One of the most important contributions of epidemiology to the fightagainst cancer has been the demonstration that many of the prevalentforms of human cancer are preventable. Specific etiologic agents, andready methods of prevention, havebeen identified for several varieties ofcancer, one of which—cancer of thelung—is the single most importantneoplasm in American males. In addition, indirect evidence has been accumulated that environmental agents, asyet unidentified, play important etiologic roles in many other commonforms of neoplasia. Continuing epidemiologic study is motivated primarilyby its potential for identifying theseagents and thus pointing to specificpreventive measures. By contri buting to knowledge of the natural courseof malignant disease, epidemiologicstudies can also play an important rolein evaluating new methods of prevention and treatment.

The Preventability of CancerSome cancers are already prevent

able. The known etiologic agents include a wide range of physical, chemical, and biological agents; the neoplasms they produce embrace a variety

Dr. MacMahon is Professor of Epidemiology,Harvard University School of Public Health, Boston, Massachusetts.

Reprinted from CANCER—A MANUAL FOR PRACTITIONERS (Fourth Edition, 1968), published andcopyrighted by the Massachusetts Division of theAmerican Cancer Society.

of cell types and organ sites. The extensive range of additional agentsknown to be capable of cancerogenesisin the laboratory animal, and the accumulation of epidemiologic evidenceof international variation, rapid timechanges, and association with socioeconomic status, religion, marital status and other demographic characteristics, indicate that the list of preventable cancers will soon be much largerthan it is now. Some of the epidemiologic evidence relating to cancers thatare not yet preventable will be described here.

National Propensity to Disease

The predominant forms of cancervary remarkably from one country toanother. In the United States, cancerof the lung is the most common neoplasm in males. In Japan, cancer ofthe stomach, and in Taiwan, cancer ofthe nasopharynx, account for abouthalf of all cancers in males, and inmany African populations cancer ofthe liver predominates. There areparts of the world where cancer ofthe esophagus is the most prevalentneoplasm; in the areas of highest incidence, cancer of the esophagus is200 times as common as in WesternEurope and the United States. Cancerof the prostate has an annual incidenceof about 40 per 100,000 in the UnitedStates and less than three per 100,000in Japan. Comparable variations arefound in females. Carcinoma of the

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Epidemiologic Aspectsof Cancer

Brian MacMahon, M.D.

breast in the United States is sixtimes as common as in Japan and tentimes as common as in the SouthAfrican Bantu; carcinoma of the corpus uteri occurs in Japan with aboutone tenth of its frequency in theUnited States, and this form of malignancy is virtually unknown amongthe Bantu.

Genetic differences between populations may contribute to these international variations, but existing evidenceon the role of genetic factors in thecommon human malignancies makes itunlikely that genetic differences couldaccount for rate differences of thisorder of magnitude. In addition, ithas been shown that migration fromone country to another results in majorchanges in cancer risk, the patternsamong the migrants shifting substantially towards those prevalent in thehost country. For some forms ofcancer, the migrant group attains therisk characteristic of the host countrywithin one or two generations. This isstrong evidence that the cancer patternof the ancestral country is the result ofcharacteristics of the environmentrather than of the genetic compositionof the population.

Social and Genetic Causes

There are also peculiarities of cancerdistribution within countries thatpoint to environmental determinationof the major malignant disorders. Notable are variations with socioeconomicstatus. Cancers of the cervix and ofthe stomach show three to four timeshigher rates in unskilled workers andtheir wives than in persons in the professional classes. On the other handcancers of the breast, leukemia, andmultiple myeloma are substantiallymore common in the higher economicclasses. Genetic differences are mostunlikely to account for this variation.

For some cancers, rapid changes infrequency over time are occurring.

The sharp increase in lung cancerrates during this century eventuallyled to the identification of cigarettesmoking as the causative agent. Lessstriking, although still substantial,increases are also seen for cancers ofthe pancreas, prostate and ovary, andleukemia. Equally significant is theremarkable decline in frequency ofstomach cancer that has occurred inthis country; rates are now less thanhalf what they were 30 years ago.Cancer of the cervix is also undergoing a marked decline which is probablynot the result of, since its beginningantedated, programs of cytologicaldetection. Such sharp changes makethe concept of preventability of thesecancers almost incontrovertible.

