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    CANCER_BRIEFING.doc.doc CANCER_BRIEFING.doc.doc Document Transcript

    • 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 foreignlanguage!” This comment from a frightened and frustratedpatient pretty well sums up the feelings of many when theyfirst encounter the language associated with cancer andbiomedical research. The purpose of this introductory material is three-fold. First, it is intended to provide a small vocabularythat will be useful in learning the material to come.Second, it is designed to present some basic principlesimportant in understanding what cancer is and is not.Third, it is hoped that this study will illustrate that thewords which make up the language of cancer are actuallylittle packages of information which provide insights inthe conditions which they describe. Once one has anunderstanding of how cancer terms are derived, then theylose much of their capacity to intimidate. Rather, theygive us some immediate information about that which we aretrying to understand. Oncology – The Study of Cancer. The word oncology isderived from two Greek words – Onkos, meaning “tumor” andLogos, meaning “to study”. Most medical terms are derivedfrom Greek or Latin root words (The term Greco-Latin and/orGreco-Roman are frequently used). The root word isfrequently some common descriptive word of the Greek orLatin vocabulary, converted to a combining form (to make iteasier to form other words) and often anglicized to fitcurrent rules of spelling and pronunciation. Why Greek and Latin? Primarily because they are deadlanguages, which means they are not subject to the naturaldrifts and evolution that active languages suffer. Also,much of the initial descriptive work on the body, itsstructures and functions, and its ailments was done byGreek physicians or scholars who used Latin. In any case,it will be the purpose of this summary to show you how tounlock the information contained in some of the mostcommonly used words of the cancer vocabulary.
    • The word cancer is derived from the Latin word for“crab” (There is a comparable Greek word – karkinos – withthe same meaning.) The origin of the word probably comesform the anatomical description of a dissected tumor, witha central mass and invasive projections of tissue whichresembled claws or clawed legs. In any case, the word isdescriptive for many reasons. Let’s back up a bit,however, and look at some other terms which will increaseour understanding. Consider the word tumor. “Tumor” isderived from a Latin word meaning “a swelling” and isdefined as “a new growth of tissue in which themultiplication of cells is uncontrolled and progressive”.Sometimes one hears “tumor” used synonymously with“cancer”, but this is incorrect. Tumors can be of twopossible types – Benign (from root words meaning mild ornon-threatening) or Malignant (from root words meaning bador wicked). The two classes of tumors have the followinggeneral properties: Benign Tumors Malignant Tumors1. 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 aretruly cancerous. Thus, words that can be considered truesynonyms are cancer, malignant tumor, malignancy,neoplastic disease, neoplasm (Note: these last two arefrom root words which mean “new tissue”.). The generalcombining form which identifies a tumor (whether benign ormalignant) is the suffix –oma (Greek oma, meaning tumor orneoplasm). The invasive nature of malignant tumors is of singularimportance. The ability of tumor cells to break away fromtheir site of origin, enter and traverse the blood streamand establish new growth in other parts of the body is aprimary basis for cancer’s life threatening nature. Thiscapacity is called metastasis (Greek meta – “beyond” andstasis – “fixed site”)How Do Cancer Cells Arise? Human beings (and all otherhigher organisms) are incredibly complex biologic entitiescomposed 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 totalidentity from each parent. We take these basic biologicalfacts for granted, but in the context of understandingcancer, they take on special significance. It is important to remind ourselves therefore thatevery cell in the body was derived from a single cell andthus has the capacity to be any or every other kind ofcell. The fact that cells develop in highly specific andcontrolled ways identifies one of the great biological“miracles”. The “sum total” of the processes by whichcells grow, change, develop their specific characteristicsand remain true to those characteristics is calleddifferentiation. The biological forces which maintain thecontrols of cell behavior and function are collectivelycalled regulation. Errors in, or damage to, the regulatorymechanisms of the body may lead to bad changes in thedifferentiated state of cells, producing disease. To get ageneral feeling for this, envision a diagram of an arrow: “Immature Cell” “Mature Cell” DIFFERENTIATION>>>>>>>------------------------------------------------(------------------------------------------------<<<<<<) (MALIGNANT TRANSFORMTION)Growth Focus Function (Job) FocusPrimitive 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 arefully mature and ready to do their assigned work. Theshaft of the arrow represents that multitude of sequential,highly controlled steps of cellular development calleddifferentiation. If cells, for whatever reason, movebackward away from the “job” focus toward the primitivegrowth focus, the process is called malignant transformationand the result is cancer. Further, it is important toremember that cancer cells originate from a normal cell.
