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J. P. NEIJT AND OTHERS REFERENCES—continued2 Young RC, Knapp RC, Perez CA. Cancer of the ovary. In: De Vita VT, ed Cancer.

Principles and practice of oncology. Pliladelphia J B Lippincott, 1982: 884-913.3. Smith JP, Rutledge FN. Random study of hexamethylmelamine, 5-fluorouracil, and

melphalan in treatment of advanced ovarian carcinoma of the ovary. Natl CancerInst Monogr 1975; 42: 169-72.

4. Young RC Chemotherapy of ovarian cancer: past and present. Sem Oncol 1975; 2:267-76

5. Wharton JT, Rutledge FN, Smith JP, Herson J, Hodge MP Hexamethylmelamine:An evaluation of its role in the treatment of ovarian cancer. Am J Obstet Gynaccol1979; 133: 833-44.

6. Hall DJ, Diasio R, Goplerud DR. Cis-platinum in gynaecologic cancer I Epithelialovarian cancer Am J Obstet Gynaecol 1981; 141: 299-304.

7. Gershenson DM, Wharton JT, Herson J, Edwards CL, Rutledge FN. Single-agent cis-platinum therapy for advanced ovarian cancer. Obstet Gynaecol 1981; 58: 487-96.

8. Bruckner HW, Cohen CJ, Goldberg JD, et al Improved chemotherapy for ovariancancer with cis-diamminedichloroplatinum and adriamycin. Cancer 1981; 47:2288-94.

9. De Palo GM, De Lena M, Bonadonna G. Adriamycin versus adriamycin plusmelphalan in advanced ovarian carcinoma. Cancer Treat Rep 1977; 61: 355-57.

10. Stanhope CR, Smith JP, Rutledge FN. Second trial drugs in ovarian cancer GynaecolOncol 1977; 5: 52-58.

11. De Palo GM, De Lena M, Di Re F, Luciani L, Valagussa P, Bonadonna G Melphalanversus adriamycin in the treatment of advanced carcinoma ofthe ovary. Surg GynecolObstet 1975; 141: 899-902.

12. Young RC, Chabner BA, Hubbard SP, et al. Prospective trial of melphalan (L-PAM)versus combination chemotherapy (Hexa-CAF) in ovarian adenocarcinoma N EnglJ Med 1978; 299: 1261-66.

13. Neijt JP, Van Lindert ACM, Vendrik CPJ, Roozendaal KJ, Struyvenberg A, PinedoHM. Treatment of advanced ovarian carcinoma with a combination of

hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) in patients with and without previous treatment. Cancer Treat Rep 1980; 64:323-26

14. Vogl SE, Berenzweig M, Kaplan BH, Mouktar M, Bulkin W The CHAD and HADregimens in advanced ovarian cancer. combination chemotherapy includingcyclophosphamide, hexamethylmelamine, adriamycin, and cis-

dichlorodiammineplatinum (II). Cancer Treat Rep 1979; 63: 311-17.15. Tobias JS, Griffiths CT Management of ovarian carcinoma N Engl J Med 1976; 294:

817-23

16. Serov SF, Scully RE, Sobin LH. International histological classification of tumours, no9. Histological typing of ovarian tumours. Geneva: World Health Organisation,1973.

17. Broders AC Carcinoma: grading and practical application Arch Pathol 1926; 2:376-82

18. Ozols RF, Garvin AJ, Costa J, Simon RM, Young RC. Advanced ovarian cancer:correlation of histologic grade with response to therapy and survival. Cancer 1980;45: 572-81.

19. Cox DR Analysis of binary data. New York: Halsted Press, 197020 Cox DR. Regression models in life tables J R Stat Soc B 1972; 34: 187-220.21 Dixon WJ (ed). BMDP statistical software 1981 London: University of California

Press, 1981.22. Miller AB, Hoogstraten B, Staquet M, Wmkler A. Reporting results of cancer

treatment. Cancer 1981; 47: 207-14.23. Katz ME, Schwarz PE, Kapp DS, Luikart S. Epithelial carcinoma ofthe ovary: current

strategies Ann Intern Med 1981; 95: 98-11124. Bush RS. Therapy of advanced ovarian cacinoma N Engl J Med 1979, 22: 676.25 Barlow JJ, Blumenson LE. Therapy of advanced ovarian carcinoma. N Engl J Med

1979; 22: 67626. Carmo-Pereira J, Costa FO, Henriques E, Ricardo JA. Advanced ovarian carcinoma: a

prospective and randomised clinical trial of cyclophosphamide versus combinationcyctotoxic chemotherapy (Hexa-CAF). Cancer 1981; 48: 1947-51.

