Chris Coppin

Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group.

PURPOSE A prospective randomized trial was conducted to determine whether the addition of concurrent cisplatin to preoperative or definitive radiation therapy in patients with muscle-invasive bladder cancer improved local control or survival. PATIENTS AND METHODS Ninety-nine eligible patients with T2 to T4b transitional cell bladder cancer participated, 64% with cT3b or cT4. Patients and their physicians selected either definitive radiotherapy or precystectomy radiotherapy; patients were then randomly allocated to receive intravenous cisplatin 100 mg/m2 at 2-week intervals for three cycles concurrent with pelvic radiation, or to receive radiation without chemotherapy. Patients were stratified by clinical tumor stage and by radiation plan. The median follow-up duration is 6.5 years. RESULTS The occurrence of distant metastases was the same in both study arms. However, 25 of 48 control patients have had a first recurrence in the pelvis, compared with 15 of 51 cisplatin-treated patients (P = .036). The pelvic relapse rate in the two groups was significantly reduced by concurrent cisplatin (P = .038, log-rank test) and this effect was preserved in a stepwise Cox regression model of prognostic factors (hazards ratio, 0.50; 90% confidence interval [CI], 0.29 to 0.86; P = .036). The hazard reduction was similar for both radiation plans. Pretreatment leukocytosis and high clinical stage were independent adverse factors in a Cox model of overall survival, but the effect of cisplatin was not significant. CONCLUSION Concurrent cisplatin may improve pelvic control of locally advanced bladder cancer with preoperative or definitive radiation, but has not been shown to improve overall survival. The use of concurrent cisplatin had no detectable effect on distant metastases.

Physical activity, medical history, and risk of testicular cancer (Alberta and British Columbia, Canada).

In order to evaluate risk factors for germ cell cancers, we conducted a case-control study of 510 men with testicular cancer aged 15 to 79 years and 996 randomly selected age-matched controls in the provinces of British Columbia and Alberta, Canada. Subjects completed a mailed questionnaire providing data on education level, ethnic origin, medical history, smoking, occupation, and recreational and sports activity. The response rate among cases was 80.3 percent and among controls was 68.1 percent. After controlling for age and ethnic origin, undescended testis was associated positively with risk of testicular cancer (odds ratio [OR]=3.5; 95 percent confidence interval [CI]=2.2–5.7) as was inguinal hernia requiring surgery (OR=2.0, CI=1.3–2.9), and hydrocoele (OR=2.6, CI=1.4–5.1). Risk of testicular cancer increased with height, with subjects taller than 180 cm having a significantly increased risk compared with those 174 cm or less (OR=1.5, CI=1.1–2.1). A moderate to high level of recreational activity level was associated inversely with testicular cancer risk (OR=0.6, CI=0.5–0.8).

The Combination of Cyproterone Acetate and Low Dose Diethylstilbestrol in the Treatment of Advanced Prostatic Carcinoma

Cyproterone acetate is a steroidal antiandrogen with weak progestational activity that results in the partial suppression of pituitary gonadotropin. We demonstrate that the associated decrease in serum testosterone is more complete and prolonged if cyproterone acetate (200 mg. daily) is combined with a low dose of diethylstilbestrol (0.1 mg. daily). The effectiveness of the combination in the treatment of prostatic carcinoma was investigated in 51 patients with stage D2 malignancy. From an initial concentration of 360 +/- 23 ng. per dl. (mean +/- standard error), serum testosterone decreased to 56 +/- 5 ng. per dl. after 1 week and reached a plateau of approximately 30 ng. per dl. after 2 months. This was accompanied by a decrease in serum prostatic acid phosphatase from a mean starting concentration of 43 +/- 11 ng. per ml. to a low of 3 +/- 1 ng. per ml. at 12 months; the proportion of normal values increased from 10 to 80 per cent. A complete response was observed in 7 patients (13 per cent), partial response in 35 (69 per cent) and stable disease in 8 (16 per cent), yielding an over-all objective response rate of 98 per cent (1980 National Prostatic Cancer Project criteria). The actuarial median time to progression was 17 months and the median survival time was 23.5 months. In 26 patients who subsequently had signs of progressive carcinoma the relapse rate in bone (85 per cent) far exceeded that in nonskeletal sites (23 per cent). The incidence of cardiovascular toxicity was 12 per cent. These results indicate that cyproterone acetate and low dose diethylstilbestrol may be co-administered to achieve a synergistic and potent androgen withdrawal effect in the treatment of advanced prostatic carcinoma.

