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

4.1 LUNG ANATOMY

Discussion of lung anatomy can help us understand where tumors are located and how they spread.

4.10 The Trachea

The beginning of the airway leading to the lung is called the trachea or windpipe. The trachea is about four and a half inches long and divides into the right and left lungs. Its function is to bring air into the lungs.

4.11 Differences Between The Right and Left Lungs

Air travels from the trachea into the lungs. There are two lungs located in the chest, or in medical parlance, the thoracic cavity. A doctor who specializes in chest surgery is called a thoracic surgeon.

The right lung 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.

The right lung has three sections called lobes. The left lung has two lobes and is smaller because the heart occupies space on the left side. A tumor= s location would typically be identified as right upper lobe or left lower lobe. Even more specifically, a place in the lung can be identified as anterior (front) or posterior (back).

The lung= s basic function is breathing, taking in oxygen and eliminating carbon dioxide gas. See Kent (2). Various tests are permitted to assess the level of lung functioning appropriately called pulmonary function tests, or spirometry.

4.121 Pulmonary Reserve and Performance Status

Surgery to remove part of a lung involves removal of healthy tissue near the tumor as well as the tumor itself. Surgeons assess the level of lung functioning before deciding on surgery. If the removal of substantial parts of the lung will significantly impair the patient= s breathing ability, surgery may be canceled and other options considered.

One measure of pulmonary function is pulmonary reserve. If a patient has a high pulmonary reserve, that means that some lung tissue can be removed without significantly impairing his breathing ability. The level of functioning of a patient generally, measured by various tests, is called his performance status.

4.122 Why Pulmonary Function May be Impaired

If surgery is considered, usually the tumor is not so advanced as to significantly impair the patient= s breathing ability. However, most patients with lung cancer are smokers, and many will have other pulmonary problems. Smokers can have emphysema or bronchitis, both of which impair breathing ability. The two conditions are related and physicians sometimes refer to an overall condition called Chronic Obstructive Pulmonary Disorder, or COPD.

If there is serious compromise of pulmonary status, surgery may not be possible.

4.13 The Pleura

The lungs are covered by a thin lining called the pleura. The inner or visceral layer of the pleura is attached to the lungs and the outer, parietal,

layer is attached to the chest wall. These two layers are held in place by a film of fluid in a manner similar to two microscope slides that are wet and stuck together. If the pleural cavity fills with air, this is called pneumothorax, and blood in the pleura is called hemothorax. Pleurisy is inflammation of the pleural membrane.

4.131 The Pleura and Mesothelioma

Mesothelioma is a rare form of lung cancer, coming from asbestos entering the pleura and creating tumors in it.

4.14 Mediastinum

The mediastinum is an area between the two lungs. Recall that lymph nodes are part of the lymph system which helps purify the blood and remove byproducts. In the mediastinal area are lymph nodes, and one test of how advanced the cancer is whether the mediastinal nodes are cancerous. 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.

4.15 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. Some scientists refer to the bronchi as the larger airways.

4.151 Squamous Cell Cancer and the Bronchi

Some patients have squamous cell carcinoma, which is a tumor involving squamous cells in the bronchus. Since smoke and dust first come in contact with the primary bronchus, it would make sense that many tumors would occur there. Squamous cell cancer in the large bronchi continues to be one of the most common forms of lung cancer.

4.152 Alveoli and Breathing

The bronchi divide to form small bronchi called the secondary or lobal bronchi. 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.

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. A descriptive name for alveoli is air sacs. The lungs consist of about 300 million alveoli where this exchange of gas and breathing functions occur.

4.153 Emphysema

During emphysema, the walls of the alveolar are destroyed by smoking:

Foreign substances cause different forms of disease. In emphysema, the area is damaged. The constant duplication of cells to repair damage can cause a growth gene to remain on, and if the duplication and multiplication of cells continues, this is cancer. This is one reason why lung cancer is associated with other lung diseases like emphysema.

4.154 Bronchioalveolar Lung Cancer

One form of lung cancer is bronchio-alveolar, which affects the alveolar regions of the lung. With the advent of filtered cigarettes, smokers inhale more deeply and cancers affecting the deeper airways are occurring more frequently.

4.16 Nodes

One of the chief dangers of cancer is that it may metastasize to other organs through lymph nodes:

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 develops in a single spot but when lymph nodes become involved, the tumor spreads to other parts of the body.

4.161 Lymph Node Location

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 sections 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. Alcase is now called the Lung Cancer Alliance. Lungcanceralliance.org).

4.162 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, and these are two indications of cancer. Unfortunately, these problems tend to manifest themselves when the tumor becomes larger and may have already reached a lymph node. Thus, a key to early diagnosis and treatment is not waiting till pain and shortness occur, but developing methods of detecting tumors before they impact bodily functions.

Shortness of breath and chest pain are non-specific symptoms, that is they can indicate a number of different diseases. Heavy smokers may experience heart problems or other pulmonary difficulties which can confuse or delay diagnosis. These facts partly explain why many lung cancers are diagnosed at later stages where treatment is more difficult.

1. Haas, The Chronic Bronchitis and Emphysema Handbook (1990).

2. What is Lung Cancer, www.educ.kent.edu.

3. Alcase, The Lung Cancer Manual (2000).

CHAPTER 5: THE CANCER PROCESS IN THE LUNG

5.11 The Carcinogenic Process in a Smoker

A gradual process of damage to lung tissue creates a tumor. Let us look at the development and spread of squamous cell lung cancer in a smoker:

Parts of this process may vary: tumors may take from 15 to 50 years to develop, non-smokers may contract cancer through seemingly different processes, lymph nodes may not always be cancerous, progression of the tumor can vary, and the location of cellular damage will also vary. Scientists have difficulty understanding which cellular changes come first, what is the order of cause and effect, which cellular abnormalities are the most important ones, which cells if repaired would impact cure or frustrate metastasis. Studies show 50 or 60% of cancer patients have a given cell abnormality, and determining which gene malfunctions cause the tumor remains problematic. Here are the major genes associated with lung cancer:

5.201 The Reader= s Role

Many readers will want as much information as possible about the science behind lung cancer and the drugs that will be prescribed. Others will not and would prefer to simply review the types of drugs customarily prescribed. You may go to later chapters to read about specific drugs, or as I would recommend, try to get a basic understanding of the underlying science.

5.21 Multiple Changes

Multiple genetic changes appear needed to create a lung tumor, though a small number of changes can create other types of cancer. For example, a single change in one gene is associated with a particular type of leukemia. We know that multiple changes are needed in lung cancer.

In one way, that is a blessing. It explains why exposure to a carcinogen such as smoke does not immediately cause a tumor and even multiple changes may not be sufficient. The need for considerable genetic change explains why it takes many years for a smoker to contract cancer and why some may never get it. Once those multiple changes do occur, it is difficult to undo a system of signaling which has undergone considerable disruption. Indeed, the most effective treatment remains removal of the tumor, not attempts to correct the existing disease.

5.22 Gene Repair and Apoptosis

Lung cancer involves damage to various genes and a failure of the body= s system of repair. One area of damage concerns apoptosis, the body= s mechanism for arranging for the orderly death or elimination of damaged or defective cells. A When nuclear DNA is damaged, normal cells initiate a response that includes cell-cycle arrest, apoptotic cell death, and transcriptional induction of genes involved in DNA repair. Induction of apoptosis is an important response to DNA damage.@ Bast (16); Wang (10). The system of apoptosis fails to some extent in lung cancer and .

measurements of apoptotic capacity were associated with survival length. Tumor suppressor genes perform help inducing apoptosis. A P53-specific growth inhibition and apoptosis of tumor cells were observed in both cell lines in vitro.@

5.221 Anti-Apoptosis Genes Cox-2

Cox-2 is a protein produced in times of perceived injury to cells. It appears to frustrate the apoptotic process. Cox-2 inhibitors are being examined as a partial treatment for lung cancer, in part to restore the body= s apoptotic process.

5.23 Tumor Suppressor Genes

5.231 P-53

The P-53 gene helps facilitate apoptosis, and acts like a policeman regulating cell development,

5.232 The Retinoblastoma (RB) Gene

The retinoblastoma (RB) gene has a protein that appears to regulate the cell cycle. 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. RB abnormalities are also present in NSLC with estimates ranging from 10-60%.

5.24 Growth Factors

In response to perceived cellular damage and other factors, various growth factors are activated in lung cancer.

5.241 Epidermal Growth Factor

The epidermal growth factor is associated with various types of tumors. We developed a chapter to the emerging area of epidermal treatment. A growth factor connects with a corresponding growth factor receptor which begins various cellular processes. Scientists are studying ways of preventing the activation of the growth factor or activation of the corresponding receptor.

Since these treatments target a specific type of cell, their impact upon the overall body will be limited, and the absence of side effects makes these treatments attractive.

5.242 Vascular Endothelial Growth Factor

VEGF is produced and helps the tumor create new blood vessels and connect tissue to facilitate metastasis. Here, too, anti-vegf and vegf receptor drugs are being tested for lung cancer. 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, (5). Thus, there is a close relationship among growth factors in the complex mechanism of cell signaling and reproduction.

We know that both growth and tumor suppresor 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 the disease. 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 malfunction in a tumor suppressor gene (or vice versa). However, it appears that each carcinogen can cause changes in both types of genes:

A Various factors, including cigarette smoking, asbestos, and diet, have been reported to correlate with the development of lung cancer. Of these factors, cigarette smoking is believed as the major carcinogen for lung cancer. Recent studies indicate that cigarette smoke carcinogens cause genetic damages at both oncogenes(K-ras) and tumor suppressor genes(p 53) of lung cancer, and hence initiate and promote the development of lung cancer.@ Yano, (3).

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

REFERENCES

6.11 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 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 metastasises, and ways of treating metastatic lung cancer are critical to any discussion of treatment options. Some of the material in this chapter is scientific and some readers may choose to skip or come back to this chapter. Others may find that while the material is weighty, understanding terms like angiogenesis may be helpful in understanding the how and why of new cancer drugs.

6.12 The Steps Involved in Metastasis

Here is a short summary of the metastasis process:

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, the first step is for cells separate from one another. A Separation of cells from the primary tumor mass must occur before long range spread can be possible. Detachment of single cells or clumps of cells may be directly related to a decreased level of cell adhesiveness in tumor populations.@ Wile, Id, at 26.

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

Certain proteins called metalloproteinases or MMP help enable the tumor to penetrate these barriers.

6.31 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 MMP drugs. At present, attention has shifted from preventing MMP, a goal which had been generally unsuccessful in humans to date, to other methods of cancer control.

6.41 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 clarity 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 the area of angiogenesis research and a book about him explains:

This process is not unique to cancer, and is part of the body= s normal processes going awry. While writing this book, I accidentally cut my forehead. Cells signaled other cells to replicate, and sources of blood supply connected with the damaged area. Angiogenesis is similar to the process of wound repair. When one smokes, cells may replicate and other functions are activated to correct the damage. Over time, this process goes awry and the cell repair function proceeds in an abnormal fashion.

6.42 Anti-Angiogenesis Research

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

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

6.5 WHERE DOES METASTASIS OCCUR?

6.51 Location and Proximity

6.52 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.

Structures vary in penetrability, 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.

6.53 Soil and Seed Hypothesis

Eighty years ago, Paget proposed the A seed and soil hypothesis.@ A seed (the carcinoma) will only give rise to a secondary tumor in organs that sustain its growth (the soil). Cancers can only successfully locate in certain organs; for others, inherent characteristics of the organ prevent or inhibit metastasis. Organs vary in their ability to resist penetration by cancer cells, A The basement membrane of different organs vary in composition and the heterogeneity in binding of tumor cells to components of the extracellular matrix may well be another mediator in the organ preference of metastasis.@ Vile (1).

6.61 Staging and Metastatic Cancer

Once a cancer has metastasized, it is more difficult to attack or cure. Indeed, the defining characteristic of stage 4 cancer, or the most advanced, is metastasis to another organ. (Interestingly, within the category of stage 4 tumors, no staging distinctions are made based upon the number of metastasises or their location). Let us look at some of the difficulties metastatic cancer presents.

6.62 Surgery and Metastatic Cancer

Surgery is the first consideration in treating a cancer; simply remove the tumor and an area of surrounding tissue. If the cancer has spread to distant 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. Surgery on the lung is almost never used if the cancer has metastasized to another organ.

Surgery is sometimes used on the particular area of metastasis. Surgery on cranial or bone metastasis is sometimes performed to relieve pain or discomfort.

6.63 Radiation and Metastasis

With metastatic cancer, radiation may be used to target the lung or particular areas of metastasis. Like surgery, this is done to relieve pain or discomfort, not as an effort to eliminate the entire cancer.

6.64 Chemotherapy

Chemotherapy is the use of drugs to kill cancer cells. To date, chemotherapy has been partially effective. It improves quality of life, kills cancer cells, and reduces spread. In many cases, it does not succeed in completely eliminating the tumor, though partial and complete responses are sometimes seen. Here are some reasons for the limitations with metastatic lung cancer.

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.

REFERENCES

7.0 THE IMPORTANCE OF CLASSIFICATION

7.1 NON-SMALL CELL AND SMALL-CELL

Lung cancer is divided into two basic types, non-small cell (NSCLC) and small cell. This classification provides a standardized system useful in estimating prognosis, selecting treatment and reporting data. While both types arise in the lungs, there are mollecular and other differences. A SCLC demonstrate more frequent losses at 4p, 4q, 5q21 ...10Q, while losses at 9p21 and 8P21-23 are more frequent in NSCLC= s.@ Miller (10).

About 80% of lung cancers are non-small cell. Non-small cell lung cancer combines three types of lung cancer: squamous cell, adenocarcinoma, and large cell carcinoma. These are classified together because their treatment and prognosis are generally similar:

Squamous cell refers to a type of cell. These line the large bronchi and squamous cell tumors are generally centrally located. Approximately 90% of squamous cell carcinomas arise in subsegmental or larger bronchi and grow centrally toward the main bronchus and infiltrate the underlying bronchial cartilage, lymph nodes, and adjacent lung parenchyma. In time, this progression may lead to the formation of large nodular masses.

Because squamous cell tumors are centrally located, they are sometimes seen on chest x-rays and through other diagnostic tests. Sputum cytology is a device to analyze sputum from a deep cough. Squamous cell tumors can frequently be detected through this test. The cytology can frequently identify early stage cancers and if sputum cytology were used more widely, many lives would be saved.

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

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 (1) at 251. With filtered cigarettes becoming more prevalent, smokers are inhaling more deeply, leading to the development of more peripheral adenocarcinomas rather than the central squamous cell carcinomas.