27 Sturgeon JFG, Fine S, Gospodarowicz MK, et al A randomised trial of melphalanalone versus combination chemotherapy in advanced ovarian cancer Proc Am SocClin Oncol 1982; 1: 108.

28. Tropé C. A prospective and randomised trial comparison of melphalan vs adriamycin-melphalan m advanced ovarian carcinoma by the Swedish Cooperative OvarianCancer Study Group (SCOCSG) Proc Am Soc Clin Oncol 1981; 22: 469

29. Omura GA, Blessing JA, Morrow CP, Buchsbaum HJ, Homesley HD. Follow-up on arandomised trial of melphalan vs melphalan plus hexamethylmelamine vs

adriamycin plus cyclophosphamide in advanced ovarian adenocarcinoma Proc AmSoc Clin Oncol 1981; 22: 470.

30. Edmondson JH, Flemming TR, Decker DG, et al Different chemotherapeuticsensitivities and host factors affecting prognosis in advanced ovarian carcinomaversus minimal residual disease Cancer Treat Rep 1979, 63: 241-47

31 Turbow MM, Jones H, Yu VK, Greenberg B, Hannigan J, Torti FM. Chemotherapyof ovarian carcinoma. A comparison of melphalan vs adriamycin-cyclophosphamide. Proc Am Ass Cancer Res 1980; 21: 196.

32. Decker DG, Flemming TR, Malkasian GD, Webb MJ, Jefferies JA, Edmonson JH.Cyclophosphamide plus cisplatinum in combination Treatment programme forstage III and IV ovarian carcinoma. Obstet Gynaecol 1982; 60: 481-87.

33. Vogl SE, Kaplan B, Pagano M, Davis TE, et al Platinum-based combination

chemotherapy versus melphalan for advanced ovarian cancer. In: Spitzy KH,Karrer K, eds. Proceedings of the 13th International Congress of Chemotherapy1983, 207: 9-13

34 Neijt JP, Ten Bokkel Hummk WW, Van der Burg MEL, et al. Combination

chemotherapy with or without hexamethylmelamine in alkylating-agent resistantovarian carcinoma. Cancer 1984; 53: 1467-72.

35 Wharton JT, Herson J, Edwards CL, Seski J, Hodge MP Long term survival followingchemotherapy for advanced epithelial ovarian carcinoma In. Van Oosterom AT,Mugia FM, Cleton FJ, eds. Therapeutic progress in ovarian cancer, testicularcancer and the sarcomas. The Hague Martinus Nijhoff, 1980: 95-112.

36 Brodovsky HS, Bauer M, Horton J, Elson PJ. Comparison of melphalan withcyclophasphamide, methotrexate, and 5-fluorouracil in patients with ovariancancer Cancer 1984, 53: 844-52.

WHO COOPERATIVE TRIAL ON PRIMARYPREVENTION OF ISCHAEMIC HEART

DISEASE WITH CLOFIBRATE TO LOWERSERUM CHOLESTEROL: FINAL MORTALITY

FOLLOW-UP

Report of the Committee of Principal Investigators*

Summary This is the final report on mortality amongstmen in the WHO cooperative trial of the

prevention of ischaemic heart disease (IHD) by clofibrate andit takes the follow-up a further 4 years to the end of 1982.Mean observation was 13· 2 years, 5· 3 in the trial and 7· 9

afterwards. 1788 deaths were recorded in 208 000 man-years.In the 877 new deaths reported here, there was an excess of 9deaths in the high cholesterol control group compared withthe clofibrate-treated group. In the whole period there were70 (11%) more deaths in the clofibrate-treated group. Excessmortality in the clofibrate-treated group was much greaterduring the "treatment period" (there was an excess of 47%during treatment compared with 5% after treatment hadended) and was due to a wide variety of causes other thanIHD. Thus, the excess mortality in the clofibrate-treatedgroup has not continued after the end of treatment. Thesubstantial excess previously reported remains unexplained.