    • Kinds of cancer. It must be emphasized that cancer is nota single disease. It is rather more than 100 differentdiseases which have in common the origin described above.As far as can be determined, any cells in the body canbecome cancerous (except for the mature red blood cell,which loses its genetic material as part of itsmaturation.). The type of cell which becomes malignant notonly determines the type of cancer, but also determines toa great extent whether the cancer can be easily treated andby what method. Cancers can be categorized in four mainclasses, however, with some exceptions, and it is useful toreview these classes because understanding theirclassification tells us a lot about their nature. Before considering the four classes of cancer, thereare a few more general terms and combined forms that arehelpful 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 whichdenotes their function or type, followed by a definingsuffix. The combining form –cyte )Greek kytos, meaningcell.) usually denotes a cell which has completed itsgrowth cycle and has begun to focus on this particularfunction. The combining form –blast (Greek –blastos,meaning germ) denotes a cell which may be completelynormal, but is still growing and dividing. For example, a growing cell which will produce fiberis called a fibroblast, while the same cells which hasreached the end stage of its growth and has begun to focuson the production of fiber (in human beings, most fibroustissue consists of the protein collagen) is called afibrocyte. Other types of cells are named in a similarmanner.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 and
    • secrete 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 CancerFibrocyte (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) LiposarcomaA further note: This identification/diagnosis is possiblebecause the cancerous cells retain features of their parentcell. In rare (and very serious) instances, the cancer isso undifferentiated that it is not possible to determinethe 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 oneof the most complex and rigidly controlled systems in thehuman body. There are hundreds of families of cells in theblood. Each population has a specific set of functions,but the various populations are profoundly interdependent.Remarkably, all these cells appear to originate from onefamily of cells, the ultimate parents of the blood-formingsystem. These cells, called pluripotential stem cells,reside in the bone marrow, and – through an exquisitelycontrolled sequential set of changes, differentiate intothe entire population of specialized cell types.
    • The result of this complexity is that, when cancers ofthe blood-forming tissues occur, they can be any of a largenumber of specific types. In general however, they fallinto three main families. One of these families containsessentially only one type of cancer, while the otherscontain many, as summarized below: A. Cancer which begins among the immature cells ofthe bone marrow itself is called Multiple Myeloma (thenormal parent cells are Myelocytes). B. Cancers which affect the cells of the solidtissues of the blood-forming tissues are classified in thecategory of Lymphoma. Individual types of lymphoma arenamed for the type of cell or origin. C. Cancers which are associated with the cells of thecirculating blood are classified in the category ofLeukemia. Individual types of leukemia depend on the typeof cell involved. Also, the nature of the leukemia furtherdivides the leukemias into two major subtypes – chronic andacute. Acute leukemia is the most common form of leukemiain children. IV. Cancers of the Central and Peripheral Nervous System.Cancers of the brain, spinal cord and nerve tissues areprimarily named for the specific cell type which becomesmalignant. In addition, tumors of the brain proper may begenerally classified by the part of the brain in which theyoccur. The Glia (Greek glia – “glue” or “matrix”), alsocalled the Gray Matter, which comprises the largest organiccomponent 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 cellswhich support, stabilize, insulate and nourish neurons.These cells are generally named for the microscopicappearance or for the type of neurons that they support.Tumors originating from neurons are called neuromas.Neuromas are less common than tumors of the varioussupporting cells of the Glia. Tumors of this group arecalled Gliomas. Individual types of gliomas are named forthe specific cell type of origin.