7.13 Adenocarcinoma

Adenocarcinoma is the second type of 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.

7.131 Adenocarcinoma, Asbestosis and Silicosis

While smoking remains the largest cause of adenocarcinoma, some scientists see an association with lung scars and occupational exposure to silica, asbestos and other dusts. Where a foreign particle deposits in the lung, and collagen forms to encapsulate the particle, some call this scar formation. For a detailed discussion of silica-related scar formation, See Castranova (2). 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:

Bronchioloalveolar carcinoma (BAC) is a type of adenocarcinoma which originates in the alveoli. Bronchioalveolar cancer is hard to detect since a clear nodule may not be seen on tests, and it can initially be confused with tuberculosis or other lung disease.

Women are being increasingly diagnosed with this disease. Showing that different subtypes can respond differently to treatment, this type of tumor is particularly responsive to the new drug, Iressa. Indeed, some studies have shown triple or quadruple the number of partial and complete responses to Iressa, particularly among non-smokers. Non-smokers are susceptible to this disease. The different patterns of response indicate that this disease is different from other forms of non-small lung cancer. Since non-smokers contract the disease, one hypothesis is that the disease involves fewer genetic abnormalities than other forms of lung cancer, so that addressing one of the growth factors which prompt cellular reproduction can have a substantial impact.

7.14 Large Cell Cancer

Large cell cancer constitutes about 15% of all cancers and the term large cell refers to large, masses of tissue usually displaying signs of necrosis (cell death). A Undifferentiated large cell carcinoma are defined by the WHO as "a malignant epithelial tumor with large nuclei, prominent nucleoli, abundant cytoplasm and usually well defined cell borders, without the characteristic features of squamous cell, small cell or adenocarcinomas.@ (9)

Large cell can sometimes be confused with a poorly differentiated adenocarcinoma or squamous cell carcinoma. However, since the treatment for adenocarcinoma, squamous cell, and large cell are generally grouped together, a physician might not be overly concerned with distinguishing cell type within the group. A subtype of large cell carcinoma is giant cell.

While squamous, adenocarcinoma and large cell have been grouped together for some time, researchers are seeing some important differences. A Studies of large number of lung cancers have shown different patterns of involvement between the two major groups of lung cancer (SCLC and NSCLC) and between the three major histologic types of lung carcinoma A The author goes on to describe different areas of genetic damage, variations in the number of genes impacted, and differences in how the disease arises. Some studies have found differences in survival periods. (1)

These differences mean the broad grouping of three types of cancer with distinct characterstics disease may be analytically incorrect. Instead, in the future, we may develop an approach honed to the specific type of cancer and perhaps analyze areas of genetic damage to create individualized treatment plans. Today, we find that Iressa and anti-epidermal growth factor drugs seem to work particularly well on patients with adenocarcinoma, particularly non-smokers. In conclusion, non-small cell category is still used to denote treatment and prognosis, but the direction of medical research is towards a more focused approach.

Physicians also classify lung cancer by its cell differentiation. Normal tissue is differentiated while cancerous tissue is haphazard, disorganized if you will:

Tumors are classified this way:

Within those categories, there may be subcategories, such as well to-moderately differentiated, or moderately to poor differentiated. Generally, the level of differentiation is a positive factor in survival with the more differentiated the cancer cell, the less chance of metastasis. One study found the DNA content of poorly differentiated adenocarcinoma significantly greater than that of well-differentiated adenocarcinoma. Carney, (7). Thus, one can assume that the loss of differentiation is associated with increasing DNA mutations in the cell. However, stage rather than differentiation remains the primary factor in determining treatment.

7.21 Related Hormonal Syndromes

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

Small cell cancer is another type of lung cancer. Because it behaves differently than non-small cell, it has its own staging system. Small cell cancer moves quickly, though, initially, it is usually susceptible to chemotherapy, with complete response (no evidence of cancer on x-ray) not unusual. Sadly the tumors frequently return, and preventing that phenomenon is a central goal for research.

Clinical trials generally do not mix small cell and non-small cell patients. Small cell is staged as limited or extensive, unlike non-small cell which has a four part staging system, with subcategories.

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

7.31 Small Cell Location and Appearance

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

7.32 Role of Surgery in Small Cell Lung Cancer

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

Some observations:

REFERENCES

CHAPTER 8: LUNG CANCER STAGES

8.1 NON-SMALL CELL LUNG CANCER STAGES

8.11 The Reason for Classification

Non-small cell lung cancer patients are classified by stage:

The TNM system provides an objective method of classifying non-small cell lung cancer. Patients with similar characteristics will be treated similarly. While we discussed the different types of lung cancer, squamous, adenocarcinoma, it is the TNM system which is given the greatest weight.

8.12 T1 Tumors

The first criterion is the size of the tumor and its relationship to adjoining structures. A T1 tumor is a small tumor confined to a specific area. Not surprisingly, physicians have excellent success in treating T1 tumors by surgically removing the tumor. Here is the T classification scheme:

A T3 tumor infiltrates the lining of the mediastinum; a T4 tumor has reached the mediastinal structure itself. Metastasis means a tumor has reached another organ, and this tumor grading gives the same indication. Thus, if a tumor has reached the trachea or esophagus, there is a metastasis.

8.13 Nodes

The second criterion is the nature and extent of lymph node involvement. Note that node evaluation is different from the tumor assessment above. We can have tumors where there has been some spread to adjoining areas, but no spread to a lymph node.

N0: No lymph node involvement.

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

8.14 Metastasis

M designates Metastasis or spread of the tumor to other organs. If the cancer has spread to another organ, surgery again is not likely to be a viable option since the cancer cannot be entirely removed. The physician will want to accurately "stage the patient" not only to assess surgery, but to gauge what type of chemotherapy or radiation is preferred. Here, the staging is simple: either M1, metastasis to another organ, or M0, no metastasis.

8.2 THE INTERNATIONAL STAGING SYSTEM FOR LUNG CANCER, STAGE 1, 2, ...

The international staging system uses the TNM classification and then gives the patients a number, i.e., stage 1, stage 4. This system is used in the United States, with treatment generally based upon patient stage. The importance of stage in clinical decisions led to the creation of substages, 1A and 1B. Here is a summary:

Using the TNM classification, we get these stages:

Stage IIIA T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0

Stage IIIB Any T-T4, N3;

8.21 Small Cell Staging

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

8.22 The Importance of Classification

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

8.23 Stage Related to Survival

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

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

8.31 Surgical Options

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

The lungs are divided into lobes. There are three lobes on the right lung, two on the left. Lobectomy involves removal of the entire section of one lobe.

8.4 SMALL CELL CANCER CLASSIFICATION

8.41 Characteristics and Subclassifications

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

REFERENCES

The majority of patients are diagnosed with advanced tumors which are difficult to treat. There have been a number of tests developed or refined during the last ten years which significantly increase our ability to spot even small lung tumors, accurately diagnose existing ones, and identify recurrences of people already diagnosed.

Despite the tremendous gains, no test for early diagnosis is recommended by major organizations like the American Cancer Society or National Cancer Institute, and it appears no test for followup has been adopted either. Outside of some University hospitals, generally we are not utilizing all the tools available. While some HMO= s may be happy that expensive tests are not routinely utilized, many patients should be asking why not. Despite its inaccuracy, the chest x-ray continues to be the main-stay of lung cancer diagnosis.

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

9.11 Chest X-Ray Interpretation Problems

Radiologists are called upon to make critical assessments based upon what are frequently almost imperceptible shadows. The chest contains tissues of different consistency, with air next to thick soft tissue and bone. Adequately producing an image which provides clear definition of all structures in the chest requires meticulous technique and attention to detail. The machine (film processor) used to develop the film should be working properly though up to 50% of x-ray film processors may have some deficiency.@ (1) While this is the most commonly performed examination, it often isdone incorrectly. Studies have shown that from 20B 40% of x-rays are incorrectly interpreted. (1) Indeed, there is a discernible difference in skill among radiologists interpreting chest x-ray films. However, even with good equipment and skilled people, the x-ray is still inaccurate.

9.12 Chest X-Ray Misses Over 75% of Treatable

Stage 1 Tumors

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

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

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

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

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

9.21 Recent Advances in Detection of Lung Cancer with Sputum Cytology

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

A Lam and colleagues developed a computer-assisted and automated image analysis method that detects aneuploidy and nuclear abnormalities in sputum samples. Between 5000 and 10,000 cells are stained with a Feulgen thionine DNA cellular stain, analyzed with a digital camera, and then screened using computer-assisted algorithms. In a series presented at the presidential symposium, Lam reported results showing that this screening technique was 70% sensitive for stage 0/1 lesions and 80% for adenocarcinomas, with a specificity of 90%.@ Lynch, 9^th World Conference on Lung Cancer, (2000) citing, Lam (3).

Others are testing sputum cytology to detect P-53 mutations. If the test can be developed, we would have an inexpensive and reliable method of detecting lung cancer in its earliest and most curable stages.

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

9.31 Accuracy of the CT Scan in Diagnosing Lung Cancer, even Small Nodules

The Early Lung Cancer Detection survey found a high rate of

reliability in detecting tumors:

9.32 Should X-Rays Continue to Be Used Where We Have a Far More Reliable Test?

The tremendous accuracy of the Ct Scan, combined with the inaccuracy of the x-ray raises serious questions about whether x-rays should continue to be used as a tool for diagnosing lung cancer. Yes, the x-rays are cheaper, but should we continue to use a tool 25% as accurate in diagnosing small tumors simply to save money. Indeed, x-rays can provide a false sense of security.

9.33 CT Scan to Detect the Nature and Extent of Disease

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

9.34 Test Specificity and Accuracy

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

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

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

9.41 How the Patient Feels During a Bronchoscopy?

Here is what the patient will experience:

9.42 Reliability of the Bronchoscopy

Reliability seems to depend upon the location of the tumor.

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

PET or Positron Emission Tomography is a useful tool for diagnosing lung cancer and ascertaining the extent of disease.

9.51 How Does PET Work?

Recent medical literature has trumpeted PET:

9.52 Combined PET and Ct Scan

The new device combines a PET Scan with a Ct Scan, providing a reading from both devices for the radiologist and a single seating for the patient. Items which could be misdiagnosed as cancer are eliminated, while the combined tests reduces the possibility that serious lesions are missed:

A Integrated PET-CT provided additional information in 20 of 49 patients (41 percent), beyond that provided by conventional visual correlation of PET and CT. Integrated PET-CT had better diagnostic accuracy than the other imaging methods. Tumor staging was significantly more accurate with integrated PET-CT than with CT alone (P=0.001), PET alone (P<0.001), or visual correlation of PET and CT.@

9.6 OTHER TOOLS FOR MOLECULAR ANALYSIS OF CELLS

9.61 Flow Cytometry

Cancer cells may be analyzed to assess their structure and DNA. Flow cytometry measures how many pairs of chromosomes the cell= s DNA contains. See American Cancer Society, (11). If a cell has a normal number of chromosomes, it is diploid. If the cell has severely disrupted DNA, it is said to be aneuploid.

9.63 P-53 Analysis

9.64 EGFR Analysis

The epidermal growth factor receptor binds with the epidermal growth factor and then through its tyrosine kinase initiates a chemical change called phosphylation which can contribute to carcinogenic processes. Patients with a malfunctioning tyrosine kinase may respond to Iressa, a new drug which targets this tyrosine kinase. The Harvard Center for Genetics and Genomics now has a test which measures damage to the tyrosine kinase. (Harvard (14). Patients with such damage may consider Iressa while others without this damage may consider other options. An analysis is performed on exons 18-24, the tyrosine kinase domain of EGFR, but the test does not detect errors in the entire gene.

REFERENCES

13. www.Healthgate.com.

CHAPTER 10: SURGERY AND DIAGNOSTIC PROCEDURES

10.1 SURGICAL DIAGNOSTIC PROCEDURES

10.11 Types of Biopsies

10.12 Other Diagnostic Procedures

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

10.2 TYPES OF SURGERY

10.21 When is Surgery Performed

Surgery is the preferred form of treatment. In the best of circumstances, surgery involves the removal of the entire tumor and the elimination of disease. That result becomes less possible as the tumor spreads and invades other structures. Thus, surgery is less likely to be an option as the cancer advances.

10.22 Surgery and Stage 1

Surgery is routinely recommended for stage 1 non-small cell patients in good physical condition. For this group, surgery is a complete cure in 55-80% of patients, with results varying upon the precise extent of disease, the physical status of the patients, and differences among study groups.

10.23 Surgery and Stage 2 Patients

Surgery is recommended for most stage 2 patients, that is, patients with limited nodal involvement.

10.24 Surgery and Stage 3 and 4 Patients

Surgery is sometimes performed upon 3A patients. Surgery is generally is not performed upon stage 3B and Stage 4 patients, that is, patients with advanced cancer. The reasoning is that is major surgery, frequently with smokers having other health problems, and the risk associated with surgery are not justified because it will be impossible to remove all the cancer.

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

10.25 Lobectomy and Pneumonectomy

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

10.31 Benefits of Laparoscopic Surgery

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

10.32 Potential Problems with Laparoscopic Surgery

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

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

10.4 HOSPITAL STAYS

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

10.41 Specialization

A recent study found lower rates of mortality when patients were operated upon by thoracic surgeons, rather than general surgeons. Silvestri, (3). Likewise, hospitals which perform a large number of particular procedures report better results. Begg,(4) (A Hospitals that treat a relatively high volume of patients for selected surgical oncology procedures report lower surgical in-hospital mortality rates than hospitals with a low volume of the procedures.@ ).

10.51 Problems at Night

Care in ICU (intensive care units) following surgery is usually excellent. One nurse may monitor 3 or 4 patients, constantly checking for small changes in heart rate and other vital functions, and ready to notify physicians of potential problems. Outside of ICU, even the best hospitals are facing increasing financial pressures, with HMO= s constantly looking to reduce costs and limit reimbursement.

HMO= s typically negotiate fixed reimbursements to participating hospitals. A large HMO will approach a hospital offering to list the hospital on its participation list, in exchange for the hospital= s agreement to accept reduced sums for care. Those hospitals which refuse such arrangements may find the number of patients reduced. Hospitals in the last 10 years have accepted lower reimbursement rates, placing increasing pressure on the hospitals to cut costs, which may include limiting the number of nurses per shift.

Care during days at most hospitals may be sufficient, with problems occurring at night. Few nurses and staff wish to work at night, and with limited budgets, there are frequent staffing problems at many hospitals which will not be apparent to the average patient or his family. Hospitals limit visiting hours and family members may not think to visit at 2:00 or 3:00 A.M. In some city hospitals, a single nurse may be responsible for monitoring many patients in serious condition, and the care can be substandard but unnoticed.

