Physician-Determined Patient Risk of Toxic Effects: Impact on Enrollment and Decision Making in Phase I Cancer Trials

Abstract

The conventional phase I trial design yields an estimate of the maximum tolerated dose (MTD) of a new drug defined from treatment toxic effects observed in a small heterogeneous cohort of patients. The MTD is specific for those patients treated in the study and may not be reproducible in another patient series, a limitation known as cohort dependency. We conducted an opinion survey of phase I investigators in an attempt to characterize physician attitudes and clinical practices regarding assessment of risk of toxic effects in patients. A physician opinion survey of scaled multiple choice and open-ended questions was distributed to oncologists (faculty and fellows) at National Cancer Institute (NCI)-funded phase I contract institutions. The target sample was narrowed to these specific institutions because of their experience in conducting various phase I trials. Each NCI-funded phase I contractor received an instruction sheet and 25 surveys and envelopes that were made available to oncologists enrolling patients in phase I trials. Of the 75 surveys distributed, 67 (89%) were returned. Most respondents agreed that unexplained variability in toxicity exists in phase I trials. However, opinion varied considerably among five participating institutions (two-sided P = .001). Informal scoring of patients for toxicity risk prior to treatment was a common practice (85% overall), although the prevalence of this practice varied somewhat among the institutions (two-sided P = .01). Physicians' opinions were mixed regarding the practice of becoming increasingly selective in enrolling patients as the MTD was approached, with strong disagreement noted among institutions (two-sided P = .001). Given background on a hypothetical phase I trial, respondents were asked to rank the usefulness of 27 patient factors for predicting the risk of dose-limiting leukopenia. Eight factors were perceived as strongly informative: Eastern Cooperative Oncology Group performance status of 2 or worse, recent weight loss of more than 10%, multiple bone marrow metastases, two or more prior chemotherapy regimens, history of treatment toxic effects, and prior treatment with carboplatin, mitomycin, or nitrosoureas. Informal assessment of the risk of toxic effects in a patient was found to be common practice among oncologists who enroll patients on phase I trials, and there was strong agreement on the usefulness of several key patient factors for such assessments. Interestingly, interinstitutional variation in opinions and practices were noted, specifically regarding patient-selection bias. Follow-up studies are required to establish if physician-determined assessments of patient risk are consistent and accurate.