SAN DIEGO-Final analysis of survival rates from patients enrolled in a major phase III clinical trial has shown that 5-year survival for patients with inoperable, locally advanced non-small cell lung cancer (NSCLC) who undergo chemotherapy and radiation is likely more than two times higher than currently accepted estimates. Survival data from the Radiation Therapy Oncology Group (RTOG) 0617 trial were presented at the American Society for Radiation Oncology Annual Meeting (Abstract 227).
The investigators found an overall survival (OS) rate of 32 percent with standard radiotherapy treatment with 60 Gray (Gy) radiation delivered in 30 fractions, compared to 23 percent OS with 74 Gy in 37 fractions. The NCI estimates that 5-year survival rates in this population range from 5 percent to 14 percent.
The trial also concluded that the EGFR inhibitor cetuximab provided no added survival benefit.
"This sets a new benchmark of survival for patients with inoperable stage III NSCLC treated with chemoradiation," said principal investigator Jeffrey D. Bradley, MD, Professor of Radiation Oncology and Director of the S. L. King Center for Proton Therapy at the Washington University School of Medicine, in St. Louis, Mo.
RTOG 0617 was a phase III randomized trial that compared the standard 60 GY dose to a dose of 74 Gy in 37 fractions for patients receiving concurrent chemotherapy with or without cetuximab. Interim analysis data presented in 2011 showed median OS with the standard dose was better than with the higher dose, at 21.7 versus 20.7. Final 2-year results, presented in 2015, showed a median survival of 28.7 percent for the standard dose versus 19.5 percent for the higher dosage.
Bradley noted the data have already changed clinical practice. "When RTOG 0617 was initially reported, the results were surprising to most oncologists... There have been numerous secondary analyses investigating the reasons for this result, and the data point toward greater radiation exposure to the heart with the higher dose as being the main problem.
"The current report establishes an overall 5-year survival standard [and] confirms that using a higher radiation dose is not beneficial and can lead to detrimental outcomes including lower survival rates and increase side effects," he stated.
Methods, Results
RTOG 0617 was conducted at 185 participating institutions in 496 patients who were eligible for analysis. Patients were randomized to one of the two chemoradiation doses.
Radiation was delivered using either intensity-modulated radiation therapy or 3D conformal radiation therapy. At the same time, all patients received concurrent weekly chemotherapy with paclitaxel and carboplatin. Patients also were randomized to receive either cetuximab or a placebo.
Median OS after standard dose chemoradiation was 28.7 versus 20.3 months, while 5-year survival was 32.1 percent and 23 percent and progression-free survival rates were 18.3 percent and 13 percent, respectively.
Analysis indicated that OS differences were largely driven by the radiation dose, planning target volume, the accrual volume of the treating institution, the presence of esophagitis/dysphagia, and V5 heart dose/volume.
Tumor recurrence in either the same location or region as the initial tumor, or further away, also favored the standard-dose regimen, although the differences failed to reach statistical significance. For the standard-dose and high-dose arms, respectively, local failure occurred in 38.2 percent versus 45.7 percent of patients; regional failure in 35.7 percent versus 38.4 percent; and distant failure in 52.3 percent versus 57.6 percent.
Treatment-related side effects were also markedly more in the high-dose cohort. While three treatment-related deaths occurred in the standard-dose arm, there were nine in high-dose recipients. Treatment-related grade 3 or higher toxicity for the standard-dose and high-dose arms were dysphagia in 3.2 percent versus 12.1 percent, esophagitis in 5.0 percent versus 17.4 percent, and severe pulmonary events in 20.6 percent versus 19.3 percent.
Cetuximab (400 mg on day 1, then 250 mg doses weekly thereafter) did not confer any benefit for OS at 5 years. Median OS for both arms was 24 months. The investigators also reported that, unlike findings earlier in the trial, cetuximab patients with EGFR H-scores above 200 showed no benefit.
Commentary
Ben Movsas, MD, Chair, Department of Radiation Oncology, Henry Ford Cancer Institute, in Detroit, Mich., said that survival rates are likely higher in this study in the standard radiation arm for a number of reasons.
"First, this is the first RTOG customized lung study that required PET staging for entry, and this leads to a component of stage migration. Beyond this, however, radiation techniques have improved over time, with better accuracy and targeting, so the standard dose of radiation may have been more effective," he told Oncology Times. "There is also better supportive care over time as well."
He pointed to a related paper for RTOG 0617 in which he was first author, published in 2016 in JAMA Oncology, in which the researchers found that the quality of life for patients who received more sophisticated treatment planning with intensity modulated radiation therapy compared to 3D conformal radiation therapy was relatively better even a year later (2016;2:359-367).
When asked whether he was surprised by the finding that cetuximab provided no added benefit, Movsas answered, "Yes and no."
"The challenge is that this study did not require eligibility screening based on EGFR expression/status. Yet, when they went back and looked at this, they found an interesting association that patients with relatively high EGFR expression appeared to benefit from cetuximab, with median survival of 42 months compared to those with low expression, where median survival was 21 months."
However, the analysis was only available in about half of the patients, he noted. "So, perhaps not too surprising that cetuximab didn't help in the overall group, but it is provocative that it might have helped in those with high EGFR expression."
Kurt Samson is a contributing writer.