10.511 Private Duty Nurses and Family Monitoring

Consider hiring a nurse or health care aid to assist in monitoring the patient during the night when problems are least likely to be detected. Unfortunately, insurance is unlikely to cover this type of expense. A private duty nurse may cost from $250-500 for an 8 hour shift, with a health care worker costing somewhat less. Such costs can strain the budgets of many families.

Alternatively, consider having a family member sleep over or remain in the room through the night to help the patient and alert nurses to any problems. If a private room is available, the sleeping accommodations are easy. Alternatively, a family member might have to remain in a chair or sleep during the day. It is important because we do not have the luxury of 24 hour closely monitored care in most hospitals. It is appropriate that all family members help after surgery and one will note that the Sixth Commandment is not limited to women.

Legally, injuries arising from a lack of staff are not always malpractice, and in any case, may be difficult to detect. One is not entitled to the best care, but simply care which meets average standards. Thus, following major surgery with most hospitals having limited staff, many family members will want to play the important role in checking the patient and notifying hospital staff of problems.

10.6 DEALING WITH YOUR DOCTOR

As medical testing has become more sophisticated and expensive, personal contact has decreased. The number of calm and compassionate physicians who can spend an hour with a patient dealing with not only medical questions but the entire patient is decreasing. Some doctors may see 35-40 patients per day and spend some of the scarce remaining time arguing with insurance carriers over reimbursement issues. What does this mean?

As a patient, you need to prepare for your examination. If you are experiencing pain or discomfort, try to identify the nature and type.

11.01 Chemotherapy= s Role in Lung Cancer

Since the ordinary course of lung cancer is metastasis, chemotherapy holds out the best possibility of cure or extension of life. Without any treatment, the patient is not likely to survive an extended period and chemotherapy remains the standard treatment for metastatic disease, though gene therapies are being developed and studied. Clinical trials measure partial response, and with most chemotherapy drugs partial responses are in the 20-25% range. That is, 50% of tumor volume has been reduced as seen on x-ray or Ct Scan, though it may later return.

11.02 Cure

The number of complete responses or overall cures is limited, though they do exist. Willis wrote the Cancer Patient= s Workbook three years after her diagnosis of stage 4 lung cancer, surprising her doctors with excellent results from chemotherapy. Participants in online newsgroups report survival 2, 3, and even 5 years from diagnosis, encouraging others to have a positive attitude. Long-term or 5 year survivals are also seen in clinical trials. With both complete and partial responses, tumors can reoccur through a complex process called multi-drug resistance (MDR) where the cancer cells become resistant to chemotherapy. Cures are rare though not unknown.

11.03 Statistical Problems

Statistics vary, so defining chemotherapy= s benefit is difficult for several reasons. First, the majority of statistics are maintained through clinical trials. Many patients enter clinical trials with very advanced disease, lessening the possibility of cure. Thus, these statistics are likely to understate the possibility of cure. In addition to an increase in survival time, many studies show an improvement in quality of life. This is because the chemotherapy can reduce the symptoms associated with lung cancer. While the drugs may cause side effects, many scientists believe that chemotherapy related side effects are less than the effects of the disease without effective treatment.

11.04 Platinum-Based Therapy as the Principal Regimen

The American Society of Clinical Oncology treatment guidelines in 1997 for unresectable disease concluded: "In stage IV disease, chemotherapy prolongs survival and is most appropriate for individuals with good performance status. Chemotherapy given to NSCLC patients should be a platinum-based regimen.@ Schiller (17)

11.05 No Optimal Drug Combination Has been Determined

Specific drugs and combinations continue to be studied and debated.

There are at least six drugs with roughly equal effectiveness; that is the percentage of partial responses in scientific studies are within 5% of one another. The percentage of partial responses remains in the 25% area, with some variation from study to study, or drug to drug. The advantages of one drug or drug combination over another remain small and two physicians could legitimately prescribe different drugs for the same patient.

Clinical trials continue to investigate the success of different combinations, with trials yielding varying and sometimes contradictory results. Trials generally divide patients by stage and category and it is possible that the particular type of tumor, squamous, adeno or large cell, might play a role in a drug= s effectiveness, or other factors as well.

Cisplatin (and its analogue Carboplatin), Taxol, Gemcitabine and Etopiside are the major drugs; but 5 or 6 other drugs have shown results in clinical trials.

Scientists are improving ways of relieving chemotherapy-related discomfort. The nausea and vomiting associated with some chemotherapy has been significantly reduced. A book entitled Living Well with Cancer states,

Drugs have been altered and improved, and medicine to minimize nausea is sometimes prescribed with the therapy. For some patients however, the effects of chemotherapy must be constantly reevaluated and those who find the treatment particularly difficult, and who are in poor health from the disease, may choose to end chemotherapy. The decisions can be difficult for the family and patient. Second-line chemotherapy refers to the second drug used, and while many will try chemotherapy, at some point many with advanced stage 4 disease will stop. Chemotherapy for patients with advanced disease can release the symptoms of the disease and prolong life but usually cannot provide a cure.

11.06 A Chemo@ or Chemical Therapy

The term A Chemo@ means chemical and chemotherapy can be broadly defined as the use of drugs to treat cancer. In that vein the term anti-cancer drug is simpler.

Chemotherapy generally mean drugs which target dividing cells. By preventing or inhibiting cell division, chemotherapy drugs frustrate the cancer process, though they can also impact normal cells. Chemotherapy drugs may affect the immune system since white blood cells reproduce and divide quickly and thus may also be affected by chemotherapy.

In contrast, some forms of gene therapy like Iressa, are narrowly crafted to attach only to certain growth factor receptors. While reducing the impact on normal cells and tailoring a drug to attach specific areas are laudable goals, the question remains whether that type of limited approach will be as successful as chemotherapy. In any case, we should try to distinguish traditional chemotherapy drugs which impact numerous types of dividing cells, from the newer gene therapies which attempt to deal with the cancer process by attacking receptors or specific targets. There have been few studies comparing traditional chemotherapy with gene therapy. Laboratory studies indicate that since the two approach cancer in different ways, ultimately they will be used together. Semantically, I will use the term chemotherapy to denote those therapies which target the cell division process, though I must acknowledge there is no completely clear dividing line.

11.07 The Advantages of Multi-Modal Chemotherapy

The mechanisms by which chemotherapy drugs attempt to attack cancer are varied. Since the drugs perform different functions, if side effects could be managed, it would make sense to use a number of different drugs simultaneously to attack cancer and that is what is being done today. For patients who are in otherwise good health and not of advanced age, drug combinations are prescribed, sometimes with radiation.

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

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

11.11 FDA Approval is Organ and Treatment Specific

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

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

11.12 Off-Label Use

While the approval is for a specific use, a doctor may decide to utilize the drug for other purposes, so-called off-label use. Such use varies since a physician may worry that an unusual use of a drug may lead to liability if a patient= s condition worsens. Some insurers do not cover off-label use.

11.13 Regular and Accelerated Approval Programs

Most drugs are approved under the FDA= s regular approval program. However, where there is no existing cure for a disease at a particular stage, the FDA may utilize an accelerated approval program:

A Regular approval is based on end points that demonstrate that the drug provides a longer life, a better life, or a favorable effect on an established surrogate for a longer life or a better life. Accelerated approval (AA) is based on a surrogate end point that is less well established but that is reasonably likely to predict a longer or a better life.... End points other than survival were the approval basis for 68% (39 of 57) of oncology drug marketing applications granted regular approval and for all 14 applications granted accelerated approval.@ Johnson (16)

11.21 Chemotherapy Generally Targets Rapidly Growing Cells

Chemotherapy attacks all body cells to some extent, but targets rapidly dividing cells such as cancer cells. Its effect on other rapidly dividing cells such as hair follicles, cells lining the stomach, and red blood cells, accounts for many of its side effects. Almost all of the drugs used in chemotherapy suppress cancer by somehow altering the cells' DNA and thus their ability to reproduce. See Bruning, (1) (an excellent book written by a woman with breast cancer) .

11.22 What Does Cell-Cycle Specific Chemotherapy Mean?

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

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

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

11.24 Considerations Before Treatment Begins

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

11.31 Activity

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

11.32 Partial and Complete Response

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

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

11.4 RESERVED

11.51 Platinum Drugs

Cisplatin is one of the first and still most widely used drugs for lung and other types of cancer. Most studies show at least 25% of patients treated with Cisplatin receive at least a partial response, elimination of 50% of tumor volume. Nonetheless, the response is usually not permanent and chemo-resistant cells generally develop.

Lung cancer patients treated with chemotherapy generally have a longer life expectancy, but whether that is a matter of months or more is difficult to determine. Some clinical trials dealing with particularly ill patients show only modest gains from Cisplatin versus best supportive care. In other cases, the number of patients with partial response and the occasional complete response show the drug is working, and a few patients with 2,3, and 5 five year survival rates show the drug= s effectiveness is not always limited to a brief extension of life.

Cisplatin is associated with some side effects. Nausea and vomiting have been particularly troublesome which has lead to the development of platinum drugs like Carboplatin which are designed to match Cisplatin= s effectiveness with fewer side effects. Patients using Cisplatin will want to consider using other drugs to minimize stomach disorders. Less common side effects include hearing abnormalities and neuropathy or leg weakness or discomfort. (BC Cancer Agency 12). Chemotherapy side effects are reviewed in the next chapter. Even though these side effects exist, most studies still find higher quality of life with chemotherapy than without.

11.5112 Chemistry and brand Name

Cisplatin is formed by an atom of platinum surrounded by chlorine and ammonia atoms. A The prefix "cis-" in cis-diamminedichloroplatinum refers to the arrangement of the atoms of this molecule around the central platinum atom.@ (13). Platinol is the commercial name of Cisplatin. Cisplatin is generally given by injection.

11.512 Carboplatin

Carboplatin produces less nausea, and other side effects with approximately the same effectiveness. It is a clear liquid also given intravenously and Paraplatin is its commercial name. Carboplatin reduces nausea but can affect white blood cells:

The manufacturer= s insert states, A Bone marrow suppression (leukpenia, neutropenia, and thrombocytenia) is dose dependent, and is also the dose-limiting toxicity.@ (Paraplatin 14). Thus the amount of Carboplatin that will be prescribed is limited to avoid these side effects. Patients have their blood tested regularly with the dosage reduced or the drug eliminated if a problem presents itself.

11.52 Taxol

Taxol is one of the newer drugs which have shown effectiveness and less nausea than Cisplatin. In addition to lung cancer, it is used to treat ovarian, testicular, breast, head, neck and melanoma. Taxol is an extract from the bark and needles of the yew tree, Taxus brevi folia. The history of Taxol is supplied on a webpage entitled The Taxol Molecule:

Taxol is a white powder which is liquified and given intravenously. It is commonly used in combination with other chemotherapy drugs such as Carboplatin, and Cisplatin. Dosages may vary but it is frequently generally given once every three weeks. Generally Taxol= s side effects are tolerable, less than drugs like Cisplatin. One well-known side effect is numbness or tingling in toes and fingers. This may be because Taxol affects bone marrow. Taxol is metabolized in the liver and dosage may be reduced for patients with liver dysfunction or liver metastasis.

11.523 Taxotere

Just as Carboplatin was designed to provide similar efficacy with fewer side effects than Cisplatin, Taxotere is designed to be better than Taxol.

11.53 Vinorelbine

This drug is active or effective with non-small cell lung cancer and has been successfully combined with cisplatin. Vinorelbine has been investigated in 4 randomized trials and found to improve survival. The combination of vinorelbine to cisplatin has been compared in two randomized trials to vinorelbine alone with significant response rate improvement with survival increase in one (5) and not in the other (6). In the first one, the comparison was also performed with a third arm treatment made of cisplatin and vindesine, with a marginal effect on survival. It should be noted that both trials have obtained high quality scores in our review (89 and 79,8%).

11.54 Gemcitabine

Gemcitabine is a newer drug whose strength is that it provides the same, or almost the same effectiveness as the platinum drugs, but with fewer side effects. Known by its trade name, Gemzar, it is a clear liquid usually given intravenously. It is a frequent choice for elderly patients or those in poorer health because of its mild side effects. It has been shown in randomized trials to be better tolerated than the Cisplatin combinations.

Unlike Cisplatin, side effects do not usually include nausea or vomiting. Instead drop in bone morrow or fatigue may occur. Anecdotally, my father-in-law felt better after taking the drug.

11.541 Gemcitabine and Platinum Combinations

Scientists continue to investigate combining Gemcitabine with other anti-cancer drugs. One study found the two drug combination more effective than Gemcitabine alone (Hitt 11). Hitt suggests that A the higher response rate, prolonged time to progression, and improved survival in the GCB arm appears to support the use of combined platinum-based therapy for patients with advanced NSCLC.@ Hitt (11). Hitt did note that thrombocytonopenia was more pronounced in the combination group. Thus, for persons in otherwise good health, Gemcitabine combinations for advanced lung cancer patients are becoming more prevalent. For persons in poorer health, Gemcitabine may be used alone to reduce side effects.

11.6 THE ERA OF MULTI-MODAL OR COMBINATION CHEMOTHERAPY

Here is a comment from the 1998 Cuneo Lung Cancer conference:

Gemcitabine is one of the most extensively evaluated single agents in NSCLC, with response rates of 20-30% world-wide (8).

11.61 Side Effects and Multi-Modal Therapy

While the addition of another drug may improve survival, it will also increase potential side effects. For the young person with early disease, an aggressive regimen may be recommended, while others with impaired health may wish to limit side effects, by perhaps using only type of drug.

11.7 MULTI-DRUG RESISTANCE

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

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

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

11.71 The Development of MDR, Multi-Drug Resistance

Unfortunately cancer cells develop resistance to certain drugs. While initially successful, chemotherapy becomes ineffective. PGP (P-glycoprotein) is produced which inhibits the ability of the drug to reach cancer cells, thus reducing A intracellular drug concentrations and hence reduced cytotoxicity.@ Twentyman, (7):

11.72 Why Dosage and Scheduling Can Be Critical

Dosage scheduling can be important and is the subject of clinical trials.

Chemotherapy administrations should not be missed without a reason. If an administration is missed, the doctor should be promptly informed.

The oncologist= s choice of drug depends on the type of cancer, its impact on bodily functions, the patient= s general health, and his assessment of various clinical trials or studies. For dual agent chemotherapy, most U.S oncologists choose Taxol and Carboplatin. In Europe, Cisplatin is more widely used. Gemcitabine is used as second agent chemotherapy, as are the tyrosine kinase inhibitors like Iressa and anti-angiogenic agents like Thalidomide.

