THE CANCER BRIEFING:WHAT IS CANCER AND WHAT ARE WE DOING ABOUT IT?

PART 1: WHAT IS CANCER?

“Cancer is not just a disease – it’s a foreign language!” This comment from a frightened and frustrated patient pretty well sums up the feelings of many when they first encounter the language associated with cancer and biomedical research.

The purpose of this introductory material is three-fold. First, it is intended to provide a small vocabulary that will be useful in learning the material to come. Second, it is designed to present some basic principles important in understanding what cancer is and is not. Third, it is hoped that this study will illustrate that the words which make up the language of cancer are actually little packages of information which provide insights in the conditions which they describe. Once one has an understanding of how cancer terms are derived, then they lose much of their capacity to intimidate. Rather, they give us some immediate information about that which we are trying to understand.

Oncology – The Study of Cancer. The word oncology is derived from two Greek words – Onkos, meaning “tumor” and Logos, meaning “to study”. Most medical terms are derived from Greek or Latin root words (The term Greco-Latin and/or Greco-Roman are frequently used). The root word is frequently some common descriptive word of the Greek or Latin vocabulary, converted to a combining form (to make it easier to form other words) and often anglicized to fit current rules of spelling and pronunciation.

Why Greek and Latin? Primarily because they are dead languages, which means they are not subject to the natural drifts and evolution that active languages suffer. Also, much of the initial descriptive work on the body, its structures and functions, and its ailments was done by Greek physicians or scholars who used Latin. In any case, it will be the purpose of this summary to show you how to unlock the information contained in some of the most commonly used words of the cancer vocabulary.

The word cancer is derived from the Latin word for “crab” (There is a comparable Greek word – karkinos – with the same meaning.) The origin of the word probably comes form the anatomical description of a dissected tumor, with a central mass and invasive projections of tissue which resembled claws or clawed legs. In any case, the word is descriptive for many reasons. Let’s back up a bit, however, and look at some other terms which will increase our understanding. Consider the word tumor. “Tumor” is derived from a Latin word meaning “a swelling” and is defined as “a new growth of tissue in which the multiplication of cells is uncontrolled and progressive”. Sometimes one hears “tumor” used synonymously with “cancer”, but this is incorrect. Tumors can be of two possible types – Benign (from root words meaning mild or non-threatening) or Malignant (from root words meaning bad or wicked). The two classes of tumors have the following general properties:

Benign Tumors Malignant Tumors

1. Relatively Slow Growth 1. Rapid Growth2. Tend to be Confined 2. Spreading3. Non-invasive 3. Invasive

Benign tumors can be dangerous and must be treated, but they are not true cancers. Only malignant tumors are truly cancerous. Thus, words that can be considered true synonyms are cancer, malignant tumor, malignancy, neoplastic disease, neoplasm (Note: these last two are from root words which mean “new tissue”.). The general combining form which identifies a tumor (whether benign or malignant) is the suffix –oma (Greek oma, meaning tumor or neoplasm).

The invasive nature of malignant tumors is of singular importance. The ability of tumor cells to break away from their site of origin, enter and traverse the blood stream and establish new growth in other parts of the body is a primary basis for cancer’s life threatening nature. This capacity is called metastasis (Greek meta – “beyond” and stasis – “fixed site”)

How Do Cancer Cells Arise? Human beings (and all other higher organisms) are incredibly complex biologic entities composed of trillions of individual cells and thousands of highly specialized tissues and organs. We begin life, however, as a single cell which derives half of its total

identity from each parent. We take these basic biological facts for granted, but in the context of understanding cancer, they take on special significance.

It is important to remind ourselves therefore that every cell in the body was derived from a single cell and thus has the capacity to be any or every other kind of cell. The fact that cells develop in highly specific and controlled ways identifies one of the great biological “miracles”. The “sum total” of the processes by which cells grow, change, develop their specific characteristics and remain true to those characteristics is called differentiation. The biological forces which maintain the controls of cell behavior and function are collectively called regulation. Errors in, or damage to, the regulatory mechanisms of the body may lead to bad changes in the differentiated state of cells, producing disease. To get a general feeling for this, envision a diagram of an arrow:

“Immature Cell” “Mature Cell”

DIFFERENTIATION>>>>>>>------------------------------------------------

(------------------------------------------------<<<<<<)(MALIGNANT TRANSFORMTION)

Growth Focus Function (Job) Focus Primitive Behavior Pattern Highly ControlledAggressive/Competitive ResponsiveInternally Controlled Externally ControlledFunction Focus Limited or Absent Very Limited Growth

The “feather” end of the arrow represents the early, undifferentiated characteristics of cells, while the “point” end describes the end stage when the cells are fully mature and ready to do their assigned work. The shaft of the arrow represents that multitude of sequential, highly controlled steps of cellular development called differentiation. If cells, for whatever reason, move backward away from the “job” focus toward the primitive growth focus, the process is called malignant transformation and the result is cancer. Further, it is important to remember that cancer cells originate from a normal cell.

