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Introduction: The CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study., Methods: Patients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms., Results: The final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board., Conclusion: A randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: We sought factors associated with the development of brain metastases after treatment of small cell lung cancer (SCLC) in patients without brain involvement at diagnosis., Methods: We analyzed 293 patients with SCLC without brain metastases who received chemotherapy, thoracic radiation therapy (TRT), or both in 2001-2015. Pretreatment hematologic markers (platelet count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lactate dehydrogenase) and other clinical characteristics were evaluated for correlation with brain metastases-free survival (BMFS). Cutoffs were established with receiver operating characteristics curves. Factors significant in univariate analysis were used to build a multivariate Cox model for BMFS., Results: Median follow-up time was 14.3 months. Brain metastases developed in 115 patients (39%)-32% of those with low pretreatment platelet counts (PPC) (≤270 × 10 9 /L) and 46% of those with high PPC (>270 × 10 9 /L). Median BMFS time for all patients was 27.9 months. Two-year BMFS rates were worse for patients with high PPC (14.6% vs. 22.1% low, P = 0.009). High PPC was independently associated with inferior BMFS (P = 0.038), as were receipt of TRT <45 Gy and no prophylactic cranial irradiation (both P < 0.001)., Conclusions: High PPC was associated with increased rates of brain metastasis in patients with SCLC with no evidence of brain disease at diagnosis., (Copyright © 2018. Published by Elsevier B.V.)

Background and Purpose: Circulating lymphocytes are exquisitely sensitive to radiation exposure, even to low scattered doses which can vary drastically between radiation modalities. We compared the relative risk of radiation-induced lymphopenia between intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT) in esophageal cancer (EC) patients undergoing neoadjuvant chemoradiation therapy (nCRT)., Material and Methods: EC patients treated with IMRT and PBT were propensity matched based on key clinical variables. Treatment-associated lymphopenia was graded using CTCAE v.4.0. Using matched cohorts, univariate and multivariable multiple logistic regression was used to identify factors associated with increased risk of grade 4 lymphopenia as well as characterize their relative contributions., Results: Among the 480 patients treated with nCRT, 136 IMRT patients were propensity score matched with 136 PBT patients. In the matched groups, a greater proportion of the IMRT patients (55/136, 40.4%) developed grade 4 lymphopenia during nCRT compared with the PBT patients (24/136, 17.6%, P < 0.0001). On multivariable analysis, PBT was significantly associated with a reduction in grade 4 lymphopenia risk (odds ratio, 0.29; 95% confidence interval, 0.16-0.52; P < 0.0001)., Conclusion: PBT is associated with significant risk reduction in grade 4 lymphopenia during nCRT in esophageal cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Prophylactic cranial irradiation (PCI) has been considered standard of care for patients with limited-stage small-cell lung cancer who achieve complete response to definitive treatment after a meta-analysis revealed its favorable effects on survival. In a European trial, PCI was also shown to confer a survival advantage for patients with extensive-stage (ES) SCLC who experienced any positive response after initial chemotherapy, leading to PCI also being considered a standard treatment for these patients as well. However, a recent Japanese trial investigating PCI for patients with ES-SCLC was stopped early when an interim analysis failed to confirm a survival benefit. This finding has motivated the thoracic oncology community to rethink the role of PCI in ES-SCLC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC)., Methods: Pretreatment blood characteristics, age, sex, performance status, race, stage (M1a vs. M1b), number and location of metastases, weight loss, smoking status, chemotherapy cycles (<4 vs. ≥4), thoracic radiotherapy dose (<45 vs. ≥45 Gy), and receipt of prophylactic cranial irradiation (PCI) were evaluated in 252 patients with ES-SCLC treated in 1998-2015. Factors significant in univariate analysis were selected as covariates for a multivariate Cox model., Results: Pretreatment TLC was below normal (<1.0 × 10 3 /µL) in 58 patients (23%). Median OS time was 11.0 months and was worse for those with TLC ≤ 1.5 × 10 3 /µL (9.8 vs. 12.0 months) and pretreatment NLR > 4.0 (9.4 vs. 13.9 months). Multivariate analysis identified low TLC (hazard ratio [HR] 0.734, 95% confidence interval [CI] 0.565-0.955, P = 0.021) and high NLR (HR 1.521, 95% CI 1.172-1.976, P = 0.002) as predicting inferior survival. Age (>63 y), sex (male), performance status (≥2), chemotherapy cycles (<4), radiation dose (<45 Gy), and no PCI also predicted worse OS (P < 0.05)., Conclusions: Pretreatment TLC and NLR may be useful for stratifying patients with ES-SCLC for treatment approaches., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To compare heart and cardiac substructure radiation exposure using intensity-modulated radiotherapy (IMRT) vs. proton beam therapy (PBT) for patients with mid- to distal esophageal cancer who received chemoradiation therapy., Methods and Materials: We identified 727 esophageal cancer patients who received IMRT (n=477) or PBT (n=250) from March 2004 to December 2015. All patients were treated to 50.4Gy with IMRT or to 50.4 cobalt Gray equivalents with PBT. IMRT and PBT dose-volume histograms (DVHs) of the whole heart, atria, ventricles, and four coronary arteries were compared. For PBT patients, passive scattering proton therapy (PSPT; n=237) and intensity-modulated proton therapy (IMPT; n=13) DVHs were compared., Results: Compared with IMRT, PBT resulted in significantly lower mean heart dose (MHD) and heart V5, V10, V20, V30, and V40as well as lower radiation exposure to the four chambers and four coronary arteries. Compared with PSPT, IMPT resulted in significantly lower heart V20, V30, and V40 but not MHD or heart V5 or V10. IMPT also resulted in significantly lower radiation doses to the left atrium, right atrium, left main coronary artery, and left circumflex artery, but not the left ventricle, right ventricle, left anterior descending artery, or right coronary