Less is More: Researchers Surprised by Radiotherapy Results Involving Locally Advanced NSCLC

Patients in a phase III trial lived longer and experienced fewer treatment-related deaths from locally advanced non-small cell lung cancer (NSCLC) after receiving the standard dose of radiotherapy, compared to those receiving a high dose, according to a study presented today at the Annual Meeting of the American Society of Clinical Oncologists (ASCO).

The findings surprised researchers, because earlier studies had suggested higher radiation doses would produce better outcomes, according to Jeffrey D. Bradley, MD, a professor of Radiation Oncology at the Washington University School of Medicine in St. Louis, Missouri.

All participants in the most recent study were stage III NSCLC patients who were also getting concurrent and consolidation chemotherapy. Those given the standard 60 gray (Gy) dose lived approximately nine months longer than those treated with the high dose of 74 Gy.

Also, those who received the high dose faced a 56% greater risk of death and a 37% greater risk of local progression of their disease compared with patients who received the standard dose, Bradley said.

Promising findings in phase I and II trials encouraged some physicians to give high-dose radiation to patients in this population with the expectation of better results, but Bradley said recently the latest findings could reverse that trend.

“We expected at the outset 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,” he said. “The biological reasons for failure of the high dose with respect to overall survival and local-regional control are not readily apparent.”

In the study, 464 patients were randomly assigned to treatment with standard dose (SD) or high dose (HD) radiation therapy along with standard chemotherapy (paclitaxel and carboplatin), with a primary endpoint of overall survival. The patients were further stratified based on the radiation technique used (3D-CRT or IMRT), performance status, the use of PET scans for staging, and squamous versus nonsquamous histology. The HD arm was closed after an interim analysis showed it was not superior to the SD arm.

In each treatment arm, the patients were also randomly assigned to receive cetuximab (Erbitux) or no additional therapy. Bradley said that data on the effects of cetuximab on survival will be reported in 2014. “Overall survival benefit of 60 Gy is independent of the cetuximab question,” he said.

Of the participating patients, 419 were eligible for analysis. The median survival for patients who received SD radiation therapy was much longer compared to that of patients who received HD radiation therapy (28.7 months vs 19.5 months) and the estimated 18-month overall survival rate was also higher for the SD arm (66.9% vs 53.9%).

Cancer recurrence rates at 18 months were higher in the HD group of patients compared with the SD group; local recurrence rates were 34.3% vs 25.1% (P = 0.03), and distant recurrence rates were 44% vs 35.3% (P = 0.04). While the primary cause of death for most patients was lung cancer (72.2% in the SD arm vs 73.5% in the HD arm, P = 0.84), there were a notably higher number of treatment-related deaths in the HD arm (10) as compared with the SD arm (2).

Adverse events that were grade 3 or higher occurred at a rate of 74.2% vs 78.2% in the SD and HD arms, respectively (P = 0.34). The only significant difference in physician-reported side effects was a slightly higher rate of esophagitis on the HD arm (21% vs 7%), Bradley reported.

Possible explanations for the poorer outcome for patients on the HD arm, Bradley said, include increased exposure of the heart to radiation; the longer duration of therapy in the HD arm (7½ weeks as compared with 6 weeks in the SD arm); unreported toxicities; or a combination of those factors.

“This is a critical study in the field of radiation oncology,” said ASCO President Sandra M. Swain, MD. “After a decade of research, we can finally close the chapter on the high-dose vs standard-dose therapy debate in lung cancer, using evidence-based data to improve care for our patients.”

Sponsored by the National Cancer Institute and Eli Lilly and Company, the study’s participating investigators represented cooperative groups including the Radiation Therapy Oncology Group, North Central Cancer Treatment Group, and Cancer and Leukemia Group B.

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: Results on radiation dose in RTOG 0617. J Clin Oncol. 2013 (suppl; abst 7501).