Effect of Postoperative Radiotherapy for Patients With pIIIA-N2 Non–Small Cell Lung Cancer After Complete Resection and Adjuvant Chemotherapy

Abstract

IMPORTANCEThe role of postoperative radiotherapy (PORT) has not been well defined in resected pIIIA-N2 non-small cell lung cancer (NSCLC).OBJECTIVE To evaluate the effect of PORT using modern techniques on survival and safety in patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS The PORT-C randomized clinical trial was conducted in 394 patients with pIIIA-N2 NSCLC treated with complete resection and 4 cycles of platinum-based chemotherapy between January 2009 and December 2017. Data were analyzed between March 2019 and December 2020. INTERVENTIONS Patients were randomized equally into the PORT arm (n = 202) or the observation arm (n = 192). The total dose of PORT was 50 Gy. MAIN OUTCOMES AND MEASURESThe primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival, and toxic effects.RESULTS In total, 394 patients were enrolled and 364 were eligible, with a median (range) age of 55 (25-70) years. There were 202 (55.5%) male and 162 (44.5%) female patients. The median follow-up was 46.0 (95% CI, 41.9-51.4) months, and 230 DFS events were reported. There were 184 patients in the PORT arm and 180 patients in the observation arm. The 3-year DFS rates were 40.5% with PORT vs 32.7% with observation (median, 22.1 vs 18.6 months), and the difference in DFS was not statistically significant without adjustment (hazard ratio [HR], 0.84; 95% CI, 0.65-1.09; P = .20), though it was significant with preplanned yet exploratory analysis (stratified analysis by the number of detected lymph nodes and positive lymph nodes, HR, 0.75; log-rank P = .04). The 3-year OS rates were 78.3% vs 82.8% (HR, 1.02; P = .93), and LRFS was 66.5% vs 59.7% (HR, 0.71; 95% CI, 0.51-0.97; P = .03), respectively. For 310 per-protocol patients (140 with PORT and 170 with observation), PORT significantly improved DFS (42.8% vs 30.6%; HR, 0.75; 95% CI, 0.57-1.00; P = .05) but not OS (HR, 0.83; 95% CI, 0.53-1.30; P = .41). The 3-year local recurrence only rates were 9.5% and 18.3% in the 2 arms, respectively (Fine-Gray HR, 0.55; Gray test P = .04). No radiotherapy-related grade 4 or 5 adverse event was observed. CONCLUSIONS AND RELEVANCEIn this phase 3 randomized clinical trial of patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy, PORT did not improve DFS. Further studies exploring patients who might best benefit from PORT are needed.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00880971

Effects of postoperative radiotherapy on cardiovascular-pulmonary disease mortality in patients with stage IIIA-N2 resected NSCLC: analysis of the SEER database

“…The definitive role of PORT in cardiopulmonary toxicity in pIIIA-N2 NSCLC remains controversial. In the recent PORT-C trial [ 12 ], no RT-induced grade 4 or 5 adverse events were observed. A total of 97 deaths (26.6%) occurred; among the 8 noncancer-related deaths, only 3 (3.1%) were due to cardiopulmonary disease [ 12 ].…”

“…In the recent PORT-C trial [ 12 ], no RT-induced grade 4 or 5 adverse events were observed. A total of 97 deaths (26.6%) occurred; among the 8 noncancer-related deaths, only 3 (3.1%) were due to cardiopulmonary disease [ 12 ]. The findings of the Lung ART study differed from the previous abovementioned study [ 9 ], and cardiopulmonary-specific mortality was observed in 2 (2.0%) patients in the Non-PORT cohort and 16 (16.2%) patients in the PORT cohort, respectively.…”

“…The lung V20 was limited to less than 31% in patients after lobectomy and 22% after pneumonectomy, heart V30 less than 35% [ 9 ]. Another explanation for the low rate of cardiopulmonary-specific mortality in the PORT-C study is the markedly tighter dose restrictions for normal healthy tissues, especially the lungs and heart [ 12 ]. More effective modern RT techniques might have attenuated this risk.…”

“…Previous studies have shown that postoperative radiotherapy (PORT) in patients with stage IIIA-N2 NSCLC reduces the risk of local recurrence and thus is an appealing means of improving outcomes in NSCLC patients [ 10 , 11 ], but whether PORT can bring overall survival (OS) benefits to those patients remains controversial [ 9 – 12 ]. Several retrospective studies and meta-analyses have shown the survival benefits of PORT [ 5 , 10 , 11 , 13 – 15 ].…”

“…Several retrospective studies and meta-analyses have shown the survival benefits of PORT [ 5 , 10 , 11 , 13 – 15 ]. However, recent multi-institutional randomized phase III trials (Lung ART and PORT-C) indicated that PORT failed to improve disease‐free survival and OS [ 9 , 12 ]. In the Lung ART study, the incidence of grade 3–5 late cardiopulmonary toxicity was 20% versus 7.7%, and the cardiopulmonary specific mortality was 16.2% versus 2% in the PORT versus Non‐PORT cohort, respectively [ 9 ].…”