Kinds of cancer. It must be emphasized that cancer is not a single disease. It is rather more than 100 different

diseases which have in common the origin described above. As far as can be determined, any cells in the body can become cancerous (except for the mature red blood cell, which loses its genetic material as part of its maturation.). The type of cell which becomes malignant not only determines the type of cancer, but also determines to a great extent whether the cancer can be easily treated and by what method. Cancers can be categorized in four main classes, however, with some exceptions, and it is useful to review these classes because understanding their classification tells us a lot about their nature.

Before considering the four classes of cancer, there are a few more general terms and combined forms that are helpful to know:

Organs are made up of tissues (often different kinds); tissues are made up of cells (often different kinds). Cells are usually identified by a Greco-Latin term which denotes their function or type, followed by a defining suffix. The combining form –cyte )Greek kytos, meaning cell.) usually denotes a cell which has completed its growth cycle and has begun to focus on this particular function. The combining form –blast (Greek –blastos, meaning germ) denotes a cell which may be completely normal, but is still growing and dividing.

For example, a growing cell which will produce fiber is called a fibroblast, while the same cells which has reached the end stage of its growth and has begun to focus on the production of fiber (in human beings, most fibrous tissue consists of the protein collagen) is called a fibrocyte. Other types of cells are named in a similar manner.

The body consists of four principal kinds of tissue

1. Connective Tissue, which consists of muscle tissue(striated or smooth); bone, fibrous tissue, and fat. These are the tissues which give the body its structure and support.

2. Glands, which make up the tissues which produce andsecrete the body’s essential substances, and Membranes, which line and contain the body’s gland and organs. Note: The Skin, which is a highly specialized membrane,

is the body’s largest organ, containing many specialized cells.

3. The Blood-Forming Tissues, which make up the entire spectrum of cells of the blood and lymph, together with the solid tissues of the body’s circulatory and defenses systems. These include, the Bone Marrow, the Lymph Nodes, the Spleen, the Thymus, and the circulating cells of the Blood and Lymphatic System.

4. The Central Nervous System (Brain and Spinal Cord)and the Peripheral Nerves.

I. Connective Tissue Cancers: Cancers which originate from cells of connective tissues belong to a particular class called sarcomas (Greek Sarcos, meaning “body” or “flesh”, plus –oma). Individual types of connective tissue cancers are named for the specific type of normal cells which became malignant. The various cancers are named by using the main descriptor of the normal cell of origin in a combining form, added to the suffix sarcoma. Below are some examples:

Cell of Origin Cancer

Fibrocyte (fiber-producing cell) FibrosarcomaOsteocyte (bone-forming cell) OsteosarcomaStriated Muscle cell(Note: Gr. Rhabdos – “stripe”

Myos – “muscle” RhabdomyosarcomaSmooth Muscle cell(Note: Gr. Leios – “smooth” LeiomyosarcomaLipocyte (fat cell) Liposarcoma

A further note: This identification/diagnosis is possible because the cancerous cells retain features of their parent cell. In rare (and very serious) instances, the cancer is so undifferentiated that it is not possible to determine the cell of origin. These cancers are deemed “undifferentiated” cancers or cancers of “unknown origin”.

II. Cancers of Glandular or Membrane Tissues: Glands and Membranes are composed of highly specialized cells called epithelium. Epithelial cells, in turn, or of two distinct types: glandular, or adenoidal,

epithelium (from Greek adenos – “gland”) and flat, or squamous, epithelium (from Greek – squamous, - “scale” or “plate”), from their plate-like appearance under the microscope). Cancers which originate from epithelial cells belong to the class called carcinoma (Greek karkinos – “crab”).

Carcinomas which originate from glandular epithelium are called adenocarcinomas, while those which originate from squamous epithelium are called squamous carcinomas. May people mistakenly believe that the word “carcinoma” is a synonym for cancer, an error which is understandable, since more than three quarters of all naturally-occurring cancers in human adults are carcinomas.

The many types of carcinomas are denoted by (1) the name of the involved organ, and (2) the type of epithelial cell of origin.

Examples: Adenocarcinoma of the Breast; Adenocarcinoma of the Thyroid; Colo-Rectal Adenocarcinoma; Squamous Cell Carcinoma of the Cervix; Adenocarcinoma of the Lung; Small Cell Carcinoma of the Lung (This is an example of a carcinoma named for a special characteristic of the cell of origin); Gastric Adenocarcinoma.

