeping the characteristics that define them as cells from a specific organ such as the liver.@ Johns Hopkins Center (1)

Not only may cells behave differently in a laboratory, the endpoints are different. One cannot test a drug to see if it effects a cure, the scientist must use a surrogate measurement such as levels of cell death or division, and postulate that this will translate into positive treatment results in humans. Thus, results from cell culture studies are only a first step, and given only limited weight.

2.74 Animal Studies

After a treatment has shown promise in cell culture studies, it will face evaluation in animal studies. To the extent possible, the scientist will try to create a similar dose and treatment context. Ethical questions arise as we become increasingly aware of animal suffering. As with cell culture, no drug will be approved based simply upon positive results with animals.

2.75 Human Clinical Trials

A new drug will be tested in three phases of clinical trials on humans. In stage 1, the drug will be tested principally to define its optimum dose. Thus patients could be given a new treatment in three doses with the trial attempting to determine which achieves maximum effectiveness without significant side effects. Placebos are rarely given in cancer clinical trials since the testing is objective, what does a CT Scan show about tumor spread, rather than a person= s perception. In stage 2, using the optimal dose, scientists will begin taking careful measures of partial and complete response, side effects, and other data to ascertain if the drug is showing sufficient promise to merit FDA approval. In stage 3 after the drug has been determined to be effective, it is tested against the conventional treatment used today.

3.11 DNA and Chromosomes

In the nucleus of our cells is a molecule called DNA (deoxyribonucleic acid). Think of DNA as the brain of these cells. This DNA is arranged in 46 sections called chromosomes, with 23 chromosomes from the father and 23 from the mother.

3.12 Genes

These 46 chromosomes contain approximately 100,000 different genes. Genes determine a person= s sex, height, hair color, and virtually every fact about our lives. Genes also manufacture proteins which help us grow and perform other functions. Genes provide signals to other genes to grow, duplicate, die, or signal other genes.

3.121 Two Copies of Most Genes

We have two copies of most genes and a defect in one of the two will generally not cause serious problems. For example, defects in both P-53 tumor suppressor genes are generally associated with cancer. This may be one reason why cancer is a slow process, sometimes dating from 20 years from date of exposure to a carcinogen (cancer-causing agent). At least two mutations are probably needed to alter a single gene, and a number of genes must be altered to create a tumor.

3.13 Chromosome and Gene Location

Think of the chromosome as an X shape. The top part of the X is called p, and the bottom part of the X is called q. Each section of chromosome is also numbered, say from 1-32, going from the centre out, so if you see a gene (or a genetic alteration) as being located at 3p32, that means the top part of chromosome 3 at the very end.

3.14 Types of Chromosome Damage

Cancer involves abnormalities in genes on certain chromosomes. Exposure to toxic substances such as cigarettes can alter our genes and chromosomes. The combination of damage to a number of chromosomes can cause cancer.

Scientists classify the chromosome damage into different types. We have deletions (where some of the chromosome is missing), translocation (where parts of 2 different chromosomes exchange places) and amplifications (where some of the chromosome is amplified). Knowing the specific type of abnormality helps us to identify specifics about a tumor, and to refine our treatment. Here is an illustration of a normal and abnormal adult:

3.15 Where Do Damage Causing Lung Tumors Occur?

In the last 15 years, scientists have done much to identify the type and location of gene damage which causes lung cancer.

3.151 Loss of 3P

A Loss of function at 3p has been identified in 75% of non-small cell lung cancer cases. 3p21 in particular is identified. 3p damage appears to be more closely associated with squamous cell cancer.@ Pass (8) at 509. However, 3p damage occurs in a number of tumors. Pass concludes, A loss of 3p may represent an important generalized tumorrigenic event common to various solid tumors, including NSCLC. Cancers have some common features in terms of development. Scientists have also identified damage at 9p and 17p.@ Pass (8) at 509.

3.16 Application to Screening

In the future, physicians may perform gene testing to identify early damage to genes, warn smokers of specific damage caused by smoking and detect lung cancer when it is most treatable.

3.2 GENES

There is a complex and multi-faceted relationship among genes, with genes signaling and receiving signals, regulating growth, and replicating. Each of these genes is a potential target for cancer research. Clinical trials can help reveal the importance of a particular gene in the cancer process.

3.3 CELL CYCLE

3.31 Why We Need to Understand Cell Cycles

Understanding how and why cells proceed from one stage to another has been a major goal of cell cycle investigation and cancer research overall. If we could stop cancer cells at a specific stage, we could provide a cure or at least a hindrance. Some anti-cancer drugs are directed to specific points in the cell cycle. Understanding cell cycles helps you understand how these drugs work. 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.

3.32 Phases of the Cell Cycle

The cell cycle process is divided into 4 broad phases: G1 or Gap 1, S or Synthesis, G2 or Gap 2, and M or Mitosis, cell division. The cell progresses to division this way: Gap 1 ± G 2 ± S ± M.

