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THE LANCET

Œsophageal Cancer on the CaspianLittoral

’The Caspian Sea is deservedly rank’d among theWonders of the Worlde Sir Thomas Herbert.Travels in Persia 1627-29.’There is not in the same parallel of latitude a more

unhealthy strip of country in the world’. Lord Curzon.Persia and the Persian Question. 1892.

THE epidemiology of oesophageal cancer presentsa number of interesting anomalies.1-7 There is hugevariation-at least two-hundred-fold and perhapsmuch greater-between the highest and lowestincidence-rates in different countries. The incidencevaries strikingly between localities separated by only afew hundred kilometres. Wide variations in sex inci-dence provide a third feature, with male/female ratiosvarying from 30/1 to 1/1-5. And there is evidencethat the incidence of oesophageal cancer may be risingin certain parts of the world, notably in the Transkei.At present there are three principal geographic

areas with a very high incidence of oesophagealcancer. Best documented are certain eastern andsouthern regions of sub-Saharal Mrica 7-10 particu-larly the Transkei; parts of Rhodesia (Bulawayo), andwestern Kenya. A second region of high incidenceconsists of Curacao and parts of Brazil (here detailedinformation is lacking). The third zone comprises anenormous tract of central Asia made up of Iran,Afghanistan, Soviet central Asia, Siberia, Mongolia,and north and west China. One particular part ofthis region-the Caspian littoral-is attracting con-siderable attention, and the investigations of KMETand MAHBOUBl 11,12 are of outstanding interest.

Preliminary observations dating from 1966 first

suggested a wide variation in the incidence of aeso-phageal cancer along the southern shores of the Cas-pian sea, ranging from a very high incidence in partsof the eastern province of Mazenderan to a lowincidence in the western province of Gilan. A cancerregistry was set up in the coastal town of Babol in1969, carefully organised to deal with the particularproblems of collecting accurate information in this1. Union Internationale contre le Cancer. Cancer Incidence in Five

Continents; vol. I. Berlin, 1966.2. ibid. vol. II. Berlin, 1970.3. Dunham, L., Bailar, J. C. J. natn. Cancer Inst. 1968, 41, 155.4. Segi, M., Kurihara, M. Cancer Mortality for Selected Sites in 24

Countries. No. 6. (1966-1967). Japan Cancer Society, 1972.5. Doll, R. Br. J. Cancer, 1969, 23, 1.6. Doll, R. Proc. R. Soc. Med. 1972, 65, 49.7. Warwick, G. P., Harington, J. S. Adv. Cancer Res. 1973, 17, 82.8. Ahmed, N., Cook, P. Br. J. Cancer, 1969, 23, 302.9. Cook, P. ibid. 1971, 25, 853.

10. Cook, P. J., Burkitt, D. P. Br. med. Bull. 1971, 27, 14.11. Kmet, J., Mahboubi, E. Science, 1972, 175, 846.12. Mahboubi, E., Kmet, J., Cook, P. J., Day, N. E., Ghadirian, P.,

Salmasizadeh, S. Br. J. Cancer, 1973, 28, 197.

kind of terrain. Results from Babol are now be-

ginning to appear, first up until June, 1970,11 andlately extended to June, 1971.12

It was in their earlier paper 11 that KMET andMAmouBi first documented the remarkable gradientin the incidence of oesophageal cancer around theCaspian’s southern coastline and drew attention to

the no less dramatic changes in the natural environ-ment. In parts of the eastern coastal province ofMazenderan, the age-standardised incidence of aeso-phageal cancer (per 100,000 per annum) was found tobe 108-8 for men and 174 for women; the corre-