    • Unfortunately, unlike other cancer naming systems, thename of the tumor does not always reflect whether the tumoris malignant or benign, so one often encounters a gradingsystem number attached to the name of the tumor. The mostdangerous brain tumors are those which are the mostprimitive and most highly undifferentiated. These highlyaggressive tumors are usually designated in one of twoways” 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 inadults is Glioblastoma. Also very aggressive and highlydangerous are anaplastic astrocytomas. The brain contains a number of large cavities filledwith shock absorbing and nutrient-rich fluid. Thecavities, called ependyma, are lined with cells that haveboth structural and nerve functions. Cancers whichoriginate from any of these cells are called ependymomas.Nervous system tumors are more common in children than inadults, but adults have the same general kinds of braincancer as children. In recent years, it appears that adultbrain tumors are being diagnosed more frequently than inthe past. Whether this is due to better diagnostictechniques or to an actual increase in the incidence ofadult brain tumors is under study, but current data suggestthat both play roles. The Natural History of Cancer When we accept the principle that cancer is a group ofdiseases associated with differentiation, then it followsthat all differentiated organisms have at least thecapacity for development of one or more forms of cancer.Indeed, this is the case. In every animal group that hasbeen studies, there is evidence of cancer, whether theanimals are relatively primitive (like molluscs, forexample) or highly advanced and complex (including humans).Though more study is warranted on more primitive animalfamilies, the statement that all differentiated tissues canbecome malignant appears to hold up, though fewer forms ofcancer have been found in cold-blooded animals. However,there are some important differences in the kinds of cancerthat age prevalent among some of the major classes andsubclasses of animals. One possible exception that shouldbe mentioned concerns a prevalent view thatChondrocraniates (sharks and rays) have little or nocancer.
    • This issue has been studied, but must receive furtherattention before a definite conclusion can be drawn. Ifthe view proves correct, an important experimental questionwill be “how does this resistance occur?”. In lower mammals, particularly rodents, cancers of theblood-forming tissues, particularly leukemia and lymphomaare by far the most prevalent forms of cancer, withsarcomas second in frequency and carcinomas a distantthird. This same pattern is true in fowl, which haveessentially the same spectrum of cancers as mammals, with ahigh prevalence of leukemia, a lower prevalence of sarcomasand even fewer carcinomas. Interestingly, the fossilrecord suggests that dinosaurs (the distant ancestors ofmodern birds) were susceptible to osteosarcoma (bonecancer) and probably many other forms of cancer as well.In dogs, leukemias, lymphomas, and bone cancers arecommonly diagnosed. Over the years, there have been manycases and many deaths of domestic cats from a contagiousform of leukemia, though now there is a very effectivevaccine. 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-formingtissues and probably other forms as well. In human adults, the most prevalent forms of cancerare carcinomas. Malignancies of the blood-forming tissues(leukemia, lymphoma and myeloma) are second, whilemalignant melanomas, central nervous system tumors, andsarcomas make up the remaining predominant forms of cancer.In human children (age fifteen or younger), cancers of theblood-forming tissues, especially leukemias and lymphomas,and connective tissue cancers (sarcomas) are more prevalentthan carcinomas, a feature more in common with otherspecies than with aging human adults. This differenceprobably represents differences in growth rates among thevarious tissues, time differences in hormonal activation ofglandular tissues, longer periods of exposure to cancer-causing agents, longer incubation periods for glandularcancers, or some combination. These variations in natural history and occurrence ofthe different forms of cancer among different classes ofanimals may reflect both genetic and longevity patterns inthese species. Animals with rapid growth-to-maturity ratesand a short life span exhibit higher incidence of sarcomasand cancers of the blood-forming tissues, whereas animals