3.33 Cell Cycle Regulation, Transition and Checkpoints

Growth and replication are carefully regulated:

If a cell is defective, it may not pass through the cell cycle process. We have checkpoints where defects are monitored and signals sent to stop transition:

A When the cell-cycle control system receives an inhibitory signal such as that generated by an incomplete cell-cycle process, it blocks the cell-cycle at transitions known as checkpoints. There are three major checkpoints. The first is at Start (often called the G1/S checkpoint), where entry into the cell cycle is blocked when cell growth or environmental conditions are inappropriate for continued division. The second major checkpoint is found at the entry into mitosis (G2/M checkpoint), where cell-cycle arrest occurs if DNA replication is incomplete or if the DNA is damaged. The third major checkpoint is the metaphase-to-anaphase transition (mitotic exit or the M/G1 checkpoint), where cell-cycle progression can be arrested if chromosomes are not attached correctly to the mitotic spindle.@ Morgan (16).

The human body has a number of safeguards to prevent replication of defective cells. We have a system of identifying cellular defects, repairing them, and providing for delayed transition. One hallmark of cancer is a defect in cell repair.

3.34 Apoptosis

A If damage is irreparable, the body then provides signals for cell death, called apoptosis.@ Cancer Genes (17). Cancer frequently involves defects in the system of cell death. One way this occurs is that anti-apoptotic genes are produced which stop or inhibit the normal process of apoptosis. Cancer represents several areas of damage or failure:

Cancer is the creation of unnecessary signals to duplicate, and the failure of the body= s cell-cycle checkpoints. It= s like a bank robbery where we not only need a criminal to do damage, but the failure of our guards and alarm system. It takes a number of gene abnormalities or system signaling failure to create a lung tumor. That is why the disease has a long latency, or time between first exposure and disease diagnosis, typically in the 20 year range. Some chemotherapy drugs induce apoptosis.

3.35 The Role of P-53

P-53 is a gene which monitors malfunctions at various checkpoints and performs critical functions in cell repair and apoptosis. A defect in P-53 is seen in many types of cancers, with about 50-60% of lung cancer patients having P-53 malfunctions.

Restoring normal P-53 functions is a goal of cancer research.

3.36 Telomers

The body has an inherent protection against excessive duplication. Telomers are essentially counters that allow a certain number of cell replications and count down to zero, terminating cell replication at that point. Each time a cell replicates, it loses a little bit off the end till it can no longer replicate. That is probably one reason why we are not immortal; at some age we lose the ability to replicate cells, with telomers preventing unlimited duplication.

Nonetheless, in the body there are safeguards and means to get around these safeguards. For example, if an individual was severely burned, the body would need to extensively regenerate cells. Something called telomerase allows for additional regeneration of cells, essentially lengthening the ends of cells, so the cell can continue to replicate. Telomerase is seen in embryos and is produced in unusual situations where a number of replications are needed. Unfortunately it is produced in cancer. Some studies have found the existence of teleromerase in the body a sign of a serious carcinogenic process and unfavorable prognosis. Oncologists are looking at ways of inhibiting the production of Telomerase as a way of limiting cell reproduction. Some new drugs address this issue, but none has been FDA approved for lung cancer as of 2003.

Growth and cell duplication are normal bodily functions and as part of that process, cells provide signals to one another. Growth factors prompt other cells to divide and perform other functions:

3.41 Growth Factors and Receptors

A growth factor binds to a growth factor receptor like a lock and key.

Receptors are becoming the target of many of the new cancer drugs.

3.42 Structure of the Receptor

New cancer drugs are directed to the receptor. Some drugs address the tyrosine kinase, trying to prevent phosphorylation while other attempt to prevent binding. For example, IMC 225, is an antibody that binds to the extra- cellular domain of the epidermal growth factor receptor attempting to prevent binding. In contrast, Iressa and Tarceva work at the tyrosine kinase level trying to inhibit phosphorylation.

Additionally patients seem to have different areas of genetic damage. Many patients with bronchoalveolar lung cancer have damage to the tyrosine kinase, and tyrosine kinase inhibitors seem to be particularly effective with them. In contrast, the drugs seem less effective with squamous cell patients most of who do not have damage in the tyrosine kinase. In the near future, we may be testing patients for specific genetic damage, and tailoring treatment to what we find.

3.5 COMPLEXITY OF GROWTH FACTORS AND RECEPTORS

There are many tyrosine kinase receptors in the human body performing various functions. We can identify two receptors associated with cancer, epidermal growth factor receptor (egfr), and vascular endothelial growth factor receptor (vegfr). (See chapter 2). These receptors are important targets for lung cancer research. VEGFR is associated with metastasis or angiogenesis, and how cancerous tissue spreads to other cells and organs.

