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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Background: The aim of this study was to retrospectively analyze the effect of postoperative intensity-modulated radiotherapy (IMRT) on recurrence and survival in lymph node-positive or stage III thoracic esophageal squamous cell carcinoma (TESCC) patients, and evaluate its role in TESCC therapy. Methods: We enrolled 538 patients who underwent radical resection with (S + R) or without (S) postoperative IMRT. The median total postoperative IMRT dose was 60 Gy. The Kaplan-Meier method, log-rank test, and chi-square test were used for survival rate calculation, univariate analysis, and sites of failure analysis, respectively. Results: The 5-year overall survival (OS) and disease-free survival rates were 32.7 and 27.3%, respectively. The 5-year OS rates of lymph node-positive S and S + R patients were 28.4 and 38.8%, respectively (p < 0.001). The 5-year OS rates of stage III S and S + R patients were 24.0 and 38.0%, respectively (p = 0.001). Postoperative IMRT resulted in significantly decreased intrathoracic and supraclavicular recurrence, and obviously delayed median local recurrence and systemic metastases. Systemic metastases increased following postoperative IMRT. Conclusion: Postoperative IMRT reduces local recurrence and improves survival in lymph node-positive or stage III TESCC patients, providing a rationale for selection criteria for postoperative IMRT in TESCC.

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Protein phosphatase 1 (PP1), a major protein phosphatase important for a variety of cellular responses, is activated in response to ionizing irradiation (IR)-induced DNA damage. Here, we report that IR induces the rapid dissociation of PP1 from its regulatory subunit inhibitor-2 (I-2) and that the process requires ataxiatelangiectasia mutated (ATM), a protein kinase central to DNA damage responses. In response to IR, ATM phosphorylates I-2 on serine 43, leading to the dissociation of the PP1-I-2 complex and the activation of PP1. Furthermore, ATM-mediated I-2 phosphorylation results in the inhibition of the Aurora-B kinase, the downregulation of histone H3 serine 10 phosphorylation, and the activation of the G 2 /M checkpoint. Collectively, the results of these studies demonstrate a novel pathway that links ATM, PP1, and I-2 in the cellular response to DNA damage.Optimal cellular responses to DNA damage are mediated by protein kinases and phosphatases in order to promote survival and limit genetic instability. The ataxia-telangiectasia mutated kinase, ATM, plays a crucial role in the cellular response to DNA damage. The loss of ATM functions in humans results in progressive neurodegeneration, immunodeficiency, glucose intolerance, sterility, predisposition to lymphoblastoid malignancies, and radiation sensitivity (25). Cellular phenotypes of ATM deficiency include suboptimal activation of radiationinduced cell cycle checkpoints, increased spontaneous and DNA damage-induced chromosomal breakage and gaps, and hypersensitivity to radiation, etc. Human ATM is a 3,056-amino-acid polypeptide which shares several features with other members of the phosphatidylinositol 3-kinase-like kinase family, including a FAT (FRAP, ATR, and TRRAP) domain, a phosphatidylinositol 3-kinase domain, and a FAT carboxylterminal domain (14). ATM, like other members of this protein kinase family, phosphorylates its substrates on serines or threonines that are followed by glutamine (the SQ or TQ motif) (12,22). A number of downstream targets have been identified. These substrates include many tumor suppressors, such as p53, Brca1, and Chk2, and the functional significance of ATM phosphorylation has been studied previously. For example, in response to ionizing radiation (IR), ATM phos-

ObjectiveCombined small cell lung cancer (C-SCLC) is an uncommon subgroup of small cell lung cancer (SCLC) and few clinical data can be referred. Our study is to investigate the clinical features and prognostic factors of C-SCLC, as well as the role of multimodality treatment.MethodsBetween January 2004 and December 2012, patients with histologically diagnosed C-SCLC were retrospectively analyzed. The survivals were evaluated with the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors.ResultsOne hundred and fourteen patients were enrolled, with a median age of 59 (range: 20−79) years old. The most common combined component was squamous cell carcinoma (52.6%). Among these patients, the disease was stage I, II, III and IV in 9.6%, 19.3%, 46.5% and 24.6% of the patients, respectively. Eighty patients (70.2%) received at least two of the three modalities containing chemotherapy, radiotherapy and surgery. The median follow-up was 32.5 months. The median time of overall survival (OS) was 26.2 months. On univariate analysis, smoking (P=0.029), Karnofsky performance score (KPS) <80 (P=0.000), advanced TNM stage (P=0.000), no surgery (P=0.010), positive resection margin (P=0.000), positive lymph nodes ≥4 (P=0.000), positive lymph node ratio >10% (P=0.000) and non-multimodality treatment (P=0.004) were associated with poor OS. Multivariate analysis confirmed that smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio >10% were poor prognostic features.ConclusionsC-SCLC has a relatively early stage and good prognosis, which may due to the underestimated diagnosis in non-surgical patients. Multimodality therapy is recommended, especially for limited disease. Smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio >10% are poor prognostic factors.