    • with long life spans tend to exhibit high incidence ofglandular cancers. It is noted that these glandularcancers are more prevalent with increasing age. PART II: WHAT ARE WE DOING ABOUT CANCER? The course of medical management of cancer usuallyfollows an orderly progression of steps: 1. Detection, which may come from a routinemedical checkup, form some abnormality noticed by thepatient, or from an attempt to determine why certainsymptoms have appeared. 2. Diagnosis, in which both the site and thenature of the cancer are determined to the fullest possibleextent. 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. Bothdetection and diagnostic techniques are applied duringtreatment to monitor effectiveness.` 5. Followup, which may last for years or eventhe full lifetime of the treated individual, to make surethat there is no recurrence. Cancer Detection and Diagnosis The American Cancer Society and other agencies havedone a good job of alerting people to watch for the “dangersignals” of cancer. In recent years, there has been aserious effort to increase cancer awareness and to teachself-examination as part of an effort to improve earlydetection of tumors. This is an important effort, becausewith many forms of cancer, early detection can make thedifference between successful treatment and failure. Thisis especially true for cancers which eventually metastasizeto other organs. If the cancer can be detected before itspreads, there is a very high probability of cure withlocally-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 andwhich are accessible – surgery alone is curative in nearly90% of cases. This underscores the current emphasis onearly detection, since early detection not only improvesthe chance of cure, it also improves the quality of life ofthe patient and significantly reduces the cost oftreatment. In the past, cancers were most frequently detectedafter symptoms developed, often after progression or evenmetastic spread. In the more recent past more cancers havebeen detected by self-examination or, most commonly, duringregular physical exams or by regularly-scheduled specifictests such as mammograms, pap smears, PSA tests, or thelike. It is very clear that an informed public has had agreat impact on earlier detection of the most common formsof cancer and that the result in many instances has beenmore effective treatment and increased survival. The medical detection and diagnosis of cancer usuallytake one of two forms, both of which are important andnecessary. The first consists of detection andlocalization of a tumor usually by one or more types ofimaging technology. There have been some excitinginnovations in imaging technology over the past severalyears 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 orabnormality somewhere in the body. Now, however, we seethe routine application of Computerized Axial Tomography(better known as CT-Scanning or CT-Scanning), MagneticResonance Imaging (MRI), Sonography (Ultrasound), and otherapplications designed to increase resolution andreliability of detection. As noted above, mammography isan application of imaging technology that is truly savinglives. Will there every be a simple blood test for cancer?This is a difficult question, since little about cancer isever simple, but some advances have occurred over the pastseveral years give at least a partial answer. It seemsunlikely that a single blood test will ever be developedfor all kinds of cancer, since cancer represents such adiverse group of diseases. On the positive side, though,some important blood tests for specific cancers have beendeveloped and are already receiving extensive use.
    • The most widely used of these is the PSA test, a bloodtest to detect prostate cancer. Another is the CEA test, ablood test without the specificity of the PSA, butexcellent for monitoring tumors of the gastro-intestinaltract. In the past few years, we have seen extensive useof the CA-125 test in women for the detection andmonitoring of ovarian cancer. Brief descriptions of thesethree tests are given below: PSA (Prostate-Specific Antigen) Test. PSA is aprotein produced by the cells lining the glands and ductsof the prostate. In normal prostate tissue, PSA isretained within the gland and very little is released intothe blood. When the gland is disrupted by pathologicconditions, however, PSA is released into the blood and itspresence can be diagnostic for prostate pathology,particularly (but not exclusively) cancer. Most men havelow but measurable levels of PSA in their blood. Currentstandards recommend that men over 50 have a PSA test atleast annually. In general PSA blood levels of 4ug/ml orlower are considered normal. Levels of between 4 and 7 areconsidered a basis for careful monitoring. Levels of 7 orabove indicate the need for a prostate biopsy.Particularly important are upward changes in the level,even if the trend is small but steady. A significantproblem lies in the range of 4 to 7 – many urologistsrecommend a biopsy at any level above 4, especially if thelevel represents a change from previous tests. At thislevel, however, only about one biopsy in four finds cancer.Most physicians now use a combination of the PSA test andDigital-Rectal examination to detect prostateabnormalities. Together, these two tests are about 80 – 90%accurate in diagnosing