Establishing quality indicators for neck dissection: Correlating the number of lymph nodes with oncologic outcomes (NRG Oncology RTOG 9501 and RTOG 0234).

BACKGROUND: Prospective quality metrics for neck dissection have not been established for patients with head and neck squamous cell carcinoma. The purpose of this study was to investigate the association between lymph node counts from neck dissection, local-regional recurrence, and overall survival. METHODS: The number of lymph nodes counted from neck dissection in patients treated in 2 NRG Oncology trials (Radiation Therapy Oncology Group [RTOG] 9501 and RTOG 0234) was evaluated for its prognostic impact on overall survival with a multivariate Cox model adjusted for demographic, tumor, and lymph node data and stratified by the postoperative treatment group. RESULTS: Five hundred seventy-two patients were analyzed at a median follow-up of 8 years. Ninety-eight percent of the patients were pathologically N+. The median numbers of lymph nodes recorded on the left and right sides were 24 and 25, respectively. The identification of fewer than 18 nodes was associated with worse overall survival in comparison with 18 or more nodes (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.09-1.74; P = .007). The difference appeared to be driven by local-regional failure (HR, 1.46; 95% CI, 1.02-2.08; P = .04) but not by distant metastases (HR, 1.08; 95% CI, 0.77-1.53; P = .65). When the analysis was limited to NRG Oncology RTOG 0234 patients, adding the p16 status to the model did not affect the HR for dissected nodes, and the effect of nodes did not differ with the p16 status. CONCLUSIONS: The removal and identification of 18 or more lymph nodes was associated with improved overall survival and lower rates of local-regional failure, and this should be further evaluated as a measure of quality in neck dissections for mucosal squamous cell carcinoma. Cancer 2016;122:3464-71. © 2016 American Cancer Society.

A phase I dose escalation trial of MAGE-A3- and HPV16-specific peptide immunomodulatory vaccines in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN).

BACKGROUND: We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. METHODS: Three dose levels (500, 1,000, and 1,500 µg) of GL-0810 or GL-0817 with adjuvants Montanide (1.2 ml) and GM-CSF (100 µg/m2) were administered subcutaneously q2 weeks for a total of four vaccinations in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. RESULTS: Nine and seven patients were enrolled in the HPV16 and MAGE-A3 cohorts, respectively. No dose-limiting toxicities were observed, and toxicity was predominantly local and grade 1 (erythema, pain, and itching at the injection site). In those patients who received all four vaccinations, 80 % (4/5) of the HPV16 cohort and 67 % (4/6) of the MAGE-A3 cohort developed antigen-specific T cell and antibody responses to the vaccine. Significant concordance between T cell and antibody responses was observed for both groups. No clear dose-response correlation was seen. All patients progressed by RECIST at first repeat imaging, except for one patient in the MAGE-A3 500 µg cohort who had stable disease for 10.5 months. The median PFS and OS for the MAGE-A3 cohorts were 79 and 183 days, respectively, and for the HPV16 cohort 80 and 196 days, respectively. CONCLUSIONS: GL-0810 and GL-0817 were well tolerated in patients with RM-SCCHN with T cell and antibody responses observed in the majority of patients who received all four vaccinations.

Single-fraction radiotherapy versus multifraction radiotherapy for palliation of painful vertebral bone metastases-equivalent efficacy, less toxicity, more convenient: a subset analysis of Radiation Therapy Oncology Group trial 97-14.