11.91 Where is Chemotherapy Administered?

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

11.92 How Often Will Chemotherapy be administered?

How often the therapy is administered will vary. Chemotherapy is sometimes given in on-and-off cycles that include rest periods so that the body has a chance to re-build new cells and the patient regain its strength. The time and amount are generally based upon results from clinical trials.

11.93 Goals of Chemotherapy

Chemotherapy helps patients live more comfortably by eliminating cancer cells which cause pain, discomfort or other problems. This is called palliative care, where the goal is to help the patient better function, not cure. Currently, chemotherapy is generally not an overall cure for advanced lung cancer, the type of cancer for which it is prescribed. Chemotherapy is not given for stage 1 cancer as standard treatment though clinical trials are investigating whether it would be beneficial.

11.94 Methods of Administration

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

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

Generally the goal with chemotherapy is to attack cancerous cells circulating throughout the body. Occasionally, chemotherapy may be given in a manner to directly attack cancer cells in a particular area.

11.95 Does Chemotherapy Hurt

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

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

11.96 Use of Other Medication During Chemotherapy

Some medicines may interfere with the effects of your chemotherapy. That is why you should take a list of all your medications to your doctor before you start chemotherapy. Your list should include the name of each drug, how often you take it, the reason you take it, and the dosage. Remember to include over-the-counter drugs such as laxatives, cold pills, pain relievers, and vitamins. Your doctor will tell you if you should stop taking any of these medications before you start chemotherapy. After your treatments begin, be sure to check with your doctor before taking any new medicines or stopping the ones you already are taking. A patient= s ability to work will depend upon his stage and performance status. The disease more than the therapy is likely to be the cause of a termination of employment.

REFERENCES

18. www.FDA.gov

CHAPTER 12: CHEMOTHERAPY SIDE EFFECTS

12.0 OVERVIEW

12.01 Limits of this Book

Let me add a personal note to this. It is much easier for me as author, to characterize nausea or other side effects as minor, than if I were experiencing this myself. If I have not taken the time to empathize with the patient or family member, it is because I felt that a clear, if unemotional analysis was the best way for me to communicate information. A book cannot provide the support a family member or close friend can provide.

12.02 Support Groups

Support groups play an important role in dealing with side effects. A clinical trial can only categorize side effects, it cannot give a description of what a person experiences and how to deal with that. Physicians can be busy, and the best way to discuss the pain or discomfort associated with chemotherapy can be a support group.

Association of Online cancer resources, Acor.org currently provides 3 online support groups. These are categorized by disease, for example, non-small cell lung cancer, and can provide an excellent resource. Alcase.org is a leading lung cancer advocacy group which also provides support group information. Lungcanceronline.com provides support group information as well as material about side effects. The American Cancer Society and many hospitals also provide support.

To note side effects associated with chemotherapy paints an incomplete picture. The disease itself creates many serious consequences, some of which are relieved by chemotherapy. Thus, many studies report higher quality of life with chemotherapy, along with extended survival.

12.03 Medical Reasons for Side Effects

An American Cancer Society Guide discusses the reason for side effects:

12.1 CHEMOTHERAPY CAN IMPROVE QUALITY OF LIFE BY REDUCING THE SYMPTOMS OF DISEASE

Chemotherapy causes side effects in some patients. However, it is incorrect to therefore conclude that the decision to use chemotherapy represents a tradeoff between length and quality of life. For example, one study analyzes quality of life with the chemotherapy drug Vinorelbine. (2).

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

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

12.2 NAUSEA AND ANTI-EMETIC DRUGS

Some anticancer drugs cause nausea and vomiting because they irritate the stomach lining and regurgitation can be a natural response to irritation. The severity of these symptoms depends on several factors, including the chemotherapeutic agent(s) used, and the patient's reaction. Some patients will experience only limited side effects with a drug while others will have greater ones. In most clinical trials, only a minority experience a particular side effect, and the side effects will vary from patient to patient. Diet may play a role with the patient who eats oily foods probably more likely to experience nausea when a foreign drug comes in contact with his body.

Management of nausea and vomiting occasioned by chemotherapy is an important part of care for cancer patients when it does occur. Note that our ability to combat nausea has improved, and do not assume that side effects encountered by a patients 10 years ago will occur with the same severity today.

12.21 Compazine

The Chemotherapy and Radiation Therapy Guide says:

12.22 Atavan

Atavan is also frequently prescribed for nausea:

Not surprisingly, side effects are sedation and forgetfulness, and the drug should not be used before driving.

12.23 Kytril

Kytril A works by preventing seratonin from getting through to the CTZ and causing nausea.@ (6), at 71.

12.24 Tropisetron

This newer drug was found as effective as Kytril in a recent Chinese clinical trial (7). Another recent article reports, A These results indicate that continuous administration of tropisetron could contribute to preventing patient QOL influenced by cisplatin treatment.@

12.25 Substitution of Carboplatin for Cisplatin

While effective, in treating lung cancer, Cisplatin has been associated with nausea. Some suggest that substituting Carboplatin, another Platinum drug, maintains the same level of effectiveness with fewer side effects.

12.26 Marijuana and Nausea

There has been some interest in the use of marijuana to treat a number of medical problems, including chemotherapy-induced nausea and vomiting in cancer patients. Delta-9-tetrahydrocannabinol (THC), is available by prescription for use as an antiemetic. The U.S. Food and Drug Administration has approved its use for treatment of nausea and vomiting associated with cancer chemotherapy in patients who have not responded to the standard antiemetic drugs.

THC may be useful for some cancer patients who have chemotherapy-induced nausea and vomiting that cannot be controlled by other antiemetic agents. The expected side effects of this compound must be weighed against the possible benefits. Dronabinol can causes a "high" (loss of control or sensation of unreality), which is associated with its effectiveness; however, this sensation may be unpleasant for some individuals."

12.27 Diet

Many believe that diet plays an important role. Eating light, non-oily foods, may reduce the nausea associated with some forms of chemotherapy. One guide suggests the following:

12.3 CHEMOTHERAPY AND BLOOD CELLS

Chemotherapy can increase the risk of infection. White blood cells fight infection and are constantly reproducing and may therefore be affected by chemotherapy.

12.31 Neutropenia

Drugs which inhibit the cell reproduction process can cause a reduction in white blood cells called neutropenia making the body more susceptible to infection:

12.311 Colony Stimulating Factor

Some doctors may recommend colony stimulating factors. A In 1991, small cell lung cancer (SCLC) was reported as the first tumour type where colony stimulating factor (CSF) support was clinically effective.@ Feinglass (7) Valley (8). Your doctor may prescribe Neupogen, a medication that stimulates your body to produce more white blood cells. (Neupogen website 6)

12.32 Thrombocytopenia

A low level of platelets is called thrombocytopenia. One method of treatment is platelet transfusion. Transfused platelets act as mature "stand-ins" for your developing cells until your body becomes able to produce enough platelets on its own.

12.33 Anemia and Procrit

Anemia is having less than the normal number of red blood cells or hemoglobin. A The hemoglobin (Hb) in red blood cells carries oxygen to all parts of the body, providing the strength you need. When you are anemic, less oxygen is able to reach your muscles and organs. This can leave you fatigued and unable to do the things you love to do every day.@ Procrit (9) A Hemoglobin is measured in grams (g) per deciliter (dL). The average hemoglobin value for men is 16 g/dL and for women is 14 g/dL.@ Procrit (9).

One popular drug to address anemia is Procrit, also called Epogen or epoetin alfa. The drug can increase the number of red blood cells, restore strength, and allow chemotherapy to continue. Erythropoietin is a protein produced in the kidney that stimulates red blood cell production. Procrit mimics Erythropoietin prompting increased red blood cell production. The drug is taken intravenously and generally takes 2-6 week to show results. Procrit (9). The manufacturer suggests that Procrit is generally well-tolerated, though possible side effects include elevated blood pressure, headache and diarrhea.

Another less widely used drug for anemia is Aranesp. It also mimics the body= s own Erythpoientin and its manufacturer suggests that fewer injections are needed. See Aranesp.com (11). Research and experience with this drug are more limited. Similar side effects are noted.

12.34 Testing Procedures

A common and easy test is CBC or complete blood count. On almost all laboratory tests, there is a standard or benchmark and the patient= s reading is compared to that. CBC will generally measure white blood cells, red blood cells, hemoglobin. platelets and others.

12.35 Precautions and Reducing Infections

Chemotherapy presents enhanced risk of infection and danger from infection. Most physicians recommend that the patient immediately consult a doctor if they have a temperature above 101. The chemotherapy patient needs to be carefully monitored with precautions taken to prevent infection. Some general precautions against infection:

12.4 CHEMOTHERAPY AND LIFESTYLE CHANGES

Any observer must express tremendous admiration for the typical patient. Chemotherapy can bring major changes to a person's life. It can affect overall health, threaten a sense of well-being, disrupt day-to-day schedules, and put a strain on personal relationships. No wonder, then, that many people feel tearful, anxious, angry, or depressed at some point during their chemotherapy. These emotions are perfectly normal and understandable, but they also can be disturbing. Fortunately, there are ways to cope with these emotional "side effects," just as there are ways to cope with the physical side effects of chemotherapy. (Some time after this was written, a close member of my family contracted a form of cancer, not of the lung. However, I realized that it is far easier to talk about calmness and relaxation as an onlooker, than as a patient or family member).

12.5 SOURCES OF SUPPORT

There are different sources of support for the patient:

Here are some tips from the National Cancer Institute:

12.51 Dealing with Your Doctor

Addressing chemotherapy side effects is one of the most important tasks for the oncologist, but one done with varying skill and empathy. Some doctors can be cold and clinical and others empathetic.

Note that we are in a managed care health system where doctors see substantial numbers of patients each week. Thus, you will want to clearly and concisely explain the nature of your discomfort and side effects. Consider writing down what is occuring, noting frequency, stimuli, and particular sensations.

12.6 RELIEVING STRESS

Some believe muscle relaxation techniques are useful:

12.7 LOSS OF WEIGHT, ANOREXIA AND CACHEXIA

Anorexia, the loss of appetite or desire to eat, is a common symptom in cancer patients that may occur early in the disease or later as the cancer grows and spreads. Cachexia is a wasting condition in which the patient has weakness and progressive loss of body weight, fat, and muscle.

Anorexia and cachexia can occur together, but cachexia is present in patients who are eating an adequate diet but have malabsorption of nutrients. A Tumor cells deprive normal cells of nutrients. Meanwhile the body is expending extra energy as it heals from the effects of cancer surgery, radiotherapy, or chemotherapy. In order to sustain vital functions, the body retrieves nutrients stored in fatty tissue. Once all available fat has been broken down for fuel, it sets to work on muscle. Of all nutrients, protein is the one most essential for building muscle, bone, skin, and blood cells. If the body= s cells consume more protein than you take in, muscle mass rapidly wastes away, causing the emaciated look often associated with cancer.@ (3). Maintenance of body weight and adequate nutritional status can help patients feel and look better, and maintain or improve their performance status. Teely recommends the following:

NUTRIONAL SUPPLEMENTS with your oncologist= s approval.

LIGHT EXERCISE to stimulate your appetite.

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

12.8 LOSS OF HAIR

Loss of hair can be a disturbing side effect of chemotherapy. We associate hair with virility and beauty and its rapid loss can cause significant pain. Today many sports stars like Michael Jordan are bald voluntarily with many others choosing to shave their head. Insurance policies should cover hair replacement since hair loss is a consequence of disease. One should obtain a prescription or note.

12.9 PREPARING FOR CHEMOTHERAPY

12.91 Family Assistance and Personal Information

Chemotherapy can be fatiguing. Have a family or friend accompany you if possible. Prepare an information sheet so a doctor or nurse can quickly get the necessary information about a patient= s history and status.

Personal Information. John Smith, age 63, height, 5-9, weight 165

41 Stone Street, Boston, Massachusetts, Home telephone (948)512-0121, work telephone 943-343-5512.

Current Diagnosis. Non-small cell lung cancer, adenocarcinoma, date of diagnosis 1/7/03, stage 4 metastasis to two areas of bone.

Treatment history. Radiation to lung 10 treatments, currently taking Taxol and Carboplatin.

Physician. Dr. Gordon Johnson, New York Presbyterian Hospital, Office No. 212-565-4300, Beeper 212-656-3222.

Emergency Contact. Wife, Evelyn Smith, home 914-963-5114, office, 914-565-4300.

Allergies. None.

The hospital may already have this information, but checking that things are done correctly, done in a pleasant way, is important.

REFERENCES

CHAPTER 13: RADIATION

13.0 PURPOSE OF RADIATION

Radiation is designed to kill cancer cells in a specified area. Radiation is frequently given in the area of the lung tumor, and sometimes in areas of metastases such as bone. It is designed to improve quality of life by reducing pain and discomfort emanating from a specified area. Radiation does not eliminate metastasis because it does little to alter the overall carcinogenic process.

13.01 Radiation and Stage 1

For early stage tumors where surgery is not an option (for example the patient has a severe heart condition), radiation may be used with the goal of eliminating a small tumor.

13.02 Radiation and Advanced Cancers

More commonly, the goal of radiation is palliative, that is to relieve pain and discomfort. Thus, in a stage 4 patient with metastases, radiation would be used to reduce the tumor in the lung or at the location of the metastasis. Physicians refer to radiation as palliative or local control. The radiation may reduce the size of the tumor and its direct impact, but it generally does not provide an overall cure for advanced cancer patients.

13.021 Radiation as Part of an Overall Treatment Plan

Thus radiation will commonly be used with chemotherapy or gene therapy as part of an overall treatment plan. Scientists continue to debate whether radiation before, after, or concurrent with chemotherapy is most effective.

Radiation in high doses can kill cells or prevent them from dividing:

13.2 TYPES OF RADIATION

The primary type of radiation used for lung cancer is external beam radiation which directs radiation from a machine to the area of the tumor. A type of radiation frequently used with other cancers is brachytherapy, in which a radioactive source is placed inside the body in the area of the tumor.

13.21 Hyperfractionated Radiotherapy

The standard dose of radiation is once daily. In hyperfractionated radiation, the daily dose is divided into smaller doses that are given more than once a day. One study showed beneficial results but increased side effects:

Some HMO= s may balk at the cost of this type of radiation even if there is some research showing its effectiveness. See Coyle(3). However, hyperfractionated radiation is not an unusual or strange therapy, it has been used with other forms of cancer, and there are clinical findings indicating its effectiveness with lung cancer. Thus, it should be a decision of the physician and patient as to its use. I suspect that confronted with a vigorous well-documented presentation, most HMO= s would provide reimbursement for this treatment, even if they initially rejected its use, and did not approve its use for lung cancer on a routine basis.

