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Duration of chemotherapy in advanced breast carcinoma SIR,-Professor Harris and colleagues (Jan 27, p 186) address the important question of the optimum duration of chemotherapy for advanced breast carcinoma. They describe 132 patients treated with four cycles of mitozantrone (single agent), of whom 43 with responsive or stable disease were subsequently randomised to continue chemotherapy until disease progression (22 patients) or to stop treatment until disease progression, whereupon mitozantrone was restarted (21 patients). Harris and colleagues’ results show no significant difference between these two groups of patients with respect to median survival from the start of treatment, first recurrence, and time of diagnosis, or in the time to disease progression. They conclude that a short course of mitozantrone is equally effective and preferable to continuous treatment because the group randomised to continue treatment had received 75% more chemotherapy up to the time of disease progression than the group who stopped treatment. The statistical analysis with log-rank comparisons1 based on 43 randomised patients showed survival measured from the start of treatment to be about 50% at 1 year for both treatment groups, but in view of the small number of patients the study could have failed to detect a survival difference of up to 100%; this represents an increase in survival from 50% to 100% at 1 year (a error == 5%, (3 error 10%).To demonstrate a 50% increase in survival-ie, from 50% to 75% surviving at 1 year-a two-arm randomised trial would require 170 patients. Higher statistical power could be one explanation for the different conclusion drawn in another, larger, randomised trialand we advise that Harris and colleagues’ findings should be interpreted with this in mind. =

J. GLAHOLM

Departments of Radiotherapy and Oncology

C. MORT S. ASHLEY J. R. YARNOLD

and Medical Statistics, Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK

been falling over the past decade.>-7 The table shows mortality data for twenty-eight unselected countries participating in the World Health Organisation’s mortality database for 1975 (before the introduction of cisplatin8) and for 1985. In twenty-one countries outside the Eastern bloc numbers of deaths and age-adjusted death rates from testicular cancer fell but in the seven countries from Central and Eastern Europe deaths and death rates rose. 80-90% of patients with testicular cancer can now expect to be cured of their disease,8 and in most countries this seems to be so, but not in Central and Eastern Europe where about 1 in 2 cases may die of their disease. Any fundamental difference in biological behaviour is unlikely and a more likely explanation is that the differences in mortality relate to delivery of curative chemotherapy, including cisplatin, or to deficiencies in patterns of referral. Cancer control in these parts of the world could be greatly assisted by attention to these factors. Unit of Analytical Epidemiology, International Agency for Research F-69372 Lyon 8, France

Department of Medical Oncology, University of Glasgow, Glasgow, UK

R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials prolonged observation of each patient. Br J Cancer 1977; 35: 1-39. 2. Coates A, Gebski V, Stat M, et al A comparison of intermittent and continuous treatment strategies. N Engl J Med 1987; 317: 1490-95

Cancer,

PETER BOYLE PATRICK MAISONNEUVE

STANLEY B. KAYE

P, Cullen JW. The new emphasis on cancer control. J Natl Cancer Inst 1985, 74: 543-51. 2 Doll R, Payne P, Waterhouse JAH Cancer incidence in five continents. Volume 1. Berlin: Springer-Verlag, 1966. 3. Muir CS, Waterhouse JAH, Mack T, Powell J, Whelan S, eds Cancer incidence in five continents. Vol 5. IARC Scientific Publication 88, Lyon: IARC, 1987. 4 Hakulinen T, Andersen AA, Malker B, et al. Cancer incidence in Nordic countries. Acta Pathol Microbiol Immunol Scand 1987; 94 (A): (suppl 288). 5. Boyle P, Kaye SB, Robertson AG. Changes in testicular cancer in Scotland. Eur J Cancer Clin Oncol 1987; 23: 827-30. 6. Osterlind A. Diverging trends in incidence and mortality of testicular cancer in Denmark, 1943-1982. Br J Cancer 1986; 53: 501-05 7. Brown LM, Pottem LM, Hoover R, Devesa SS, Aselton P, Flannery JT. Testicular cancer in the United States: trends in incidence and mortality. Int J Epidemiol 1986; 1 Greenwald

15: 164-70 8.

1. Peto

on

Kaye SB, Boyle P Impact of chemotherapy on germ-cell tumours. Cancer Surveys (in press).

requiring

Therapy for testicular cancer in Central and Eastern Europe SIR,-Many countries and hospitals in Central and Eastern Europe receiving financial and technical assistance from western nations and international organisations to help implement and develop

are

programmes of cancer control.’ With testicular cancer, asssitance could have a major impact on case fatality rates. The incidence of testicular cancer is increasing world wide, for reasons not yet

completely understood;

at

the

same

time

case

fatality

rates

have

NUMBERS OF DEATHS (AND AGE-ADJUSTED DEATH RATES) FROM TESTICULAR CANCER IN 1975 AND 1985

Zopiclone SiR,—We welcome your opinion that "Zopiclone may be a useful alternative to other hypnotic drugs and has fewer adverse effects than many existing compounds". However, your March 3 editorial is inaccurate in some respects. The elimination half-life is not below 4 hours but is 5-6 hours (as shown by Houghton et aP and by J. D. Gaillot and colleagues in their contribution to Pharmacology [1988, suppl no 2z Amongst the studies you cite as evidence that zopiclone 75 mg is an effective hypnotic, the one by C. B. Pull and co-workers2 was unusual amongst comparative trials in not demonstrating efficacy at this dose. We agree that the most important issue is the risk of dependence but disagree with your view that there are established methods for evaluating the dependence potential of hypnotic drugs. An accepted routine for evaluating dependence in man has not yet evolved.3 Nevertheless, we have sponsored over thirty studies addressing the issue of dependence, not just the six to which you refer. In monkeys, T. Yanagita2 has shown that the severity of withdrawal after up to 8 weeks’ administration of zopiclone was less than that with diazepam and similar to that with nitrazepam. This difference between zopiclone and diazepam has been confirmed in a new mouse model (Piot 0, Betschart J, Stutzmann JM, Blanchard JC, unpublished) in which administration and subsequent withdrawal of zopiclone (4-400 mg/kg daily) do not modify the sensitivity of the y-aminobutyric acid receptor complex to the partial inverse agonist FG 7142, whereas convulsions develop after daily doses of diazepam 8 and 16 mg/kg and lorazepam 16 mg/kg, and the hypnotic drugs triazolam 16 mg/kg and flunitrazepam 4

mg/kg.

Reproduced

with

permission of Cancer Surveys

It is inaccurate to state that rebound insomnia and dependence potential after treatment with zopiclone has not been studied in patients with insomnia. Six published studies (including three in sleep laboratories) have assessed the effects of discontinuation of