BACKGROUND: The Radiation Therapy Oncology Group (RTOG) trial 97-14 revealed no difference between radiation delivered for painful bone metastases at a dose of 8 gray (Gy) in 1 fraction (single-fraction radiotherapy [SFRT]) and 30 Gy in 10 fractions (multifraction radiotherapy [MFRT]) in pain relief or narcotic use 3 months after randomization. SFRT for painful vertebral bone metastases (PVBM) has not been well accepted, possibly because of concerns about efficacy and toxicity. In the current study, the authors evaluated the subset of patients that was treated specifically for patients with PVBM. METHODS: PVBM included the cervical, thoracic, and/or lumbar spine regions. Among patients with PVBM, differences in retreatment rates and in pain relief, narcotic use, and toxicity 3 months after randomization were evaluated. RESULTS: Of 909 eligible patients, 235 (26%) had PVBM. Patients with and without PVBM differed in terms of the percentage of men (55% vs 47%, respectively; P = .03) and the proportion of patients with multiple painful sites (57% vs 38%, respectively; P < .01). Among those with PVBM, more patients who received MFRT had multiple sites treated (65% vs 49% for MFRT vs SFRT, respectively; P = .02). There were no statistically significant treatment differences in terms of pain relief (62% vs 70% for MFRT vs SFRT, respectively; P = .59) or freedom from narcotic use (24% vs 27%, respectively; P = .76) at 3 months. Significant differences in acute grade 2 through 4 toxicity (20% vs 10% for MFRT vs SFRT, respectively; P = .01) and acute grade 2 through 4 gastrointestinal toxicity (14% vs 6%, respectively; P = .01) were observed at 3 months, with lower toxicities seen in the patients treated with SFRT. Late toxicity was rare. No myelopathy was recorded. SFRT produced higher 3-year retreatment rates (5% vs 15%; P = .01). CONCLUSIONS: Results for the subset of patients with PVBM in the RTOG 94-17 randomized controlled trial were comparable to those for the entire population. SFRT produced less acute toxicity and a higher rate of retreatment than MFRT. SFRT and MFRT resulted in comparable pain relief and narcotic use at 3 months.

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials.

Importance: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. Objective: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). Design, Setting, and Participants: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. Exposures: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. Main Outcomes and Measures: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. Results: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). Conclusions and Relevance: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

Prevalence and correlates of symptoms and uncertainty in illness among head and neck cancer patients receiving definitive radiation with or without chemotherapy.

PURPOSE: This repeated measures, prospective study was designed to explore and describe symptom dimensions, depressive symptoms, and uncertainty in newly diagnosed oropharyngeal and laryngeal cancer patients during and 1 month following treatment. MATERIALS AND METHODS: A non-probability sample of 21 oropharyngeal and laryngeal cancer patients receiving definitive radiation completed the Memorial Symptom Assessment Scale, Beck Depression Inventory, and Mishel's Uncertainty in Illness Scale at treatment initiation, and at 5, 9, and 12 weeks. RESULTS: A common pattern of 11 symptoms, which changed as treatment progressed, was problematic for patients. Physical symptoms increased by 50% at week 5 and 9. Depression was experienced by 24% of patients. Uncertainty was found to be high at all time points and unexpectedly remained unchanged over time (p = 0.73). Positive correlations (p < 0.05) were found among number of symptoms, symptom distress, and depressive symptoms. Uncertainty was correlated (p < 0.05) statistically only to symptom distress. CONCLUSION: This study is the first to identify uncertainty in illness among oropharyngeal and laryngeal cancer patients and found it to be higher than for other cancer populations. Findings provide insights into the uncertainty of living through treatment and provide information for patient care. The consistent pattern of high levels of uncertainty during and 1 month after treatment suggests that the uncertainty related to acute illness could extend into chronic uncertainty which may interfere with a cancer survivor's adaption to daily living after treatment. Further research is needed to investigate other variables that influence uncertainty during treatment as well as 1 to 6 months after treatment for head and neck cancer.

Risk groups of laryngeal cancer treated with chemoradiation according to nomogram scores - A pooled analysis of RTOG 0129 and 0522.

OBJECTIVES: To develop nomograms predicting overall survival (OS), freedom from locoregional recurrence (FFLR), and freedom from distant metastasis (FFDM) for patients receiving chemoradiation for laryngeal squamous cell carcinoma (LSCC). MATERIAL AND METHODS: Clinical and treatment data for patients with LSCC enrolled on NRG Oncology/RTOG 0129 and 0522 were extracted from the RTOG database. The dataset was partitioned into 70% training and 30% independent validation datasets. Significant predictors of OS, FFLR, and FFDM were obtained using univariate analysis on the training dataset. Nomograms were built using multivariate analysis with four a priori variables (age, gender, T-stage, and N-stage) and significant predictors from the univariate analyses. These nomograms were internally and externally validated using c-statistics (c) on the training and validation datasets, respectively. RESULTS: The OS nomogram included age, gender, T stage, N stage, and number of cisplatin cycles. The FFLR nomogram included age, gender, T-stage, N-stage, and time-equivalent biologically effective dose. The FFDM nomogram included age, gender, N-stage, and number of cisplatin cycles. Internal validation of the OS nomogram, FFLR nomogram, and FFDM nomogram yielded c = 0.66, c = 0.66 and c = 0.73, respectively. External validation of these nomograms yielded c = 0.59, c = 0.70, and c = 0.73, respectively. Using nomogram score cutoffs, three risk groups were separated for each outcome. CONCLUSIONS: We have developed and validated easy-to-use nomograms for LSCC outcomes using prospective cooperative group trial data.