Introduction

THE results of the WHO cooperative trial of the preventionof ischaemic heart disease (IHD) by clofibrate were publishedin 1978.1 There was a 2507o reduction (p<0 05) in non-fatalmyocardial infarction among healthy men with plasmacholesterol in the upper third of the distribution who were

given clofibrate, compared with randomly selected controls.There was no significant difference in mortality from IHD.

Mortality from all causes and causes other than IHD wassignificantly higher in the clofibrate-treated group. No

particular disease accounted for the overall excess, there

being non-significant increases in cancer, and other majordiseases, though not in deaths due to accidents and violence.There was also a significant excess in the death-rate from allcauses, and from causes other than IHD, in the treated groupcompared with a second, low cholesterol, control group aftercorrection for differences in age and other factors present atthe start of the trial.The first report of post-trial follow-up, to the end of 1978,

was published in 1980.2 It showed 2507o more deaths in theclofibrate-treated group than in the comparable, high serumcholesterol, control group (p<0. 01). This excess mortalitywas most marked for deaths which occurred during the trial(an average period of 5 - 3 years). No relation could be shownbetween excess mortality in the treated group and eithercholesterol reduction during the trial or the length of timethat subjects were receiving clofibrate.These results were sufficiently disturbing to warrant a

follow-up of mortality for a further 4 years, to the end of 1982,

*Report prepared by Prof M. F. OLIVER, Dr J. A. HEADY, Prof J N.MORRIS, and Ms J. COOPER.Principal investIgators: L Gyarfas, Hungarian Institute of Cardiology,Budapest (G. Lamm 1966-74); J. Widimsky, Institute for Clinical and

Experimental Medicine, Prague (H. Geizerova 1968-1980; J Fodor,1966-68); K. G. Green, ICI, Macclesfield; J. A. Heady, Medical ResearchCouncil, Royal Free Hospital School of Medicine, London; G. Lamm,Ruprecht-Karls-Universitat, Heidelberg (WHO, Copenhagen 1974-81);J. N Morris, Medical Research Council, London School of Hygiene andTropical Medicine; M. F. Oliver, Royal Infirmary, Edinburgh; T. Strasser,WHO, Geneva, 1973-83 (Z. Fejfar 1966-73).

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the results of which are reported here. The average length offollow-up is now 13-2 2 years. 43 deaths that were missed in theprevious follow-up to the end of 1978 are also reportedtogether with corrections caused by their addition to the 911deaths previously reported.

Methods

The design and methods used in the trial have been describedearlier.1-3 It started in 1965 and the active phase-ie, the period oftreatment-lasted on average for 5’ 3 years (range, 4-8 years). Thevolunteers, drawn from the three centres, Edinburgh, Budapest,and Prague, were initially free of clinical IHD and were classifiedinto three equal-sized groups according to serum cholesterol level.Those in the high third of the cholesterol distribution were

randomly allocated to treatment by clofibrate (1’ 6 g daily, group i)or to an identical capsule containing olive oil (group II); comparisonbetween groups I and 11 was therefore double-blind as well asrandomised. Half the men in the low third of the cholesteroldistribution constituted a second control group and also receivedthe olive oil capsule (group III). None of the men in the other half ofthe low third, or any of those in the middle third of the distributionwas studied.The methods described in the previous follow-up2 were used to

establish whether the men were alive (or, if not, the causes of theirdeaths) at the end of 1982. After intensive re-check we now believethat death or survival has been established in over 99% of subjects ineach centre. There was no statistically significant differencebetween groups I and n in this respect. The statistical techniquesused were those described in earlier reports.

Results

Overall MortalityThe average length of time from entry to the trial to the end

of 1982, or previous death, was 13’ 2 years-5 - 3 years in thetreatment phase and 7.9 afterwards. 1788 deaths are nowreported in 208 000 man-years of observation. Table I showsnumbers of deaths and age-standardised rates for selectedcauses.