13.22 Stereotactic Radiosurgery or Gamma Knife

Another newer form of radiation is stereotactic radiosurgery. Currently this is being used to treat cranial metastases. Gamma waves are narrowly directed to specific areas.

13.3 HOW RADIATION IS PERFORMED

13.31 Personnel Involved

There are different medical professionals involved with radiation as follows:

13.4 SIDE EFFECTS

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

13.41 Tiredness

Tiredness and fatigue are associated with radiation, though the precise causes are not known. According to the American Cancer Society Guide, A fatigue is likely to begin early and increase using the course of treatment, peaking between the third and fifth weeks.... Why the body reacts to radiation in this way isn= t exactly understood, though there are a number of plausible explanations. It may be that the healing process drains the body= s energy. Another reason may be the buildup of toxic wastes resulting from cell destruction. An increase in the body= s metabolism may play a role, too. Furthermore, daily trips to a radiation center disrupt the normal activities of life.@ (5).

Are there different types of fatigue, one writer suggests so :

13.411 Measurements of Fatigue

Some use the Piper Fatigue Scale as an objective way of measuring fatigue. A general measure of quality of life is The Lung Cancer Symptom Scale.

13.42 Poor Appetite

Related to fatigue, loss of appetite can result. Changes in some cells affect hunger signals or the stress of illness reduces appetite. However, since cachexia, (loss and body weight and muscle from tumor) can arise, maintaining good appetite and eating habits is important. One study found that while fatigue and loss of appetite were common symptoms, there was no clear correlation between the two. A Fatigue and nutrition are major problems for patients with lung cancer, but nutritional changes do not correlate with fatigue.@ Beach (8)

13.43 Skin Problems

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

13.44 Addressing Side Effects

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

13.45 Measuring the Positive Consequences of Radiation

The primary purpose of radiation is generally to relieve pain or symptoms associated with the disease. For a small group of stage 1 patients ineligible for surgery, radiation= s purpose is curative. In the majority of patients, radiation is designed to kill tumor cells in a specific area and relieve symptoms caused by the tumor. That process may extend life but since a metastatic tumor cannot be completed eradicated by radiation, it generally is not intended to provide an overall cure.

As a tool in relieving pain and discomfort, radiation is frequently successful. A (R)esults suggest symptomatic benefit from radiotherapy even in those NSCLC patients with advanced disease.@ Lutz (12) A The rate of palliation of local symptoms is high, being 60-80% for chest pain and hemoptysis, while breathlessness and cough are controlled at a somewhat lower rate (50-70%).@ Numico (9) A Radical radiotherapy offers palliation of respiratory symptoms and improved QoL (quality of life) in a substantial proportion of patients with NSCLC who have relatively good prognostic features.@ Langendijk (10).

13.5 CURRENT DEBATES WITH RADIATION

Should radiation be used for small cell cancer? While local control is helpful, its utility is debatable since metastasis is the primary danger of small cell lung cancer. A 1997 article argues for its use,

If distant metastases occur, the significance of local control is limited. Many would argue that radiation= s use would be palliative, not curative.

REFERENCES

CHAPTER 14: DEALING WITH THE CONSEQUENCES OF CANCER: PAIN, WEIGHT LOSS, FATIGUE

14.1 FATIGUE

14.11 Disease-related Causes

The tumor's theft of nutrients, a state related to tumor growth, infection, and disruption of cellular processes can account for fatigue. (2) (3)

14.12 Treatment-Related Causes

Radiation is sometimes reported to cause fatigue. One possible cause may be the increased energy needed to repair damaged tissue. Fatigue is likewise associated with chemotherapy. Where anemia results from chemotherapy, fatigue may occur as a result.

14.13 Remedies for Fatigue

Any program should be approved by a physician and is dependent upon the patient= s physical status. Fatigue may be associated with depression. Providing support through family, friends, in-person and on-line support groups can help. Acor.org runs specific programs for lung cancer.

14.2 THE SIGNIFICANCE OF WEIGHT LOSS

A About half of all cancer patients experience a wasting syndrome called cachexia in which the tumor induces metabolic changes in the host leading to loss of adipose tissue and skeletal muscle mass.@ (Tisdale 7). A When the problem is tumor-induced weight loss, increasing food intake isn't the answer, as the metabolic alterations that occur in these patients would appear to prevent the effective use of additional calories, resulting in ongoing wasting.@ Rogers (2) Substantial weight loss is a negative sign in a patient= s prognosis. A Tumor-induced weight loss (TIWL) is a common cause of morbidity and mortality in patients with advanced cancer. It differs from simple starvation in that it cannot be reversed by the provision of apparently adequate nutrition.@ Barber (5), Rogers, (6).

14.21 Distinguishing Cachexia from anorexia.

Anorexia is eating significantly less than normal requirements and should be distinguished from cachexia:

14.22 Increased Consumption of Protein

A Whole body protein turnover has been found to be increased in the majority of advanced cancer patients compared with starved normal individuals and weight-losing noncancer patients and appears to increase further with progression of disease.@ Barber (1) A Cachectic cancer patients exhibit relative glucose intolerance and insulin resistance with an increased rate of glucose production and recycling via lactate (the Cori cycle). These changes may become more pronounced with progression of the disease.@ Barber (1)

The precise mechanisms are unclear. While weight loss is associated with poor prognosis and is frequently seen in advanced cancer patients, cachexia can occur early in the course of cancer. A clear correlation between, for example, cancer size and the extent of cachexia is not seen.

14.221 Influence of Cytokines

One theory is that cytokines such as tumor necrosis factor A mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively.@

14.23 Nutritional Programs

Increasing calorie intake can help mitigate the effects of cachexia. Helping the cancer patient to eat may mean some modifications. A If the patient indicates that they eat best in the morning, the largest meal should be served in the morning and small snacks eaten throughout the remainder of the day. Dietary restrictions should be eliminated since adherence to restrictions may decrease the caloric intake that is essential to the individual with cancer.@ Rogers (6).

One study found that A a nutritional supplement enriched with fish oil will reverse weight loss in patients with pancreatic cancer cachexia.@ Barber (5). A In animals bearing a murine colon adenocarcinoma, EPA - one of the most important fish oil w-3 fatty acids - has been shown to inhibit cancer cachexia...Diets in which 50% of total energy was provided as fish oil also reversed tumor-associated weight loss in rats with an experimental prostate tumor.@ (Burns 11).

The problem is not easily solved. In one study, a program of Total Perenteral Nutrition or (TPN) failed to produce significant improvement in small cell lung cancer patients. Some patients benefit from appetite stimulants like Megace. Disease combined with chemotherapy diminish many patient= s desire to eat. A The appetite stimulant megestrol acetate (Megace) has been reported to induce a weight gain of greater than 5% in 15% of the patients treated, although significant changes in lean body mass were not generally observed.@ (Tisdale 9).

14.3 DEPRESSION

14.31 Incidence

Approximately 40% of lung cancer patients encounter depression with the incidence related to the severity of the disease and its symptoms. Aldridge (13). Various people and people can provide support during this difficult time including: family and friends, nurses and counseling professionals, psychologists and social workers, clergman, cancer organizations like the American Cancer Society and Alcase devoted to lung cancer, and online cancer support groups like Acor.

REFERENCES

15.0 THE EPIDERMAL GROWTH FACTOR PATHWAY_

Duplication of genes is a normal process in the human body. Proteins called growth factors provide signals for cell replication, but malfunctions in these growth factors are a critical part of cancer. A basic model of cancer suggests it is a product of a growth factor prompting unnecesary duplication of cells and the failure of a tumor suppresor gene to regulate them.

A more sophisticated model suggests cancer presents a complex system with many growth factors, multiple tumor suppresor genes, and damage to other cellular regulators. As we enter the 21st century we are learning that both models may be correct for different types of cancers- there are simple ones with only a few components of growth and more complex ones with numerous contributing factors. In the 60's and 70's, we learned that cancers acted differently depending upon their site; today we are seeing that lung cancer represents a heterogenous group of cancers, some of which respond very differently to treatment than others. We now look to one important growth factor, (EGF) and its treatment.

The epidermal growth factor EGF and its associated receptor (EGFR) plays a role in normal human development with functions which include repair of damaged tissue and development of_ new tissue in fetuses. Klein (49). Its role in healthy non-developing adults is unclear, and scientists are not sure whether functioning EGF is needed for normal processes. EGF is a critical factor in various cancers.

The body has mechanisms to deal with chromosome damage, one of which is apoptosis, the elimination of damaged cells. When activated EGF appears to frustrate that process, and has an anti-apoptotic effect protecting mutated cells from orderly elimination. EGFR activation seems to promote tumor growth by sending signals for growth downstream, to other cellular regulators and growth factors.

To initiate cell reproduction, a growth factor links with an associated receptor, like a lock and key. EGF links with EGFR, the epidermal growth factor receptor. A Growth factor receptors are found on the surface of cells and normally play a role in the regulation of cellular growth and differentiation processes. The discovery that these receptors are present in unusually high_ numbers in many tumours then suggested that they play a role in carcinogenesis. Various attempts were therefore made to selectively inhibit {EGFR} signaling pathways. In one approach, antibodies that block the extracellular part of these receptors were developed, while another approach resulted in the development of low-molecular-weight substances known as cell signaling inhibitors that block the intracellular part of the receptors.@ In recent years, the receptor rather than the growth factor itself has become the target of new drugs.

15.1 THE STRUCTURE OF EGFR

The receptor has two basic parts. The first part is called the extracellular ligand-binding domain. There the receptor receives a signal from a growth factor and a process called ligand binding occurs. Once binding occurs, a signal is sent to the second part of the receptor called the tyrosine kinase domain, and a process called autophosphorylation occurs. A chemical change occurs and signals are sent to other cells:_ _ "In each receptor a molecule of adenosine triphosphate (ATP) becomes attached and an energy-rich phosphate group is transferred to the amino acid tyrosine. Activation of tyrosine kinase and phosphorylation of tyrosine residues leads to activation of intracellular signaling pathways." Roche (61).

15.12 The Tyrosine Kinase Portion of the Receptor_

What does the tyrosine kinase do?

In cancer, the signals generated by this chemical process are abnormal, and other cells are told to duplicate or perform other aberrant functions. Tyrosine kinases are becoming a primary target for cancer research:

Cancer drugs can work in two basic ways, they can try to prevent binding, or autophosphorylation. The fact that there are two separate functions means that drugs may later be combined, and anti-EGFR drugs are likely to have different degrees of effectiveness depending upon the specific area of cell damage in the epidermal growth factor receptor.

EGFR is part of the Erb family of receptors, and is also called Erb1. There are four receptors in the Erb receptor family, Erb1, 2, 3, and 4. It would be simple if there were a single growth factor and single receptor. Unfortunately the human body is far more complex. Multiple growth factors can contact EGFR to initiate signaling. The primary one we address here is the epidermal growth factor. In a simple model, EGF contacts EGFR. In a more complex but accurate model, other growth factors may contact EGFR, and when binding occurs, EGFR will send signals to other members of the Erb family, "cross-talk."

15.2 CLINICAL TRIAL RESULTS

Initial studies with Iressa found that about 12% of patients achieved a partial response, that is, reduction of 50% of the tumor. More patients found their diseases stabilized. FDA Trial 16 found about 35% of patients experienced disease stabilization ._ _ FDA (1). In addition to extending life, the drug improved quality of life, with one third of patients reported relief of at least one pulmonary related symptom. FDA Advisory Committee (1). Funokuora reported symptom improvement rates of 40.3% and 37.0% in his study. (45). Nonetheless, Iressa did not significantly extend life for most patients, though disease stabilization and symptom relief were clearly important.

Based upon these studies, the FDA approved Iressa for third line treatment of non-small lung cancer. That is, Iressa would be recommended after two types of chemotherapy were no longer effective. Chemotherapy has response rates of about 20%. Because these response rates were higher than Iressa's 12%, the new drug could not be recommended for routine treatment. Nonetheless, Iressa was reported to improve symptoms and stabilize disease in some patients along with providing responses in some. Therefore, Iressa was approved as third line therapy, to be used after platinum based chemotherapy (Cisplatin or Carboplatin) and Taxol. While the FDA's recommendation is important, physicians can prescribe the drug off label, in other ways. Further studies reported in 2003 and 2004 have provided important information about who is likely to benefit from Iressa.

The category non-small cell lung cancer includes adenocarcinoma, squamous cell carcinoma, large cell cancer, and a host of subgroups within these categories. In the past 40 years, many similarities among these types were found, particularly their responsiveness to radiation, chemotherapy, and surgery. Non-small cell lung tumors share the common characteristic of behaving differently than small cell cancers. Within the non-small category, treatment has been essentially the same for all three types for the last half century. This may change with Iressa.

Recent studies found that patients with bronchioloalveolar lung cancer (BAC), a subtype of adenocarcinoma, particularly seemed to respond to Iressa. Additionally, non-smokers with lung cancer also benefited:

The authors then tested tissue from lung cancer patients and found the type of damage to the tyrosine kinase to be relatively rare. Only one of sixty one randomly selected patients had it. However, almost all who responded to Iressa had it._ _ Cell analysis confirmed the efficiency of Iressa. When cells from patients with the defect were tested, Iressa was effective at 100 milligrams. However, 100 times the dosage was required to duplicate that response with other cell lines. Paez (56). Genetic testing of patients to determine whether they are likely to respond to Iressa makes sense. The how, why, and cost of such testing remains to be determined.

Other studies have shown similar results. In one study, non-smokers had a response rate of 29.4% (10/34) compared with 4.6% (5/108) for smokers. FDA (1) (43). In Wong's study, "6 out of 7 responders were non-smokers." FDA Center (48, at 7). In Shah's study, "bronchioalveolar carcinoma and having never smoked were the only predictors of response." FDA Center (48, at 7).

A clear pattern is arising. Iressa is very effective with patients with tyrosine kinase defects. Nonsmokers, patients with BAC, and some adenocarcinoma patients appear to have that genetic damage, it plays a prominent role in their cancers, and Iressa is effective for a substantial percentage. The response rates for BAC patients and non-smokers far exceed those with chemotherapy or radiation.

Nonsmokers are unlikely to have the extensive genetic abnormalities affecting growth factors, receptors, and tumor suppressor genes that smokers have. Instead their tumors appear to be largely EGFR driven, and for some, Iressa the silver bullet that attacks the specific abnormality. For non-smokers and brief former smokers, a single or small number of gene abnormalities is causing or prompting their cancers. Thus, if that area of damage can be identified and addressed, the prognosis may be good.