artery. Factors associated with lower MHD included PBT (P<0.001), smaller planning target volume (PTV; P<0.001), and gastroesophageal junction (GEJ) tumor (P<0.001). Among PBT patients, factors associated with lower MHD included IMPT (P=0.038), beam arrangement other than AP/PA (P<0.001), smaller PTV (P<0.001), and GEJ tumor (P<0.001)., Conclusions: In patients with mid- to distal esophageal cancer, PBT results in significantly lower radiation exposure to the whole heart and cardiac substructures than IMRT. Long-term studies are necessary to determine how this cardiac sparing effect impacts the development of coronary artery disease and other cardiac complications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: To assess the impact of histology on recurrence patterns and survival outcomes in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT)., Methods: We analyzed 590 consecutive EC patients who received definitive CRT from 1998 to 2014, including 182 patients (30.8%) with squamous cell carcinoma (SCC) and 408 (69.2%) with adenocarcinoma. Recurrence pattern and timing, survival, and potential prognostic factors were compared., Results: After a median follow-up time of 58.0months, the SCC group demonstrated a comparable locoregional recurrence rate (42.9% vs. 38.0%, P=0.264) but a significantly lower distant failure rate (27.5% vs. 48.0%, P<0.001) than adenocarcinoma group. No significant difference was found in overall survival or locoregional failure-free survival between groups, whereas the SCC group was associated with significantly more favorable recurrence-free survival (P=0.009) and distant metastasis-free survival (P<0.001). The adenocarcinoma group had higher hematogenous metastasis rates of bone, brain, and liver, whereas the SCC group had a marginally higher regional recurrence rate. Among patients who received salvage surgery after locoregional recurrence, no significant difference in survival was found between groups (P=0.12)., Conclusions: The patterns and sites of recurrence, survival outcomes, and prognostic factors were significantly different between esophageal SCC and adenocarcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Relative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC). We assessed whether the type of radiation therapy (RT) modality used was associated with postoperative outcomes after neoadjuvant chemoradiation (nCRT)., Patients and Methods: Contemporary data from 580 EC patients treated with nCRT at 3 academic institutions from 2007 to 2013 were reviewed. 3D conformal RT (3D), intensity modulated RT (IMRT) and proton beam therapy (PBT) were used for 214 (37%), 255 (44%), and 111 (19%) patients, respectively. Postoperative outcomes included pulmonary, GI, cardiac, wound healing complications, length of in-hospital stay (LOS), and 90-day postoperative mortality. Cox model fits, and log-rank tests both with and without Inverse Probability of treatment Weighting (IPW) were used to correct for bias due to non-randomization., Results: RT modality was significantly associated with the incidence of pulmonary, cardiac and wound complications, which also bore out on multivariate analysis. Mean LOS was also significantly associated with treatment modality (13.2days for 3D (95%CI 11.7-14.7), 11.6days for IMRT (95%CI 10.9-12.7), and 9.3days for PBT (95%CI 8.2-10.3) (p<0.0001)). The 90day postoperative mortality rates were 4.2%, 4.3%, and 0.9%, respectively, for 3D, IMRT and PBT (p=0.264)., Conclusions: Advanced RT technologies (IMRT and PBT) were associated with significantly reduced rate of postoperative complications and LOS compared to 3D, with PBT displaying the greatest benefit in a number of clinical endpoints. Ongoing prospective randomized trial will be needed to validate these results., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Prophylactic cranial irradiation (PCI) can improve overall survival (OS) and suppress brain metastases (BM) in patients with limited-stage small cell lung cancer (LS-SCLC) after complete response to primary therapy. However, PCI can be toxic. We sought to identify characteristics of patients who may not benefit from PCI., Methods: We identified 658 patients who received chemoradiotherapy at MD Anderson in 1986-2012; 364 received PCI and 294 did not. Median follow-up time was 21.2months (range 1.2-240.8months). Cox proportional hazards regression, competing-risk regression, and Kaplan-Meier analyses were used to identify factors influencing OS and BM., Results: PCI reduced risks of death [HR 0.73, 95% CI 0.61-0.88, P=0.001] and BM [HR 0.54, 95% CI 0.39-0.76, P<0.001]. Having tumors ⩾5cm increased the risk of BM [HR 1.77, 95% CI 1.22-2.55, P=0.002] but not death [HR 1.16, 95% CI 0.96-1.40, P=0.114]. Among patients ⩾70years with ⩾5-cm tumors, PCI did not improve OS [2-year rates 39.4% vs 40.9%, P=0.739]., Conclusions: PCI remains standard therapy after complete response to chemoradiotherapy for LS-SCLC. However, older patients may be at risk from comorbidity or extracranial disease. Further work is warranted to identify patients who may not benefit from PCI., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The aim of this phase I/II study was to assess the long-term clinical benefits and toxicities of proton beam therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC)., Patients and Methods: From June 2006 to September 2011, 35 patients with medically inoperable T1N0M0 (central or superior location, 12 patients) or T2-3N0M0 (any location, 23 patients) NSCLC were treated with 87.5Gy at 2.5Gy/fraction of proton therapy. