A systematic methodology review of phase I radiation dose escalation trials

Madelon Pijls-Johannesma*, Ghislaine van Mastrigt, Steve M. Hahn, Dirk De Ruysscher, Brigitta G. Baumert, Guido Lammering, Jeroen Buijsen, Soren M. Bentzen, Yolande Lievens, Andrew Kramar, Philippe Lambin

*Corresponding author for this work

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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.
Original languageEnglish
Pages (from-to)135-141
JournalRadiotherapy and Oncology
Issue number2
Publication statusPublished - May 2010


  • Systematic review
  • Radiotherapy and clinical trial phase I

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