Categorical Course: Clinical Trials for the Clinical Oncologist

All trials should address a research question of importance. However, it is easier to perform a clinical trial comparing similar strategies that may exert only a small impact on practice than to perform a trial comparing very different strategies, even though results from the latter could produce large shifts in practice. Some research questions of fundamental importance have never been satisfactorily answered because of an inability to recruit patients or physicians. The following examples help to illustrate this point: ● Should chemotherapy for metastatic, but asymptomatic, colorectal cancer be instituted at diagnosis or when symptoms develop? A North American intergroup study designed to answer this question closed after 4.7 years because of poor accrual (67 of a planned sample size of 144 patients) (unpublished). ● Should we screen for prostate cancer? A National Cancer Institute trial aiming to enroll 74,000 men began to randomize patients in November 1993. This trial is still open to accrual although it was estimated that accrual would be complete in 3 years. ● Should patients with metastatic renal cell carcinoma undergo nephrectomy? Results of this trial were published recently after accrual of 246 patients from 80 institutions over a period of 7.3 years. These difficulties are in marked contrast to a group of four trials comparing single-agent cisplatin therapy with cisplatin combination chemotherapy in non–small-cell lung cancer. These trials managed to accrue more than 400 patients each in approximately 16 months, despite median survival times of between 6 and 9 months in all arms. Many oncologists would agree that the regimen selected in the control arm (single-agent cisplatin) is not one that is in wide clinical use. More importantly, the lack of quality-oflife assessments in these trials renders their question of palliation in advanced lung cancer patients unanswered. Once established, the research question should be put into a testable form—the hypothesis. The statement of the hypothesis should be explicit as to the dependent (outcome) variable(s) and the independent variables. One usually attempts to disprove the null hypothesis, as it is easier to refute a hypothesis than to prove it is true. In single-arm studies, the null/alternate hypotheses will be framed as “the response rate of tumor x to treatment y is / z %.”