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.0., Results: The median follow-up time was 83.1months (95% CI: 69.2-97.1months). For all 35 patients, the 1, 3, and 5-year overall survival rates were 85.7%, 42.9%, and 28.1%, respectively. The 5-year local recurrence-free, regional recurrence-free, and distant metastasis-free survival rates were 85.0%, 89.2%, and 54.4%, respectively. Different T stages had no effect on local and regional recurrence (p=0.499, p=1.00). However, with the increase in T stages, the distant metastasis rate increased significantly (p=0.006). The most common adverse effects were dermatitis (grade 2, 51.4%; grade 3, 2.9%) and radiation pneumonitis (grade 2, 11.4%; grade 3, 2.9%). Other grade 2 toxicities included esophagitis (2.9%), rib fracture (2.9%), heart toxicities (5.7%), and chest wall pain (2.9%)., Conclusions: According to our long-term follow-up data, proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. Systemic therapy should be considered to reduce the rate of distant metastasis in cases of T2 and T3 lesions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: To evaluate radiation modality effects on pericardial effusion (PCE), pleural effusion (PE) and survival in esophageal cancer (EC) patients., Materials and Methods: We analyzed data from 470 EC patients treated with definitive concurrent chemoradiotherapy (CRT). Bayesian semi-competing risks (SCR) regression models were fit to assess effects of radiation modality and prognostic covariates on the risks of PCE and PE, and death either with or without these preceding events. Bayesian piecewise exponential regression models were fit for overall survival, the time to PCE or death, and the time to PE or death. All models included propensity score as a covariate to correct for potential selection bias., Results: Median times to onset of PCE and PE after RT were 7.1 and 6.1months for IMRT, and 6.5 and 5.4months for 3DCRT, respectively. Compared to 3DCRT, the IMRT group had significantly lower risks of PE, PCE, and death. The respective probabilities of a patient being alive without either PCE or PE at 3-years and 5-years were 0.29 and 0.21 for IMRT compared to 0.13 and 0.08 for 3DCRT. In the SCR regression analyses, IMRT was associated with significantly lower risks of PCE (HR=0.26) and PE (HR=0.49), and greater overall survival (probability of beneficial effect (pbe)>0.99), after controlling for known clinical prognostic factors., Conclusions: IMRT reduces the incidence and postpones the onset of PCE and PE, and increases survival probability, compared to 3DCRT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We report long-term disease control, survival, and toxicity for patients with locally advanced non-small cell lung cancer prospectively treated with concurrent proton therapy and chemotherapy on a nonrandomized case-only observational study., Methods: All patients received passive-scatter proton therapy, planned with 4D-CT-based simulation; all received proton therapy concurrent with weekly chemotherapy. Endpoints were local and distant control, disease-free survival (DFS), and overall survival (OS)., Results: The 134 patients (21 stage II, 113 stage III; median age 69 years) had a median gross tumor volume (GTV) of 70 cm(3) (range, 5-753 cm(3)); 77 patients (57%) received 74 Gy(RBE), and 57 (42%) received 60-72 Gy(RBE) (range, 60-74.1 Gy(RBE)). At a median follow-up time of 4.7 years, median OS times were 40.4 months (stage II) and 30.4 months (stage III). Five-year DFS rates were 17.3% (stage II) and 18.0% (stage III). OS, DFS, and local and distant control rates at 5 years did not differ by disease stage. Age and GTV were related to OS and DFS. Toxicity was tolerable, with 1 grade 4 esophagitis and 16 grade 3 events (2 pneumonitis, 6 esophagitis, 8 dermatitis)., Conclusion: This report of outcomes after proton therapy for 134 patients indicated that this regimen produced excellent OS with tolerable toxicity., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: MicroRNAs (miRNAs) are small, highly conserved non-coding RNAs that regulate many biological processes. We sought to investigate whether three serum miRNAs related to immunity or inflammation were associated with esophagitis induced by chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC)., Material and Methods: We measured serum miR-155, miR-221 and miR-21, before and during week 1-2 of CRT for 101 NSCLC patients by real-time PCR. Associations between miRNA and severe radiation-induced esophageal toxicity (RIET) were analyzed by logistic regression., Results: We found that patients with stage IIIB-IV disease, higher mean esophagus dose or esophageal V50 had higher rates of severe RIET. Furthermore, high levels of miR-155 and miR-221 at week 1-2 of CRT were also risk factors for severe RIET (miR-155: OR=1.53, 95% CI: 1.04-2.25, P=0.03; miR-221: OR=2.07, 95% CI: 1.17-3.64, P=0.012). In addition, the fold change of miR-221 was also predictive of severe RIET (OR=1.18, 95% CI: 1.02-1.37, P=0.026). However, pretreatment miRNAs was not predictive of severe RIET., Conclusions: High serum miR-155 and miR-221 during the first 2 weeks of CRT were associated with the development of severe RIET, suggesting that these miRNAs may be useful as an early surrogate for this form of toxicity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab+chemoradiation for stage III non-small cell lung cancer., Methods: Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin + paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP)., Results: Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n = 51) or without (n= 36) EGFR IHC data, or with (n = 45) or without (n = 42) FISH data. However, patients without IHC data had worse OS (HR = 1.63, P = 0.05), worse PFS (HR = 1.88, P = 0.008), and worse TTP [HR = 1.99, P = 0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP., Conclusions: Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Radiation esophagitis (RE) represents an inflammatory reaction to radiation therapy (RT). We hypothesized that aspects of the physiologic acute phase response (APR) predicts RE., Material and Methods: We retrospectively analyzed 285 patients with non-small cell lung cancer (NSCLC) treated with definitive radiation. The primary analysis was the association of pretreatment lab values reflective of the APR with symptomatic (grade ⩾ 2) RE. Univariate and multivariate odds ratios (ORs) were calculated to test associations of clinical and pretreatment lab values with RE. Optimal cutpoints and multivariable risk stratification groupings were determined via recursive partitioning analysis., Results: Pretreatment platelet counts were higher and hemoglobin levels lower in patients who developed RE (P<0.05). Based on these two pre-treatment risk factors, an APR score was defined as 0 (no risk factors), 1 (either risk factor), or 2 (both risk factors). APR score was significantly associated with RE in both univariate (OR = 2.3 for each point, 95% confidence interval [CI] 1.5-3.4, P = 0.001) and multivariate (OR = 2.1, 95% CI 1.3-3.4, P = 0.002) analyses., Conclusions: The APR score may represent a novel metric to predict RE. However, pending validation in an independent dataset, caution is advised when interpreting these results given their retrospective and thus exploratory nature., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Options are limited for patients with intrathoracic recurrence of non-small cell lung cancer (NSCLC) who previously received radiation. We report our 