3.51 Multiple Receptors and Growth Factors

At its simplest level, there would be a single growth factor and an associated receptor, i.e, egf and egfr. The process is more complex and one of the things that distinguishes us from simpler species is the complexity of our signaling network. EGFR is part of the Erb family which includes four receptors in which there are four: egfr or erb 1, erb 2, erb 3, and erb4. It appears receptors at erb1 and erb 2 can interact with the epidermal growth factor. Likewise, there are multiple growth factors that can interact with a receptor.

3.52 Treatment Barriers

The existence of multiple growth factors and multiple receptors shows the complexity of ordinary functioning and the cancer process. This makes developing a cure more difficult. Scientists are working on identifying which growth factors and receptors are most important and the mechanisms by which they are activated.

3.53 Upstream and Downstream Signaling

The basic model of growth factor combining with tumor suppressor (accelerator and brakes) has been supplanted with a model involving participation of many genes. Scientists now look at a gene and talk of upstream, to the gene, and downstream, by the gene. For example, let us look at a simplified model of VEGF: Growth factors ± production of VEGF ± production of blood vessels, other growth factors.

3.6 EPIDERMAL GROWTH FACTOR

There are specific growth factors and related tyrosine kinase receptors involved with lung cancer. One critical one is the epidermal growth factor or (EGF). Epidermal means skin and EGF is associated with the replenishment of skin cells and other cells. EGF is also a part of many cancers with higher levels of EGF shown in tumors. EGF binds to the epidermal growth factor receptor (EGFR).

3.61 Family of ERB Receptors

The epidermal growth factor receptor is called Erb1, and is part of a family of Erb receptors (3). We have Erb 1, 2, 3, and 4. Erb 2 is associated with breast cancer and the drug Herceptin is an Erb2 inhibitor. There is debate over the importance of each member of the Erb family, whether Erb 1 plays the most important role in lung cancer, and the role of Erb2. See Giatromanolaki (5). Signals are also exchanges within the Erb family, cross-talk, and to other growth actors and receptors.

Altering the path of the epidermal growth factor is one type of gene therapy showing significant promise. Scientists are grappling with the question of targeting the specific receptor, Erb1 which Iressa and Tarceva do, another receptor, or the entire Erb family of receptors. The ability of one member of the family, say Erb 1, to provide signals to another member, is called cross-talk. We review epidermal growth factor research in depth in our chapter on Iressa and epidermal growth factors.

3.7 VASCULAR ENDOTHELIAL GROWTH FACTOR

Metastasis is the chief evil of lung cancer, and patients die from distant metastasis rather than consequences in the lung itself. Angiogenesis, the formation of new capillaries, allowing the tumor to expand and infiltrate to nearby structures is essential to cancer growth:

In the metastatic process, vascular endothelial growth factor (VEGF) plays a key role.

3.71 VEGF= s Role in Developing Tissue

VEGF performs some important functions for normal development. Animals lacking VEGF will die because their cardio-vascular system does not properly develop, and embryos lacking correct VEGF genes have cells that do not properly develop.@ Neufeld (7) VEGF helps establish new sources of blood supply to damaged tissue. Unfortunately when the process goes awry, VEGF helps connect tumor tissue to adjoining areas and establish new blood vessels for the tumor. There are several types of anti-angiogenic drugs being investigated to inhibit VEGF.@ Herbst (4).

3.72 VEGF Receptors

One way to address VEGF would be to prevent VEGF from connecting with one or both of the receptors.

3.73 The Difficulty in Developing a Cure, Multiple Growth Factors and Receptors

If there were a single growth or tumor suppressor gene, our task in developing a cancer cure might only be to identify that gene, and develop a virus or antidote which inhibited the growth factor or prevented it from connecting to its receptor. For example, scientists have isolated a particular gene involved with a particular form of leukemia and developed a therapy to correct that abnormality. See Magic Bullet (12).

With lung cancer our task is unfortunately far more complex. There are a large number of growth factors, receptors, tumor suppressor genes, signaling genes and other cellular products associated with the disease. Indeed, overall, we are beginning to recognize the complexities of cell interaction in the human body:

In the lung cancer model, outside stimulus causes changes in gene A which prompts changes in growth factor B, which sends a message to receptor C, prompting a reaction in D, ultimately resulting in replication of a cell. We may be working with 10 or more gene components, with the significance of each difficult to ascertain.

Scientists have had some success in developing growth factor inhibitors, with the chances of cures growing as the science improves. The critical questions are essentially these:

Chemotherapy drugs can affect different types of cells in the body leading to side effects. Since these growth factor drugs are more narrowly targeted, aiming only at certain growth factors and receptors, they hold the promise of limiting the spread of disease or even preventing its development, without creating significant side effects.

REFERENCES

Gap or G1

G1 Restriction Point

Iressa and G1

Phase 2, Synthesis

Phase 3, G2

G2 and Radiation

Interphase Process

Mitosis or Cell Division