III. Cancers of the Blood-Forming Tissues: Thedevelopment of the myriad cells of the blood system is one of the most complex and rigidly controlled systems in the human body. There are hundreds of families of cells in the blood. Each population has a specific set of functions, but the various populations are profoundly interdependent. Remarkably, all these cells appear to originate from one family of cells, the ultimate parents of the blood-forming system. These cells, called pluripotential stem cells, reside in the bone marrow, and – through an exquisitely controlled sequential set of changes, differentiate into the entire population of specialized cell types.

The result of this complexity is that, when cancers of the blood-forming tissues occur, they can be any of a large number of specific types. In general however, they fall into three main families. One of these families contains

essentially only one type of cancer, while the others contain many, as summarized below:

A. Cancer which begins among the immature cells ofthe bone marrow itself is called Multiple Myeloma (the normal parent cells are Myelocytes).

B. Cancers which affect the cells of the solidtissues of the blood-forming tissues are classified in the category of Lymphoma. Individual types of lymphoma are named for the type of cell or origin.

C. Cancers which are associated with the cells of thecirculating blood are classified in the category of Leukemia. Individual types of leukemia depend on the type of cell involved. Also, the nature of the leukemia further divides the leukemias into two major subtypes – chronic and acute. Acute leukemia is the most common form of leukemia in children.

IV. Cancers of the Central and Peripheral Nervous System.

Cancers of the brain, spinal cord and nerve tissues are primarily named for the specific cell type which becomes malignant. In addition, tumors of the brain proper may be generally classified by the part of the brain in which they occur. The Glia (Greek glia – “glue” or “matrix”), also called the Gray Matter, which comprises the largest organic component of the brain, contains many types of cells, though these cells fall principally into two families: nerve cells, called neurons, and a second family of cells which support, stabilize, insulate and nourish neurons. These cells are generally named for the microscopic appearance or for the type of neurons that they support. Tumors originating from neurons are called neuromas. Neuromas are less common than tumors of the various supporting cells of the Glia. Tumors of this group are called Gliomas. Individual types of gliomas are named for the specific cell type of origin.

Unfortunately, unlike other cancer naming systems, the name of the tumor does not always reflect whether the tumor is malignant or benign, so one often encounters a grading system number attached to the name of the tumor. The most

dangerous brain tumors are those which are the most primitive and most highly undifferentiated. These highly aggressive tumors are usually designated in one of two ways” either they are called anaplastic or else the term “blast” is incorporated into their naming. For example, the most aggressive and dangerous form of brain cancer in adults is Glioblastoma. Also very aggressive and highly dangerous are anaplastic astrocytomas.

The brain contains a number of large cavities filled with shock absorbing and nutrient-rich fluid. The cavities, called ependyma, are lined with cells that have both structural and nerve functions. Cancers which originate from any of these cells are called ependymomas. Nervous system tumors are more common in children than in adults, but adults have the same general kinds of brain cancer as children. In recent years, it appears that adult brain tumors are being diagnosed more frequently than in the past. Whether this is due to better diagnostic techniques or to an actual increase in the incidence of adult brain tumors is under study, but current data suggest that both play roles.

The Natural History of Cancer

When we accept the principle that cancer is a group of diseases associated with differentiation, then it follows that all differentiated organisms have at least the capacity for development of one or more forms of cancer. Indeed, this is the case. In every animal group that has been studies, there is evidence of cancer, whether the animals are relatively primitive (like molluscs, for example) or highly advanced and complex (including humans). Though more study is warranted on more primitive animal families, the statement that all differentiated tissues can become malignant appears to hold up, though fewer forms of cancer have been found in cold-blooded animals. However, there are some important differences in the kinds of cancer that age prevalent among some of the major classes and subclasses of animals. One possible exception that should be mentioned concerns a prevalent view that Chondrocraniates (sharks and rays) have little or no cancer.

This issue has been studied, but must receive further attention before a definite conclusion can be drawn. If the view proves correct, an important experimental question will be “how does this resistance occur?”.

In lower mammals, particularly rodents, cancers of the blood-forming tissues, particularly leukemia and lymphoma are by far the most prevalent forms of cancer, with sarcomas second in frequency and carcinomas a distant third. This same pattern is true in fowl, which have essentially the same spectrum of cancers as mammals, with a high prevalence of leukemia, a lower prevalence of sarcomas and even fewer carcinomas. Interestingly, the fossil record suggests that dinosaurs (the distant ancestors of modern birds) were susceptible to osteosarcoma (bone cancer) and probably many other forms of cancer as well. In dogs, leukemias, lymphomas, and bone cancers are commonly diagnosed. Over the years, there have been many cases and many deaths of domestic cats from a contagious form of leukemia, though now there is a very effective vaccine. Non-human primates, from the most primitive (e.g. lemurs and South American monkeys) to the most advanced (e.g. chimpanzees) suffer from cancers of the blood-forming tissues and probably other forms as well.