5-year experience with the toxicity and efficacy of proton beam therapy (PBT) for reirradiation., Materials and Methods: Thirty-three patients underwent PBT reirradiation for intrathoracic recurrent NSCLC at a single institution. All patients had had RT for NSCLC (median initial dose 63 Gy in 33 fractions), with median interval to reirradiation of 36 months. Median reirradiation dose was 66 Gy (RBE) in 32 fractions. Toxicity was scored with CTCAE v4.0, and survival outcomes were estimated using Kaplan-Meier., Results: Thirty-one patients (94%) completed reirradiation. At a median 11 months' follow-up, 1-year rates of overall survival, progression-free survival, locoregional control, and distant metastasis-free survival were 47%, 28%, 54%, and 39%. Rates of severe (grade ≥3) toxicity were 9% esophageal, 21% pulmonary; 1 patient had grade 4 esophagitis, and 2 had grade 4 pulmonary toxicity. Nine patients experienced a second in-field failure., Conclusions: PBT is an option for treating recurrent NSCLC. However, the rates of locoregional recurrence and distant metastasis are high and the potential for toxicity significant. The risks and benefits of PBT must be carefully weighed in each case., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Previous studies have shown that increased cardiac uptake of (18)F-fluorodeoxyglucose (FDG) on positron emission tomography (PET) may be an indicator of myocardial injury after radiotherapy. We reviewed patients treated with thoracic stereotactic body radiation therapy (SBRT) and established correlations between SBRT dose and observed changes in cardiac FDG-PET uptake., Material and Methods: Retrospective analysis identified 39 patients that were treated with SBRT for lung tumors close to the heart. Patients were grouped according to whether or not they had changes in cardiac FDG-PET uptake within the planned SBRT field., Results: At a median follow-up interval of 39 months (range, 6-81 months), nine patients (23%) showed increased cardiac FDG uptake associated with the heart V₂₀. Of the 19 patients who received 20 Gy to ≥5 cm(3) of the heart, nine (47%) developed increased FDG uptake (vs. 0% for the 20 patients who received 20 Gy to <5 cm(3)) (P=0.0004), all within the 20-Gy isodose line. Patients with hypercholesterolemia prior to SBRT were also more likely to show increased cardiac FDG uptake (P=0.0190)., Conclusion: Increased FDG uptake in the heart after SBRT was observed when the 20 Gy isodose line exceeded 5 cm(3) of the heart., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Introduction: We report the long-term results of RTOG 9801, a randomized trial investigating the ability of amifostine, a radioprotector, to reduce chemoradiation-induced esophagitis., Methods: Patients with stages II and IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m2 intravenously (IV) and carboplatin area under the curve (AUC) 6 both days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m2) and carboplatin (AUC 2), with hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy BID). Patients were randomly assigned to amifostine (AM) 500 mg IV four times per week or no-AM during chemoradiotherapy. Stratification factors included age (<70 vs. ≥70 years), stage and performance status., Results: 243 patients (pts) were enrolled; 120 received AM, 123 received no-AM. Two pts on each arm were found ineligible. Overall, 85% of patients were ≤70 years; 75% had a KPS ≥90. 34% had squamous histology. With median follow-up of 96.3 months (for patients still alive), overall survival was identical (hazard ratio 1.03 (0.79-1.34), NS): five-year survival 17% in both arms. The incidence of late grade 3-5 toxicities was 16% in the AM arm and 19% in the control arm (hazard ratio 1.24 (0.66-2.32), NS). There was no significant difference between the arms regarding overall survival, disease-free survival or long-term toxicity., Conclusion: The chemoradiation regimen of carboplatin and paclitaxel produced long-term results in the multi-institutional setting comparable to other regimens. Amifostine did not appear to compromise survival. As done in RTOG 9801, more consistent reporting of long term toxicity is needed for comparison of different chemoradiation regimens., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Improved radiation delivery and planning has allowed, in some instances, for the retreatment of thoracic tumors. We investigated the dose limits of the aorta wherein grade 5 aortic toxicity was observed after reirradiation of lung tumors., Material and Methods: In a retrospective analysis, 35 patients were identified, between 1993 and 2008, who received two rounds of external beam irradiation that included the aorta in the radiation fields of both the initial and retreatment plans. We determined the maximum cumulative dose to 1 cm(3) of the aorta (the composite dose) for each patient, normalized these doses to 1.8 Gy/fraction, and corrected them for long-term tissue recovery between treatments (NIDR)., Results: The median time interval between treatments was 30 months (range, 1-185 months). The median follow-up of patients alive at analysis was 42 months (range, 14-70 months). Two of the 35 patients (6%) were identified as having grade 5 aortic toxicities. There was a 25% rate of grade 5 aortic toxicity for patients receiving composite doses ≥120.0 Gy (vs. 0% for patients receiving <120.0 Gy) (P=0.047)., Conclusions: Grade 5 aortic toxicities were observed with composite doses ≥120.0 Gy (NIDR ≥90.0 Gy) to 1cm(3) of the aorta., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We investigated the association between single nucleotide polymorphisms (SNPs) in the transforming growth factor β1 (TGFβ1) gene and the risk of radiation-induced esophageal toxicity (RE) in patients with non-small-cell lung cancer (NSCLC)., Methods and Materials: Ninety-seven NSCLC patients with available genomic DNA samples and mostly treated with intensity modulated radio(chemo)therapy from 2003 to 2006 were used as a test dataset and 101 NSCLC patients treated with 3-dimensional conformal radio(chemo)therapy from 1998 to 2002 were used as a validation set. We genotyped three SNPs of the TGFβ1 gene (rs1800469:C-509T, rs1800471:G915C, and rs1982073:T869C) by the polymerase chain reaction restriction fragment length polymorphism method., Results: In the test dataset, the CT/TT genotypes of TGFβ1 rs1800469:C-509T were associated with a statistically significant higher risk of RE grade⩾3 in univariate (P=0.026) and multivariate analysis (P=0.045) when compared with the CC