A systematic methodology review of phase I radiation dose escalation trials.

Background And Purpose: The purpose of this review is to evaluate the methodology used in published phase I radiotherapy (RT) dose escalation trials. A specific emphasis was placed on the frequency of reporting late complications as endpoint.

Materials And Methods: We performed a systematic literature review using a predefined search strategy to identify all phase I trials reporting on external radiotherapy dose escalation in cancer patients.

Results: Fifty-three trials (phase I: n = 36, phase I-II: n = 17) fulfilled the inclusion criteria. Of these, 20 used a modified Fibonacci design for the RT dose escalation, but 32 did not specify a design. Late toxicity was variously defined as > 3 months (n = 43) or > 6 months (n = 3) after RT, or not defined (n = 7). In only nine studies the maximum tolerated dose (MTD) was related to late toxicity, while only half the studies reported the minimum follow-up period for dose escalation (n = 26).

Conclusion: In phase I RT trials, late complications are often not taken into account and there is currently no consensus on the methodology used for radiation dose escalation studies. We therefore propose a decision-tree algorithm which depends on the endpoint selected and whether a validated early surrogate endpoint is available, in order to choose the most appropriate study design.