Observations such as these generallydo not lead directly to practical preventive measures. To prevent carcinoma of the breast it would not bepractical to advise women to changetheir nationality a generation ago,marry an unskilled worker, and to havesix children, two right breasts, andan oophorectomy prior to age 40. Butthe observations that underlie such“¿�advice―leave little doubt that thereexists some environmental eti ologicagent to which women are exposed invarying degree and whose identification may form the basis of an effectivepreventive measure. As has alreadyhappened in the case of cancer of thelung, such observations may also leadto the development of hypotheses regarding the specific nature of the responsible agent.

Known Environmental CausesClinical, laboratory, and epidemio

logic studies have all played importantparts in identifying specific agentsknown to cause cancer. Here will bementioned only the most important,from the point of view of known numbers of cancer cases produced, andthose in which epidemiologic observations are of particular interest.

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ToBAcco

Tobacco, in one form or another, isresponsible for more human cancercases and deaths than any other knownagent. Most clearly documented is therelationship of cigarette smoking tocancer of the lung, yet tobacco smoking is also probably causally related tocancers of the mouth and bladder.

Cancer of the lung. During the 40

years of its course to date, the currentepidemic of carcinoma of the lung hascaused almost a million deaths in theUnited States alone, and another million can be confidently predicted before the epidemic subsides. The predominance of males among lung cancerpatients, as well as the remarkable increase in rates observed in this countryand Western Europe beginning about1920, suggested that cigarette smokingmight be responsible. Several dozenstudies have subsequently shown thatthe risk of developing lung cancer increases regularly in proportion to thenumber of cigarettes an individualsmokes. Smokers of two or more packsof cigarettes per day have about 20times the risk of nonsmokers; aboutten percent of smokers of two or morepacks per day can be expected to develop lung cancer. Smokers of cigarsand pipes have lung cancer risks thatare definitely higher than those of nonsmokers but are lower, ounce forounce of tobacco, than those of cigarette smokers.

The view that lung cancer is causedby cigarette smoking, rather than beingthe result of some idiosyncrasy ofcigarette smokers, is supported by theobservation of low rates in populationsthat do not smoke (e.g., Seventh DayAdventists), decline in risk for persons who discontinue smoking, thefinding of multiple premalignantchanges in the lungs of smokers, andthe presence in cigarette smoke ofmany known carcinogens. It is esti

mated that over 90 percent of thepresent lung cancer incidence in thiscountry could be prevented by the elimination of the effect of cigarette smoking.

Cancer of the bladder. It has beenconsistently observed that cigarettesmokers have a higher risk of bladdercancer than do nonsmokers. Thestrength of the relationship is considerably less than in cancer of thelung, although smokers of two packsor more per day have a bladder cancerrate about five times as high as dononsmokers. A causative associationbetween an inhaled substance and aneoplasm of the urinary excretory apparatus seems, at first sight, unlikely.However, a number of the end-products of inhaled smoke are excreted inthe urine, and biochemical mechanismsthat would reasonably explain such arelationship have been identified.

Cancer of the mouth. Both tobaccosmoking, particularly in the form ofpipes or cigars, and alcohol intake areassociated with increased risk of oralcancer. The two customs are, of course,highly correlated and it is difficult toseparate their effects. It seems likely,however, that both have independentcausal relationships to oral cancer. InIndia and other countries where betelchewing is prevalent, cancers of thecheek, tongue, and other buccal sitesare very common. The betel quid contains various combinations of driedbetel nut, tobacco, lime, spices, andbetel leaf; it is held in the gingivobuccal fold for long periods of time. Cancers tend to develop in the sites wherethe quid is lodged. The evidence thattobacco is probably the main carcinogenic component is that oral cancer isnot particularly frequent in areaswhere the quid does not contain tobacco.

IoNIzING RADIATION

Epidemiologic studies have played

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the major role in attempts to delineatethe circumstances under which ionizing radiation is cancerogenic in man.The problem is an important one, notonly because of the universal and increasing exposure of populations toionizing radiation, but also becauseof the possible contributions to basicknowledge of the mechanisms of carcinogenesis. While a great deal moreis known now than was known 20 yearsago, it must be admitted that we stilldo not have most of the data thatwould be required for an informedjudgment on the maximum limits ofexposure advisable for individuals orpopulations.