sponding figures from the western province of Gilanwere 17-2 for men and 5-5 for women. There is thus atenfold gradient for men and a thirty-fold gradientfor women, occurring over a distance of approximately600 km. In the highest-incidence zone-the north-eastern corner of Mazenderan, and especially in thevicinity of Gorgan and Gonbad, towards the borderbetween Iran and Soviet Turkmenistan-the in-cidence of oesophageal cancer is one of the highestever recorded. The two regions of extreme high andlow incidence are bridged by an intermediate zone inthe south-eastern and central part of the Caspianlittoral: here, age-corrected incidences (per 100,000)for oesophageal cancer are 25 4 for men and, for women,a more striking fall to 18-0, reversing the sex ratiofound in north-eastern Mazenderan. The boundarybetween low and medium incidence zones is roughlydemarcated by the Tehran meridian. Differences inthe environmental and demographic characteristics ofthe high-incidence and low-incidence zones are

equally striking. The high-incidence regions in theeast have very little rain and consist largely of low-lying steppe and desert: HERODOTUS described it as" an immense tract of flat country over which the eye

wanders till it is lost in the distance ".13 The soil isstrongly saline and supports a correspondinglyhalophilic vegetation. Agriculture, where possible,consists of dry farming-wheat, barley, and cotton.The country is thinly populated with a predominanceof Turkomans, many of them still nomadic and livingin movable round felt tents (yaourts). The low-incidence zone in the south-west littoral comprisesanother world. Lying within the humid Caspianrain-belt, some of the land is still densely forested withoak and boxwood. The non-saline soil is heavilyleached and supports extensive wet-farming with

paddy fields and tea estates. As Sir ROGER STEVENS hasobserved 14: " ... by turns India, Indonesia, NorthernItaly or the Riviera, the Caspian rain-belt has nothingthat we normally associate with Iran ". The region isdensely populated, mainly by Iranians. In the moreremote rural areas, the houses are thatched and standon wooden stilts above the waterlogged ground.The difficulties involved in collecting reliable

information in surveys of this kind are daunting;and the current paper from Iran 12 discusses in muchdetail the epidemiological methods used and their

potential error and bias. Demographic data wereavailable from the national census of Iran, made in1966, from which gazetteers for individual villages hadbeen prepared; additional information on rural13. Herodotus. The Histories; book I, p. 205.14. Stevens, R. The Land of the Great Sophy. London, 1971.

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communities was forthcoming from the records ofthe current malaria-eradication scheme. The registryused a simple questionary, devised to include all

cancers, and strenuous efforts were made to establishand maintain contacts with doctors working in remotecountry areas. About 80% of the cesophageal cancerswere diagnosed by a combination of clinical methodsand radiology; histological confirmation of biopsymaterial was available in a little over a quarter. Figures,compiled from individual administrative districts

(shahrestans), were placed in six geographicallycontiguous groups-two in the western province ofGilan and four in Mazenderan-for statistical analysis.Three sets of values were calculated: annual incidence-rates age-standardised to the world population bothfor oesophageal cancer and for other tumours; thetruncated incidence-rate (35-64 age-groups); and thecrude annual incidence-rate. Some important con-clusions emerged. The existence of wide regionalvariations in the incidence of oesophageal cancer inthe southern littoral of the Caspian was confirmed,with the proviso that the excess incidence amongwomen in north-eastern Mazenderan was less obvious:the incidence of the disease now appeared to be moreor less equally high in both sexes. Possible distortionsdue to local variations in reporting and diagnosis seemto have been largely eliminated-under-reporting,because of a scarcity of doctors, is indeed most likelyin the area with the highest incidence. Comparableregional variations in the incidence of other tumourswere not found in men and women aged between 35 and64. The uniform geographical incidence of cancersof the mouth, tongue, and oropharynx is particularlyimportant; cancer of the stomach, the next most

common site after the oesophagus, also showed no

regional variation in patients in this age-group.(There may be some regional variation in these othernon-oesophageal tumours in patients aged over 65-hence the use of truncated incidence-rates for com-

parative purposes.) In north-eastern MazenderanKMET and MAHBOUBI conclude that the actuarial riskof acquiring oesophageal cancer before the age of 65is about 1 in 6 for both men and women-an appallingfigure, comparable to that for bronchial carcinoma

among heavy cigarette smokers in the United Kingdom.Although concentrating on the two coastal provinces

of Gilan and Mazenderan, KMET and MAHBOUBI haveencountered an adjacent inland region where theincidence of oesophageal cancer is raised-the plateaudistrict of Ardebil, in eastern Azerbaijan, populatedby Iranians. Effective registration in this area has notbeen in operation for long, but preliminary resultssuggest that the incidence may approach that foundamong the Turkomans in parts of Mazenderan.Information on the incidence of oesophageal cancerelsewhere in Iran is meagre: a comparatively highincidence has been reported from Shiraz 15 in southernIran (where there is a large medical centre), butdetailed information on incidence and regional dis-tribution is not available.