15.231 Should Iressa be First-Line Treatment for BAC Nonsmokers and Adenocarcinoma Patients?

Physicians will need to investigate whether Iressa should be first-line treatment for patients in this group. Currently Iressa is recommended as third-line treatment after two forms of chemotherapy. See FDA (1). However, Iressa's 35-40% response rates with certain groups dwarfs the 20% response rates found in chemotherapy. Additionally, since Iressa targets only a specific kinase, it generates far fewer side effects than chemotherapies which impact a large number of dividing cells.

Whether oncologists will accept these results and prescribe Iressa first-line for BAC and adenocarcinoma patents, particularly nonsmokers, remains to be seen. Some will follow the current FDA recommendations which recommend Iressa as third-line treatment, and wait for a pronouncement from a major organization before adopting a different approach. Major research institutions may be more agressive and innovative in treatment strategies. Patients will have some tough decisions and may switch oncologists to obtain what they see as the most beneficial treatment.

15.232 Insurance Questions

Insurance issues will arise. The studies indicate cell testing can predict who is likely to respond to Iressa. Will insurance pay for such testing? Since that test is not publicly available, the cost is uncertain.

Results are discouraging for squamous cell and large-cell patients. Few responses came in these two groups and the pattern of genetic damage in the tyrosine kinase region does not appear to be generally present in squamous cell or large cell patients.

The FDA recommendation and findings would seem accurate for these groups. That is, Iressa is third line treatment to be used after two forms of chemotherapy are no longer effective. The overall response rate for Iressa was about 11%, we now know that the rates are appreciably higher for certain forms of cancer, and correspondingly lower for squamous cell and large cell. For the squamous cell and large cell groups, Iressa may stabilize disease and relieve symptoms. This is presumably because EGF plays some role in cancer spread, but not a critical or dispositive one for these patients.

An ASCO presentation (American Society of Clinical Oncology) suggested there are three groups involved with Iressa response. First are adenocarcinoma and BAC patients, non and former light smokers with tyrosine kinase damage, who will substantially benefit from Iressa, secondly, squamous cell and other patients may secure a modest benefit from Iressa, and thirdly, those with properly functioning EGFR but other abnormalities who will receive no benefit from Iressa.

Some of these patients may look to other forms of treatments. If the patients do not have the defect in the tyrosine kinase region, a tyrosine kinase treatment seems misdirected. For EGFR treatment, they might consider Tarceva which attacks the binding process or other drugs. Perhaps their cancers are not primarily EGFR driven in which case other types of treatment like cox-2 inhibitors and anti-angiogenic drugs are preferable. More research is needed. In the upcoming months, cell tests may be developed, and drugs could be tested in a laboratory rather than on the patient.

For patients of all types, when can a response be expected? Trial 39 reported, "the majority of patients (72%, 16/22) who achieved a response did so by the third (4 patients) or fourth week (12 patients); 3 patients achieved a response by week 7, 1 by week 12, and 2 by week 16. FDA (46). The final FDA report likewise concluded that those who benefit do so relatively quickly: "Many patients had a prospectively defined improvement in disease-related symptoms: the symptom improvement rates were 40% in IDEAL 1 and 43% in IDEAL 2. Symptom relief was rapid: the median time to improvement was 8 days in IDEAL 1 and 10 days in IDEAL 2 (the times of the first post-baseline assessment for each study).

There was a significant improvement in disease-related symptoms in most patients with a partial/complete response or stable disease in the FDA Ideal studies. Natale (8). Response is correlated with the development of a rash.

15.26 Dosage

Optimal dosage remains unclear. Some studies reported no significant increase in efficacy from 250mg to 500mg. The FDA evaluated both 250 mg (milligrams) per day and 500 mg dosages, but reached no clear conclusion. In their studies, the efficacy was similar between two dosages with some fewer side effects at the lower dose. FDA (46), at 51. The FDA also noted a higher response rate for women than men. More women experienced tumor responses at either the 250-mg/day and 500/mg day doses." (FDA 47). In trial 39, the response rate (diminution of 50% tumor volume) for women was 17.5% but 5% for men." FDA statistical review, 48 at 4. Janne found all those who had responses were women. FDA statistical review. _ FDA Approval Package at 62.

15.3 IRESSA AND CHEMOTHERAPY AND RADIATION

The use of different drugs in combination has become standard in treating lung cancer. Logically one could believe that Iressa would compliment chemotherapy and there are cell studies supporting that hypothesis:

While commentators suggested that Iressa would improve chemotherapy= s effect, a positive result was not demonstrated in a recent clinical trial.

Two large scale clinical trials found Iressa did not improve the effects of chemotherapy. (50). The well-publicized clinical trial compared patients who took chemotherapy and Iressa with those who took chemotherapy alone. The group taking the combination did no better than the group using chemotherapy alone. Rates of survival, partial response, and complete response were similar between the two experimental groups using 250mg and 500 mg Iressa + chemotherapy, versus the control group taking chemotherapy alone with placebo.

The lack of benefit may be a product of a plateau effect known in other areas where the addition of new drugs does not significantly improve results. For example, adding a third chemotherapy drug to a patient= s treatment does not significantly improve response rates or survival. The patients were in a group with very advanced cancer, so either chemotherapy alone or with Iressa could provide only limited help. The study was limited to patients with advanced lung cancer. It remains to be seen whether earlier intervention with a combination of chemotherapy and Iressa would be beneficial to patients with less advanced disease.

15.4 SIDE EFFECTS

The most prevalent side effect is a localized rash. Patients have reported it but it appears to be localized and is not usually serious. Additionally, some studies have found the existence of a rash indicates Iressa is working with patients with rashes having longer survival rates, though other studies found no impact. (53)

Diarrhea though not particularly severe has also been reported.

15.43 Pneumonitis

One serious side effect has been an unusual form of pneumonia. Pneumonia is associated with lung cancer and chemotherapy generally. However, there have been a series of pneumonitis deaths linked to Iressa initially reported in Japan:

FDA describes the onset this way, A patients often present with the acute onset of dyspnea (difficulty breathing), sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization.@ FDA (1).

Careful monitoring for this side effect has been recommended. Patients on Iressa should monitor temperature rises, fevers, and immediately report problems to their oncologist. FDA suggests that A persons with concurrent pulmonary fibrosis have a higher mortality rate.@ This would presumably include people with silicosis, asbestosis and similar fibrotic disease.

15.5 OTHER EPIDERMAL GROWTH FACTOR THERAPIES

Tarceva (also called OSI-774 or Orlotinib) is a less publicized epidermal growth factor inhibitor. Like Iressa, it is directed to the tyrosine kinase portion of the epidermal growth factor receptor. A phase 1 clinical trial reported, A OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease.@ (17). One study found a 12% response rate with symptom improvement, findings similar to Iressa. Perez-Soler (59). Like Iressa, the occurence of a rash correlated with response to the drug. An important study compared Tarceva with a placebo and found it improved survival. Asco (63).

Initial results are similar to Iressa, with a response rate of 9%, a small bit lower than Iressa but within the range of chance. As with Iressa, non-smokers seem to benefit most with Iressa. 25% of non-smokers responded compared with 4% of smokers. Asco (63). For smokers, the survival rate was almost the same with or without the drug. See Asco (63) citing Tribute trial.

The percentage of adenocarcinoma responders was 14% compared with 4% for other. Women had a 14% response rate compared with 6% for men. Interestingly, performance status, a measure of how sick the patient is as indicated by mobility and like factors was not a significant factor. As with Iressa, there appears to be a narrow group of non-smokers with adenocarcinoma who benefit greatly from Tarceva. At the other end, smokers with squamous cell cancer and normal functioning EGFR seem to benefit little, if at all. In the middle, there seems to be a group who have a modest benefit in disease stabilization, and a mild increase in survival, with that group perhaps having small abnormalities in EGFR, or multiple growth factors.

An important blind trial assessed side effects, with patients not knowing whether they were being given placebo or Tarceva. Many side effects were reported including anemia, vomiting and fatigue. However, the results for most side effects were essentially the same for placebo and drug._ _ Two were significant. Again, patients reported a rash at substantially higher rates. Diarhrea was higher with the drug. Patients participating in the Acor online newsgroup reported though, that it could be controlled.

One study showed no substantial benefit from adding Tarceva to chemotherapy, mirroring results with Iressa. Asco (63)._ _ However, favorable results were reported with a combination of Bevacizubak and Tarceva. (Asco (63). The 51% one year survival rate was higher than the 34% one year rate reported in the Tarceva trial alone.

An application has been submitted to the FDA, with a presentation similar to Iressa focusing on disease stablization and symptom relief. Since its mode of action is similar to Iressa, it is unclear what Tarceva does that Iressa does not.

Erbitux (IMC-C225 or Cetuximab) is a monoclonal antibody (Maps) directed against ligand binding in the extracellular domain of EGFR. While it is an epidermal growth factor inhibitor like Iressa, it has a different mode of action, since it prevents ligand binding rather than autophosphylation. Erbitux has been used with colon cancer. (58)

Adding Iressa to chemotherapy provided no additional efficacy. However, the combination of Erbitux and chemotherapy did create higher response rates in a clinical trial. Molecular mechanisms predicting response to cetuximab therapy are currently not well understood and studies are ongoing to assess the single-agent activity of cetuximab in metastatic NSCLC. Mattar (56).

As we saw above, squamous cell and large cell patients generally had few responses from Iressa. These patients generally did not have the tyrosine kinase damage that is the hallmark of the non-smoker BAC lung cancers that responded to Iressa. For squamous cell and large cell patients, Erbitux should be considered since its mode of action may conceivably be more effective against these cancers. More research is needed and how much weight a single clinical trial should be given is difficult to say.

Herceptin (Trastuzumab) has been FDA approved for metastatic breast cancer. The drug targets Erb2 which is a A molecular marker of ductal breast cancer although it is overexpressed in other adenocarcinomas as well (e.g. endometrial, colorectal and lung cancers).@ While drug effectiveness is organ specific, lung, colon, and breast are categorized as solid tumors and have some common characteristics. For example, the chemotherapy drug Taxol is used for both breast and lung cancer.

A The safety and effectiveness of Herceptin were studied in two trials with women whose metastatic breast cancers produced excess amounts of HERB 2. In one clinical trial, women received either Herceptin and chemotherapy or chemotherapy alone. The women who received Herceptin and chemotherapy had slower tumor growth, greater reduction in tumor size, and longer survival than the women who received chemotherapy alone. In another trial, women received Herceptin by itself. In 14 percent of these women, the tumor got smaller or disappeared. Scientists continue to study the safety and effectiveness of Herceptin in clinical trials.@

The FDA has not approved Herceptin for lung cancer. Since it is an FDA approved drug, a few physicians might consider it for lung cancer. The role of Erb2 in lung cancer is unclear. A 2002 report found that patients who overexpressed erb2 had poorer survival. Predictive Role of Her-2 (30).

The National Cancer Institute provides this list of side effects for breast cancer patients taking Herceptin.

There were also a small number of reports of heart problems.

Iressa is designed to inhibit one specific epidermal growth factor receptor at erb1. A new drug developed by Pfizer, CI-1033 was created to inhibit the entire family of receptors at erb-1, and erb-2-4.

15.541 Side effects

If targeting one receptor has caused only limited side effects, targeting the family of receptors seems to have increased adverse effects. A study reported about a one forth of patients experiencing nausea, vomiting or diarrhea. (Asco 33).

15.542 Irreversibility

It appears the impact upon epidermal growth factors is irreversible. (34). That fact may indicate it is more powerful, but should be used only on patients with advanced cancer.

15.55 Relationship Between EGFR and Erb2

Some preliminary studies have found that two or more of the epidermal growth inhibitor drugs can be used together with increased effectiveness. Normanno (26). EGFR or Erb1, the target for Iressa, and Erb2, the target for Herceptin, are part of the Erb family. Some suggest that activation of Erb1 may prompt or coincide with activation of Erb2. A Co-expression of EGFR and its ligands has also been found in primary breast carcinomas, suggesting that an autocrine loop may be operating in these tumors.@ Given that the two receptors are related, using two drugs to target the combination makes logical sense.

Surprising and disappointing many, Iressa and related therapies have not improved the efficacy of chemotherapy according to two clinical trials.

Combining two types of drugs makes sense particulary among those patients without a clearly identifiable tyrosine kinase defect. Some have found success with dual treatment in cell studies.

Given the limited response to Iressa among squamous cell and large cell patients and tolerability of EGFR drugs, a combination makes sense for these groups. For these groups, Iressa is unlikely to provide significant relief, while a drug combination holds forth that possibility.

Celebrex is a Cox-2 inhibitor. Since Cox-2 plays an important role in lung cancer, scientists have looked at combining the two treatments.

15.7 CELL TESTING

The Harvard Gene laboratory is now offering a test to detect EGFR mutations. Their press release states:

It appears the test will cost $895.00. What type of sample is needed is unclear, though samples from a standard bronchosopy may be sufficient. One can presume cost will decrease, health care insurers will arrange for volume discounts, and other laboratories will develop similar tests. At this time, doctors and patients will want to consider tests to identify the treatment most likely to benefit them. Basically, adenocarcinoma and BAC patients, particularly non-smokers and light former smokers will want to consider Iressa and have the test to confirm tyrosine kinase mutations. Smokers with squamous cell cancer may want to use the test to exclude Iressa, or use it in conjunction with other drugs.

67. Research continues. One study found EGFR positive cells,

16.1 ANGIOGENESIS

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

16.11 What is Angiogenesis?

Angiogenesis is the disturbing ability of cancer cells to form new sources of blood supply to facilitate their expansion into other organs.

16.12 Size and Angiogenesis

The process of angiogenesis is necessary for tumors to survive, and conversely, shutting off or inhibiting the process may limit the spread of the cancer or even reduce the size of the tumor itself:

A One promising avenue of cancer research is the study of a group of

16.13 Practical Difficulties with Anti-Angiogenesis Drugs

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

16.21 Overview

Newer therapy attempts are being made to frustrate cancer spread through molecular therapy. The task is to identify agent with tumor specificity and low toxicity. More specifically, we want to identify a molecular target

Stating goals is easier than meeting them. A May 21, 2002 article provides a summary of anti-angiogenic agents:

16.31 Neovastat

In laboratory studies, Neovastat was shown to be effective in inhibiting angiogenesis and improved the efficiency of standard chemotherapy drugs:

Neovastat is derived from cartilage of the dog-fish shark. Shark cartilage was a controversial experimental treatment advocated in the early 90's featured in a book, Sharks Don= t Get Cancer.