Leukemia. There is no question butthat large doses of ionizing radiationare leukemogenic in man. The exposedpopulations that have a demonstratedsusceptibility to leukemia (Japanesesurvivors of the atomic bombings, patients treated with X-rays for ankylosing spondylitis, British and American radiologists, infants irradiated forthymic enlargement, patients receivinginjections of thorotrast') are so variedthat their radiation exposure is theone common factor to which their increased risk can reasonably be attributed. The cell types which are increasedinclude the acute leukemias and chronicmyelocytic leukemia; chronic lymphocytic leukemia is not associated withradiation exposure. The risk reachesa peak four to eight years after exposure; however, it remains higherthan normal for at least 15 years andperhaps much longer.

Risk increases with dosage of radiation received. Data from the atomicbomb survivors and the ankylosingspondylitis patients give an estimatedrisk of one to two cases of leukemiaper year per million population exposedfor each rad of exposure. Thus, 1,000persons exposed to 500 rads would beexpected to have one half to one caseof leukemia annually, or five to ten

cases in the subsequent ten years. Thisformula gives a reasonable approximation to the data for exposures between 100 and 1,500 rads. It is notknown whether a similar linear relationship exists at lower doses orwhether there is a “¿�threshold―belowwhich leukemia risk is not increased.

A series of studies of children exposed to diagnostic doses of X-rayswhile in utero, as for example in thecourse of pelvimetry, indicates an increased risk of leukemia and otherchildhood cancers in them. Since thedosage received in such procedures isof the order of one to five rads, thesestudies suggest that, if there is athreshold for leukemia induction, itlies below the dosage levels commonlyreceived in the course of medical diagnostic procedures. There are also studies suggesting high frequencies of diagnostic X-rays of the trunk in the histories of adult patients with chronicmyeloid leukemia. For practical purposes, it would therefore seem prudent,for the moment, to assume that thereis no threshold in the leukemogeniceffect of radiation. A great many moredirect observations are needed on theeffects of dose rate, fractionation, partial body exposures and, particularly,on populations exposed to doses under100 rads.

Cancer of the lung. A fatal respiratory disease, originally known as“¿�mountainillness,―has been recognizedin the cobalt and uranium miners ofSchneeberg and Joachimsthal in Czechoslovakia for several centuries. In earlier times, it accounted for almosthalf the deaths of miners in theseareas. The disease was identified assquamous carcinoma of the lung earlyin this century and is now attributedto exposure to radioactivity from breakdown products of uranium.

The Czechoslovakian experience isnow being repeated in the UnitedStates, in the Colorado Plateau, where

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substantial uranium mining has beenin progress since the 1940's. Over 50cases of lung cancer have been reportedin the last decade in a population ofabout 3,500 underground workers, anda clear relationship has been demonstrated between lung cancer risk andduration and severity of exposure toradioactivity. The average underground experience of American minersis still relatively short and a muchlarger number of cases will occur astime passes and experience lengthens.Although determined efforts are nowbeing made to reduce radioactivitylevels, the achievement of recommended standards is extremely difficultin many mines.

Cancer of bone. Cancer of the bonehas been described among workerspainting the dials of watches withluminous, radium-containing paint.The practice was to “¿�tip―the brusheswith the lips to obtain a fine point,and thus considerable amounts ofradium were swallowed. Some of theworkers, mostly exposed in the 1920's,died from acute effects, includingaplastic anemia and bone necrosis, particularly of the jaw. Some of the original group are still being followed toidentify long-term effects of internallydeposited radioactive material. The relationship of this experience to morecommon, although considerably lesssevere, exposures, such as the lifetimeconsumption of water high in radioactive materials, is not known. To dateno deleterious effects have been demonstrated from residence in areas ofhigh natural radioactivity, or fromconsumption of affected water or food,but the technical problems of suchstudies are considerable. Not least isthe fact that diagnoses of bone cancerappearing on death certificates are lessreliable than for almost any other siteof cancer.

Other cancers. Cancer of the skin isa well-known complication of radiation

and frequently among the first radiumand X-ray workers. Cancer of thethyroid and other head and neck tumors have been reported among children treated with X-rays in infancy forsupposed thymic enlargement. Amongthe British ankylosing spondylitis patients studied for leukemia incidence,an excess of tumors was found in manydifferent tissues that received heavyirradiation in the course of the treatment. Perhaps, indeed, most forms ofmalignant disease can be induced byirradiation in appropriate form anddosage, even though this is not theusual mechanism.