The 877 deaths which are added by this report consist of834 which occurred in 1979-82, and 43 which occurredearlier and were missed in the previous follow-up to the end of1978. These 43 deaths will be discussed below, with anassessment of the effect of their inclusion on previouslyreported findings. Meanwhile, the main feature of the 877additional deaths is that 9 more of them (333) occurred in thehigh cholesterol control group II than in the treated group I(324). This reverses by a small margin, the trend previouslyreported. Of the 834 deaths which occurred in 1979-82, 312occurred in group u and 310 in group I).There is an excess of 70 deaths in group I (11%) in the whole

period from entry to the end of 1982 compared with 79 (or25%) in the previous report. This excess of 70 deaths from allcauses is not quite significant at the 5% level (p=0’06) andthe difference of 907o in standardised rates (8-6 6 and 7’9 perthousand, per annum) is not significant (p = 0 - 12). Analysisby life-table methods shows an excess hazard of 11% in groupI compared with group II, which when corrected for age,becomes 10% (0- .10>p>0. 05).

Mortality During and After the "Treatment" PeriodDifferences between the two high cholesterol groups in all

causes mortality occurring after treatment vary in direction atdifferent stages, there being an excess in the control group inthe first 2 years post-treatment and more than 8 years post-treatment, but an excess in the clofibrate-treated group inbetween these two stages (table II). None of these differencesis statistically significant and the net effect is of a 5% excessmortality in group I for all post-treatment deaths.

These results are summarised in table III which shows thenumbers of deaths and age-standardised rates during andafter treatment for the two high cholesterol groups and theratios of these numbers and rates.The excess of deaths in the clofibrate-treated group

compared with those in the high cholesterol control groupwas far greater in the treatment phase-47% for deaths fromall causes compared with an excess of 5% for deaths aftertreatment ended (44% and 4% in terms of age-standardisedrates).Excess mortality in the clofibrate-treated group during the

treatment phase did not occur in deaths from IHD (when ageis taken into account) and post-treatment mortality washigher than the mortality during treatment in both groups,particularly for deaths from IHD (table III). This latter pointand its relation to withdrawals from the study on medical andother grounds was discussed in the previous report.

Individual Causes of Death

In terms of particular causes, a comparison of table I withthe published table for the follow-up to the end of 1978 showslittle difference between the clofibrate-treated group and the

high cholesterol control in the numbers of new deaths due toany of the causes shown, except for deaths due to "othercirculatory disease" (an excess of 15 new deaths in group II)and those due to cancer (an excess of 17 in group II).Although a result of the additional four years of follow-up

to the end of 1982 is a reduction in the proportional excess in

TABLE I-CAUSES OF DEATH IN AND OUT OF TRIAL UP TO DEC 31,1982

*Age-standardised death rate per 1000 per annum by the indirect method (ageat death, ages 40-69).tICD (8th revision) nos. 390-404, 420-429, 440-452, 454-458.:j::lncluded in previous publication under the heading "Regional Pathology".’ICD (8th revision) nos. 011, 460-519.Includes "unknown causes".Significant difference between corresponding numbers or rates in groups I

and II (p<0.01).**Significant difference (p<0.05).

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TABLE II-DEATHS IN TRIAL AND AT VARIOUS INTERVALS AFTER LEAVING TRIAL BY MAIN CAUSE OF DEATH (FOLLOW-UP TO DEC 31, 1982)

*Age-standardised death-rates per 1000 per annum by indirect method-age at death, ages 40-69-are shown in parentheses below numbers of deaths.Ca =malignant neoplasms.

Subarachnoid haemorrhage, venous thromboembolism, and other circulatory condiuons.

overall mortality in the clofibrate-treated group comparedwith the high cholesterol control group, there is, when thetotal experience is taken together, still an excess in the treatedgroup in deaths from every major cause shown except for"other circulatory disease" (table I). The largest proportionaldifferences are in "stroke" and "other medical causes".

