NCI-RTOG translational program strategic guidelines for the early-stage development of radiosensitizers

Yaacov Richard Lawrence, Bhadrasain Vikram, James J. Dignam, Arnab Chakravarti, Mitchell MacHtay, Boris Freidlin, Naoko Takebe, Walter J. Curran, Soren M. Bentzen, Paul Okunieff, C. Norman Coleman, Adam P. Dicker

Research output: Contribution to journalReview articlepeer-review

57 Scopus citations


The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry's diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials-acute toxicity and maximum-tolerated dose-are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II "screening" trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation.

Original languageEnglish (US)
Pages (from-to)11-24
Number of pages14
JournalJournal of the National Cancer Institute
Issue number1
StatePublished - Jan 2 2013

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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