Esophagus-Sparing vs Standard Palliative Radiation for Patients With Advanced Central NSCLC

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As reported in JAMA Oncology by Louie et al, the Canadian phase III PROACTIVE trial showed that esophagus-sparing intensity-modulated radiotherapy (ES-IMRT) did not significantly improve esophageal quality of life vs standard radiotherapy in patients with advanced central non–small cell lung cancer (NSCLC) tumors, but the method was associated with reduced risk of esophagitis.

Study Details

In the multicenter trial, 90 patients with stage III/IV disease were randomly assigned between June 2016 and March 2019 to receive standard radiotherapy (n = 45) or ES-IMRT (n = 45) at physician’s choice of 20 Gy in 5 fractions (n = 18 in each group) or 30 Gy in 10 fractions (n = 27 in each group). In the ES-IMRT group, target coverage was compromised to ensure the maximum esophagus dose was ≤ 80% of the radiotherapy prescription dose. The primary endpoint was esophageal quality of life at 2 weeks post-radiotherapy, as measured by the esophageal cancer subscale (ECS) of the Functional Assessment of Cancer Therapy-Esophagus questionnaire. Higher subscale scores indicate improved quality of life, with a two- to three-point change considered clinically meaningful.

Key Findings

In the standard radiotherapy arm, the mean and maximum esophagus radiotherapy doses were 10.2 Gy and 25.3 Gy, respectively. In the ES-IMRT group, the mean and maximum doses were 9.8 Gy and 23.8 Gy.

Among patients evaluable for the primary endpoint, the mean (standard deviation [SD]) ECS score at 2 weeks after radiotherapy was 50.5 (SD = 10.2; 95% confidence interval [CI] = 47.2–53.8) among 39 patients in the standard radiotherapy group vs 54.3 (SD = 7.6; 95% CI = 51.9–56.7) among 41 in the ES-IMRT group (P = .06; corresponding effect size = 3.8, 95% CI = −0.2 to 7.8).

In a post hoc analysis, mean scores were 51.1 (SD =10.7) vs 56.4 (SD = 7.1) among patients receiving 30 Gy (P = .06) and 49.7 (SD = 9.8) vs 50.9 (SD =7.2) among those receiving 20 Gy (P = .68).

Among all 90 patients receiving treatment, grade ≥ 2 radiotherapy-associated esophagitis occurred in 24% (n = 11) of patients in the standard radiotherapy group vs 2% (n = 1) in the ES-IMRT group (P = .002). In a post hoc analysis, grade ≥ 2 esophagitis occurred in 30% (n = 8) vs 0% of patients receiving 30 Gy (P = .004) and in 17% (n = 3) vs 6% (n = 1) receiving 20 Gy (P = .60).

Median overall survival was 8.6 months (95% CI = 5.7–15.6 months) in the standard radiotherapy group vs 8.7 months (95% CI = 5.1–10.2 months) in the ES-IMRT group (P = .62).

Apart from esophagitis, no differences in adverse events were observed between groups.

The investigators concluded, “In this phase III randomized clinical trial, ES-IMRT did not significantly improve esophageal quality of life but significantly reduced the incidence of symptomatic esophagitis. Because post hoc analysis found that reduced esophagitis was most evident in patients receiving 30 Gy of radiotherapy, these findings suggest that ES-IMRT may be most beneficial when the prescription dose is higher (30 Gy).”

Alexander V. Louie, MD, PhD, of Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, is the corresponding author for the JAMA Oncology article.

Disclosure: The trial was funded by a Canadian Cancer Society Quality of Life Research grant. For full disclosures of the study authors, visit

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