Are the Results of RTOG 0617 Mysterious?

On June 17, 2011, two of the four arms in the Radiation Therapy Oncology Group (RTOG) 0617 protocol were closed to accrual when a planned interim analysis showed that the higher radiation dose being tested, 74 Gy, could not produce an overall survival benefit compared with the lower, standard dose of 60 Gy . This four-arm study was designed to test radiation with carboplatin and paclitaxel, with or without cetuximab, for Stage III non–small-cell lung cancer (NSCLC). Survival was compared between the two 74-Gy groups and the two 60-Gy groups, and overall survival was found to be better in the lower dose groups (1-year overall survival rate, 70.4% in the 74-Gy groups vs. 81% in the 60-Gy groups—both respectable rates for this stage of disease). However, even though 17 patients died in the 74-Gy arms compared with 7 in the 60-Gy arms, the toxicity rates were no different between the two dose groups. These findings are not only counterintuitive, they run counter to a large body of evidence showing that higher radiation doses lead to better tumor control at numerous sites. Deaths related to the effects on the normal lungs and perhaps the heart from high-dose three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated RT (IMRT) are the most likely explanation of the findings from the RTOG 0617. Considerable evidence, summarized below, supports the hypothesis that the pulmonary or cardiopulmonary effects of thoracic RT can contribute to death.