Immunotherapy for renal cell cancer in the era of targeted therapy

Until recently, cytokine therapy has been the only validated option for patients with advanced renal cancer. IFN-α is one of very few treatments that have demonstrated improved median survival compared with the appropriate control. In patients with synchronous metastases at diagnosis, debulking nephrectomy prior to interferon, further improves overall survival. High-dose IL-2 appears to be able to cure a small percentage of highly selected patients. There is potential to further improve patient selection for these options. The demonstrated value of cytokines should not be overlooked in the rush to use new drugs. In the adjuvant setting, vaccine therapy has provided the only systemic approach that has any promise. New insights into the complexities of the immune system at the molecular level, as well as the ingenuity and enthusiasm of immunotherapists, will undoubtedly lead to continuing attempts to identify and overcome obstacles to achieve the grail of human tumor rejection in clinical practice. Targets within the immune regulatory system and the use of vaccines as targeting agents may bring together the fields of immunotherapy and targeted therapy in the near future.

Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer.

PURPOSE The Canadian multicenter trial for advanced non-small-cell lung cancer (NSCLC) reported survival benefit for chemotherapy when best supportive care was compared with vindesine-cisplatin (VP) and the combination of cyclophosphamide, doxorubicin, and cisplatin (CAP). We examined received drug delivery to document dose-intensity (DI) and total dose of drugs given to various groups in this patient population. PATIENTS AND METHODS Plots of cumulatively received chemotherapy against time were used to evaluate drug delivery by regimen, major prognostic factors, and response status. RESULTS Individual CAP patients show a narrow range of received DI, with the median similar to protocol. Drug delivery analysis exposed a wide range of received DI for both drugs in the more intensive VP regimen, and the median received DI was below protocol. The median received DI for cisplatin was still higher for VP than CAP, but only during the first 8 weeks of protocol treatment (20 v 10 mg/m2/wk); thereafter, the ongoing received cisplatin DI was the same (10 mg/m2/wk). The median received DI for cisplatin in each regimen was not influenced by stage, performance status, prior weight loss, sex, or response status. VP-treated patients received a higher total dose of cisplatin than CAP patients (median, 255 mg/m2 v 112.5 mg/m2; P < .0001). Median cisplatin total dose was similar for patients with a chemotherapy response or stable disease and threefold greater than for patients with progressive disease for both regimens. Although patients with chemotherapy response and stable disease had similar survival outcomes for both CAP and VP, the VP regimen had a higher proportion of patients without progressive disease (P = .004), which resulted in an overall survival advantage (P = .01). CONCLUSION The major prognostic factors for advanced NSCLC do not exert their influence on outcome by affecting deliverable chemotherapy DI. Regimen and treatment response determined total dose. Because stable disease patients usually outnumber responding patients in advanced NSCLC trials, controlled studies should be performed that allow assessment of the impact of total received dose on outcome according to response status.

Carboplatin and vinblastine for the treatment of metastatic transitional cell carcinoma of the urothelial tract

Many patients with metastatic transitional-cell carcinoma (TCC) are not appropriate candidates for standard cisplatin-based combination, because of inadequate renal function, poor performance status (PS), and other comorbid medical conditions. We have evaluated the efficacy and toxicity of a combination of carboplatin and vinblastine (CV) as a palliative regimen in these patients. The medical records of patients with metastatic TCC, who had been treated with CV at the British Columbia Cancer Agency from 1995 until 1999, were retrospectively reviewed. Treatment consisted of carboplatin (area under the curve = 5) on day 1, and vinblastine (4 mg/m2) on days 1 and 8, repeated every 4 weeks. A total of 42 patients were included in this study, of whom 39 had measurable disease. Median age was 73 years. Fifty-two percent of patients had a PS (Eastern Cooperative Oncology Group) of 2 or 3. Node-only disease was present in 26% of patients, bone metastasis in 26%, and liver metastasis in 24%. A total of 119 cycles were administered. Grade IV granulocytopenia occurred in 26% of patients, grade III anemia in 12%, and there were 3 episodes of febrile neutropenia occurring in two patients. The major nonhematologic toxicity was grade III fatigue in 17% of patients. There were no grade IV nonhematologic toxicity or treatment-related deaths. The overall response rate was 33% (13 of 39). Five patients (13%) achieved a complete response and 8 patients (20%) a partial response. The median duration of response was 32 weeks and median overall survival for all patients was 26 weeks. The combination of carboplatin and vinblastine given in this schedule is a feasible, well-tolerated, and active alternative for patients with metastatic TCC unfit for standard chemotherapy.