911

thecally. 32 of the first group of 35 patients scheduledto receive this combination began treatment in 1967after remission had been induced with prednisone andvincristine; 21 were alive in September, 1972, from51 to 57 months after the start of treatment, 18 ofwhom had been in continuous complete remissionand off all treatment for 14-28 months-a 4-yeardisease-free rate of 51 %. Dr. Pinkel concluded that ofall the variations in treatment he had investigated theonly major contributor to the improved duration ofremission and of continuous long-term completeremission was adequate prophylaxis against meningealrelapse.Are the long survivors to be regarded as cured, or

do they merely represent the tail-end of an exponentialsurvival curve ? Dr. Pinkel presented the logarithmicsurvival curves of each series of patients. All the curveswere biphasic and showed an initial linear fall, indi-cating a constant death-rate, followed by a plateau,indicating the patients in continuous complete remis-sion. From the curves for the groups of patients whobegan treatment before 1967, it was apparent that thepatients in continuous complete remission for morethan 2! years were indeed likely to be free of disease.Comparison of those curves with that of the series of95 patients, the first of whom began treatment in 1970,suggests that a high proportion of the 59 now incomplete remission between 9 and 25 months later arelikely to remain free of disease after 5 years.

Dr. Pinkel’s results are impressive, not least for themethodical manner in which seemingly intractable

problems were solved by careful planning at eachstage. He does not minimise the many remainingproblems; neither does he underestimate the diffi-culties inherent in carrying out the exacting treatmentschedules nor the importance of the toxic effects andrisks of the treatment. Much remains to be done.Meanwhile, it is clear that acute leukaemia is best treatedby those with special knowledge, and there is now nolonger a place for palliative management by thecasual practitioner. In Great Britain, controlledclinical trials are in progress under the auspices of theMedical Research Council at many centres, and evenremote districts are within easy reach of expert care.

ORAL CONTRACEPTIVES AND CANCER

Six years ago the Committee on Safety of Drugsannounced that it would require from manufacturersevidence of long-term toxicity tests in two species ofanimal given oral contraceptives for most of their life-span. These tests, on mice treated for eighty weeks andrats treated for two years, were completed by Novem-ber, 1970. The results of the manufacturers’ findingshave now been analysed by the Committee on Safetyof Medicines with the help of a three-man working-party from the Royal College of Pathologists. Copiesof the report were posted to all doctors in the UnitedKingdom on the day before publication. Three doseswere chosen for each oral contraceptive-2-5 (low),50-150 (medium), and 200-400 (high) times the

1. Carcinogenicity Tests of Oral Contraceptives: a report by theCommittee on Safety of Medicines. H.M. Stationery Office. 25p.

human oral-contraceptive dose-and progestagen andoestrogen components were tested separately.

In 1966 there had been a report of hepatoma forma-tion in rats given mestranol-indeed this report wasthe basis for the Committee on Safety of Drugs’stricter requirements about toxicity testing. Theearlier findings are not confirmed in the latest report:there were positive findings in rats at higher doses butnot in mice, and the conclusion is that " there is littleevidence of production of benign or malignant hepa-tomas by these many compounds ". The mainconclusion of the whole study is that " although acarcinogenic effect can be produced when some of thepreparations are used in high doses throughout thelife-span in certain strains of rat and mouse, thisevidence cannot be interpreted as constituting a

carcinogenic hazard to women when these preparationsare used as oral contraceptives ". The Secretary ofState for Social Services has said he is " much relieved

by the outcome " of the inquiry.Amenorrhoea of varying duration is quite a common

finding after oral contraceptives have been used, andthe most common tumour in these experiments wasa pituitary adenoma, the frequency being higher intests where oestrogen was used alone than where the

progestagen alone was given, and the frequency forthe combination approximately equalling the sum ofthe frequencies for the components of the oral

contraceptive. In control female CF-LP mice, forexample, the frequency of this benign tumour was5%, but in almost all the treated groups of animals thefrequency was greater than this, rising to 62-5% inforty animals on the highest dose of one combination.The differences in strain susceptibility to tumours

can be illustrated by the figures for pituitary adenomain female rodents given ethinyloestradiol alone-32%in one experiment with CF-LP mice, 2-5% in another;4-2% in BDH-SPF mice; 0% in one group of rats(12% in controls), and 34-7% in another (41-3% incontrols). These complexities make the report ratherheavy going. The Committee suggests that in allcases of amenorrhoea after the use of oral contra-ceptives there should be careful documentation andfollow-up; a full investigation will then be undertaken.

PATHOLOGY OF INJURY

TRAUMA has become immensely important, botheconomically and from the point of view of humansuffering. Nevertheless, scientific investigation of thesubject seems to have advanced remarkably slowly.In view of this, the Royal College of Pathologists setup a working-party in 1967 " to review the state ofknowledge of pathology in the field of trauma, to assessthose areas where knowledge is limited and where ad-vance is required in the interests of basic science andimprovement of therapy, and to make recommenda-tions ". The working-party’s report 1 fulfils those aimsadmirably. Despite its five-year gestation it is a concise,up-to-date, and very comprehensive review of research

1. Pathology of Injury: Current Knowledge and Future Development.Report of a Working Party of the Royal College of Pathologists.Edited by A. C. HUNT. London: Harvey Miller and Medcalf.1972. £2.00.