prostate cancer, as indicated bypositive followup biopsy. CEA (Carcinoembryonic Antigen) Test. CEA is aprotein that is produced by some cells in the developingfetus (thus the name) and – abnormally – by certain cellsthat have undergone malignant transformation. There may bevery low levels of CEA in normal individuals and in personswith certain non-cancerous conditions such as Krohn’sDisease, sever IBS, pancreatitis and others. In several forms of cancer, however – particularlycancers 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 thiscontext. The CEA test is never definitive and must befollowed up by more thorough examinations of other types,which may include exploratory surgery. Most oncologistsfollow CEA levels in patients with certain types of cancer(especially colo-rectal cancers) in order to monitoreffects of treatment or probable recurrence of disease. CA-125 Test. The protein called CA-125 is producedby several types of cells in the ovaries, ducts, anduterine lining. Many normal women have measurable levelsof CA-125 in their blood and many women with early stateovarian cancer have “normal” levels of CA-125. For thisreason, CA-125 testing for the diagnosis of early ovariancancer has been disappointing. On the other hand, in womenwith ovarian cancer (about 80% of the total), CA-125 levelsare high and – most importantly – fluctuate with the levelof tumor present. Therefore, the CA-125 test has become animportant tool in monitoring effects of treatment andpotential recurrence of disease. Further, recentimprovements in the sensitivity and precision of the testhas improve its diagnostic value significantly. The testhas become both common and very important in ovarian cancerdiagnosis. Several other such tests are in the development stagenow and within a few years we can expect further laboratorytests which will aid in early detection of several seriouscancers. In the previous paragraphs, the term biopsy has beenintroduced. A biopsy is an actual sample of tissue takenfrom within the tumor. The biopsy may require a surgicalprocedure, a scraping, a needle aspiration, blood sample,or other procedure to obtain enough cells to apply specialtreatments and dyes to ensure a clear microscopicdetermination of the type of cells and their abnormal(pathologic) appearance. The tissue sample is thenexamined under the microscope by a trained pathologist. Accurate diagnosis of the type of cancer is crucial inchoosing the proper treatment. To help understand thebasis for the diagnosis of cancer, it is useful to recallone of the basic principles presented earlier in thissummary, namely that every cancer cells originates from a‘normal cell’ (the term ‘normal cell’ is set in quotes herebecause there may be abnormalities that are not readily
    • detectable in cells which become cancerous.) Two otherprinciples which derive from this fact apply to the medicaldiagnosis of cancer. First, cancer cells differ (oftendramatically) from their normal counterparts in microscopicappearance. These difference often reflect their abnormalcell division and damaged internal structure. Second, withrare exceptions, the cancer cells retain enough of thecharacteristics of their normal parent cells so that theirorigin can be determined. For example, cells of anosteosarcoma (cancer of the bone) can be readilydistinguished microscopically from normal osteocytes(normal bone-producing cells), but retain osteocytecharacteristics which permit determination of their cellof origin. In some cases, the pathologist’s diagnosis willinclude a notation that a tumor is highly differentiated orhighly undifferentiated. Cells of a highly differentiatedtumor are malignant and abnormal, to be sure, but they havemore in common with the normal parent cells than highlyundifferentiated tumors. Rarely, these latter tumorsbecome so undifferentiated that it is difficult orimpossible to determine their cell of origin. These tumorsare progressive and particularly dangerous, but by the sametoken may be more susceptible to the effects of treatment. Genetic Testing. In recent years, intense researchhas been focused on the development and relevance ofgenetic tests in both diagnosis of certain types of cancer,in assessing prognosis (prediction of outcome) and inassessing cancer risk (more on this aspect in a latersection). Genetic technology has advanced dramatically inthe past 10 years and it is hoped that a picture of geneticanomalies in cancer and their importance in both diagnosisand treatment will emerge as more data are accumulated.The mapping of the human genome (The “genome” is the sumtotal of all genetic information encoded in our DNA.) hasfurther raised both the possibilities and the hopes ofestablishing genetic tests for cancer and for cancersusceptibility. Several are being evaluated now and agrowing catalogue of genetic abnormalities in various kindsof cancer is providing material for study.