OCCUPATIONAL EXPOSURES

The study of occupational exposuresto specific chemical and physical agentsis potentially one of the most importantways in which epidemiologic methodscan contribute to the knowledge ofcancer etiology. The demonstration ofa specific occupational hazard is, ofcourse, of importance to the workers inthat particular occupation. In addition,and perhaps ultimately of even greaterconsequence, occupational exposuresgive an opportunity for the study,under relatively controlled conditions,of the effects of high doses of substances to which the population atlarge may be exposed in lower doses.Thus, the observation of high leukemiarates among radiologists was one ofthe stimuli to the initiation of largescale studies of the leukemogenic effectof ionizing radiation. It has been shownthat workers occupationally exposed toasbestos fibers have high rates of carcinoma of the lung; the increasingprevalence of such fibers in the general environment, and the increasingfinding of asbestos fibers and asbestosbodies in the lungs of persons withoutoccupational exposure, have led to concern regarding the possible role of nonoccupational exposure to asbestos inthe causation of lung cancer.

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The number and variety of occupational exposures that may be cancerigenic are considerable, and only afew of particular epidemiologic interestcan be described here. Several comprehensive treatises are published onthe subject.

Cancer of the skin. A great many ofthe end products of the combustion ofcoal are responsible for occupationalcancers of the skin. A number of specific carcinogenic agents are involved,the most important of which is benzpyrene. However, exposure is notusually to the pure agent, but to acrude product such as soot, pitch, tar,creosote, or anthracene. The range ofoccupations involving such exposuresincludes eighteenth century chimneysweeps and twentieth century Gloucester fishermen, to name only two.Characteristically, the tumor occurs atthe site of maximum exposure, commonly the hands or forearm, but, again,the sites characteristic of particularoccupations have considerable variety.

Certain crude oils have been associated with cancer of the skin, particularly of the scrotum, and particularlyin occupations in which skin and clothing remain saturated for long periods.The classical example is “¿�mule-spinner's cancer― of the scrotum, inducedby saturation of the clothing of thelower part of the trunk with oil as theworkers lean over their machines, or“¿�mules.―

Cancers of the skin may also befound in occupations associated withrisk of inhalation or ingestion of inorganic arsenic. The handling of arsenical insecticides is one such. Similarcancers are seen in persons given arsenic as a medicinal agent over a longperiod of time. The cancers result fromdeposition of arsenic in the basal layers of the skin, and are not necessarilyrelated to the site of maximum externalexposure. The palms and soles arecharacteristic sites.

Cancer of the skin also illustratesthe importance of occupational studiesin pinpointing etiologic factors of moregeneral significance; the observationof high rates in farmers, sailors, andother outdoor occupations helped toestablish the etiologic significance ofsunlight in this condition.

Cancer of the lung. The induction oflung cancer by occupational exposureto radon gas and asbestos has alreadybeen referred to. Other occupationsinvolving high lung cancer risk include those in chromate, mustard gas,nickel, and coal gas production. Thevariety of agents capable of inducingcarcinoma of the lung is of interest.Their investigation is complicated bythe quantitatively overwhelming effectof cigarette smoking in our present society.

Cancer of the bladder. Exposure tobetanaphthylamine and other aromaticamines is associated with increasedrisk of cancer of the bladder. Such exposures occur in the chemical industryin the course of production of the aniline dyes, and also in the rubber andcable industries. It has been estimatedthat ovei' 500 cases of occupationalbladder cancer have occurred amongAmerican chemical workers. However,a reliable estimate of the total contribution of occupational exposure to theoverall bladder cancer incidence hasnot yet been made. Perhaps, of all malignant disease, cancer of the bladderis the one in which detailed occupational histories of affected individualsare most likely to turn up exposures ofpossible etiologic significance. Bladdercancers of known occupational origincannot be distinguished clinically oi'pathologically from “¿�idiopathic―cases.

The Natural Course of Cancer

It is accepted medical philosophytoday that cancer must be treatedas early and as energetically as circumstances permit. The great majority

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of our population have ready access tomedical care, utilize physicians frequently, and come under the influenceof this philosophy. As a consequence,we have little or no information onthe natural course of cancer. This ismore than a nice academic problem,for such information is crucial forplanning and evaluation of effectiveness of programs of treatment or control.

