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

Purpose To compare three-dimensional (3D) and 4D computed tomography (CT)– based treatment plans for proton therapy or intensity-modulated radiation therapy (IMRT) for esophageal cancer in terms of doses to the lung, heart, and spinal cord and variations in target coverage and normal tissue sparing. Materials and Methods IMRT and proton plans for 15 patients with distal esophageal cancer were designed from the 3D average CT scans and then recalculated on 10 4D CT data sets. Dosimetric data were compared for tumor coverage and normal tissue sparing. Results Compared with IMRT, median lung volumes exposed to 5,10, and 20 Gy and mean lung dose were reduced by 35.6%, 20.5%,5.8%, and 5.1 Gy for a two-beam proton plan and by 17.4%,8.4%,5%, and 2.9 Gy for a three-beam proton plan. The greater lung sparing in the two-beam proton plan was achieved at the expense of less conformity to the target (conformity index CI=1.99) and greater irradiation of the heart (heart-V40=41.8%) compared with the IMRT plan(CI=1.55, heart-V40=35.7%) or the three-beam proton plan (CI=1.46, heart-V40=27.7%). Target coverage differed by more than 2% between the 3D and 4D plans for patients with substantial diaphragm motion in the three-beam proton and IMRT plans. The difference in spinal cord maximum dose between 3D and 4D plans could exceed 5 Gy for the proton plans partly owing to variations in stomach gas-filling. Conclusions Proton therapy provided significantly better sparing of lung than did IMRT. Diaphragm motion and stomach gas-filling must be considered in evaluating target coverage and cord doses.

Purpose-Proton doses are sensitive to intra-and interfractional anatomic changes. We analyzed the effects of interfractional anatomic changes in doses to lung tumors treated with proton therapy.Methods and Materials-Weekly four-dimensional computed tomography (4D-CT) scans were acquired for 8 patients with mobile Stage III non-small cell lung cancer who were actually treated with intensity-modulated photon radiotherapy. A conformal proton therapy passive scattering plan was designed for each patient. Dose distributions were recalculated at endinspiration and end-expiration breathing phases on each weekly 4D-CT data set using the same plans with alignment based on bone registration.Results-Clinical target volume (CTV) coverage was compromised (from 99% to 90.9%) in 1 patient because of anatomic changes and motion pattern variation. For the rest of the patients, the mean CTV coverage on the repeated weekly 4D-CT data sets was 98.4%, compared with 99% for the original plans. For all 8 patients, however, a mean 4% increase in the volume of the contralateral lung receiving a dose of at least 5 Gy (V5) and a mean 4.4-Gy increase in the spinal cord maximum dose was observed in the repeated 4D-CT data sets. A strong correlation between the CTV density change resulting from tumor shrinkage or anatomic variations and mean contralateral lung dose was observed.Conclusions-Adaptive re-planning during proton therapy may be indicated in selected patients with non-small cell lung cancer. For most patients, however, CTV coverage is adequate if tumor motion is taken into consideration in the original simulation and planning processes.

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