    • Cancer Treatment It is not possible to provide a thorough discussion ofcancer treatment in this summary, but the following is abrief overview: There are four major modalities for cancer treatmentwhich, depending on the diagnosis and clinical presentationof the disease, may be used individually or in combination.The trend for modern cancer treatment is multi-modality, inwhich two or more methods of treatment are used. Themodalities are: Surgery. The oldest and still vital method oftreatment is surgical removal of all identifiable cancertissue. It should be noted that surgery provides a veryhigh 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 thebulk of the cancer in order to provide a better chance ofsuccess with additional forms of treatment. Researchdirected toward improvement of surgical technology isongoing and remarkable advances have been made over thepast several years. Laser surgery, cryosurgery, surgerywith ultrasonic scalpels, limb-sparing surgery,microsurgery and other new technologies now provide moreeffective removal of cancers with reduced trauma to normaltissues. Radiotherapy. Directed and controlled exposure ofcancer cells to radiation is widely utilized to destroycancers which are not accessible to surgical removal or todestroy cancer cells known or suspected to remain aftersurgery. Radiation of various types may be applied,depending on the type and/or location of the cancer. Chemotherapy. The use of one or more chemicalagents to selectively destroy cancer cells was firstdeveloped to treat leukemia, lymphoma and other “systemic”forms of cancer. Over the past half-century, however,chemotherapy has become more and more widely used intreatment of most forms of cancer. A number of differenttypes of chemical agents, with a variety of toxic effectson cells, make up our chemotherapy arsenal, and new drugsare continually discovered (or synthesized) and tested as
    • we continue to work to improve cure rates for all forms ofcancer. Modern chemotherapy is a product both of serendipityand of our growing understanding of the biology of livingcells. The first ideas of using chemicals to combat cancercells came from the World War I observation that soldierswith leukemia who were exposed to mustard gas developedremissions of their disease. One of the firstchemotherapeutics for cancer was nitrogen mustard – a closerelative of the chemical weapon. As the structure andfunction of DNA and the basic phenomena of cell growth anddivision became more clearly understood, scientists beganto attempt the design of drugs that would specificallytarget cancer cell growth. The first of these drugs was 5-fluorouracil, a compound synthesized specifically tointerfere with vital steps in the synthesis of DNA andtherefore vital to cell growth. The current arsenal of anti-cancer drugs – numberingmore than 200 – is the result of three fundamental areas ofresearch: the screening of tens of thousands of naturaland synthetic compounds to determine their anti-cancereffects; the synthesis and testing of new compounds basedon existing understanding of the mechanisms of abnormalcell growth; and the study of fundamental processes ofnormal and abnormal cell behavior in order to deter highlyspecific areas of vulnerability on the part of cancercells. For the first 50 or 60 years of its history, cancerchemotherapy has been focused on the same principle as thatwhich governs radiotherapy – that cancer cells grow muchfaster and/or less normally than healthy cells andtherefore they can be damaged more effectively by agentswhich destroy rapidly growing cells. Two enormous problemsemerge from this principle, however. The first is thatthere are normal cells which turn over rapidly in the body(i.e. grow rapidly). The second is the biological factwhich we have visited before: namely, that cancer cellsoriginate from and have characteristics in common withtheir normal counterparts. These two issues are the basisfor the often devastating side effects which accompanysystemic chemotherapy.
    • The overlying goal in chemotherapy research anddevelopment, then, is the achievement of selectivity – thedevelopment of drugs and/or drug combinations that destroycancer cells with little or no damage to normal tissue.The research effort to achieve selectivity in cancertherapy has primarily focused on two areas. The first areaof emphasis is called targeting. Targeting strategiesattempt to concentrate drug in the tumor or its vicinity inthe hope of minimizing the drug’s system effect on normaltissues. A variety of approaches – some of them rathernovel – have been applied in this effort. In recent years,a few tumors have been found to have virtually uniqueproteins on their surfaces. These proteins have been usedto produce antibodies which, when injected into thebloodstream, will seek out and specifically combine withthe cancer cells. Linked to potent anti-cancer drugs,these antibodies become ‘smart missiles” which target thecancer cells. The large appetites of cancer cells causethem to quickly absorb the antibody/drug combination and toundergo the cytotoxicity (i.e. cell damage or killing).This approach, still in its early applications has twogreat advantages: sparing of normal tissues, andeffectiveness with much lower concentrations of drug. Thismakes drug which are difficult to produce more viable forbroader use in treating the cancers against which