A case in point is carcinoma of thecervix uteri. The stages in the development of a clinically evident invasivecancer are fairly well establishedfrom squamous epithelial metaplasia,through carcinoma in situ and asymptomatic invasive carcinoma to symptomatic invasive cancer. Questions thatneed to be answered if a logical program of early detection and treatmentis to be planned include: Can the earlyforms of abnormality, e.g., carcinomain situ, regress spontaneously? Whatproportion of cases in each stage wouldprogress to the next stage if leftalone? What is the average time spentin the various stages and at what intervals would screening have to be donein order to detect all, or most, of thecases in a particular stage? Are thecases of early abnormality which progress to frank invasion typical of allcases, particularly with respect to timespent in the various stages? Whatproportion of invasive cases passthrough the early stages so rapidlythat there is little prospect of detectingthem by periodic screening?

As new cytological and other earlydetection techniques are developed,such questions become pertinent formore and more sites of cancer. Theycannot be answered by follow-up studies of series of individual cases, sincethe discovery of an early lesion immediately leads to interference with itsnatural history, usually to its eradication. Comparison of incidence and prevalence rates of the various stages of

abnormality in a population offers oneapproach.

Before illustrating this approach, itis necessary to define briefly the various measures of disease frequency andto describe their interrelationships.

MEASURES OF DISEASE FREQUENCY

Incidence is the number of new casesof a disease occurring in a populationwithin a defined unit of time, usuallyone year. The definition of a “¿�new―case could be a case with onset withinthe time period, but, more practically,it is a case newly diagnosed within theperiod. If all cases come to eventualdiagnosis, the two definitions will giveidentical values.

Prevalence is the number of cases ofa disease that exist in a population ata particular point in time.

Mortality is the number of personsin a population dying from a diseasewithin a defined unit of time, usuallyone year. In that mortality is a countof events occurring within a time period, rather than of status at a pointin time, it is more similar to incidencethan to prevalence.

Incidence, prevalence and mortalityare usually expressed as rates per unitpopulation. The term “¿�incidence―isfrequently used to denote either incidence, i.e., number of cases, or incidence rate.

Case fatality ratio is the number ofpersons dying from a particular disease expressed as a proportion, not ofthe population, but of the number ofpersons developing the disease.

Under the condition that frequencyand duration of a disease are remaining fairly constant over time, there arecertain simple relationships betweenthese measures. One is that prevalenceis the product of incidence and averageduration. For example, a disease withan incidence of 50 per 100,000 population per year and an average durationof five years would have an average

prevalence, at any point in time, of250 per 100,000. From this relationship, given the values of any two parties (e.g., incidence and prevalence)the third (e.g., average duration) canbe estimated. The second useful relationship is that the mortality rate isthe product of the incidence rate andthe case fatality ratio. Again, givenany two values, the third can be estimated. Thus a disease with incidence50 per 100,000 and a mortality rate of25 per 100,000 would have a casefatality ratio of 0.5.

Application

Suppose that a disease has threestages, for example, carcinoma in situ,asymptomatic invasive cancer, andsymptomatic invasive cancer. Supposealso that cases of invasive cancer mustpass through an in situ stage, and thatall symptomatic cases must passthrough an asymptomatic stage. If thedisease is inevitably progressive andall in situ cases progress to invasionand all invasive cases eventually become symptomatic, then the incidencerates of all three stages will be thesame. Thus the finding that the incidence of new cases of in situ canceris the same as the incidence of invasivecancer would suggest that all in situcases ultimately become invasive. Onthe other hand, if the incidence of insitu cases is twice as high as that ofinvasive cases, this would indicate thatonly half of the in situ cases becomeinvasive.

Incidence and prevalence of symptomatic invasive cancers can be estimated from the number of diagnosedcases of the disease in a population.On the other hand, estimation of frequency of the preclinical stages willrequire special surveys. For example,if a population is screened cytologicallyfor cancer of the cervix, the numberof cases of carcinoma in situ found atthe first screening gives an estimate ofthe prevalence of this stage. The num

ber of invasive cases newly discovered(assuming them to have been asymptomatic) represents the prevalence ofthe invasive asymptomatic stage. If,then, the women found normal at thefirst examination are rescreened a yearlater, the number of in situ cases foundat the second examination representsincidence of this stage, since it is thenumber of new eases that have developed in the year's interval. Thus, whileprevalence can be estimated from oneexamination, estimation of incidencerequires at least two.