Optimal beam arrangement for stereotactic body radiation therapy delivery in lung tumors.

PURPOSE: To compare the different beam arrangement and delivery techniques for stereotactic body radiation therapy (SBRT) of lung lesions using the criteria of Radiation Therapy Oncology Group (RTOG) 0236 protocol. MATERIAL AND METHODS: Thirty-seven medically inoperable lung cancers were evaluated with various planning techniques including multiple coplanar multiple static beams, multiple non-coplanar static beams and arc delivery. Twelve plans were evaluated for each case, including five plans using coplanar fixed beams, six plans using non-coplanar fixed beams and one plan using arc therapy. These plans were compared using the target prescription isodose coverage, high and low dose volumes, and critical organ dose-volume limits. RESULTS: The prescription isodose coverage, high dose evaluation criteria and dose to critical organs were similar among treatment delivery techniques. However, there were differences in low dose criteria, especially in the ratio of the volume of 50% isodose of the prescription dose to the volume of planning treatment volume (R(50%)). The R(50%) in plans using non-coplanar static beams was lower than other plans in 30 of 37 cases (81%). CONCLUSION: Based on the dosimetric criteria outlined in RTOG 0236, the treatment technique using non-coplanar static beams showed the most preferable results for SBRT of lung lesions.

Resection following concurrent chemotherapy and high-dose radiation for stage IIIA non-small cell lung cancer.

OBJECTIVE: Concern exists regarding surgery after thoracic radiation. We aimed to assess early results of anatomic resection following induction therapy with platinum-based chemotherapy and full-dose thoracic radiation for resectable N2+ stage IIIA non-small cell lung cancer. METHODS: Two prospective trials were recently conducted by NRG Oncology in patients with resectable N2+ stage IIIA non-small cell lung cancer with the primary end point of mediastinal node sterilization following concurrent full-dose chemoradiotherapy (Radiation Therapy Oncology Group trials 0229 and 0839). All surgeons demonstrated postinduction resection expertise. Induction consisted of weekly carboplatin (area under the curve, 2.0) and paclitaxel (50 mg/m2) and concurrent thoracic radiation 60 Gy (0839)/61.2 Gy (0229) in 30 fractions. Patients in study 0839 were randomized 2:1 to weekly panitumumab + chemoradiotherapy or chemoradiotherapy alone during induction. Primary results were similar in all treatment arms and reported previously. Short-term surgical outcomes are reported here. RESULTS: One hundred twenty-six patients enrolled; 93 (74%) had anatomic resection, 77 underwent lobectomy, and 16 underwent extended resection. Microscopically margin-negative resections occurred in 85 (91%). Fourteen (15%) resections were attempted minimally invasively, including 2 converted without event. Grade 3 or 4 surgical adverse events were reported in 26 (28%), 30-day mortality in 4 (4%) and 90-day mortality in 5 (5%). Patients undergoing extended resection experienced similar rates of grade 3 or 4 adverse events (odds ratio, 0.95; 95% confidence interval, 0.42-3.8) but higher 30-day (1.3% vs 18.8%) (odds ratio, 17.54; 95% confidence interval, 1.75-181.8) and 90-day mortality (2.6% vs 18.8%) (odds ratio, 8.65; 95% confidence interval, 1.3-56.9). CONCLUSIONS: Lobectomy was performed safely following full-dose concurrent chemoradiotherapy in these multi-institutional prospective trials; however, increased mortality was noted with extended resections.

Insurance Status is an Independent Predictor of Overall Survival in Patients With Stage III Non-small-cell Lung Cancer Treated With Curative Intent.