In human adults, the most prevalent forms of cancer are carcinomas. Malignancies of the blood-forming tissues (leukemia, lymphoma and myeloma) are second, while malignant melanomas, central nervous system tumors, and sarcomas make up the remaining predominant forms of cancer. In human children (age fifteen or younger), cancers of the blood-forming tissues, especially leukemias and lymphomas, and connective tissue cancers (sarcomas) are more prevalent than carcinomas, a feature more in common with other species than with aging human adults. This difference probably represents differences in growth rates among the various tissues, time differences in hormonal activation of glandular tissues, longer periods of exposure to cancer-causing agents, longer incubation periods for glandular cancers, or some combination.

These variations in natural history and occurrence of the different forms of cancer among different classes of animals may reflect both genetic and longevity patterns in these species. Animals with rapid growth-to-maturity rates and a short life span exhibit higher incidence of sarcomas and cancers of the blood-forming tissues, whereas animals with long life spans tend to exhibit high incidence of glandular cancers. It is noted that these glandular cancers are more prevalent with increasing age.

PART II: WHAT ARE WE DOING ABOUT CANCER?

The course of medical management of cancer usually follows an orderly progression of steps:

1. Detection, which may come from a routinemedical checkup, form some abnormality noticed by the patient, or from an attempt to determine why certain symptoms have appeared.

2. Diagnosis, in which both the site and thenature of the cancer are determined to the fullest possible extent.

3. Staging, in which the severity and possiblespread of the cancer is evaluated.

4. Treatment, by any or a combination of themethods to be reviewed later in this summary. Both detection and diagnostic techniques are applied during treatment to monitor effectiveness.

` 5. Followup, which may last for years or even the full lifetime of the treated individual, to make sure that there is no recurrence.

Cancer Detection and Diagnosis

The American Cancer Society and other agencies have done a good job of alerting people to watch for the “danger signals” of cancer. In recent years, there has been a serious effort to increase cancer awareness and to teach self-examination as part of an effort to improve early detection of tumors. This is an important effort, because with many forms of cancer, early detection can make the difference between successful treatment and failure. This is especially true for cancers which eventually metastasize to other organs. If the cancer can be detected before it spreads, there is a very high probability of cure with locally-directed treatments (e.g. surgery or radiotherapy). In fact, we know that – in the case of solid tumors that have not spread beyond the originally affected organ and which are accessible – surgery alone is curative in nearly 90% of cases. This underscores the current emphasis on early detection, since early detection not only improves the

chance of cure, it also improves the quality of life of the patient and significantly reduces the cost of treatment.

In the past, cancers were most frequently detected after symptoms developed, often after progression or even metastic spread. In the more recent past more cancers have been detected by self-examination or, most commonly, during regular physical exams or by regularly-scheduled specific tests such as mammograms, pap smears, PSA tests, or the like. It is very clear that an informed public has had a great impact on earlier detection of the most common forms of cancer and that the result in many instances has been more effective treatment and increased survival.

The medical detection and diagnosis of cancer usually take one of two forms, both of which are important and necessary. The first consists of detection and localization of a tumor usually by one or more types of imaging technology. There have been some exciting innovations in imaging technology over the past several years and the imaging has become very sophisticated, accurate and precise. The old standby – conventional X-Ray – still has great value in initial detection of a mass or abnormality somewhere in the body. Now, however, we see the routine application of Computerized Axial Tomography (better known as CT-Scanning or CT-Scanning), Magnetic Resonance Imaging (MRI), Sonography (Ultrasound), and other applications designed to increase resolution and reliability of detection. As noted above, mammography is an application of imaging technology that is truly saving lives.

Will there every be a simple blood test for cancer? This is a difficult question, since little about cancer is ever simple, but some advances have occurred over the past several years give at least a partial answer. It seems unlikely that a single blood test will ever be developed for all kinds of cancer, since cancer represents such a diverse group of diseases. On the positive side, though, some important blood tests for specific cancers have been developed and are already receiving extensive use.