There is no reason to suppose that the remarkable

gradient of oesophageal cancer is confined to the

15. Haghighi, P., Nabijadeh, I., Aswadi, S., Molallatee, E. A. Cancer,1971, 27, 965.

southern shores of the Caspian. The high incidenceamong Turkomans in Mazenderan almost certainlyspreads over the political borders into Turkmenistan,and extremely high incidence-rates of oesophagealcancer have been recorded in the Kazakhstan cityof Ghuryev, situated up on the north-eastern shoresof the Caspian. 5, 7,11,16 Crude incidence-rates of 150cases per 100,000 population have been cited, andthe cancer seems to affect the Kazakh tribesmenmuch more than the Russians living in the Ghuryevarea. There is a sevenfold difference for Kazakhs

aged under 40, falling to something over a twofolddifference in older individuals. 16 Interestingly enough,the high-incidence region of Ghuryev is flanked bythe Urals and by the central Soviet plains, where theincidence of cesophageal cancer is low; similar re-gions of localised high incidence have been describedin other parts of Kazakhstan, the contiguous low-incidence zones being characterised in each case byhigh rainfall. 11

Given this remarkable local variation in cancer

incidence, corresponding variations in the physicalenvironment, and a predominantly rural populationwhose simple way of life has remained largely un-changed, one might expect that some xtiologicalfactors would soon become apparent. But no definiteleads have yet emerged and at present one can do nomore than list some of the relevant points. Despitethe high incidence in Turkomans in Mazenderan,oesophageal cancer is not confined to any one ethnicgroup.11 The positive family histories recorded amongKazakhs in the Ghuryev district almost certainlyindicate environmental rather than genetic factors.l’In contrast to Africa 7 and the West,18 alcohol canbe disregarded. It is improbable that tobacco,whether smoked or chewed in the form of nass, canbe implicated; attempts to induce oesophageal can-cers in rats with nass have been unsuccessful. 19 Thereis no recognised exposure to exogenous carcinogenssuch as the polycyclic hydrocarbons, nitrosamines(some of which are potent cesophageal carcinogensin laboratory animals 7), or any of the known naturallyoccurring carcinogens such as aflatoxin that mightcontaminate stored foodstuffs. The main field ofinterest centres round the interlocking features ofsoil, crops, and diet. Primary deficiencies in tracemetals may occur in the soil in different locations,or may arise as an indirect consequence of malab-

sorption : the staple diet of unleavened bread con-tains large amounts of phytate, which binds metallicions.2° Iron deficiencies have been noted in Kazakh

patients,16 though the interpretation is bedevilled

by blood-loss from unrelated sources. The dailydietary habits in the Caspian littoral are being in-16. Kaufman, B. D., Liberman, I. S., Tyshetskii, V. I. Vop. Onkol.

1965, 11, 78.17. Satpaeva, R. A., Tarasova, G. V. ibid. 1970, 16, 3.18. Wynder, E. L., Bross, I. J. Cancer, 1961, 14, 389.19. Rahmatian, H., Modjtabai, A. Acta med. iran. 1965, 8, 1.20. Reinhold, J. G., Nasr, K., Lahimgarzadeh, A., Hedayati, H.

Lancet, 1973, i, 283.

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vestigated, but adequate analysis of even the simplestdiets is a massive undertaking. Diets in the high-riskareas of Mazenderan have been described as " greatlydeficient in animal protein, Vitamin A, riboflavin andVitamin C but much more information isneeded. The occurrence of a high cancer-risk popu-lation, still exposed to a traditional natural environ-ment, in a country with a rapidly expanding economyand growing medical and research facilities is almostunique; and clearly the opportunities are beingbrilliantly exploited.

