CHAPTER 2: CANCER 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 measures 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, 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 level 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 effected. Scientists may refer to the number or extent of side effects as "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.

2.3 MEASUREMENTS OF MORTALITY

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 researcher 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 forms the lining of different parts of the body. Cancers in the lung, breast, prostrate, and colon are all carcinomas. Cancers that involve tissue or bone are called sarcomas. Cancers involving blood cells are known as lymphomas or leukemias.

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 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.

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, epidemiologist 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 the considerations researchers use:

The extent of the difference between the study group and control group. The greater the difference between the two groups, the more likely the drug is having an impact.

Whether a dose relationship is identified. Assume we are testing a new drug. If response rates increase with the amount of the drug given, that indicates the drug is causing the response. However, if response rates do not depend on dose, it may be that other factors are at work. For example, with cigarettes, scientists found that the rate of disease increases with the number of cigarettes smoked, which indicates a causal connection.

Size of the Study Group A study with positive findings involving 500 people will be given more weight than one with 20.

Ability to Duplicate Findings in Other Studies Drugs generally need to proceed through a number of clinical trials before they are FDA approved. In 1997, a scientist reported that more than half of rats experience a complete elimination of tumors using a new form of treatment. Newspapers reported a new cure. However, when the findings could not be replicated, the weight of the initial report was reduced, and when positive findings were not made in clinical trials, the drug was not FDA approved.

Biological Plausibility Does the theory make sense and accord with the medical knowledge we have. Note that this can require some detailed medical knowledge. Some complex theories put forth on the Internet may be based on faulty science which would not be apparent to a non-scientist.

Cell Studies and Animal Studies While no treatment can be FDA approved based simply upon laboratory studies, they can support, undermine, or help explain findings in clinical trials.

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 using these criteria try to make an intelligent determination.

2.55 Applying the Research, How to Measure the Success of New Drugs.

With tools like Medline and a basic understanding of cancer research, we can take a first step toward evaluating new drugs. Newspaper and magazine reports can be misleading and company self-reporting can be equally unreliable. The astute patient or family member will want to go to medical journals themselves. Here are some basic standards.

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 generally 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. Thus, 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:

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

Evaluate the test on animals,

Perform initial tests to see if the new drug is tolerated by humans, define the appropriate dose, (Phase 1 Clinical Trial)

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

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

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.

2.73 In Vitro Testing

The first step is to test a proposed new cure on cells in a laboratory. "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.

2.81 Overview

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

"{Highly specific proteins} are essential to the growth and repair of human tissues. Those that directly stimulate cell division are called growth factors.... Growth factors bind to receptors on a cell's surface thereby activating proliferation or differentiation. Some growth factors are highly specific in function and cell type while others are more broad spectrum."

2.82 Repair of a Wound

Consider how a wound heals. When a wound occurs in a tissue, blood clots assemble to stanch the bleeding. Integral to clot formation are the blood platelets which gather at the site of bleeding and aggregate to form a physical barrier that prevent further loss of blood. At the same time, these platelets release several growth factors- notably a factor called platelet-derived growth factor (PDGF) that stimulates nearby connective tissue cells to grow. These connective tissue cells begin reconstruction of the damaged tissue, thereby healing the wound. Cells divide and duplicate, and connect with damaged cells as part of an overall repair. Some of these characteristics unfortunately also occur with cancer.

2.83 Growth factors and Receptors

A growth factor prompts reproduction. As part of that process, a growth factor generally binds to a growth factor receptor. One type of receptor is a tyrosine kinase. Many newer drugs are tyrosine kinase inhibitors, and attempt to inhibit these growth factors or prevent them from binding with related receptors.

2.84 Epidermal Growth Factor

Epidermal means skin and the epidermal growth factor (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. 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 has been 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 is most critical, and the role of Erb2. See Giatromanolaki (5).

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 new drugs Iressa and OSI-774 do, or the entire family of receptors, which other drugs do. The ability of one member of the family, say erb 1, to provide signals to another member, is called cross-talk.

2.86 Vascular Endothelial Growth Factor

By the mid-1980s, considerable experimental evidence had been assembled to support the hypothesis that tumor growth is angiogenesis dependent. The idea could now be stated in its simplest terms: "Once tumor take has occurred, every further increase in tumor cell population must be preceded by an increase in new capillaries which converge upon the tumor. The hypothesis predicted that if angiogenesis could be completely inhibited, tumors would become dormant at a small, possibly microscopic size. (Cancer Medicine 12).

 

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.

2.861 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).

2.862 Vegf Receptors

Like the epidermal growth factor, VEGF has corresponding receptors.

"Vascular endothelial growth factor (VEGF) binds to and mediates its activity mainly through two tyrosine kinase receptors, VEGF receptor 1 and VEGF receptor... The importance of VEGF and its receptors in tumor angiogenesis suggests that blockade of this pathway by antibody therapy would be an effective therapeutic strategy for inhibiting angiogenesis and tumor growth Xenia (9)

The VEGF ligand stimulates its functions through binding and activating VEGF-receptor (VEGFR)-1 and VEGFR-2, two membrane receptor tyrosine kinases that are predominantly expressed on endothelial cells within blood vessel walls. Binding of VEGF to these receptors initiates downstream signaling events leading to effects on gene expression, cell survival, proliferation, and migration. Vegf.com (10)

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

2.87 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 factors or prevented it from connecting to its receptor. As an 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 is a large number of growth factors, receptors, tumor suppressor genes, signaling genes and other cellular products associated with the disease. 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:

1) will the new drug frustrate the growth factor or growth factor,

2) how important is the growth factor to the cancer process,

3) can we deliver the drug to the needed area(s) in sufficient amounts to make a large difference in the course of the disease,

4) can we do (3) without causing substantial side effects, or put another way,

5) if side effects can be limited, can we combine 1 or more drugs, to increase cancer-fighting ability without significant interference with ordinary bodily functions or side effects.

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.

1. Zurlo, Animal and Alternatives in Testing: History, Science and Ethics,Johns Hopkins Center for Alternatives to Animal Testing,

2. Astra-Zeneca, (manufacturers of Iressa), EGFR-Info.com

3. The ErbB Family of Receptors and Their Ligands, Multiple Targets for Therapy, Signal, Volume 2, Issue 3, 4-11. Signal is a new journal, available online, and focusing on epidermal growth factor treatments and related research.

4. Herbst, Angiogenesis Inhibitors in Clinical Development for Lung Cancer, Seminars in Oncology, Vol. 29, No. 1 Supp 4 February 2002: pp. 66-77

5. Giatromanolaki , Non-small cell lung cancer: C-erbB-2 Overexpression Correlates with Low Angiogenesis and Poor Prognosis.

6. M.D.Anderson Medical Center website.

7. Neufeld, Vascular endothelial growth factor (VEGF) and its receptors,The FASEB Journal. 1999;13:9-22.)

8. Santos, Enhanced Expression of Vascular Endothelial Growth Factor in Pulmonary Arteries of Smokers and Patients with Moderate Chronic Obstructive Pulmonary Disease American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1250-1256, (2003)
9.Xenia, Complete Inhibition of Vascular Endothelial Growth Factor (VEGF) Activities with a Bifunctional Diabody Directed against Both VEGF Kinase Receptors, fms-like Tyrosine Kinase Receptor and Kinase Insert Domain-containing Receptor, Cancer Research 61, 7002-7008, October 1, 2001 1

12. Holland, Cancer Medicine, (1999), available online at no charge from the National Library of Medicine,http://www.ncbi.nlm.nih.govhttp://www.nci.nlm.

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