genotype. These results were again observed in both univariate (P=0.045) and multivariate (P=0.023) analysis in the validation dataset., Conclusion: We found and validated that the TGFβ1 rs1800469:C-509T genotype is associated with severe RE. This response marker may be used for guiding therapy intensity in an individual patient, which would further the goal of individualized therapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: A rare and unique occurrence of radiation-induced pulmonary injury was observed outside the tangential field for early breast cancer treatment. The findings appeared to be idiopathic and were termed radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome. The goal of this study was to report and determine the incidence, analyze the characteristics of the pulmonary lesions on the images and also investigate the treatment methods., Materials and Methods: A retrospective analysis was conducted of 616 consecutive patients that underwent breast-conserving therapy (BCT) from January 1992 to December 2008. The patients were observed at least one year after radiotherapy for BCT. Radiotherapy was administered by 4 MV photons in all patients. The patients underwent chest X-rays periodically. If the BOOP syndrome was found, chest computed tomography (CT) were conducted to identify the characteristics of the pulmonary lesion outside the radiation field., Results: The incidence of the radiation-induced BOOP syndrome was 12 patients (1.9%). Six of them had fever and cough, 6 had no symptoms. The pulmonary lesions were classified into four patterns on chest CT. Progression of the pulmonary lesions observed on chest X-ray were classified into three patterns. BOOP syndrome appeared within 5.6 months after radiotherapy and completely disappeared within 12 months after its onset. Their clinical conditions were not severe and these pulmonary lesions disappeared gradually without use of steroids in our institution. There was no death caused by BOOP syndrome., Conclusions: Although the incidence of BOOP syndrome and its associated prognosis are not significant, this clinical condition must be carefully followed using diagnositic imaging in order to not over administer steroids., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To analyze the patterns of failure, the toxicity profile, and the factors influencing efficacy of stereotactic body radiation (SBRT) for early-stage non-small-cell lung cancer (NSCLC)., Methods and Materials: A search was based on PubMed electronic databases. All searches were conducted in May, 2009., Results: The local control ranged from 80% to 100% in most studies with adequate isocentric or peripheral biologically effective dose (BED). Recurrences were associated with increased tumor size. The main pattern of failure after SBRT was distant metastasis. Grades 3-5 toxicity occurred mostly in centrally located tumors, and adjuvant chemotherapy may further decrease all recurrences; possibly translating to a survival benefit in large or centrally located tumors where high BED cannot be safely reached., Conclusion: SBRT is an excellent treatment option for early-stage, and mostly medically inoperable, NSCLC. BED at both the isocenter and the tumor periphery is very important for optimal tumor control; higher doses are required for large (T2) lesions; SBRT for centrally located tumors can be feasible with a much less aggressive dose regimen than 60-66Gy/3 fractions and adjacent critical structures excluded from the target volume; chemotherapy may optimize the clinical outcome in large or centrally located lesions., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To identify clinical risk factors and dose-volume thresholds for treatment-related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC)., Methods and Materials: Data were retrospectively collected from patients with inoperable NSCLC treated with radiotherapy with or without chemotherapy. TRP was graded according to Common Terminology Criteria for Adverse Events, version 3.0, with time to grade > or = 3 TRP calculated from start of radiotherapy. Clinical factors and dose-volume parameters were analyzed for their association with risk of TRP., Results: Data from 576 patients (75% with stage III NSCLC) were included in this study. The Kaplan-Meier estimate of the incidence of grade > or = 3 TRP at 12 months was 22%. An analysis of dose-volume parameters identified a threshold dose-volume histogram (DVH) curve defined by V(20) < or = 25%, V(25) < or = 20%, V(35) < or = 15%, and V(50) < or = 10%. Patients with lung DVHs satisfying these constraints had only 2% incidence of grade > or = 3 TRP. Smoking status was the only clinical factor that affected the risk of TRP independent of dosimetric factors., Conclusions: The risk of TRP varied significantly, depending on radiation dose-volume parameters and patient smoking status. Further studies are needed to identify biological basis of smoking effect and methods to reduce the incidence of TRP.

Purpose: To quantify the internal motion margin requirements for radiotherapy of tumors near the gastroesophageal junction (GEJ)., Methods and Materials: Four-dimensional computed tomography (4DCT) scans were obtained for 25 patients with primary tumors located near the GEJ. The gross tumor volume (GTV) was manually contoured on the exhale-phase image from the 4DCT image set. A deformable image registration method was used to automatically propagate the contours to other phases of the 4DCT images. To quantify target motion, we measured the displacement of the GTV centroid and the variations in the target boundary and volume. Internal margins were calculated in the lateral (RL), anterior-posterior (AP), and superior-inferior (SI) directions., Results: The mean+/-standard deviation peak-to-peak GTV centroid motion was 0.39+/-0.27cm (range, 0.04-1.09cm) in the RL, 0.38+/-0.23cm (range, 0.10-0.94cm) in the AP, and 0.87+/-0.47cm (range, 0.43-2.63cm) in the SI directions, respectively. On average, the internal target volume was 72% (range, 9-172%) larger than the GTV defined on a single-phase CT image. Variations in tumor boundaries due to tissue motion and deformation suggested asymmetric margins: 1.0cm left [toward the stomach], 0.8cm right, 1.1cm anterior, 0.6cm posterior, 1.0cm superior (toward the distal esophagus), and 1.6cm inferior (toward the stomach)., Conclusion: Because tumors near the GEJ are subject to a marked but asymmetric amount of respiratory-induced intrafractional tumor motion, the use of asymmetric internal margins may be beneficial.

