New survival benchmark set for patients with inoperable stage III NSCLC

The 5-year overall survival rate for patients with stage III non-small cell lung cancer (NSCLC) after standard dose radiation treatment is now over twice as high (32%) as previously estimated (5% to 14%), according to results from the RTOG 0617 study, presented at the 59th annual meeting of the American Society for Radiation Oncology (ASTRO).

“Based on the 2-year results reported in 2015, RTOG 0617 has already changed practice and established the standard radiation dose for patients receiving chemoradiation for stage III NSCLC,” said principal investigator Jeffrey D. Bradley, MD, FASTRO, professor of radiation oncology and director, S.L. King Center for Proton Therapy, Washington University School of Medicine, St. Louis, MO.

Further, these results also confirmed that a standard dose of radiation therapy—60 Gy delivered in 30 fractions—is preferable to a higher dose, and that cetuximab brought about no additional survival benefits in these patients.

“When RTOG 0617 was initially reported, the results were surprising to most oncologists because the standard dose of 60 Gy was superior to the higher dose of 74 Gy in this setting. There have been numerous secondary analyses investigating the reasons for this result, and the data point toward greater radiation exposure to the heart in the high-dose arm being the main problem,” noted Dr. Bradley.

For this phase III study, Dr. Bradley and colleagues included 496 patients (median age: 64 years; 59% male; 41% white; median follow-up: 5.1 years) with unresectable stage III NSCLC from 185 institutions throughout the United States and Canada. Researchers randomized patients to one of two chemoradiation dose groups. Patients in the standard-dose group received 60 Gy total radiation dose, while those in the high-dose group received 74 Gy total dose. Radiation was delivered in 2 Gy daily fractions via either intensity-modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3-D CRT).

Concurrent weekly chemotherapy with paclitaxel and carboplatin was administered to all patients. They were also randomized to treatment with either cetuximab or placebo.

Dr. Bradley and colleagues found that 5-year overall survival (OS) rates after chemoradiation were higher in patients in the standard-dose group compared to those in the high-dose group 32.1% vs 23%, respectively (P=0.004), as was median overall survival (28.7 vs 20.3 months [HR: 1.35; P=0.004]).
Similarly, 5-year progression-free survival rates were also higher in the standard-dose treatment arm compared to the high-dose arm (18.3% vs 13% [P=0.055]).

Upon multivariate analysis, these researchers found that the differences in OS were driven by the following:

• Radiation dose, favoring the standard-dose regimen (P=0.03);
• Planning target volume (P=0.022);
• Accrual volume of the treating institution (P=0.017);
• Presence of esophagitis/dysphagia (P=0.008); and
• V5 heart dose/volume (P=0.005).

Tumor recurrence patterns—either in same location as the initial tumor or further away—also were better with the standard-dose regimen, but the differences between the two groups were not statistically significant.

Local failure rates for the standard-dose versus high-dose arms were 38.2% vs 45.7%, respectively (P=0.068); regional failure rates were 35.7% vs 38.4% (P=0.5); and distant failure rates, 52.3% vs 57.6% (P=0.3).

Patients in the high-dose group had more treatment-related side effects, with nine treatment-related deaths, compared with three in the standard-dose group. Treatment-related grade 3 or higher toxicity included dysphagia (3.2% in standard-dose vs 12.1% in high-dose group; P < 0.0001), esophagitis (5.0% vs 17.4%, respectively; P < 0.0001), and severe pulmonary events (20.6 vs 19.3%; P > 0.05).

These researchers also found that cetuximab, given as a 400-mg dose on day 1, and then 250-mg doses weekly thereafter, provided no benefit for 5-year OS. The median OS for patients who received cetuximab was the same as that in patients who did not (24 vs 24 months; P=0.048). In addition, they found no benefit from cetuximab in those patients with epidermal growth factor receptor H-scores above 200, which was the opposite of earlier findings from this same study.

“The current report establishes an overall 5-year survival standard for patients receiving standard-dose chemoradiation for stage III NSCLC that is substantially higher than previously estimated. This report also confirms that using a higher radiation dose is not beneficial and can lead to detrimental outcomes including lower survival rates and increase side effects,” concluded Dr. Bradley.