BY ROBERT H. CARLSON
Radiation oncologists have debated for years whether a dose higher than the standard 60 Gy would lead to better outcomes in non-small cell lung cancer (NSCLC).
The answer is in – it does not.
In a Phase III study comparing 60 vs. 74 Gy in patients with advanced NSCLC undergoing concurrent chemotherapy, patients receiving the higher dose had a 56 percent greater risk of death than did those receiving 60 Gy, and a 37 percent greater risk of local failure.
The standard-dose was also associated with significantly fewer treatment-related deaths.
The RTOG 0617 study was highlighted in a news conference by the American Society of Clinical Oncology, held in advance of the Annual Meeting (Abstract 7501).
“After a decade of research, we can finally close the chapter on the high-dose vs. standard-dose therapy debate in lung cancer therapy,” said ASCO President Sandra M. Swain, MD. And while 60 Gy is the standard dose for this patient population, “I’m sure many doctors were expecting that using the higher dose would have a better outcome, so these were very surprising results, especially using better radiation techniques that were designed to be more precise.”
One of those surprised was the study’s lead author, Jeffrey D. Bradley, MD, Professor of Radiation Oncology at Washington University School of Medicine in St. Louis, who noted that earlier Phase I and Phase II clinical trials with high-dose radiotherapy in NSCLC did show promising increases in median survival.
“But a lot of Phase III trials turn out negative when the Phase II trials were looking good -- that’s why we do Phase III trials,” said Bradley, representing the Radiation Therapy Oncology Group.
He said the researchers expected at the outset of RTOG 0617 that high-dose radiation therapy would lead to better outcomes.
“We were surprised, though also pleased, to discover that less-intense treatment led to better control of cancer progression and spread, and even improved overall survival.”
From 464 patients with Stage III NSCLC, the researchers randomly selected patients to receive radiation at 60 Gy or 74 Gy. All patients received concurrent weekly paclitaxel (45 mg/m2) and carboplatin (AUC=2). The study had a double randomization, and approximately half of the patients were randomly selected to receive cetuximab, in a 400 mg/m2 loading dose on day 1 followed by weekly doses of 250 mg/m2.
For 419 patients eligible for analysis, at a median follow up of 17.2 months, median survival was 28.7 months for the 60 Gy arm (213 patients) vs. 19.5 months for the 74 Gy arm (206).
Eighteen-month overall survival rates were approximately 67 percent vs. 54 percent, respectively.
“The survival data for both study arms were higher than what has been seen in previous RTOG studies,” Bradley said.
The rates of Grade 3/4 adverse events were about 74 and 78 percent, respectively, and the only large statistically significant difference was in esophagitis, with a 37 percent increased risk in the high-dose arm.
The primary cause of death was lung cancer, similar in both groups at 72.2 vs. 73.5 percent, respectively. But there were more treatment-related deaths on the 74 Gy arm -- 10, vs. two on the 60 Gy arm.
Local failure rates were quite different – about 25 percent at 18 months for 60 Gy vs. 39 percent for 74 Gy. The distant failure rates were approximately 42 percent vs. 48 percent, respectively.
Bradley said higher radiation dose, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volume above 5 Gy were predictive of less favorable overall survival on multivariate analysis.
The high-dose arm was closed after an interim analysis showed that it was not superior to the standard-dose arm, as Bradley reported at the plenary session of the American Society for Radiation Oncology Annual Meeting. He noted that the new data, on the overall survival benefit of 60 Gy, is independent of the effect of cetuximab, and that patients receiving 60 Gy with or without cetuximab are still being followed.
“At this point there is no clear reason for the lack of benefit in the high-dose arm,” he said, noting that one possible explanation is increased dose to the heart, although left ventricular ejection fractions were not evaluated by the researchers.
Other possible explanations are extended therapy duration, unreported toxicities, or possible too-tight margins in the high-dose arm.
The study was supported by grants from the National Cancer Institute and Eli Lilly and Company.