The most widely used of these is the PSA test, a blood test to detect prostate cancer. Another is the CEA test, a blood test without the specificity of the PSA, but excellent for monitoring tumors of the gastro-intestinal tract. In the past few years, we have seen extensive use of the CA-125

test in women for the detection and monitoring of ovarian cancer. Brief descriptions of these three tests are given below:

PSA (Prostate-Specific Antigen) Test. PSA is a protein produced by the cells lining the glands and ducts of the prostate. In normal prostate tissue, PSA is retained within the gland and very little is released into the blood. When the gland is disrupted by pathologic conditions, however, PSA is released into the blood and its presence can be diagnostic for prostate pathology, particularly (but not exclusively) cancer. Most men have low but measurable levels of PSA in their blood. Current standards recommend that men over 50 have a PSA test at least annually. In general PSA blood levels of 4ug/ml or lower are considered normal. Levels of between 4 and 7 are considered a basis for careful monitoring. Levels of 7 or above indicate the need for a prostate biopsy. Particularly important are upward changes in the level, even if the trend is small but steady. A significant problem lies in the range of 4 to 7 – many urologists recommend a biopsy at any level above 4, especially if the level represents a change from previous tests. At this level, however, only about one biopsy in four finds cancer. Most physicians now use a combination of the PSA test and Digital-Rectal examination to detect prostate abnormalities. Together, these two tests are about 80 – 90% accurate in diagnosing prostate cancer, as indicated by positive followup biopsy.

CEA (Carcinoembryonic Antigen) Test. CEA is a protein that is produced by some cells in the developing fetus (thus the name) and – abnormally – by certain cells that have undergone malignant transformation. There may be very low levels of CEA in normal individuals and in persons with certain non-cancerous conditions such as Krohn’s Disease, sever IBS, pancreatitis and others.

In several forms of cancer, however – particularly cancers of the alimentary tract (colon, rectum, stomach, esophagus) – elevated levels of CEA can indicate the presence of growing tumor and is a useful test in this context. The CEA test is never definitive and must be followed up by more thorough examinations of other types, which may include exploratory surgery. Most oncologists follow CEA levels in patients with certain types of cancer (especially colo-rectal cancers) in order to monitor effects of treatment or probable recurrence of disease.

CA-125 Test. The protein called CA-125 is produced by several types of cells in the ovaries, ducts, and uterine lining. Many normal women have measurable levels of CA-125 in their blood and many women with early state ovarian cancer have “normal” levels of CA-125. For this reason, CA-125 testing for the diagnosis of early ovarian cancer has been disappointing. On the other hand, in women with ovarian cancer (about 80% of the total), CA-125 levels are high and – most importantly – fluctuate with the level of tumor present. Therefore, the CA-125 test has become an important tool in monitoring effects of treatment and potential recurrence of disease. Further, recent improvements in the sensitivity and precision of the test has improve its diagnostic value significantly. The test has become both common and very important in ovarian cancer diagnosis.

Several other such tests are in the development stage now and within a few years we can expect further laboratory tests which will aid in early detection of several serious cancers.

In the previous paragraphs, the term biopsy has been introduced. A biopsy is an actual sample of tissue taken from within the tumor. The biopsy may require a surgical procedure, a scraping, a needle aspiration, blood sample, or other procedure to obtain enough cells to apply special treatments and dyes to ensure a clear microscopic determination of the type of cells and their abnormal (pathologic) appearance. The tissue sample is then examined under the microscope by a trained pathologist.

Accurate diagnosis of the type of cancer is crucial in choosing the proper treatment. To help understand the basis for the diagnosis of cancer, it is useful to recall one of the basic principles presented earlier in this summary, namely that every cancer cells originates from a ‘normal cell’ (the term ‘normal cell’ is set in quotes here because there may be abnormalities that are not readily detectable in cells which become cancerous.) Two other principles which derive from this fact apply to the medical diagnosis of cancer. First, cancer cells differ (often dramatically) from their normal counterparts in microscopic appearance. These difference often reflect their abnormal cell division and damaged internal structure. Second, with rare exceptions, the cancer cells retain enough of the

characteristics of their normal parent cells so that their origin can be determined. For example, cells of an osteosarcoma (cancer of the bone) can be readily distinguished microscopically from normal osteocytes (normal bone-producing cells), but retain osteocyte characteristics which permit determination of their cell of origin.

In some cases, the pathologist’s diagnosis will include a notation that a tumor is highly differentiated or highly undifferentiated. Cells of a highly differentiated tumor are malignant and abnormal, to be sure, but they have more in common with the normal parent cells than highly undifferentiated tumors. Rarely, these latter tumors become so undifferentiated that it is difficult or impossible to determine their cell of origin. These tumors are progressive and particularly dangerous, but by the same token may be more susceptible to the effects of treatment.