they areeffective. The method is not broadly applicable yet, buteach year sees a longer list of such drugs. To identifythese drugs, look for the suffix “-mab”. This usuallydenotes a targeting molecule attached to a cytotoxiccompound. The second area of research emphasis in this category,often called cancer cell-specific therapy, focuses onfinding unique requirements of cancer cells which are notshared by normal cells. This approach holds enormouspromise, but has been realized in only a few unusualcancers thus far. We have learned that cancer cellsfrequently switch on and utilize genes that normal cellshave “permanently” shut down. Focusing on the needs ofthese “oncogenes” has given rise to the development ofdrugs that interfere with these cancer-specific processes.There is also a considerable research effort now focused onunderstanding why these genes begin functioning again incancer cells with the hope of finding ways to shut themdown again. A most significant outcome of this researchthus far is learning that at least some forms of cancer can
    • in fact be slowed or returned to normal by regulation oftheir abnormal genes. A question that all cancer patients and all cancerresearchers repeatedly ask is, “Why does cancer oftenrecur after chemotherapy?” Like all other aspects ofcancer, the answer to this question is complex and involvesseveral factors. One obvious reason is that insufficientdrug(s) reach the cancer (here, management of serious sideeffects is most often the limiting feature). This lack ofaccessibility may occur at the original site of the tumor,more frequently occurs when the cancer cells metastasize toanother organ like the brain, where it is much moredifficult to achieve effective doses of a drug. At least two other biological properties of cancercells, however, offer more challenging reasons. One isthat, within a tumor, the cancer cells grow at differentrates. Some cells grow rapidly, while others grow slowlyor even remain dormant for long periods of time. Theresult is that drugs which attack rapidly growing cellsspare the more sluggish and/or dormant cells, which maybegin growing after therapy is discontinued. Second is thecapacity of small populations of cancer cells within atumor to develop active resistance to a drug. Theprimitive behavior and actively mutating growth pattern ofsome cancer cells cause them to lose the capacity tointernalize the drug, with the result that the drug cannotenter the cells in order to do its damage. The most successful approach to combat these twoproperties of cancer cells has been the development ofcombination chemotherapy. This approach, which involvesthe use of two or more drugs in carefully scheduled amountsand regimens, has improved the survival and quality of lifefor many patients, particularly those with metastaticcancer. Yet another exciting and promising area of researchhas been focused on understanding and blocking the abilityof cancer cells to metastasize. A number of substanceshave been found to interfere with the metastatic process.Also not available for general use now, the goal is the useof these drugs to prevent spread of the cancer so that thecancer can be successfully treated by local methods likesurgery 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 notin as yet. Biotherapy. Compared to the three modalitiessummarized above, biotherapy is the “new kid on the block”.Biotherapy can be viewed as any form of therapy whichenhances or restores the body’s own ability to combat thedisease. The body mounts a very sophisticated and complexeffort to control any abnormal behavior of cells. Cancerusually develops either a result of some breakdown n thisbiological defense system or as a result of the cancercells’ ability to disguise and elude the body’s defenses.Biotherapy focuses on restoration, mobilization and/oraugmentation of the body’s natural control and combatmechanisms. Some of the most exciting and promisingdiscoveries in all of biomedical research today are in thearea of biotherapy. Several avenues of research are being pursued in thisarena. Some have found their way into “conventional”treatment at present. A growing application of human geneproducts such as interferon or the interleukins in thetreatment of some forms of leukemia and lymphoma falls intothe category of biotherapy. These products are produced intherapeutic quantities by transferring the human gene intovarious microbes, then producing the gene product much inthe way that antibiotics are produced. Another fertile are for research and clinicalapplication in biotherapy has been the development andtesting of substances which mobilize and enhance the body’s“early warning” and “first line of defense” systems. Theprimary responsibility for this type of defense is carriedout by macrophages, fairly primitive cells which roamthrough the body, ingesting and destroying any foreignentities. A family of substances has been found to givethese macrophages a specific appetite for tumor cells. Atleast one exciting clinical experiences has shown that – insome patients at least – this approach can eradicate earlymetastic growth of osteosarcoma cells in the lungs ofchildren. Extensive further study and clinical testing areunderway in institutions all over the world. A component of biotherapy, which is beginning to claimtitle as a separate disciple is gene therapy. As notedearlier 