’

Within "other medical causes" the biggest difference is

again in "diseases of the liver, gall bladder, and intestines"(28 in group I and 9 in group II; p<0.01) but there is nodifference between groups I and II in deaths due to malignantdisease of these organs. Deaths associated with the

respiratory system are more common in the clofibrate-treatedgroup than in the high cholesterol control group (80 vs 61).This difference is almost entirely due to deaths from

malignant disease, but it is now not statistically significant.The difference between the high cholesterol groups in canceras a whole is now reduced (206 vs 197), and disappears when

data are standardised for age.

Mortality rates from all causes in the low cholesterol group(group III) are markedly lower than those in the two highcholesterol groups, because of the much lower death ratesfrom IHD. This accords with other epidemiological studies.

Deaths After the End of "Treatment" in Patients with NewIHD Events

Of the 131 men in group I who were withdrawn from thetrial because of a non-fatal myocardial infarction, 54 had diedby the end of 1982, 40 from IHD. Of 174 such men in group11, 62 had died, 48 from IHD.Amongst all the deaths that occurred after leaving the trial

for whatever reasons, there were 272 deaths from IHD in

group I and 249 in group 11 (table II). Since 40 of these deathsin group I and 48 in group II were in men who had a firstinfarction in the trial, it follows that 232 in group I and 201 in

603

TABLE III-RATIOS OF MORTALITY IN GROUPS I AND II BY MAIN CAUSE OF DEATH

Age-standardised death rate per 1000 per annum by the indirect method (age-at-death, ages 40-69).*Sigmficantly different from 1 00 (p<0.05).**Significantly different from 1-00 (p<0. 01).

group II were deaths from infarctions arising after the end oftreatment, a non-significant excess of31 (15%) in group I. (Inthe last report the corresponding difference was 38%,p<0.05).Deaths not Included in the Previous ReportSince the publication of the report on the mortality follow-

up to the end of 1978,2 information has become available on43 deaths which occurred before the end of 1978 and which,therefore, should have been included with the 911 includedthere. Of the 43 deaths, 28 were in the Edinburgh centre, 6 inBudapest, and 9 in Prague.Most of the Edinburgh deaths were not notified because of

a failure in the mechanism of tracing deaths through theNational Health Service Register. This became clear when aspecial search for cancer in the Cancer Records Officerevealed deaths not previously recorded. The officers of theScottish National Health Service Register then undertook acomplete re-check of that register. This check revealed 12more deaths not previously notified, but left 118 men whocould not be traced in the register. These latter were then thesubject of an intensive search by trial staff and 5 more deathswere found in this way. Eventually, all but 7 of the men weretraced in the register, were known to be alive or dead bypersonal enquiry or were known to have emigrated. At theother two centres the methods of tracing were based onpersonal enquiry in the first place and the extra deaths werediscovered in a complete re-check of survivors.

14 of the extra deaths were in the clofibrate-treated group,21 in the high cholesterol control group, and 8 in the lowcholesterol control group. This leaves an overall excess of 72deaths from all causes in group I compared with group II inthe corrected data instead of 79 (21% instead of 25%). Age-standardised death rates are now 8 - 4 and 7’ 1 per thousandper annum, the excess being significant at the p<0. 02 levelrather than p<0. 0 1. The corrected proportions surviving tenyears as calculated by life-table methods are 92 - 0% and93 6%, respectively, in the two groups instead of 92’ 3% and94 0%. The causes of the extra deaths were as follows: IHD

group 18, group II 4, group III 4, cancer 2, 9, 2, other causes 4,8, 2. The significance of the excess of "regional pathology"deaths is unaffected. Since all the extra deaths occurred afterthe end of treatment, patterns during treatment are

unaffected as also is the first paper reporting the trial results. 1It remains true in the corrected results that mortality from allcauses and all causes other than IHD is higher in group I thanin group 11 in each centre, and also in each ten-year age-groupwith the single exception of mortality from all causes otherthan IHD at ages 60-69.The results relating to length of exposure to treatment, to

cholesterol reduction, and to the men who showed thegreatest reduction in IHD during the trial in the first report,are virtually unaffected. A table giving the corrected figuresfor table I of the previous report is available on request.

