A clinical trial comparing two treatments for cancer is bound to extend over several years, partly because of the time required to collect sufficient numbers of patients and partly because of the time required before the results of treatment can be assessed. It is, therefore, common practice to make surveys of the results to date at intermediate stages of the trial. These preliminary assessments may be used to stop the trial if a new unproven treatment method is seen to be unexpectedly much worse than the usual technique, or if the results from the new treatment are already found to be significantly better. While such surveys are ethically desirable, since their aim is to minimize the number of patients treated by an inferior method, it is not always appreciated that, as pointed out by Boag, Haybittle, Fowler and Emery (1971), the procedure may seriously invalidate the use of a conventional test of significance in comparing the results. Armitage, McPherson and Rowe (1969) have examined this effect in data having a binomial, normal or exponential distribution, and it is of equal interest to study the situation when survival rates are compared in a typical clinical trial of cancer treatment. This has been done by the simulation experiment described in the next section. SIMULATION EXPERIMENT-NULL HYPOTHESISThe model simulated was as follows. Suppose 2N patients enter a trial of maximum duration *T years, and suppose that T-year (T<*T) survival rate is taken as the parameter for comparing the two groups. After * T + T-years the difference *D in T-year rates can be obtained directly and compared with the standard error of the difference. If there is no real difference between the two treatment groups, then the probability of *D being greater than 1-96 times its standard error is P=0-05, i.e. in 1,000 such trials one would only find such a difference in about 50. By using the actuarial or lifetable method it is possible to estimate the T-year survival rate at an earlier stage in the trial, provided at least some of the patients have been followed for T-years. Suppose this is done at yearly intervals from T-\-l to *T-1 years after the beginning of the trial. Again the standard errors of the rates may be calculated (Greenwood, 1926) and the difference in rates compared with its standard error (taken to be the square root of the sum of the squares of the separate standard errors). The point of interest is how much the probability of finding a "significant" difference (i.e. difference more than 1-96 times its standard error) is increased by making these early analyses.To answer this question a computer program was written in Titan Autocode to simulate a large number of clinical trials on the Cambridge University Titan computer. The program randomly selected 2N survival times assuming a model for the survival curve having a proportion, c, cured and a lognormal distribution of survival times in the uncured group with logmean p and standard deviation a (Boag, 1948). The 2N patients were assumed to enter the trial regularly ov...

No abstract

No abstract

Summary Sixty patients with advanced breast cancer unresponsive to tamoxifen have been randomised to receive four course of mitozantrone, 14 mg m2 (n = 30) intravenously every 3 weeks (9 weeks total) or megesterol acetate, 160 mg bd (n = 30). One in three patients (11 from each group) had substantial disease control for a minimum period of 6 months i.e., lack of progression; seven patients (23%) showed objective response to mitozantrone compared to four (13%) receiving megesterol. Non-progressive disease occurred in all sites, including visceral metastases and receptor negative patients. There were no significant differences between treatment groups in the median time (5 months each) to disease progression/response duration or survival (13 months megesterol, II months mitozantrone) from commencing second-line therapy. Toxicity was considerably higher in the mitozantrone group.Second-line hormonal therapies can produce similar therapeutic results as those achieved from a short course of a 'short option' single agent cytotoxic in patients who were previously thought hormone insensitive. Provided that the patient does not have life threatening disease a trial of megesterol acetate is worth consideration in that it does not prejudice subsequent response to combination cytotoxic chemotherapy.

The second British Institute of Radiology trial of dose fractionation in radiotherapy compared two groups of prospectively randomized patients with squamous carcinoma of the laryngo-pharynx; one group was treated in a short (less than or equal to 4 weeks) and the other in a long (greater than 4 weeks) overall time. Treatment in any one centre could be given, with no planned gap in the course of treatment, either as a conventional, daily (5 fractions per week regime) or as 3 fractions per week. A total of 611 patients were allocated to treatment, of whom nine have had to be excluded from the analysis for a lack of information. Patients were admitted to the trial from January 1976 to December 1985 and were followed up for a maximum of 10 years and a minimum of 3 years. A reduction in total dose was made for use in the short compared with the long treatment regime. This reduction in total dose varied between 18% and 22% depending on whether 5 fractions or 3 fractions per week regimes were used. Overall, no statistically significant differences have been found between the two arms of the trial. The patients treated with 5 fractions per week in a short overall treatment time showed fewer late normal tissue effects. An analysis based on stratification by age, stage and anatomical site gave a relative risk (short/long overall treatment time) for deaths of 1.23 with a 95% confidence interval from 0.96 to 1.59. Analyses stratified for stage and site gave relative risks with 95% confidence intervals of 1 x 10 (0.84-1.44) for local recurrences/tumour persistence, and 1.01 (0.70-1.45) for laryngectomies.