16.311 Human Studies

There are reports (as indicated above) of favorable human studies.

However, as of June, 2002, we were unable to locate these in a recognized medical journal. One article states,

However, the citation is to an article in progress. An intelligent assessment of Neovastat must await published results. Based on the reports, it may be a plausible alternative for patients with advanced cancer.

In the 60's, Thalidomide was source of birth defects, as it cut the supply of blood and the development of new vessels in the fetus. It is precisely this characteristic which indicates promise as a potent anti-angiogenic agent.

If nothing else, the story of Angiostatin and Endostatin is a lesson in the tendency of early clinical results to be given excessive weight, the tendency of news reporters to herald a new cancer cure from limited results in a single animal study, and the interrelationship between corporate goals and scientific research. After numerous early studies on the theory of angiogenesis, Dr. Folkman, a Noble-Prize winning Harvard researcher, reported that tumors in 50% of rats were markedly reduced by administration of Endostatin. The results became national, indeed, world-wide news as the new media profiled the new cancer cure.

Later scientists had difficulty reproducing the results and in any event, the promise was not translated to human studies. Today the future of Endostatin and Angiostatin remain uncertain, and are one of perhaps five hundred anti-cancer drugs which continue to be investigated.

However, translating theoretical effectiveness to practical results and getting the drug to where significant results can be achieved has been the difficulty.

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

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

16.41 Cox 1 and 2

16.411 Cox-2's role in Inflammation and Cancer

While Cox-1= s role helps regulate many normal bodily functions and is present in normal tissues. Cox-2= s role is more specialized. Cox-2 is produced in response to injury and is associated with inflammatory processes involving repair. Cox-2 is frequently undetectable in normal tissue, but is induced by cytokines, growth factors, and chemical carcinogens, and intercellular signals indicating cell damage. Cox-2 is present in many cancer cells of various types, and is specifically associated with various carcininogenic behaviors. Overexpression of tumor Cox-2 may be important in angiogenesis, resistance to apoptosis, suppression of host immunity. A Moderate to strong Cox-2 expression was detected in approximately 40%-80% of the total neoplastic (cancer) cells in most tumors. In addition to expression of Cox-2 within neoplastic cells per se, Cox-2 was also detected in the angiogenic vasculature present within the tumors and preexisting vasculature adjacent to cancer lesions. Cox-2 was observed in the angiogenic vessels in most of the human cancers analyzed thus far, including head and neck and pancreas@ Maspherer (17). A 2004 study suggests Cox-2 induces VEGF (see below) and Erb 2 production. (14).

16.42 The Role of Cox-2 in Lung Cancer

Cox-2 is involved with the development and spread of lung cancer.

One study found Cox 2 expressed in over 90% of adenocarcinomas, a type of non-small lung cancer. That study found that tumors that overexpressed p53 (mutant or disfunctional form) had higher levels of Cox-2.@ (6). Cox-2 inhibitors have shown success in a laboratory setting:

16.43 Success of Cox-2 Inhibitors

Developing a new drug poses two important challenges. First, how does one deliver the drug to the relevant area. This is where many anti-angiogenic drugs have failed; in cells tests, the drug suppresses cancer cells in the laboratory or in large quantities upon an animal, but in the complexity of the human body, little impact is seen. Secondly, how do we avoid disruption of normal cells and bodily functions, the obstacle facing many chemotherapy drugs. These problems have been solved to some extent with Celebrex and other drugs.

Celebrex has been able to reduce the inflamation associated with arthritis for many people, displaying few side effects. A NSAID's have been widely used with comparatively few side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) annually account for 70 million prescriptions and 30 billion over-the-counter (OTC) medications sold in the United States alone.@ The side effects appear limited compared with traditional forms of chemotherapy. Cox-2 inhibitors represent a promising alternative in treatment with established impact and limited side effects.

16.44 Celebrex

Maspherer (17) showed that Celebrex suppressed growth of lung and colon tumors in mice, A Celecoxib supplied in the diet continuously from date of implant at doses between 160-3200 pip significantly retarded the growth of these primary tumors. The inhibitory effect of celecoxixib was dose dependent and ranged from 48% to 85% when compared with untreated tumors.@

16.45 Side Effects

NSAID's have been used for the past decade with comparatively few side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) accounted for 70 million prescriptions and 30 billion over-the-counter (OTC) medications sold in the United States. Nonetheless, in 2004, heart problems were seen with both Cox-2 inhibitors, Vioxx, and Celebrex. In a placebo trial for early stage colon cancer, users of Vioxx had almost twice the risk of serious heart disease:

Vioxx was recalled because a clinical trial identified a substantial increase in heart attack or stroke. These findings were significant for the target group, healthy primarily middle aged patients with arthritis but in otherwise decent health.

Different considerations would apply to the use as an anti-cancer drug, particularly among stage 4 patients. Many stage 4 lung cancer patients would expire from cancer causes during a three year study period. If the drug increased life expectancy, a small increase in cardiac events might not preclude the use of the drug in a high-risk population. The above trial compared the drug with placebo, if compared with powerful chemotherapy drugs, the cox-2 inhibitors might well be less. Clinical trials are needed to test Vioxx and other drugs in stage 4 patients.

16.46 Celebrex

Initially some thought the adverse risks were limited to Vioxx. In late December, 2004, a clinical trial reported similar hazards from Celebrex. A The Food and Drug Administration on Friday warned physicians to consider alternatives to the popular arthritis drug Celebrex because of new evidence that, like the similar drug Vioxx, removed from the market in September, it doubles the chances of heart attacks and strokes.@ (25 FDA Warns of Health Risk).

16.47 Assessing the Risks of NSAID= s

Why do it? Why risk it? He didn= t die from the cancer, it was the drug they gave him that killed him, some family members will say while considering legal action. Indeed, as lawsuits against Pfizer and Merck (makers of Celebrex and Vioxx) are being readied, some of those lawsuits will include claims against physicians who failed to investigate risks, failed to notify patients, and are otherwise liable for adverse events connected with the drugs. Most physicians will not want to risk years of litigation and potential liability to provide a drug whose efficacy is debated.

Celebrex= s availability may be limited to clinical trials, or university settings where warnings of adverse events are prominently displayed, and use is carefully circumscribed.

16.472 Considerations for the Patient

For the stage 4 lung cancer patient, Celebrex may still be an option. The course of the disease presents serious risks, chemotherapy is not a permanent cure, and health effects from Celebrex may still be less than those of other drugs. Celebrex does not cause nausea, hair loss, and other discomfort like, for example, the widely used chemotherapy drug Cisplatin. Clinical trials may continue to examine Celebrex= s efficacy, alone or with chemotherapy.

16.5 VEGF INHIBITORS

Vascular endothelial growth factor (VEGF) is associated with angiogenesis and metastasis and is thus a target for new drugs. A VEGF stimulates new blood vessel formation, or angiogenesis, by binding to specific receptors on nearby blood vessels to stimulate extensions to existing blood vessels.@ Gene.com (12)

16.51 The Rationale for VEGF Receptor Drugs

A growth factor comes into contact with a receptor, like a key and lock, and begins a process of cell reproduction and changes. Some newer drugs attempt to prevent the two from connecting. The process is complex since related growth factors and receptors are activated also. As with other forms of gene therapy, targeting the offending protein rather than all cells can reduce harmful side effects. A The high selectivity achieved with neutralizing antibodies, soluble receptors and ribozymes reduces the risk of adverse reactions not related to VEGF inhibition itself.@ Investigational Drugs (13).

16.52 Flovopirodol

The drug is an analogue of a naturally occurring flavonoid isolated from the stem bark of Dysoxylum binectariferum, a plant native to India. Shapiro (10).

Results in a phase 2 trial were modest. No complete or partial responses were observed. Thus, the drug is unlikely to be effective alone. However, a limited impact was seen and toxicity was also limited. Flovopirodol holds some promise as a treatment in conjunction with chemotherapy. See ElSayed (12). Clinical trials comparing chemotherapy with and without the drug can be performed.

16.53 Avastin

Avastin also known as rhuMAb VEGF or bevacizumab, is a promising anti- VEGF drug:

A VEGF stimulates new blood vessel formation, or angiogenesis, by binding to specific receptors on nearby blood vessels to stimulate extensions to existing blood vessels. Research has shown that angiogenesis, by supplying blood to tumors, plays an important role in both tumor growth and metastasis.... Genentech scientists developed a humanized antibody, rhuMAb-VEGF, that is designed to bind to VEGF preventing it from binding to its receptors and therefore potentially inhibiting tumor growth.@ (16).

See( 23) Anti-Angiogenic Therapy

Some increased side effects were seen with an increase rate of neutropenia and a small increase in hemorrage. Thus patients should be carefully monitored. (14). A prior trial had found squamous cell patients to be particularly at risk. Whether the type is significant or coincidental needs to be determined. Some insurers will not cover the cost of Avastin outside of adenocarcinoma.

16.6-7 RESERVED

16.8 P-53 GENE THERAPY

16.81 P-53's Functions

P-53 is perhaps the most important tumor suppressor gene.

Consider its importance in cancer research:

Study of P-53 is important for several reasons. First, P-53 may be an indicator of cancer or carcinogenic processes. Thus P-53 presence might be tested in smokers to determine who is at risk. P-53 may be assessed in patients particularly stage 1 patients whose tumors were removed. Abnormal levels of P-53 might indicate the need for further treatment even where no signs of tumor are apparent on CT or other test. Finally P-53 research holds forth the possibility of improved treatment - a vaccine perhaps- to be used alone or with existing treatments like chemotherapy or radiation.

16.811 Description of P-53

P-53 is a protein of 53 kilodaltons (hence the name). It is located on chromosome 17 (p13). There are two types of P-53. First, we have 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, it may even contribute to carcinogenic processes:

P-53 protein is located in the nucleus of cells and is unstable. In a normal person, the body activates P-53, it performs its function of either correcting cell damage or inducing the death of damaged cells, and disintegrates. Malfunctioning or mutant P-53 can maintain itself in cells with the finding of P-53 indicating an abnormality. P-53 damage is seen in approximately 50% of breast colon, stomach, bladder, and non-small cell lung cancers. In non-small cell lung cancer (NSCLC), most series report that 50% to 60% of tumors have identifiable mutations. A 1999 study found that over 50% of small cell patients had traces of P53 in bronchial specimens.

16.812 When Do P-53 Mutations Occur in the

Cancer Process?

Scientists have not been able to determine precisely when P-53 mutations occur. Curie suggests P-53 alteration is an early event:

Szak in contrast postulate that P53 mutations occur about midpoint in tumor development, just as damaged tissue becomes cancerous, A Most studies indicate that in the development of squamous cell lung cancer, loss of heterozygosity at 17p (suggesting loss of wild-type p53 function) occurs at the transition of preneoplasia to carcinoma in situ.@ (7)

16.82 P-53 and Patient Prognosis

Determining P-53 impact upon lung cancer prognosis has been unclear:

One hypothesis is that even after a tumor has developed, P-53 can play a role in limiting cell proliferation. We know that there is a group of tumors where apoptosis, or cell death, equals proliferation, and those patients have a good prognosis. Under this theory, P-53 mutations would affect survival for early stage patients, but only minimally impact patients with advanced tumors, where P-53 would be limited in its function:

Even here, though, results are equivocal. Szak states,

16.83 The Rationale for Treatment

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

In NSCLC it was initially shown that introduction of a vector containing the wt-53 (wild type) into cell lines, which {had} either a deletion or a missense mutation in p53, markedly reduced cell proliferation and tumorigenicity.

16.84 Studies and Trials Using P-53

Some limited, promising results were seen in phase 1 P-53 clinical trials. In one trial, tumor regression was seen, though it did not affect survival since the patients had advanced metastatic cancer. A recent trial found no impact of P-53 treatment, A There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone.@ (1). The treatment cannot be disposed of based upon one clinical trial. In the study, P-53 patients had slightly more favorable results. More importantly, it may be possible to develop more effective methods of delivery.

One strong argument for gene therapy is that the therapy will have limited side effects. Chemotherapy targets or affects different groups of dividing cells, cancerous and normal. On the other hand, gene therapy is designed to create new sources of P-53, and the presence of additional P-53 in the body, or the performance of ordinary functions by P-53, should not involve significant side effects.

16.85 Hurdles to Successful Treatment

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

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

16.86 Use in Conjunction with Chemotherapy

The optimal use of P-53 treatment may be to compliment chemotherapy. That type of role must be confirmed in human clinical trials which is one reason why at the time of publication, P-53 was not an FDA approved drug. In one well-known study, that complimentary impact was not demonstrated.

16.9 CONCLUSIONS AND DIRECTIONS FOR
FURTHER RESEARCH

The suppression of normal P-53 and expression of its mutated form, expression of Cox-2, the production of epidermal growth factor, expression of VEGF, are steps in the development and spread of lung cancer, with each step a target for research and treatment. Lung cancer has been difficult to cure, probably because so many genes are disrupted, and repair of a small part does not restore normal functioning. Thus future treatment may focus on the use of a variety of drugs, to the extent possible without substantial side effects.

We review treatment by stage in later chapters, but a brief summary is appropriate here. One difficulty with today= s treatment is that newer drugs are tested upon the patients with the most advanced illnesses, and thus the toughest to cure. Lung cancer patients tend to enter clinical trials when other forms of treatment have been exhausted.

Unfortunately, the only reliable cure has been surgical removal of tumors in stage 1 patients, and even then here is approximately 30-40% recurrence. Patients may want to consider promising newer forms of treatment at earlier stages. The downside is that the drugs are unproven. The upside is that if the side effects are limited, the patient can benefit at a time when the disease is not advanced.

Drugs like Celebrex present tough choices but may still be an option for stage 4 patients notwithstanding the various side effect. Patients may want to consult with major research facilities and monitor the medical literature for important developments.

REFERENCES

22. Cancer Therapy,www.conference-cast.com/ webtie/sots/lung/transcripts/teichertran.htm

23. Anti-Angionenic Therapy for Advanced NCSLC, www.professional.cancerconsultants.com

In the next four chapters, we take our knowledge of lung anatomy, chemotherapy, surgery, and radiation, and apply it to non-small cell lung cancer, the most common form of lung cancer. Treatment is divided by stage, with each chapter reviewing treatment of a particular stage. The material can still be challenging, though I believe a good knowledge of this will be important for the patient or family member seeking to understand the nature of treatment and any options presented.