Discussion

The main point to be made in this final report of the follow-up of the men who participated in the WHO cooperative trialof the primary prevention ofIHD by clofibrate is that there isno evidence of a continuing adverse effect in those -whoreceived clofibrate during the trial. The findings of this latestfollow-up to the end of 1982 confirm and expand the results ofthe previous report to the end of 1978 and they indicate thatthe excess of deaths from diseases other than IHD was almost

entirely confined to the period of’exposure to clofibrate. Theratios of numbers of deaths, and of death rates, in group I

compared with group II do not depart materially from unityduring the follow-up period in contrast to the high ratios fornon-IHD death rates during the period of the actual trial(table III).

’

The report of the previous follow-up, to the end of 1978,emphasised that the significant excess in mortality in theclofibrate-treated group compared with the high cholesterolcontrol group was unexplained. We speculated on variouspossibilities,2 such as the production of more unopposed freeradicals, but no definite pharmacological or biologicalexplanation has been identified. After a further 4 years offollow-up, the basic question remains. Some points have,however, become clearer. The excess in mortality was verylargely confined to the treatment period. Total mortality inthe two high cholesterol groups in the extra 4 years of follow-up was almost exactly equal. This fact, amongst others,makes one suggested explanation of the previous results veryunlikely; namely, that the initial randomisation was somehowfaulty. Had this been true, the excess mortality wouldpresumably have continued in the follow-up period; but it didnot.

Several differences between the high cholesterol controlgroup and the clofibrate group were also considered in the

previous report-a different trend of mortality with age, anexcess mortality in the high cholesterol control group afterthe end of the treatment period, and, in particular, a very lowmortality due to nori-malignant diseases of the liver, gallbladder, and intestines. To these might now be added asomewhat lower mortality from cancer of the lung, bronchus,and larynx than in the low cholesterol control group in whichthere were more non-smokers. None of these differences,however, is significant and they are no more than might beexpected from intensive scrutiny of a large number of smallsub-groups.There was a non-significant excess of 29 deaths due to IHD

occurring during the first 8 years of post-treatment follow-up,largely accounting for the slightly greater number of deaths ingroup I from all causes-and 25 of the excess of 29 deathsoccurred during the first 6 years. There was a significantreduction during the trial in the incidence of non-fatal

myocardial infarction in men taking clofibrate, although notin mortality from IHD, and a beneficial effect related to

604

clofibrate or cholesterol reduction was presumed to be

responsible. Withdrawal of this protective effect might beassociated with an increased incidence of IHD in group I

compared with group 11, and may explain the slight excess inIHD mortality during the post-trial period. Unfortunately, ithas not proved practicable to conduct an adequate follow-upof morbidity caused by myocardial infarction in hospitalpatients and outpatients and no data are available for analysisof any change in incidence of non-fatal infarction during thefollow-up surveys.The importance of undertaking a complete follow-up in

long-term clinical trials cannot be over-emphasised. it should,we believe, be an integral part of the responsibity andcommitment of investigators at the inception of a trial. Ofcourse, it presents its own problems: as the years go by, theresponse, enthusiasm and interest of participants and

investigators wane. A big effort may be needed. We have hadour particular difficulties in that the follow-up to the end of1978, which we considered was complete, has proved not tobe; 43 deaths have had to be added to the previouslypublished figures. Their distribution between the three

groups is such that the addition has only a minimal effect onthe results already reported. The experience, however, re-emphasised the need to have more than one system ofascertainment even in the most straightforward of mortalitystudies.The overall results of the WHO clofibrate trial indicate the

power of a clinical trial of adequate scale with sufficientfollow-up. All potent drugs used in the primary prevention ofdisease must be examined during and after their period ofadministration. There is no short-cut, except perhaps whenthe risk of the disease is likely to be as great or greater than therisk of the drugs, as in the top few percentage at risk-eg inthose with familial hypercholesterolaemia.Indeed, similar comprehensive trials are needed to prove

the safety of all new and potent drugs as much as theirefficacy. At present, there is no monitoring system to providesound data on the risks of drugs used over many years. Theestablishment of drug data banks by drug regulatoryauthorities should allow small but significant changes in theincidence of, or mortality from, commonly occurring diseasesto be detected. It is in such a context that prescriptionmonitoring systems4 have to be assessed.The initial hypothesis behind this trial-namely, that

reduction of high plasma cholesterol would reduce theincidence of IHD-was confirmed, though only for non-fatalinfarction. Clofibrate was merely the chosen method ofreduction. The excess of deaths in the "treated" group has,not unnaturally, diverted attention from this result.