Background and Purpose: To evaluate the feasibility whether intensity-modulated radiotherapy (IMRT) can be used to reduce doses to normal lung than three-dimensional conformal radiotherapy (3 DCRT) in treating distal esophageal malignancies., Patients and Methods: Ten patient cases with cancer of the distal esophagus were selected for a retrospective treatment-planning study. IMRT plans using four, seven, and nine beams (4B, 7B, and 9B) were developed for each patient and compared with the 3 DCRT plan used clinically. IMRT and 3 DCRT plans were evaluated with respect to PTV coverage and dose-volumes to irradiated normal structures, with statistical comparison made between the two types of plans using the Wilcoxon matched-pair signed-rank test., Results: IMRT plans (4B, 7B, 9B) reduced total lung volume treated above 10 Gy (V(10)), 20 Gy (V(20)), mean lung dose (MLD), biological effective volume (V(eff)), and lung integral dose (P<0.05). The median absolute improvement with IMRT over 3DCRT was approximately 10% for V(10), 5% for V(20), and 2.5 Gy for MLD. IMRT improved the PTV heterogeneity (P<0.05), yet conformity was better with 7B-9B IMRT plans. No clinically meaningful differences were observed with respect to the irradiated volumes of spinal cord, heart, liver, or total body integral doses., Conclusions: Dose-volume of exposed normal lung can be reduced with IMRT, though clinical investigations are warranted to assess IMRT treatment outcome of esophagus cancers.

To determine the influence of adjuvant therapy on the risk of DID following resection of NSCLC, we compared the actuarial rate of non-cancer related deaths of patients who had been entered in Eastern Cooperative Oncology Group E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIA NSCLC) to the actuarial death rate of age and gender matched controls. Following surgery, patients were randomized to receive either PORT (5040 cGy in 28 daily fractions) or CPORT (PORT plus four cycles of cisplatin (60 mg/m2, day 1) and etoposide (120 mg/m2, days 1-3) administered concurrently). The study accrued 488 patients, 242 to the PORT only arm and 246 to the CPORT arm. The overall 4 years actuarial rate of DID for the two arms combined, with a median follow-up of 82 months, was 12.9%, not significantly different from the 10.1% expected rate of DID, based on mortality rates for age and gender matched controls derived from US vital statistics and corrected for smoking status (p=0.16). Survival distributions with regard to DID did not differ between the two treatment arms (p=0.96). DID increased with age (treated as a continuous variable, p<0.01), but was not affected by histology, side of chest irradiated, type of surgery, FEV1 or weight loss in the previous 6 months. The risk of DID following resection of stages II and IIIA NSCLC is not increased in patients who received PORT or CPORT.

Background: In LD-SCLC, combined modality therapy has emerged as the standard of practice in good performance status (PS) patients (pts). Pignon's meta-analysis [N Engl J Med 1992;327:1618-24] showed that combination chemotherapy (CT) and thoracic radiation (XRT) in LD-SCLC yielded an absolute 5.4% increase in 3-year survival versus chemotherapy alone. Concurrent chemoradiation upfront has generated the highest survival rates [Murray. J Clin Oncol 1993;11:336-44; Jeremic. J Clin Oncol 1996;15:893-900; Takada. J Clin Oncol 2002;20:3054-60]. In stage III NSCLC, multiple studies have shown therapeutic superiority for combination chemotherapy and XRT versus RT alone; and recent literature suggests a therapeutic advantage for concurrent chemoradiation versus chemotherapy followed by XRT [Curran. ASCO 2000;19:484a; Furuse. JCO 1999;17:2692-9; Zatloukal. ASCO 2002;A-1159]. Data are less secure regarding the role of chemotherapy in stage I and II NSCLC., Material and Methods: A stratified two-step cluster sampling technique was used for data collection. Five hundred and forty-one individuals diagnosed between 1998 and 1999 with lung cancer, either LD-SCLC or stages I-III NSCLC were sampled from 58 institutions featuring radiotherapy facilities, giving a weighted sample size (wss) of 42,335 patients. All pts had Karnofski performance status (KPS) >or=60. We determined the percentage who received chemotherapy; the nature of chemotherapy and its timing with respect to XRT. SUDAAN statistical software was used to allow the incorporation of the design elements and weights to reflect the relative contribution of each institution and each patient in the analysis, Results: Of 72 (wss=6138) pts with LD-SCLC, 100% received XRT and 95% received chemotherapy (CT); 66% received concurrent (con) CT and XRT, of whom 29% also received CT pre XRT; 22% received CT post XRT as well, and 23% received both: 63% received sequential CT-->XRT+/-con CT; and 38% received some CT after XRT. Fifty-two percent received cisplatin (DDP), and 38% received carboplatin (CBDCA); 73% received etoposide (VP-16), while 10% received paclitaxel. Of 469 pts (wss=36,197) with NSCLC, 52% received CT, including 30% with stage I disease, 48% with stage II NSCLC, 60% with stage III NSCLC, and 50% with unknown stage. Thirty-nine percent received sequential CT-->XRT+/-CT, of whom 49% received CT pre XRT only. Seventy-four percent received con CT and XRT; and 27% received posterior CT, of whom 84% also received con CT/XRT. Forty-five received some CT in the pre-op setting and 15% in the post-op setting. Twelve percent received DDP-based therapy, while only 13% and 7% received VP-16 or vincas, respectively; 67% received CBDCA. Seventy-two percent received taxanes, of whom 96% received paclitaxel. Gemcitabine was administered to 3% of NSCLC pts., Conclusions: Combined modality therapy is typically employed in the therapy of LD-SCLC and LA-NSCLC. The majority of those treated for SCLC receive concurrent CT/XRT, while nearly 3/4 of those treated with CT and XRT for LA-NSCLC received concurrent CT/XRT. Current practice in the US generally matches evidence-based literature, although a significant percentage of practitioners substitute CBDCA for DDP in both venues and use paclitaxel in lieu of vincas or etoposide in NSCLC.

