Higher-Dose Radiotherapy for Stage III Lung Cancer Patients Results in Inferior Survival

In a recent US randomized phase III clinical trial, high-dose (HD) radiotherapy compared with standard-dose (SD) radiotherapy (RT) with concurrent chemotherapy (CT) did not improve overall survival of patients with stage III non-small-cell lung cancer (NSCLC).

Of all the patients in the United States with lung cancer, the country’s leading cause of cancer death, 75%–80% of them have NSCLC, with 30%–40% of those being considered locally advanced (stage IIIA or IIIB). Although RT plus CT has been the standard of care for locally advanced NSCLC, more research has centered on the integration of appropriate CT drugs than on revisiting the 60-Gy RT dose established over 30 years ago.

Worries over local tumor progression rates near 85% following treatment for stage III NSCLC with CT in addition to traditional RT doses and research findings revealing increased median survival time tied to a 74-Gy RT dose led to the development of RTOG 0617 [Radiation Therapy Oncology Group clinical trial study number 0617], which sought to identify the optimal RT dose for the treatment of patients with locally advanced NSCLC. The trial also assessed the hypothesis that the addition of cetuximab, an agent that targets the epidermal growth factor receptor (EGFR) pathway and has radiation-sensitizing properties, to chemoradiation would lead to improved survival.

The trial randomized 464 patients with pathologically diagnosed unresectable stage IIIA or IIIB NSCLC to SD (60 Gy) or HD (74 Gy) arms. All patients received concurrent CT of weekly paclitaxel and carboplatin, as well as additional cycles of consolidation CT following combined CT and RT.

The Radiation Therapy Oncology Group (RTOG; Philadelphia, PA, USA) trial’s final findings on radiation dose were presented June 4, 2013, at the American Society of Clinical Oncology 2013 annual meeting, held in Chicago (IL, USA), by lead investigator Jeffrey D. Bradley, MD, a professor in radiation oncology, and chief of thoracic service at Washington University School of Medicine (St. Louis, MO, USA; http://wustl.edu). Median follow-up time of the trial’s 419 evaluable patients was 17.2 months, with a median survival time of 28.7 vs. 19.5 months and 18-month overall survival rates of 66.9% vs. 53.9% for the SD and HD arms, respectively. Local failure rates at 18 months similarly favored the SD over the HD arms. “In the setting of concurrent chemotherapy with daily radiation therapy for stage III lung cancer, these results definitively confirm that 60 Gray is superior to 74 Gray, with a clear detriment associated with the higher radiation dose,” concluded Dr. Bradley.

Although participants were stratified according to the RT technique used (three-dimensional [3D] vs. intensity- modulated RT [IMRT]), analysis of survival, patterns of failure, and physician-reported toxicity did not identify one technique to be better or worse than the other, according to Dr. Bradley. He pointed to two emerging research directions that benefit from the knowledge gained by the RTOG 0617 trial. “With the identification of a number of genetic driver mutations, targeted therapy is clearly the next phase of treatment for NSCLC,” clarified Dr. Bradley. RTOG 1306 is an example of a phase II study evaluating newly developed agents that block EGFR or anaplastic lymphoma kinase (ALK) mutations. “Patients will receive either a targeted agent for a few months followed by chemoradiation or chemoradiation alone, which represents the standard arm in RTOG 0617.”

A second research direction addresses how to improve RT in the setting of concurrent CT with the efficacy of the lower RT dose now confirmed. According to Bradley, efforts will focus on evaluating the use of adaptive RT, which involves changing the radiation treatment plan delivered to a patient during a course of RT. In RTOG 1106 protocol, for example, a patient on the experimental arm undergoes a PET scan after 20 RT treatments, and the RT plan is then refocused on the remaining tumor volume, with a higher dose per fraction given for the remaining 10 treatments.”

“These results stand as an excellent example of the importance of rigorously testing new radiotherapy strategies and of RTOG’s essential role in conducting clinical trials to provide the evidence to guide clinical care,” said Walter J. Curran, Jr. MD, RTOG group chair and executive director of the Winship Cancer Institute of Emory University (Atlanta, GA, USA).

Related Links:

Radiation Therapy Oncology Group
Washington University School of Medicine