How Many Doctors?ONE year the organisers of the E.C.F.M.G. ex-

amination in the Philippines had to hire a footballstadium to accommodate all those who wanted toobtain this passport to medical practice in the UnitedStates. Which country needed them the more ?From Europe, too, the U.S.A. has taken its toll of

doctors, and Europe in its turn is tapping the de-veloping world. Germany employs more than 5000doctors from other countries, many from Turkeywhose doctor/population ratio is a quarter that of

Germany; France looks to Tunisia; and Britain’sdependence on doctors qualifying on the Indian sub-continent, though not increasing, has long been

disturbingly high. The traffic is all one way-thewrong way.

No country admits to having too many doctors,least of all Britain, which not so many years ago madethe grave error of predicting a surplus and thenacting on this prediction. However, the problem ismore often one of distribution and efficient use

rather than actual shortage. In Britain the southis more attractive than the industrial areas; in theUnited States doctors move east and west to thecoasts and leave the heartlands underdoctored;and in the predominantly rural developing world it isthe temptations of urban practice that are strongest.With efficient management and teamwork in a

properly organised health service there must be alimit to the number of doctors required-or at leasta point when it is no longer necessary for the numberto expand at a rate faster than that of the population-and many Western countries are already close to it.All of them should aim first at self-sufficiency,coupled with a carefully prepared programme ofhelp for the developing world based on exchanges,medical-school places for countries without them,and postgraduate training schemes which recognisethe limited relevance of some aspects of Westernmedical practice to the countries to which traineeswould return. This commitment to self-sufficiencyneeds to be made, not just by Britain or the CommonMarket, but by all the richer countries. The argumentthat in free societies the movement of skilled per-sonnel cannot be stopped is convenient but no longertenable.

After twenty-five years the National HealthService is anything but self-sufficient. The figuresspeak for themselves: 16% of general practitioners,13° of consultants, 25% of senior registrars, 55%of registrars, 61% ° of senior house-officers, and

16% of house-officers received their undergraduatemedical education outside the U.K. and Irish

Republic. And " outside " usually means Dacca notDurban, Bombay not Brisbane. In a country witha substantial immigrant population a proportion ofimmigrant general practitioners, community phy-sicians, and hospital doctors is important, and weshould be glad that the door to a consultancy has notbeen closed to those who decide to stay. However, insome parts of Britain and in some specialties (notablygeriatrics and psychiatry) dependence is fast be-

coming total; and patients in these unfavoured areasdeserve, and may soon begin to demand, somethingdifferent.

Manpower planning is not easy, but if it cannotbe done in a country which (unlike many of itsE.E.C. partners) controls medical-school entry andwhich runs a national service in which most doctorswill spend their working lives, can it be done at all ?In the short term there are one or two things thatthe Department of Health, the Central ManpowerCommittee, and the profession could do now touse hospital medical manpower more effectively.Expansion of the consultant grade has long beena commitment, but there have been difficulties:in the early days this grade expanded, but moreslowly (instead of faster as planned) than juniorposts; consultants have been demanding more

juniors, and, with domestic output only now be-ginning to pick up, new senior-house-officer postshave been filled from outside; some regions havebeen favoured in the allocation of new consultant

posts but have not been given the money to take uptheir options. Some duplication of duties could beavoided, and inter-specialty cross-cover is worth

looking at. In the long term, however, self-sufficiencycan only come from an increase in medical-schoolplaces.The Royal Commission on Medical Education

outlined our needs up to the year 1995, and few havequarrelled with its figures. True, population trendsare not going the way Todd or anyone else predicted;emigration of doctors is not the problem it was inthe 1960s; and the Department has introduced someimaginative plans to encourage women to stay inmedicine. The report said that we would need an

average of 4300 places for the years 1975-79 formedical students of British origin-in other words,a five-year entry of 21,500. The Government hasset a target (it is a ceiling as well) of 4100 home andoverseas students by the year 1979, though theactual figure will fall a little short of this. With

steady expansion from now on and with, say, no