Genetic Testing. In recent years, intense research has been focused on the development and relevance of genetic tests in both diagnosis of certain types of cancer, in assessing prognosis (prediction of outcome) and in assessing cancer risk (more on this aspect in a later section). Genetic technology has advanced dramatically in the past 10 years and it is hoped that a picture of genetic anomalies in cancer and their importance in both diagnosis and treatment will emerge as more data are accumulated. The mapping of the human genome (The “genome” is the sum total of all genetic information encoded in our DNA.) has further raised both the possibilities and the hopes of establishing genetic tests for cancer and for cancer susceptibility. Several are being evaluated now and a growing catalogue of genetic abnormalities in various kinds of cancer is providing material for study.

Cancer Treatment

It is not possible to provide a thorough discussion of cancer treatment in this summary, but the following is a brief overview:

There are four major modalities for cancer treatment which, depending on the diagnosis and clinical presentation of the disease, may be used individually or in combination. The trend for modern cancer treatment is multi-modality, in which two or more methods of treatment are used. The modalities are:

Surgery. The oldest and still vital method of treatment is surgical removal of all identifiable cancer tissue. It should be noted that surgery provides a very high rate of complete cure for those cancers which are (1) localized and (2) accessible. In cases of progressive and/or metastasis cancer, surgery is essential to reduce the bulk of the cancer in order to provide a better chance of success with additional forms of treatment. Research directed toward improvement of surgical technology is ongoing and remarkable advances have been made over the past several years. Laser surgery, cryosurgery, surgery with ultrasonic scalpels, limb-sparing surgery, microsurgery and other new technologies now provide more effective removal of cancers with reduced trauma to normal tissues.

Radiotherapy. Directed and controlled exposure of cancer cells to radiation is widely utilized to destroy cancers which are not accessible to surgical removal or to destroy cancer cells known or suspected to remain after surgery. Radiation of various types may be applied, depending on the type and/or location of the cancer.

Chemotherapy. The use of one or more chemical agents to selectively destroy cancer cells was first developed to treat leukemia, lymphoma and other “systemic” forms of cancer. Over the past half-century, however, chemotherapy has become more and more widely used in treatment of most forms of cancer. A number of different types of chemical agents, with a variety of toxic effects on cells, make up our chemotherapy arsenal, and new drugs are continually discovered (or synthesized) and tested as we continue to work to improve cure rates for all forms of cancer.

Modern chemotherapy is a product both of serendipity and of our growing understanding of the biology of living cells. The first ideas of using chemicals to combat cancer cells came from the World War I observation that soldiers with leukemia who were exposed to mustard gas developed remissions of their disease. One of the first chemotherapeutics for cancer was nitrogen mustard – a close

relative of the chemical weapon. As the structure and function of DNA and the basic phenomena of cell growth and division became more clearly understood, scientists began to attempt the design of drugs that would specifically target cancer cell growth. The first of these drugs was 5-fluorouracil, a compound synthesized specifically to interfere with vital steps in the synthesis of DNA and therefore vital to cell growth.

The current arsenal of anti-cancer drugs – numbering more than 200 – is the result of three fundamental areas of research: the screening of tens of thousands of natural and synthetic compounds to determine their anti-cancer effects; the synthesis and testing of new compounds based on existing understanding of the mechanisms of abnormal cell growth; and the study of fundamental processes of normal and abnormal cell behavior in order to deter highly specific areas of vulnerability on the part of cancer cells.

For the first 50 or 60 years of its history, cancer chemotherapy has been focused on the same principle as that which governs radiotherapy – that cancer cells grow much faster and/or less normally than healthy cells and therefore they can be damaged more effectively by agents which destroy rapidly growing cells. Two enormous problems emerge from this principle, however. The first is that there are normal cells which turn over rapidly in the body (i.e. grow rapidly). The second is the biological fact which we have visited before: namely, that cancer cells originate from and have characteristics in common with their normal counterparts. These two issues are the basis for the often devastating side effects which accompany systemic chemotherapy.

The overlying goal in chemotherapy research and development, then, is the achievement of selectivity – the development of drugs and/or drug combinations that destroy cancer cells with little or no damage to normal tissue. The research effort to achieve selectivity in cancer therapy has primarily focused on two areas. The first area of emphasis is called targeting. Targeting strategies attempt to concentrate drug in the tumor or its vicinity in the hope of minimizing the drug’s system effect on normal tissues. A variety of approaches – some of them rather novel – have been applied in this effort. In recent years, a few tumors

have been found to have virtually unique proteins on their surfaces. These proteins have been used to produce antibodies which, when injected into the bloodstream, will seek out and specifically combine with the cancer cells. Linked to potent anti-cancer drugs, these antibodies become ‘smart missiles” which target the cancer cells. The large appetites of cancer cells cause them to quickly absorb the antibody/drug combination and to undergo the cytotoxicity (i.e. cell damage or killing). This approach, still in its early applications has two great advantages: sparing of normal tissues, and effectiveness with much lower concentrations of drug. This makes drug which are difficult to produce more viable for broader use in treating the cancers against which they are effective. The method is not broadly applicable yet, but each year sees a longer list of such drugs. To identify these drugs, look for the suffix “-mab”. This usually denotes a targeting molecule attached to a cytotoxic compound.

