Esophageal-Sparing Intensity-Modulated Radiotherapy Improves Symptomatic Esophagitis in Advanced NSCLC

While quality of life did not improve with esophageal-sparing intensity-modulated radiotherapy, patients with stage III/IV non–small cell lung cancer did experience a reduction in symptomatic esophagitis.

Patients with stage III/IV non–small cell lung cancer (NSCLC) treated with esophageal-sparing intensity-modulated radiotherapy (ES-IMRT) did not have an improvement in quality of life, but did see a significant reduction in symptomatic esophagitis, according to a phase 3 PROACTIVE trial (NCT02752126) published in JAMA Oncology.

Patients had an esophageal cancer subscale (ECS) score of 50.5 (95% CI, 47.2-53.8) in the standard radiotherapy arm compared with 54.3 (95% CI, 51.9-56.7) in the ES-IMRT arm (P = .06). Symptomatic radiotherapy-associated esophagitis was observed in 24.0% of patients in the control arm and 2.0% of patients in the ES-IMRT arm (P = .02).

A total of 90 patients with incurable stage III/IV NSCLC were randomized across 6 centers in Canada, 71% of whom had stage IV disease. Additionally, 72% had an ECOG status of 0 to 1. Treatment was administered to 40% of patients at 20 Gy in 5 fractions and 60% received 30 Gy in 10 fractions. In the control arm, the mean esophagus dose was 10.2 Gy with a maximum dose of 25.3 Gy. In the ES-IMRT arm, the mean dose was 9.8 Gy and the maximum dose was 23.8 Gy.

In the ES-IMRT arm, 22 of 45 patients had cancer in direct contact with the esophagus and required a 20% reduction in dosing in that area. In the control arm, the mean number of cycles received was 7.7 vs 5.1 in the ES-IMRT arm (P = .68).

Two weeks following radiotherapy, 80 patients completed the ECS quality of life form. The post-hoc analysis found when dividing patients by stratification factors, benefit was primarily observed in patients receiving 30 Gy with a score of 51.1 in the standard arm vs 56.4 in the ES-IMRT arm (P = .06) compared with 20 Gy at 49.7 vs 50.9, respectively (P = .68).

The incidence of grade 2 esophagitis was observed in 24% of patients in the radiotherapy arm and in 2% of those in the ES-IMRT arm. The benefit was primarily observed among those who received the 30 Gy dosage, including 30% patients vs 0% in each respective arm (P = .004) compared with the 20 Gy group at 15% vs 6%, respectively (P = .60).

In the exploratory multivariable analysis, investigators identified that treatment with prior chemotherapy (OR, 9.33; 95% CI, 1.53-56.82; P = .02) was predictive of symptomatic esophagitis, as well as randomization to the control arm, stratified by the intended dose, (OR, 16.83; 95% CI, 1.85-152.84; P = .01). However, the intended dose of 30 Gy or 20 Gy was not significantly predictive of symptomatic esophagitis (OR, 1.37; 95% CI, 0.38-5.00; P = .63), but randomization in the control arm was significantly predictive (OR, 9.74; 95% CI, 1.70-55.87; P = .01).

In the trial, 56 patients died during the 1-year follow-up period, 27 of whom were in the control arm and 29 were in the ES-IMRT arm. Between arms, the overall survival was 8.6 months (95% CI, 5.7-15.6) in the control arm compared with the ES-IMRT arm at 8.7 months (95% CI, 5.1-10.2).


Louie AV, Granton PV, Fairchild A, et al. Palliative radiation for advanced central lung tumors with intentional avoidance of the esophagus (PROACTIVE): a phase 3 randomized clinical trial. JAMA Oncol. Published Online February 24, 2022. doi:10.1001/jamaoncol.2021.7664