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 both normal 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 difficultyin assessing the potential side effects of genemanipulation. A recent gene therapy program in France washalted because – even though the treated children werecured of the disease produced by their genetic defect –they developed a different and very serious condition whichwas potentially life-threatening. Such concerns are thefocus of intense current research. Cancer Prevention “Is cancer inevitable?: “If we live long enough, arewe certain to develop cancer?” “Can anything be done toreduce our risk of developing cancer?” These questions arevery much on the minds of an increasingly informed andconcerned public. Further, these issues are very much onthe minds of biomedical researchers. There is mounting evidence that we can personallyintervene to decrease our risk of developing many forms ofcancer, including some of the most prevalent and life-threatening forms. In addition, our growing understanding
    • of the biological basis of cancer may make medicalintervention to prevent cancer a reality in the nearfuture. Our current understanding indicates that as much as80% of naturally occurring cancers may be associated withour lifestyles and environment. The primary lifestyleassociations with increased cancer risk relate to tobaccouse, diet and exposure to sun. Current data suggest thatsmoking and high fat, low fiber diets are associated withsome 65% of cancers, predominantly (but not exclusively)cancers of the lung, colon and breast. Avoidance ofsmoking (as well as use of smokeless tobacco); a sensible,well-balanced diet rich in fruits, vegetables and wholegrains and low in animal fats; protection from the burningrays of the sun – all these strategies can reduce cancerrisk and are well worth doing. Every concerned person should make a priority oflearning all that is possible about cancer prevention andearly detection. Although actual statistics are notavailable, we are aware than in increasing number ofcancers are detected by the patients themselves and many ofthese are found because the patients are aware andvigilant. The old cliché “Knowledge is Power” has never beentruer than when applied to cancer prevention. The more weknow about cancer, the better prepared we will be toprotect ourselves, our families and our community fromcancer. CONCLUSION: LOOKING OVER THE MOUNTAIN Promise and Problems in the Coming Years When we look back and recall the cancer incidence anddeath rates, it is clear that –although we are gainingground each year – that the conquest of cancer has not beenachieved. Enormous progress has been made, both in thecontrol of cancer and in the understanding of thebiological processes involved the in the conversion ofnormal cellular behavior to malignant behavior. As we bring this overview to conclusion, it may beuseful to point out some goals, some possibilities, andsome concerns about cancer control.
    • Improvement in Therapeutic Techniques and Strategies.Research and development continues in all technical aspectsof cancer detection, diagnosis and treatment. Advances inall four major modalities of treatment – surgery,radiotherapy, chemotherapy and biotherapy – have improvedboth long-term survival and quality of life for thousandsof cancer patients. A variety of technologies – some brandnew and some old – have been improved and re-evaluated.These include techniques like focused heat, ischemictherapy ( the use of mechanical devices to cut off theblood supply to a tumor). Reliable Risk Assessment. We honestly do not knowat present who is specifically at risk for cancer and whoisn’t. Familiar risk has been identified in someindividuals, but the goal of individual risk profiles seemrealistic. In this case, both the technology and thesocietal implications of risk profiles must be addressed –not only by physicians and scientists, but also byethicists and sociologists. Chemo-prevention. Results in some studies suggestthat – in persons with pre-cancerous conditions or at highrisk – there are substances which retard or block the earlystages of cancer growth. The goal of these studies is tohold at bay or even completely reverse the process ofmalignant transformation. Cancer As A Chronic Disease. A result of advancesmade already in detection and treatment of many forms ofcancer is that there are many many people who are not dyingof their cancer nor are they cured. Rather, they areliving with their cancers. Many physicians and bio-medicalresearchers are beginning to think of treating cancer as achronic disease, like diabetes, for example – with ongoingtherapeutic management, but not necessarily with theexpectation of complete cure. Cure is the ideal and much-hoped for goal, but maintenance of the disease accompaniedby health and full productivity may be more realistic inmany instances. As we bring this overview to a close, I am reminded ofthe old song about a bear going over the mountain to seewhat he could see. The song ends with the statement thatthe bear gets over the mountain, only to see anothermountain. The fight against cancer has been much like that
    • over the past years. However, we have become betterclimbers and we still believe that we fill finally get tothe top of a mountain and see our ultimate goal – theeradication 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