The second area of research emphasis in this category, often called cancer cell-specific therapy, focuses on finding unique requirements of cancer cells which are not shared by normal cells. This approach holds enormous promise, but has been realized in only a few unusual cancers thus far. We have learned that cancer cells frequently switch on and utilize genes that normal cells have “permanently” shut down. Focusing on the needs of these “oncogenes” has given rise to the development of drugs that interfere with these cancer-specific processes. There is also a considerable research effort now focused on understanding why these genes begin functioning again in cancer cells with the hope of finding ways to shut them down again. A most significant outcome of this research thus far is learning that at least some forms of cancer can in fact be slowed or returned to normal by regulation of their abnormal genes.

A question that all cancer patients and all cancer researchers repeatedly ask is, “Why does cancer often recur after chemotherapy?” Like all other aspects of cancer, the answer to this question is complex and involves several factors. One obvious reason is that insufficient drug(s) reach the cancer (here, management of serious side effects is most often the limiting feature). This lack of accessibility may occur at the original site of the tumor, more frequently occurs when the cancer cells metastasize to

another organ like the brain, where it is much more difficult to achieve effective doses of a drug.

At least two other biological properties of cancer cells, however, offer more challenging reasons. One is that, within a tumor, the cancer cells grow at different rates. Some cells grow rapidly, while others grow slowly or even remain dormant for long periods of time. The result is that drugs which attack rapidly growing cells spare the more sluggish and/or dormant cells, which may begin growing after therapy is discontinued. Second is the capacity of small populations of cancer cells within a tumor to develop active resistance to a drug. The primitive behavior and actively mutating growth pattern of some cancer cells cause them to lose the capacity to internalize the drug, with the result that the drug cannot enter the cells in order to do its damage.

The most successful approach to combat these two properties of cancer cells has been the development of combination chemotherapy. This approach, which involves the use of two or more drugs in carefully scheduled amounts and regimens, has improved the survival and quality of life for many patients, particularly those with metastatic cancer.

Yet another exciting and promising area of research has been focused on understanding and blocking the ability of cancer cells to metastasize. A number of substances have been found to interfere with the metastatic process. Also not available for general use now, the goal is the use of these drugs to prevent spread of the cancer so that the cancer can be successfully treated by local methods like surgery or limited radiotherapy. In experimental systems, a number of these drugs do work. Human trials have been underway for several months now, though the results are not in as yet.

Biotherapy. Compared to the three modalities summarized above, biotherapy is the “new kid on the block”. Biotherapy can be viewed as any form of therapy which enhances or restores the body’s own ability to combat the disease. The body mounts a very sophisticated and complex effort to control any abnormal behavior of cells. Cancer usually develops either a result of some breakdown n this biological defense system or as a result of the cancer cells’ ability to disguise and elude the body’s defenses. Biotherapy focuses on restoration, mobilization and/or

augmentation of the body’s natural control and combat mechanisms. Some of the most exciting and promising discoveries in all of biomedical research today are in the area of biotherapy.

Several avenues of research are being pursued in this arena. Some have found their way into “conventional” treatment at present. A growing application of human gene products such as interferon or the interleukins in the treatment of some forms of leukemia and lymphoma falls into the category of biotherapy. These products are produced in therapeutic quantities by transferring the human gene into various microbes, then producing the gene product much in the way that antibiotics are produced.

Another fertile are for research and clinical application in biotherapy has been the development and testing of substances which mobilize and enhance the body’s “early warning” and “first line of defense” systems. The primary responsibility for this type of defense is carried out by macrophages, fairly primitive cells which roam through the body, ingesting and destroying any foreign entities. A family of substances has been found to give these macrophages a specific appetite for tumor cells. At least one exciting clinical experiences has shown that – in some patients at least – this approach can eradicate early metastic growth of osteosarcoma cells in the lungs of children. Extensive further study and clinical testing are underway in institutions all over the world.

A component of biotherapy, which is beginning to claim title as a separate disciple is gene therapy. As noted earlier in this summer, there has been a recent surge in genetic research both in agriculture and in medicine. Medical research has focused primarily in two areas:

(1) The identification and mapping of bothnormal and abnormal genes and the association of various genetic abnormalities with individual diseases or types of disease. A number of gene defects associated with several forms of cancer and with other diseases such as cystic fibrosis have already been identified and the catalogue of normal and aberrant genes seems to grow weekly.

