Standard-dose conformal radiotherapy (60 Gy) is more effective and safer than high-dose radiotherapy (74 Gy) in patients with locally advanced stage III non–small cell lung cancer (NSCLC) undergoing chemotherapy, according to results of the phase III randomized, controlled Radiation Therapy Oncology Group (RTOG) 0617 trial presented at the ASCO Annual Meeting.¹

Earlier phase I and II clinical trials suggested that high-dose radiotherapy might have advantages over standard-dose radiotherapy in this setting, but this study found that high-dose radiotherapy increased the risk of death by 56% compared with standard-dose radiotherapy. Further, the risk of local failure was increased by 37% in the high-dose arms of the trial compared with standard doses.

Take-home Message

“We expected to find that high-dose radiation therapy would achieve better outcomes. We are both surprised and pleased to discover that less intense treatment led to better control of cancer progression and spread, and even improved overall survival,” said lead author Jeffrey D. Bradley MD, S. Lee Kling Professor of Radiation Oncology, Chief of the Thoracic Service, and Director of the S. Lee Kling Center for Proton Therapy at Washington University School of Medicine in St. Louis. Dr. Bradley said the biologic explanation of these findings is not clear.

“The take-home message from this trial is that radiation oncologists outside of clinical trials should be using the standard dose of 60 Gy in patients with stage III NSCLC treated with concurrent chemotherapy,” Dr. Bradley stated.

Sophisticated and precise techniques were used to deliver radiotherapy in this trial, including three-dimensional radiotherapy and intensity-modulated radiotherapy. The study had a 2×2 factorial design and randomly assigned 464 patients to treatment with lower-dose and high-dose radiation therapy along with standard chemotherapy.

In each treatment arm, patients were also randomly assigned to treatment with cetuximab (Erbitux) or no additional therapy. Data on cetuximab’s effects will be reported in 2014, Dr. Bradley said.  The high-dose arm was closed when an interim analysis found that it was not superior to standard-dose radiation.

Overall survival was superior in the standard-dose arm: 90 deaths were reported with 60-Gy radiation vs 117 in the 74-Gy arm (P = .0007), representing a 56% increased risk of death with high-dose radiation. Median survival was 28.7 months for standard-dose therapy vs 19.5 months for the high-dose arm. The estimated 18-month overall survival rates were higher for the standard-dose arm: 66.9% vs 53.9%.

Local failure was also significantly worse in the high-dose arm: 81 failures vs 65 failures in the standard-dose arm (P = .0319). At 18 months, local recurrence rates were 34.3% vs 25.1%, respectively, while distant recurrence rates were 44% vs 35.3%, respectively.

The only significant difference in side effects between the two arms was a higher rate of esophagitis in patients undergoing high-dose radiation: 21% vs 7%, respectively. The number of treatment-related deaths was higher in the high-dose arm: 10 vs 2, respectively.

Surprising Results

“These are surprising results, especially with more precise modern techniques. After a decade of research, we can finally close the chapter on the high-dose vs standard-dose therapy debate in stage III lung cancer therapy,” stated ASCO Immediate Past President
Sandra M. Swain, MD, FACP.

“This study should influence practice and reduce the use of higher-dose radiation for NSCLC,” said ASCO President  Clifford A. Hudis, MD. ■

Disclosure: Dr. Swain’s institution has received research funds from Bristol-Myers Squibb. Drs. Bradley and Hudis reported no potential conflicts of interest.

Reference

1. Bradley JD, Paulus R, Komaki R, et al: A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer. ASCO Annual Meeting. Abstract 7501. Presented June 4, 2013.