The investigators are again indebted to the individuals and organisationsmentioned in the earlier reports. 1,2

Requests for reprints should be addressed to M. F. O. CardiovascularResearch Unit, Hugh Robson Building, George Square, Edinburgh EH89XF.

REFERENCES

1. Committee of Principal Investigators A cooperative trial in the prevention of ischaemicheart disease using clofibrate. Br Heart J 1978; 40: 1069-118

2. Committee of Principal Investigators. WHO cooperative trial on primary prevention ofischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Lancet 1980; ii: 379-85.

3. Heady JA A cooperative trial on the primary prevention of ischaemic heart diseaseusing clofibrate: Design, methods and progress. Bull WHO 1973; 48: 243-56.

4. Inman, WHW. Postmarketing surveillance of adverse drug reactions in generalpractice. Br Med J 1981, 282: 1131-32, 1216-17.

LOW-DOSE AMINOGLUTETHIMIDE INTREATMENT OF ADVANCED BREAST CANCER

R. STUART-HARRIST. BOZEK

J.-C. GAZETA. KURKURE

M. DOWSETT

J. A. MCKINNAS. L. JEFFCOATE

L. CARRI. E. SMITH

Division of Medicine and Medical Breast Unit,Royal Marsden Hospital, London SW3; and Department ofEndocrinology, Chelsea Hospital for Women, London SW3

Summary The clinical and endocrine effects oflow-dose aminoglutethimide without

hydrocortisone in patients with advanced breast cancer wereinvestigated. In a dose escalation study low-dose

aminoglutethimide alone (62-5-125 mg twice daily) was aseffective as conventional doses with hydrocortisone in

lowering serum oestrone and oestradiol concentrations butcaused minimum adrenal inhibition, as assessed by serumdehydroepiandrosterone sulphate. 11 of 57 (19%) evaluablepatients had tumour regression by objective criteria on thistreatment, but the frequency of side-effects was similar to thatwith conventional doses. Low-dose aminoglutethimide isactive in the treatment of breast cancer. It appears to work byinhibition of the aromatase enzyme system in peripheraltissues rather than adrenal suppression.

Introduction

AMINOGLUTETHIMIDE with hydrocortisone is an effectiveendocrine therapy for postmenopausal patients withadvanced breast cancer and achieves tumour regression inapproximately 30% ofpatients.1,2 At the conventional dosageof 1 g daily with hydrocortisone 20 mg twice daily adrenalsteroid synthesis is suppressed, principally by inhibition ofthe desmolase enzyme system which converts cholesterol to

pregnenolone; 3-5 the treatment has therefore sometimes beencalled "medical adrenalectomy". The main disadvantage oftherapy is a significant frequency of troublesome side-effects,including lethargy, ataxia, and rash, causing discontinuationof treatment in up to 10% of patients.2,6,7Aminoglutethimide also inhibits the aromatase enzyme

system which converts androgen precursors to oestrogens inperipheral tissues throughout the body.s-ll Aromataseconversion is believed to be the major mechanism for

oestrogen production in postmenopausal women.12,13 In-vitro aromatase inhibition occurs at lower concentrations of

aminoglutethimide than are necessary for desmolaseinhibition." We therefore postulated that it might be

possible to achieve oestrogen suppression and tumour

regression in postmenopausal patients by aromatase

inhibition with lower doses of aminoglutethimide than thosenecessary to induce adrenal suppression, and without theneed for supplementary hydrocortisone. We also hoped thatthis approach might be associated with a lower frequency ofside-effects, since lethargy and ataxia are dose related andseem to be related to serum levels of the drug.14 We nowreport our endocrine and clinical findings with low-doseaminoglutethimide used alone in the treatment ofpostmenopausal patients with advanced breast cancer.

Patients and Methods

Two sequential studies were carried out. The dose escalationstudy was aimed at assessing the extent to which low-dose

aminoglutethimide without hydrocortisone supplements could