910

of the total pulmonary resistance,51 and complexmeasurements such as the frequency dependence ofcompliance 52 are required to detect considerableobstruction in them. Closing volume as a means ofmonitoring early signs of small-airway disease mayprove very useful.

RADICAL TREATMENT OF ACUTE LEUKAEMIAIN CHILDHOOD

THE approach to the treatment of acute lympho-blastic leuksemia of childhood has changed com-pletely in the past decade. 58 Dr. Donald Pinkel,medical director of St. Jude’s Children’s ResearchHospital, Memphis, Tennessee, was the first to

explore systematically the feasibility of treating thedisease with cure as the goal, at a time when the pre-vailing opinion was that palliation alone was possibleand the obstacles to a more radical approach seemedinsurmountable. As annual guest lecturer of theLeuksemia Research Fund on Oct. 11, Dr. Pinkeldescribed to an entranced audience the series ofclinical studies begun when the hospital was openedin 1962. Each step involved the random allocationof every new untreated patient to one of two or moretreatment schedules designed to answer specificquestions following logically from the results of thepreceding study. The results, with complete follow-upto September, 1972, have shown that lymphoblasticleukaemia need no longer be an inevitably fatal disease,and that long-term survival can now be achieved in asubstantial proportion of cases, with the prospectof half the patients remaining in complete remissionfor at least 5 years. Dr. Pinkel concluded that a

palliative approach to treatment was now unacceptable.Before 1962, workers did not look beyond palliationbecause drug-induced remissions could not be main-tained indefinitely owing to drug resistance, whilewith more successful control of the bone-marrowinfiltration the incidence of incurable meningealleukaemia was increasing.

In 1962, it was already known that several drugsadministered in combination were more effectivethan the same ones administered alone, and thatcertain drugs were more useful for inducing remission,others for maintenance. Dr. Pinkel’s basic chemo-therapy programme has remained essentially unaltered.Remission is induced with prednisolone and vin-

cristine, the agents that are least toxic and most

rapidly effective; and for maintenance mercaptopurine,methotrexate, and cyclophosphamide are used. Suc-cessive trials showed that addition of daunorubicinto prednisone and vincristine did not increase theproportion of remissions, and that, after remissionhad been induced, neither the inclusion of one weekof intensive treatment with the " maintenance "

drugs administered at high dosage intravenously,nor the 3-monthly repetition of

" inducer " courses of

prednisone and vincristine, increased the efficacy ofthe maintenance therapy. However, the dosage of the51. Macklem, P. T., Mead, J. J. appl. Physiol. 1967, 22, 395.52. Woolcock, A. J., Vincent, N. J., Macklem, P. T. J. clin. Invest. 1969,

48, 1097.53. Spiers, A. S. D. Lancet, Sept. 2, 1972, p. 473.

maintenance drugs could not be reduced much belowlevels which incurred some myelosuppression-andhence some risk during remission of potentially lethalinfections, often with viruses, fungi, and protozoa-without increasing the incidence of early relapse tounacceptably high figures. Maintenance therapywas continued for 2-3 years, after which all treatmentwas discontinued.b4 4

In the early 1960s about half the children in com-plete bone-marrow remission were relapsing withmeningeal leukaemia, and it was essential to

prevent this if the incidence of long-term survivalwas to be increased. The leukaemic cells responsiblefor the meningeal deposits gained access to the arach-noidal trabeculae through the walls of the veins, andthe growing infiltrates later ruptured the trabeculae,thus permitting escape of cells into the cerebrospinalfluid. The total number of cells in the central nervoussystem was likely to be minimal at the time of remission,when they should be most easily destroyed by ionisingradiation. In early studies cranial irradiation to dosesof 500 rads and 1200 rads (13 and 24 children, re-spectively, in complete haematological remission)failed to prevent the relapse from meningeal leukaemiain 15 cases. In a study begun in 1967, cranialirradiation was administered at a total dose of 2400rads, and five doses of methotrexate were administeredintrathecally. 33 children in complete haematologicalremission were treated thus, and only 3 relapsed withmeningeal leukaemia. In 1968 investigation was begunof the possible value of spinal irradiation to a total doseof 2400 rads in addition to the cranial irradiation.94 children in complete haematological remission wereentered into the study, 45 of whom received cranio-spinal irradiation. Only 2 of them relapsed withmeningeal leukaemia, compared with 32 of the 49children in the unirradiated group. Craniospinalirradiation was thus highly effective when administered" prophylactically " early in the course of the disease,when very small numbers of cells were presumed tobe present in the central nervous system. However,the same treatment was far less effective in the treat-ment of the established meningeal leukaemia; it con-trolled the condition in only 15 of the 34 cases, in 9of which a second relapse of meningeal leukaemiasubsequently developed. Craniospinal irradiationcaused considerable myelosuppression, which neces-sitated interruption of the maintenance chemo-therapy. A study was begun in 1970 in which 95patients in complete hsematological remission re-

ceived cranial irradiation; by random allocation, 49received spinal irradiation in addition, while 46received 5 intrathecal doses of methotrexate. In

September, 1972, 32 of the former and 27 of the latterpatients had been in continuous complete remissionfor 9-25 months. The incidence of meningeal relapsewas very low in both groups, but that of severe

neutropenia was four times higher in the group inwhich the spine had been irradiated. Thus the pre-ferred method of prophylaxis against central-nervous-system leukaemia at present is to combine cranialirradiation and methotrexate administered intra-

54. Pinkel, D., Simone, J., Omas Hustin, M., Aur, R. J. A. Pediatrics,1972, 50, 246.

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.