If both incidence and prevalence canbe estimated, the relationship betweenthem can be used to estimate durationof the disease stage. For example, ithas been found that the prevalence ofcarcinoma in situ is about four timesas high as the annual incidence, indicating the average duration of thisstage to be about four years. A similarorder of duration is suggested for presymptomatic invasive cervical cancer,although it must be stressed that thenecessary data are only just beginningto be assembled, and many more willbe required before such estimates canbe made with confidence. If four yearsdoes turn out to be a reliable estimateof the average duration of each ofthese preclinical stages, then there isa reasonable chance of picking up mostcases by annual, or even biannual, examinations, provided that the cases arereasonably homogeneous and do notinclude a large group with very shortdurations counterbalanced by a groupwith very long durations.

Lastly, an evaluation of the resultsof a program of early detection andtreatment can be made from a comparison of trends over time in the incidence of the various stages. Thus, anearly detection program would not beexpected to decrease the incidence ofcarcinoma in situ, but, if the programis effective, there should be a decreasein incidence of symptomatic invasivecancer and, particularly, a decline in

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the mortality rate from the disease inthe population. In the large BritishColumbia program of cervical cancerdetection a decline in incidence of invasive cancer has been demonstrated,but the crucial decline in mortality hasnot so far been observed. Of course,in view of the estimated durations ofthe various stages of this disease, adecline in mortality cannot be expecteduntil a program has been in operationfor 10 to 15 years or more. In the caseof cervical cancer, the evaluation iscomplicated by the “¿�natural―declinein incidence of this disease, which hasbeen in progress since the 1930's. Nevertheless, a comparison of the slopesof the declines for incidence of carcinoma in situ and of invasive cancerand for mortality from invasive cancerwould allow an evaluation of the effectiveness of a program.

Other Epidemiologic Aspects

CLUSTERING

The large volume of evidence on thesignificance of viruses in the etiologyof cancer in laboratory and domesticanimals has led to considerable interest in the question of whether humancancer cases tend to cluster in timeand/or space. Long-standing impressions as to the existence of “¿�cancerhouses―have been reinforced by recent“¿�outbreaks―of leukemia, such as thatin Niles, Illinois.

However, in the case of leukemiaspecifically, studies in which the question has been statistically evaluated inseries that have not been selected posthoc because of intuitive suspicion ofclustering, have produced negative orequivocal results. It is quite clear thatthe great majority of cases of leukemiado not cluster in the small units ofeither time or space associated withthe spread of the classical infectiousdiseases. The possibility that rare clusters do occur, particularly in acute lymphoblastic leukemia in young children,can not be categorically denied, al

though the evidence for the suggestionis not strong. Even if there weresuch rare clusters, their interpretationwould be difficult in view of the quitenegative evidence regarding communicability of the great majority of cases.

The only human tumor for whichthere is reasonably reliable evidenceof clustering is Burkitt's lymphoma.This condition has been shown to cluster in particular districts of Ugandaand to move from one district to another in different years. This evidencesupports the view that Burkitt's lymphoma may well be the first humanneoplasm to be shown to be associatedwith a communicable agent.

EPIDEMIOLOGY OF SURVIVAL

Just as the study of the distributionof disease incidence can help to formulate hypotheses as to etiology, thestudy of the relationship of survivalage, sex, race, and other demographicvariables may assist in the identification of factors associated with the survival of affected individuals. Interestin this problem is relatively recent andthe field is not developed. Examples ofobservations made so far, for whichexplanations are being sought, includea lower survival rate among males withcarcinoma of the lung than among females with similar type and stage ofdisease, and a substantially better survival from carcinoma of the breastamong Japanese than among Americanand European patients.

Data being collected in national andstate cancer registries will be invaluable in this field. There are now morethan 30 such registries in various partsof the world with coverage of entiredefined populations. The U.S. NationalCancer Institute also coordinates a national program for the reporting ofend results from over a hundred U.S.hospitals; these are being utilized foranalyses of epidemiologic informationas well as comparisons of therapeuticregimens.

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