Palliative Radiation for Advanced Central Lung Tumors With Intentional Avoidance of the Esophagus (PROACTIVE): A Phase 3 Randomized Clinical Trial

Abstract

Importance: Palliative thoracic radiotherapy (RT) can alleviate local symptoms associated with advanced non-small cell lung cancer (NSCLC), but esophagitis is a common treatment-related adverse event. Whether esophageal-sparing intensity-modulated RT (ES-IMRT) achieves a clinically relevant reduction in esophageal symptoms remains unclear.

Objective: To examine whether ES-IMRT achieves a clinically relevant reduction in esophageal symptoms compared with standard RT.

Design, setting, and participants: Palliative Radiation for Advanced Central Lung Tumors With Intentional Avoidance of the Esophagus (PROACTIVE) is a multicenter phase 3 randomized clinical trial that enrolled patients between June 24, 2016, and March 6, 2019. Data analysis was conducted from January 23, 2020, to October 22, 2021. Patients had up to 1 year of follow-up. Ninety patients at 6 tertiary academic cancer centers who had stage III/IV NSCLC and were eligible for palliative thoracic RT (20 Gy in 5 fractions or 30 Gy in 10 fractions) were included.

Interventions: Patients were randomized (1:1) to standard RT (control arm) or ES-IMRT. Target coverage was compromised to ensure the maximum esophagus dose was no more than 80% of the RT prescription dose.

Main outcomes and measures: The primary outcome was esophageal quality of life (QOL) 2 weeks post-RT, measured by the esophageal cancer subscale (ECS) of the Functional Assessment of Cancer Therapy: Esophagus questionnaire. Higher esophageal cancer subscale scores correspond with improved QOL, with a 2- to 3-point change considered clinically meaningful. Secondary outcomes included overall survival, toxic events, and other QOL metrics. Intention-to-treat analysis was used.

Results: Between June 24, 2016, and March 6, 2019, 90 patients were randomized to standard RT or ES-IMRT (median age at randomization, 72.0 years [IQR, 65.6-80.3]; 50 [56%] were female). Thirty-six patients (40%) received 20 Gy and 54 (60%) received 30 Gy. For the primary end point, the mean (SD) 2-week ECS score was 50.5 (10.2) in the control arm (95% CI, 47.2-53.8) and 54.3 (7.6) in the ES-IMRT arm (95% CI, 51.9-56.7) (P = .06). Symptomatic RT-associated esophagitis occurred in 24% (n = 11) of patients in the control arm vs 2% (n = 1) in the ES-IMRT arm (P = .002). In a post hoc subgroup analysis based on the stratification factor, reduction in esophagitis was most evident in patients receiving 30 Gy (30% [n = 8] vs 0%; P = .004). Overall survival was similar with standard RT (median, 8.6; 95% CI, 5.7-15.6 months) and ES-IMRT (median, 8.7; 95% CI, 5.1-10.2 months) (P = .62).

Conclusions and relevance: In this phase 3 randomized clinical trial, ES-IMRT did not significantly improve esophageal QOL 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 RT, these findings suggest that ES-IMRT may be most beneficial when the prescription dose is higher (30 Gy).

Trial registration: ClinicalTrials.gov Identifier: NCT02752126.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Louie reported receiving grants from the Canadian Cancer Society Research Institute during the conduct of the study and personal fees from AstraZeneca for advisory board participation, personal fees from Varian Medical Systems for a speaking engagement, and personal fees from RefleXion for a speaking engagement, outside of the submitted work. Dr Gopaul reported receiving personal fees from AstraZeneca, TerSera, Bayer, Ferring, and AbbVie for advisory board participation outside the submitted work. Dr Brade reported receiving personal fees from AstraZeneca for advisory board participation outside of the submitted work. Dr. Sun reported receiving personal fees from AstraZeneca for advisory board participation outside of the submitted work. Dr Palma reported receiving grants from the Ontario Institute for Cancer Research Clinician-Scientist Grant during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Depiction of Standard Radiation, Delivered as a Parallel-Opposed Pair (POP) in the Control Arm and Esophageal-Sparing Intensity-Modulated Radiotherapy (ES-IMRT) in the Experimental Arm

The target is shown in blue color wash, the esophagus in green color wash, with the scale for dose lines shown at top left. Note the bowing-in of the higher isodose lines away from the esophagus in the ES-IMRT panel. (Figure from Granton et al; reproduced under Creative Commons CC-BY license.)

Figure 2.. Consolidated Standards of Reporting Trials Diagram

ES-IMRT indicates esophageal-sparing intensity-modulated radiotherapy; QOL, quality of life; and RT, radiotherapy.

Figure 3.. Overall Survival

ES-IMRT indicates esophageal-sparing intensity-modulated radiotherapy.