(2) The development and refinement of techniques for

manipulating genes for purposes of gene repair and replacement. The identification of defective function by a particular gene provides a potential opportunity for replacement of the defective or supplementation of its missing function. The molecular and cellular methodologies for removal of a gene from one location and its transfer to another location already exist and are already in limited use in treatment or prevention of genetic diseases, though much more research is necessary to fully realize their potential.

Of monumental concern in this area is the difficulty in assessing the potential side effects of gene manipulation. A recent gene therapy program in France was halted because – even though the treated children were cured of the disease produced by their genetic defect – they developed a different and very serious condition which was potentially life-threatening. Such concerns are the focus of intense current research.

Cancer Prevention

“Is cancer inevitable?: “If we live long enough, are we certain to develop cancer?” “Can anything be done to reduce our risk of developing cancer?” These questions are very much on the minds of an increasingly informed and concerned public. Further, these issues are very much on the minds of biomedical researchers.

There is mounting evidence that we can personally intervene to decrease our risk of developing many forms of cancer, including some of the most prevalent and life-threatening forms. In addition, our growing understanding of the biological basis of cancer may make medical intervention to prevent cancer a reality in the near future.

Our current understanding indicates that as much as 80% of naturally occurring cancers may be associated with our lifestyles and environment. The primary lifestyle associations with increased cancer risk relate to tobacco use, diet and exposure to sun. Current data suggest that smoking and high fat, low fiber diets are associated with some 65% of cancers, predominantly (but not exclusively) cancers of the lung, colon and breast. Avoidance of smoking (as well as use of smokeless tobacco); a sensible, well-balanced diet rich in fruits, vegetables and whole grains

and low in animal fats; protection from the burning rays of the sun – all these strategies can reduce cancer risk and are well worth doing.

Every concerned person should make a priority of learning all that is possible about cancer prevention and early detection. Although actual statistics are not available, we are aware than in increasing number of cancers are detected by the patients themselves and many of these are found because the patients are aware and vigilant.

The old cliché “Knowledge is Power” has never been truer than when applied to cancer prevention. The more we know about cancer, the better prepared we will be to protect ourselves, our families and our community from cancer.

CONCLUSION: LOOKING OVER THE MOUNTAIN

Promise and Problems in the Coming Years

When we look back and recall the cancer incidence and death rates, it is clear that –although we are gaining ground each year – that the conquest of cancer has not been achieved. Enormous progress has been made, both in the control of cancer and in the understanding of the biological processes involved the in the conversion of normal cellular behavior to malignant behavior.

As we bring this overview to conclusion, it may be useful to point out some goals, some possibilities, and some concerns about cancer control.

Improvement in Therapeutic Techniques and Strategies. Research and development continues in all technical aspects of cancer detection, diagnosis and treatment. Advances in all four major modalities of treatment – surgery, radiotherapy, chemotherapy and biotherapy – have improved both long-term survival and quality of life for thousands of cancer patients. A variety of technologies – some brand new and some old – have been improved and re-evaluated. These include techniques like focused heat, ischemic therapy ( the use of mechanical devices to cut off the blood supply to a tumor).

Reliable Risk Assessment. We honestly do not know at present who is specifically at risk for cancer and who isn’t. Familiar risk has been identified in some

individuals, but the goal of individual risk profiles seem realistic. In this case, both the technology and the societal implications of risk profiles must be addressed – not only by physicians and scientists, but also by ethicists and sociologists.

Chemo-prevention. Results in some studies suggest that – in persons with pre-cancerous conditions or at high risk – there are substances which retard or block the early stages of cancer growth. The goal of these studies is to hold at bay or even completely reverse the process of malignant transformation.

Cancer As A Chronic Disease. A result of advances made already in detection and treatment of many forms of cancer is that there are many many people who are not dying of their cancer nor are they cured. Rather, they are living with their cancers. Many physicians and bio-medical researchers are beginning to think of treating cancer as a chronic disease, like diabetes, for example – with ongoing therapeutic management, but not necessarily with the expectation of complete cure. Cure is the ideal and much-hoped for goal, but maintenance of the disease accompanied by health and full productivity may be more realistic in many instances.

As we bring this overview to a close, I am reminded of the old song about a bear going over the mountain to see what he could see. The song ends with the statement that the bear gets over the mountain, only to see another mountain. The fight against cancer has been much like that over the past years. However, we have become better climbers and we still believe that we fill finally get to the top of a mountain and see our ultimate goal – the eradication of cancer as a threat to life and health.

Thanks to each of you for your interest in this class.

Cordially,

James M. Bowen, Ph.D.February, 2007