Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group.

PURPOSE: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION: The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Thirty years of Medical Research Council randomized trials in solid tumours.

This paper reviews the survival outcome from the randomized Phase III trials in solid tumours published on behalf of, or in collaboration with, the Cancer Therapy Committee (CTC) of the British Medical Research Council over a 30-year period to 31 December 1995. We review briefly the innovations in statistical methodology that have occurred over the period. We also note the ways in which standards of reporting the trials have improved, with more recent publications including, for example, estimates of the size of effect and confidence intervals. In all, 32 trials, involving over 5000 deaths in more than 8000 patients, have been published. Tumour types have included bladder, bone, brain, cervix, colon and rectum, head and neck, kidney, lung, ovary, prostate and skin. This paper presents a bibliography of these trials and gives details of the treatment comparisons made, the numbers of patients randomized and included in the analysis for each treatment arm, the observed numbers of deaths, and an estimate of the hazard ratio with associated 95% confidence intervals. The bibliography also indicates the main endpoint of each trial, whether recurrence-free survival or survival, and whether the trial was aimed at finding a difference or showing equivalence. The MRC trials have made an impact on both clinical practice and research activities. For example, the lung cancer programme has helped to establish the role of chemotherapy in small cell lung cancer and has developed better palliative treatment for non-small cell lung cancer. Trials of the radiosensitizer misonidazole have demonstrated that it has no role in the treatment of a number of cancers, trials of hyperbaric oxygen have defined the biological activity of this approach, and the appropriate dose of radiotherapy in patients with brain tumours has been found. The individual trials recruited between 44 and 824 patients (median 213). A better measure of the information in a trial is the number of deaths reported, which varied from 28 to 661 (median 145). A large proportion of the comparisons (8/29 or 28%) anticipating a survival difference, demonstrated such a difference at the 5% level of significance. Despite this, it is concluded that some of the trials should have been larger. In such cases, hindsight suggests either that an overoptimistic view of the anticipated survival benefit was taken at the design stage, or, for equivalence trials, the planned confidence interval was too wide for definitive statements to be made. As a consequence, the current CTC profolio of ongoing randomized trials open to patient accrual at 1 January 1996 have a projected median size of 600 and range from 120 to 2000 patients.

Analysis of thermal parameters obtained during phase III trials of hyperthermia as an adjunct to radiotherapy in the treatment of breast carcinoma.

An analysis of 351 HT treatment sessions administered to 101 patients receiving radiotherapy and hyperthermia (RT + HT) who were entered into Phase III concurrent randomized trials for recurrent (BrR) and intact (BrI) breast tumours is presented. A complete response (CR) was recorded in 50 of 84 (59.5%) fields in the case of recurrent breast patients and in 10 of 17 (59%) fields in the case of the intact breast patients. In comparison, 15 of 60 (25%) patients entered into BrR who received RT alone and 8 of 12 (66.7%) patients receiving RT alone entered into BrI trial achieved CR. A set of thermal parameters is defined and evaluated on a treatment by treatment basis. Patient and tumour characteristics influential on CR are identified and thermal parameters which have additional prognostic value are investigated. Multivariate logistic analysis of the non-thermal data showed that maximum depth of tumour, presence or history of disease outside the treated area and RT regimen were most influential on CR. Tumour volume (cm3) (OR = 0.996, 95% CI = 0.993-1.004, p = 0.08) was not a strong prognostic covariate; tumour area and linear dimensions were even less significant (p = 0.41). The cumulative minimum thermal isoeffect dose (equivalent minutes at 43 degrees C) accrued over the 1st, 1st and 2nd, and 1st, 2nd and 3rd treatment sessions was the only thermal parameter to exhibit an association with CR consistently, Other thermal parameters found to contribute to the predictive models were MINTIME > 42 degrees C calculated for the first treatment session and %sensors > 43 degrees C (peak) calculated for the 2nd treatment session.

A medical research council randomized trial in patients with primary cerebral non-Hodgkin lymphoma: cerebral radiotherapy with and without cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy.

BACKGROUND: The role of chemotherapy in the treatment of patients with primary central nervous system lymphoma (PCL) remains unclear, with no randomized trials available to aid in the interpretation of the current data. The Medical Research Council therefore conducted the current randomized trial to assess the impact on survival of postradiotherapy chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in nonimmunocompromised adult patients with pathologically proven PCL. METHODS: After surgery, patients were randomized at a ratio of 1:2 to radiotherapy alone (RT: 40 grays [Gy] in 20 fractions to the whole brain followed by a 14-Gy boost to the tumor plus a 2-cm tumor margin) or to the same radiotherapy followed by six cycles of CHOP chemotherapy given at 3-week intervals (RT-CHOP). The target sample size was 90 patients, which allowed 90% power to detect a doubling of the median survival time. RESULTS: Between 1988 and 1995, 53 patients were randomized: Fifteen patients were randomized to RT, and 38 patients were randomized to RT-CHOP. The trial closed earlier than planned through poor accrual. The median patient age was 57 years, 57% of the patients were male, and 75% of the patients had unifocal disease. The median number of chemotherapy cycles received was 6 (mean, 4 cycles). Forty-three patients have died, and the median follow-up of survivors is 5 years (range, 1-9 years). There was no evidence of a benefit from RT-CHOP with respect to overall survival (hazard ratio [HR], 1.19; 95% confidence interval, 0.51-2.76) after adjustment for prognostic factors (patient age and neurologic performance status) in an analysis in which HR > 1 favored the control (RT) group. CONCLUSIONS: CHOP has no clear role in the postradiotherapy treatment of patients with PCL. Chemotherapy is poorly tolerated and largely palliative in older, less fit patients. In younger patients, initial chemotherapy designed to penetrate the blood-brain barrier warrants further investigation.