Purpose: To evaluate tumor resectability after induction chemotherapy and to determine disease-free and overall survival rates of patients with locally advanced unresectable thymoma that received a multimodal treatment regimen., Patients and Methods: Twenty-two patients (9 men, 13 women) with histologically confirmed invasive thymoma were treated with a multidisciplinary regimen consisting of three courses of induction chemotherapy, surgical resection, and radiation therapy, followed by three courses of consolidation chemotherapy. The median age was 47 years (range, 25-70). Eleven patients had stage III disease, 10 patients, stage IVA, and one patient, IVB. The most common histologic type was lymphocytic. Induction chemotherapy consisted of 500 mg/m(2) of cyclophosphamide on day 1; doxorubicin (20 mg/m(2) per day) on days 1-3 via continuous infusion (a total of 60 mg/m(2)); cisplatin (30 mg/m(2) per day) on days 1-3 (a total of 90 mg/m(2)); and prednisone (100 mg per day) on days 1-5. This cycle was repeated three times at 3-4-week intervals. Patients then underwent surgery for tumor resection and received radiotherapy. Consolidation chemotherapy given at 80% of the induction chemotherapy doses of cyclophosphamide, doxorubicin, and cisplatin and 100% of the dose of prednisone was then repeated every 3-4 weeks for a total of three courses., Results: Induction chemotherapy produced major responses in 17 (77%) of the 22 patients including 3 (14%) complete responses (CR) and 14 (63%) partial responses (PR). Twenty-one patients underwent surgical exploration: 16 (76%) had complete resection and 5 (24%) had incomplete resection; one patient refused surgery. All 22 patients received radiation therapy. Nineteen of 22 patients completed the planned therapy, and all but one had completed consolidation chemotherapy at the time of analysis. With a median follow-up time of 50.3 months, 18 of the 19 patients who completed the multidisciplinary approach were disease-free. Of the 22 patients originally registered, 20 were alive at the time of analysis (one patient died of endocarditis, and one died of recurrent disease). The overall survival rate was 95% at 5 years (95% confidence interval (CI), 0.87-1.0) and 79% at 7 years (95% CI, 0.55-1.0). The progression-free survival rates were 77% at 5 years (95% CI, 0.58-1.0) and 77% at 7 years (95% CI, 0.58-1.0). The major side effect from induction and consolidation chemotherapy was myelosuppression. Nine patients experienced grade III/IV neutropenia, which included neutropenic fever in two patients, and grade III thrombocytopenia in two patients. The most common nonhematologic side effects were fatigue, nausea and vomiting, and decreased appetite. One patient experienced acute respiratory distress syndrome after surgical resection and required a prolonged hospitalization. No patients developed cardiac toxic effects, and no surgical mortality occurred., Conclusions: The use of induction chemotherapy to optimize surgical resectability of thymoma followed by radiation therapy and consolidation chemotherapy lead to good control of residual disease and high overall survival rates. We believe that this combined multidisciplinary approach prolongs lives and may cure locally advanced unresectable malignant thymomas. Future prospective multi-institutional studies are needed to further verify or define the best treatment for this patient population.

The occurrence of second primary tumors (SPTs) following adjuvant therapy for resected stages II and IIIa non-small cell lung cancer (NSCLC) was investigated. Data regarding SPTs were prospectively collected in all patients accrued to Eastern Cooperative Group Oncology E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC). Four hundred eighty-eight patients were accrued to the study, 242 to the RT arm and 246 to the CRT arm. Median follow-up was 73 months. Thirty patients (6.1%) developed 33 SPTs, 20 in the RT arm and ten in the CRT arm. Ten SPTs occurred within the upper aerodigestive tract, six in the RT arm and four in the CRT arm. Twenty-three SPTs occurred in other organs, 17 in the RT arm and six in the CRT arm. Median time to detection of a SPT for those patients randomized to RT and CRT was 43 and 36 months, respectively. The incidence of SPTs was 1.8% per patient-year of follow-up. Excluding skin tumors, the relative risk of death following diagnosis of a SPT for patients randomized to the CRT arm as compared with those randomized to RT alone was 2.26 (95% confidence interval, 0.78-5.58, P=0.12). Patients are at risk for developing a SPT following resection of stages II and IIIa NSCLC. The majority of SPTs occur outside the aerodigestive tract. Following development of a non-skin SPT, the survival difference between patients who had received adjuvant CRT and those treated with adjuvant RT alone was not significant.