17.01 Suggestions to Make the Material Easier

Try to read each section, consult the definitions at the end of the book, and have a medical dictionary on hand. If you become confused about different stages, review the discussion of different stages. If you are able to digest the information here, you may be able to reduce the general information which takes up time in doctor-patient conferences, better understand your condition and the treatment which is proposed, and be able to ask your physician knowledgeable questions about treatment procedures and alternatives.

17.02 Division into Stages 0, 1a, 1B

Scientists divide stage 1 cancer into three substages: occult, also called stage 0, the very earliest type of tumor, stage 1A, a small discrete tumor with no involvement of the main bronchus or adjoining areas, and 1B, a tumor with no lymph node involvement or metastasis, but which is larger than 3cm, had made contact with the main bronchus, visceral pleura, or is associated with pneumonia or ateclasis.

STAGE TUMOR SIZE POSITIVE NODES FIVE YEAR

As the tumor increases in size, the patient= s long-term survival prospects decrease though they still remain excellent throughout stage 1. The division into three stages reflects increasing specificity and sophistication in the treatment of these early stage tumors. For all stages, surgery will be recommended if the patient is in good health, and specifically, has sufficient pulmonary reserve- enough breathing capacity to survive the removal of a sufficient part of the lung. The hot topic today is whether some type of treatment before or after surgery should be recommended before a recurrence is seen and to improve the patient= s prospects. Clinical trials are investigating whether chemotherapy before or after surgery should be prescribed, and before any evidence of spread of the tumor is observed.

Additionally, scientists are investigating whether molecular markers can detect a subset of patients whose tumors are likely to spread, and to prescribe therapy for those patients before the tumor does spread. Because these approaches are experimental, they are likely to be utilized only in a university setting.

17.1 OCCULT TUMORS

An occult cancer is a microscopic tumor which cannot be seen on a

chest x-ray. Tumors discovered in this fashion are very early stage and given their limited area and lack of metastasis, usually cured by surgery.

17.11 Why Most Occult Tumors are Squamous Cell

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

17.12 Sputum Cytology as a Tool for Early Detection

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

17.13 Treatment Similarities to Stage 1a Tumors

An occult tumor detected by sputum cytology, and a small tumor detected on a CT Scan which has not metastasises to a lymph node and has a limited area, are generally treated in the same fashion. If the patient is in good enough shape for surgery, the tumor is surgically removed and the patient has an excellent prognosis, with five year survival rates ranging from 70-85%, depending upon the study.

17.14 Phototherapy

Phototherapy is an alternative to surgical resection in certain patients. This investigational treatment seems to be most effective for very early central tumors. A recent article discusses photodynamic therapy and its use with Stage 0 patients:

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

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

17.2 SURGERY AND STAGE I NON-SMALL CELL LUNG CANCER

Surgery, specifically a lobectomy- removal of the affected lobe of the lung and surrounding tissue, is the preferred option for stage 1 patients. Stage 1 patients whose tumors have been surgically removed have an excellent prognosis, with five year survival rates ranging from 55% to 85%, depending upon the study. (Since the occult tumors are even smaller, the survival rate is even higher).

17.22 Surgery and Pulmonary Reserve

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

17.23 Radiation for Stage 1 Patients with Diminished Pulmonary Reserve

NCI states,

17.3 POST SURGICAL CHEMOTHERAPY FOR

STAGE 1 TUMORS

17.31 The Argument for Chemotherapy and or Radiation Following Surgery

Even though stage 1 patients have a good prognosis with the surgery having apparently removed the tumor, approximately 40% of patients will develop metastasises to lymph nodes and other organs. As the tumor spreads, it becomes increasingly more difficult to treat. Would it not make sense to provide some type of prophylactic chemotherapy or radiation designed to kill any cancer cells not visible to the human eye to prevent relapse? That is the question scientists are confronting.

With occult tumors and stage 1A tumors, one may argue that the patient should not be put through the stress and physical changes chemotherapy or radiation may entail. However, by stage 1B, the long-term survival chances are just above 50%. Thus, there is a substantial group of patients whose tumors will recur.

Chemotherapy is a serious treatment which causes side effects based upon its impact upon normal cells. A physician should not begin damaging normal tissue without clear medical justification.

17.33 Adjuvant Chemotherapy

Chemotherapy following surgery is called adjuvant chemotherapy. If adjuvant chemotherapy was given to a patient, that means that surgery was first performed and chemotherapy later given. Giving chemotherapy first to reduce tumor size, and then performing surgery is called neoadjuvant chemotherapy.

17.34 1970's and 1980's Studies Did not Show a Survival Increase for Adjuvant Chemotherapy

The book Lung Cancer reports that studies in the 70's and 80's showed little benefit to adjuvant chemotherapy:

The National Cancer Institute states, A Trials of adjuvant chemotherapy regimens have failed to demonstrate a consistent benefit.@ NCI.net. (3). Thus, most physicians do not prescribe chemotherapy for stage 1 patients whose tumors have been successfully removed and no evidence of cancer is seen on x-ray or other tests.

17.35 Recent Studies of Adjuvant Chemotherapy

Some studies in the 80's and 90's, using more effective forms of chemotherapy have shown a benefit to chemotherapy. In a Finnish study, A survival in the chemotherapy arm was significantly better than control (61% versus 48%).@ A recent study said the following:

A The trial was designed as a randomized, two-group study with postoperative adjuvant chemotherapy versus surgery alone as control group. All patients had stage IB disease (pT2N0) assessed after a radical surgical procedure. Chemotherapy consisted of treatment with cisplatin (100mg/m(2) on day 1) and etopiside (120mg/m(2) on days 1-3) for a total of six cycles. Results: Between January 1988 and December 1994, 66 patients were included in the study. Thirty- three belonged to the adjuvant chemotherapy group and 33 to the control group. Patients were followed for a minimum period of 5 years.... The rates of locoregional recurrence and distant metastasizes were 18 and 30%, respectively, in the adjuvant chemotherapy group and 24 and 43%, respectively, in the control group. The 5-year disease-free survival rates were 59% in the adjuvant group and 30% in the control group (P=0.02)... Conclusions: Our results suggest that adjuvant chemotherapy may reduce recurrences and prolong overall survival in patients at stage IB NSCLC deemed radically operated. Despite being difficult to accept, the use of adjuvant chemotherapy might have better long- term results.@ Mineo (5).

Distinguishing the successful results here from prior studies is not easy. Taxol and Carboplatin were used here, which many believe to be the optimal combination. Did prior studies fail to utilize the optimum chemotherapy mix? Or is the fact that this subgroup was stage 1B patients, with a higher potential for metastasis the decisive factor? Another recent study showed a slight survival advantage for chemotherapy, using different chemotherapy drugs, 76% in the chemotherapy and surgery group versus 71% in the surgery group alone. Wada (8).

of Treatment

There is some recent evidence that chemotherapy does provide a survival benefit. Putting aside the issue of side effects, why wouldn= t doctors utilize the latest research in their treatment? Is my doctor unaware of the latest research? The issue is more complex than that.

There is a maxim in medicine, first do no harm. That is, the physician= s intervention should not do damage to the patient. Without a sound medical foundation, most physicians are reluctant to undertake new forms of treatment until they have become generally accepted in a particular area of practice. At this point, while some studies are favorable, they are not sufficiently widely accepted to constitute the standard of care or accepted practice. Most physicians would still consider adjuvant chemotherapy experimental.

Another reason is the concern about professional liability claims. From my perspective, that is unreasonable; the number of chemotherapy-related claims is rather low. When physicians are diagnosing many patients at advanced stages, it would seem the real danger is delayed diagnosis. Nonetheless, there is a concern, realistic or not, about using new treatments, finding out they went beyond the standard of care, and even with the best of intentions, that physician would face liability.

17.37 Accessibility to New Forms of Treatment

Where does the patient go to obtain new forms of treatment, or more accurately, known treatment given in a new context? First, there are clinical trials which assess and evaluate new forms of treatment. (Clinical trials are the subject of another chapter). Many university hospitals where clinical trials are being given may be somewhat more aggressive in providing new forms of treatment even outside the context of a clinical trial.

17.38 Differences between Stage 1A and 1B treatments

Medicine is moving towards some type of prophylactic treatment of stage 1B patients. The larger size of the tumor, and the number of patients who will have ultimately metastasises, between 40 and 50%, means that the risk of spread is real and substantial.

17.4 POST-OPERATIVE RADIATION FOR STAGE 1 TUMORS

A 1999 article in the journal Lung Cancer states, A There is no place for routine postoperative thoracic radiotherapy after complete resection of a stage 1 tumor.@ Another article suggested:

Yet investigation continues. An Italian study found beneficial results:

Whether radiation is effective for stage 1 patients continues to be debated. Absent clear proof of its benefits, few physicians will utilize it because of its effects and radiation for stage 1 patients is now reserved for clinical trials or other investigational settings. In the future, molecular markers may help us target a subgroup of stage 1 patients who would benefit from radiation or chemotherapy.

17.5 POST SURGICAL DIAGNOSTIC TECHNIQUES

One could also conclude that routine use of chemotherapy should not be recommended for stage 1 patients, but that they should be intensively watched so that any signs of spread or metastasis can be timely treated. That is not what occurs today. Most physicians prescribe a yearly or bi-yearly chest x-ray and wait until tumor spread manifests itself on such an x-ray before recommending additional treatment. The difficulty here is that the chest-ray is an imprecise tool, detecting tumors of usually at least a centimeter, and the tumor has spread before it is identified.

17.51 Ct Scan

One plausible alternative is the use of post-operative Ct Scans. The CT is significantly more accurate than the chest x-ray in detecting small tumors. Low dose Ct (Ct designed to minimize exposure presents limited risk of exposure. One difficulty is that this does not yet represent the standard of care. Therefore, some insurers might balk at paying for such CT= s if they were regarded as experimental.

17.511 Studies of Ct Scan for Post-Surgical
Stage 1 Patients

A recent study compared post-surgical evaluation with Ct Scan and x-ray. Seven smaller nodules were identified on Ct Scan while only the four larger nodules were seen on x-ray. Ray, (15).

While most stage 1 patients are cured, some are not. Scientists today are attempting to identify risk factors with stage 1 patients.

17.61 Micro-Vessel Density

Angiogenesis is the formation of new blood vessels. While it is a normal process in wound healing and other areas, in cancer, it is the primary way that metastasis occurs and the cancer spread:

The theory is not free from challenge. One study of A 69 stage I-II non small lung cancers failed to demonstrate the prognostic relevance of microvessel density.@ Junker (9) (10).

17.611 Micro-Metastases

Stage 1 patients have no lymph node metastases measured by conventional diagnostic tools. However, a Japanese study measured micro-metastases, which would be undetected by conventional means. Not surprisingly, the extent of such metastases in the lymph nodes negatively impacted long-term survival. Osaki, (16). Similar findings were made in a 1996 study:

Measurement of nodal micro-metastases has a clear factual basis. We know the extent of metastasis directly impacts survival. Micro-vessel density, a similar marker, is also reliable. Other chemical markers are showing promise but a consensus is not seen as to which is most reliable or the best predictor. Measuring micro-metastases and micro-vessel density makes sense and should be tested in clinical trials.

17.62 VEGF Factor

Microvessel density measures preliminary indications of metastasis. The metastatic process involves production of VEGF, (vascular endothelial growth factor). Some scientists suggest measuring VEGF levels, and there is some correlation with VEGF levels and later metastasis. Again, patients could be measured following surgery, and consideration given to providing chemotherapy to those patients with high microvessel density and/or VEGF levels. Because there has been some variation in the studies, some scientists would like to see consistent results or some consensus within the medical community about what to measure before providing any recommendation.

17.621 P-53

P-53 is a potent tumor suppressor which has been measured with conflicting results:

A Interestingly, we found no evidence for an effect of P53 expression

17.622 Combination of VEGF and P-53 Measurement

One study found the prognostic value of either VEGF or P-53 to be limited. However, when both were elevated in stage 1 patients, survival rates markedly decreased. Five year survival with VEGF and P-53 negative was 64% compared with 38% in patients with both factors positive. That makes sense. The activation of VEGF combined with the suppression of P-53 means that a critical factor leading to metastasis is present while a critical regulator is absent. Research is continuing but it would make sense for patients in the dual positive group to consider post-surgical treatment.

Tumor cells manage to escape apoptosis, or cell death. Where cells are damaged or deficient, apoptosis generally occurs. That process is circumvented in cancer. BCL-2 protects cells from cell death and is therefore associated with various cancers, with its role in lung cancer being researched:

17.64 Cell Death or Apoptosis

A properly working system in the body provides for cell death, and this is one way of preventing unlimited proliferation. One study measured rates of apoptosis and found that the measurement did impact the patient= s prognosis. This measurement may show at an earliest stage where the cancer is reoccurring, and direct us to early intervention for those patients with a poorer prognosis. Junker (3).

17.65 Other Measurements

17.651 Cyclin B

Similar findings were made with other types of tumors.

17.652 Glut-1

One study found rates of glucose (sugar) metabolism (Glut-1) of the resected tumor relevant in determining the patient= s survival. Minami (14).

A The appearance of Glut-1 positive clones was associated with aggressive tumor behavior and Glut-1 was significant indicator of poor prognosis in cases of NSCLC.@ Minami (14) at 56. Minami reports that A the state of Glut-1 may reflect the biologic behavior of tumor cells.... Brown reported that Glut-1 was the major glucose transporter expressed in NSCLC.@ Minami (14) at 56.

17.653 CEA

CEA (Carinoembryonic antigen) is a commonly used tumor marker. Unlike many of the items above, CEA is easily and quickly tested. A recent study found:

A We studied 118 consecutive NSCLC patients who were clinically judged operable and were eventually operated upon... In tumors pathologically classified in stage Ia to IIb, a preoperative CEA level higher than 10 ng/mL was associated with a 67% probability of tumor relapse. In the same stages of disease, a CEA level less than 10 ng/mL increased the baseline probability of no recurrence from 80% to 88%. CONCLUSIONS: In operable patients with NSCLC the frequency of abnormal serum concentrations of CEA is low (17% in our series). However, it is important to identify such a small group of high-risk patients as many of them (in our study, 55% and 70% of those with a CEA value in excess of, respectively, 5 and 10 ng/mL) will develop an early postoperative recurrence. Such patients should be investigated preoperatively by mediastinoscopy or positron emission tomography in even in the absence of suspicious symptoms and signs. Then after an apparently successful operation, they should be carefully followed up. These patients could represent a suitable target for neoadjuvant clinical trials of selected high-risk groups.@ Buccheri (18)

17.654 Cox 2 Levels

One oncologist writes, A If you look at all stage I case