This study evaluates the influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer (NSCLC). The Eastern Cooperative Oncology Group conducted a randomized prospective trial of adjuvant therapy in patients with completely resected stages II and IIIa NSCLC. A laboratory correlative study assessed the prevalence and prognostic significance of p53 and K-ras mutations. Patients were randomized to receive either radiotherapy (RT) alone or four cycles of cisplatin and VP-16 administered concurrently with radiotherapy (CRT). Median survival was 35 months for the 285 men and 41 months for the 203 women enrolled in the study (P = 0.12). The relative risk (RR) of death for men vs women was 1.19 (95% confidence interval [CI], 0.95-1.49). Median survival of the 147 men and 95 women randomized to the RT arm was 39 months each (P = 0.35). Median survival of the 138 men and 108 women randomized to the CRT arm was 30 and 42 months, respectively (P = 0.18). Disease recurrence patterns were similar between the genders. Univariate and multivariate analyses demonstrated improved survival for women with tumors of non-squamous histology (P < 0.01). The distribution of p53 and K-ras mutations was similar between the genders and had no influence on survival. Gender does not influence survival following adjuvant RT or CRT administered to patients with completely resected stages II and IIIa NSCLC. However, women with non-squamous histology have increased survival when compared to men., (Copyright 2002 Elsevier Science Ireland Ltd.)

The management of advanced non-small cell lung cancer (NSCLC) is rapidly evolving. Advances in combined chemo-radiation therapy have led to improvements in patient survival which are statistically significant, but most patients still succumb to their disease. New chemotherapeutic agents, such as taxanes (paclitaxel, docetaxel), topoisomerase inhibitors (topotecan, irinotecan), and novel analogs (gemcitabine, vinorelbine), may offer the promise of improved outcome, but have not yet been tested in phase III trials. Molecular therapeutics, such as gene therapy, drugs that target specific oncogene activation (such as Ki-ras inactivation by farnesyl transferase inhibitors), and hypoxic cell toxins (such as tirapazamine), are in clinical trials. The optimum use of these agents awaits more rapid and widespread molecular diagnostics. Finally, technological advances in radiotherapy will allow higher tumor doses, while minimizing doses to dose-limiting normal structures, such as the esophagus, normal lung and heart. We describe a move towards molecular strategies, both for therapy and diagnostics, that may result in more effective treatment. While the outcome for patients with advanced non-small cell lung carcinoma is still poor, new agents are being developed rapidly and offer the hope of improved survival.

Our previously reported randomized study of patients with untreated, potentially resectable clinical stage IIIA non-small-cell lung cancer found that patients treated with perioperative chemotherapy and surgery had a significant increase in median survival compared to patients treated with surgery alone. We have now re-analyzed the results of the study with a median time from random allocation to analysis for all patients of 82 months. The increase in survival conferred by perioperative chemotherapy was maintained during the period of extended observation.

We conducted a prospective study of cognitive function in patients with small cell lung cancer (SCLC). A previous study had shown SCLC patients to have deficits in memory, frontal lobe executive functioning, and motor skills before they received prophylactic cranial irradiation (PCI). This study was performed to determine whether these deficits were related to chemoradiation treatment. We evaluated two groups of patients: one newly diagnosed and untreated, the other post-chemoradiation and before PCI. Strict eligibility criteria were used to minimize any preexisting factors that might influence cognitive functioning. Results showed that patients with SCLC have cognitive deficits before receiving chemoradiation, specifically on tests of verbal memory, frontal lobe executive functions, and motor coordination. There was no difference between the treated and untreated patients on any test. Etiologic considerations currently under study include paraneoplastic phenomena.

Prospective trials exploring questions of dose intensity for control of the local-regional tumor have been conducted by the Radiation Therapy Oncology Group for 20 years. Early studies established radiation therapy with a total dose of 60 Gy in 30 fractions as standard (STD) for unresectable non-small cell carcinomas of the lung (NSCCL). Hyperfractionated radiation therapy (HFX) with 1.2 Gy twice daily permitted higher total doses without increased normal tissue effects and led to comparison of STD vs. HFX (total dose 69.6 Gy in 58 fractions). Induction chemotherapy followed by STD, induction followed by concurrent chemotherapy and STD, and concurrent chemotherapy and HFX, have been explored in successive trials. Preliminary results of STD combined with chemotherapy suggest that increases in dose intensity increase local-regional control and survival. Confirmatory trials of increased dose intensity by combining chemotherapy with STD and HFX have been completed or are progressing.

Unlabelled: In a major study that showed a treatment advantage for induction chemotherapy followed by radiation therapy (CALGB 8433), there was a significantly (P = 0.02) lower proportion of patients dying within 105 days of registration in the chemotherapy/radiation arm than the radiation therapy arm; without this difference, the overall survival was marginally better (P = 0.059) for the chemotherapy/radiation group. A retrospective analysis of RTOG trials sought explanations for the phenomenon., Materials and Methods: Patients who fit the CALGB eligibility criteria and received radiation therapy alone in four prospective trials of the RTOG conducted between 1983 and 1989 were analyzed to determine factors that distinguished patients dying within 105 days from longer survivors. Two were trials of altered fractionation and two used standard fractionation. Of 683 patients identified, 107 (15.7%) died within 105 days after registration. The log linear model was used to evaluate relationships between death within 105 days and known prognostic factors. Karnofsky performance status (KPS), < 90 vs. > or = 90, was the only factor significantly related to death within 105 days (P = 0.0052). A Cox model with the same factors plus fractionation and total dose found KPS and T-stage associated with overall survival (P = 0.0005 and 0.025, respectively). The choice of the hyperfractionation arm (HFX) for Phase III study (69.6 Gy at 1.2 Gy b.i.d.) was based in part on comparison with standard fractionation (STD) from a concurrent RTOG protocol, 8321. Review of early deaths showed that this HFX arm had a lower proportion of patients dying within 105 days (7.9%) than STD in 8321 (21.0%).(ABSTRACT TRUNCATED AT 250 WORDS)