INTRODUCTION: Population studies suggest an impact of insurance status on oncologic outcomes. We sought to explore this in a large single-institution cohort of patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively analyzed 342 consecutive patients (January 2000 to December 2013) curatively treated for stage III NSCLC. Patients were categorized by insurance status as uninsured (U), Medicare/Medicaid + Veterans Affairs (M/M + VA), or Private (P). The χ2 test was utilized to compare categorical variables. The Kaplan-Meier approach and the Cox proportional hazard models were used to analyze overall survival (OS) and freedom from recurrence (FFR). RESULTS: Compared with M/M + VA patients, P insurance patients were more likely to be younger (P < .001), married (P < .001), Caucasian (P = .001), reside in higher median income zip codes (P < .001), have higher performance status (P < .001), and undergo consolidation chemotherapy (P < .001) and trimodality therapy (P < .001). Diagnosis to treatment was delayed > 30 days in U (67.3%), M/M + VA (68.1%), and P (52.6%) patients (P = .017). Compared with the M/M + VA and U cohorts, P insurance patients had improved OS (median/5-year: 30.7 months/34.2%, 19 months/17%, and 16.9 months/3.8%; P < .001) and FFR (median/5-year: 18.4 months/27.3%, 15.2 months/23.2%, and 11.4 months/4.8%; P = .012), respectively. On multivariate analysis, insurance status was an independent predictor for OS (P = .017) but not FFR. CONCLUSION: Compared with U or M/M + VA patients, P insurance patients with stage III NSCLC were more likely to be optimally diagnosed and treated, resulting in a doubling of median OS for P versus U patients. Improved access to affordable health insurance is critical to combat inequities in access to care and has potential for improvements in cancer outcomes.

Tomographic image via background subtraction using an x-ray projection image and a priori computed tomography.

Kilovoltage x-ray projection images (kV images for brevity) are increasingly available in image guided radiotherapy (IGRT) for patient positioning. These images are two-dimensional (2D) projections of a three-dimensional (3D) object along the x-ray beam direction. Projecting a 3D object onto a plane may lead to ambiguities in the identification of anatomical structures and to poor contrast in kV images. Therefore, the use of kV images in IGRT is mainly limited to bony landmark alignments. This work proposes a novel subtraction technique that isolates a slice of interest (SOI) from a kV image with the assistance of a priori information from a previous CT scan. The method separates structural information within a preselected SOI by suppressing contributions to the unprocessed projection from out-of-SOI-plane structures. Up to a five-fold increase in the contrast-to-noise ratios (CNRs) was observed in selected regions of the isolated SOI, when compared to the original unprocessed kV image. The tomographic image via background subtraction (TIBS) technique aims to provide a quick snapshot of the slice of interest with greatly enhanced image contrast over conventional kV x-ray projections for fast and accurate image guidance of radiation therapy. With further refinements, TIBS could, in principle, provide real-time tumor localization using gantry-mounted x-ray imaging systems without the need for implanted markers.

Investigation of motion sickness and inertial stability on a moving couch for intra-fraction motion compensation.

BACKGROUND. Respiration-induced tumor motion compensation using a treatment couch requires moving the patient at non-trivial speeds. The purpose of this work was to investigate motion sickness and stability of the patient's external surface due to a moving couch with respiration-comparable velocities and accelerations. MATERIAL AND METHODS. A couch was designed to move with a peak-peak displacement of 5 cm and 1 cm in the S-I and A-P directions, respectively, and a period of 3.6 s. Fifty patients completed a 16-question motion sickness assessment questionnaire (MSAQ) prior to, during, and after the study. Seven optical reflectors affixed to the abdomen of each patient were monitored by infrared cameras. The relationship between reflector positions under stationary and moving conditions was evaluated to assess the stability of the patient's external surface. RESULTS AND DISCUSSION. Among the 4800 responses, 95% were 1 (no discomfort) of 9, and there were no scores of 6 or higher. Mild discomfort (scores of 4-5) was similar during couch motion and before couch motion (p = 0.39). Mild discomfort was less common after couch motion (p = 0.039) than before or during couch movement. There was a near 1:1 correspondence between marker-pair regression coefficients and phase offset values during couch-stationary and couch-moving conditions. Our results show that patients do not suffer motion sickness or external surface instability on a moving couch.

Preoperative versus postoperative chemoradiotherapy in the trimodality management of esophageal cancer.

Chemoradiotherapy (CRT) is commonly employed in the management of esophageal carcinoma-either definitively or as part of a trimodality strategy with includes surgical resection. For patients treated with trimodality therapy, the most optimal sequence of chemoradiation (CRT) in relation to surgical resection is unclear. We reviewed the efficacy, advantages, and disadvantages of preoperative CRT versus postoperative CRT in esophageal cancer patients treated with trimodality therapy. Preoperative chemoradiation enables early treatment of distant metastases while simultaneously treating the primary disease, facilitates definition of radiotherapy target volumes, and may allow resection of advanced disease. It does, however, have considerable toxicity and may reduce the ability of some patients to tolerate resection. Postoperative CRT allows for early debulking, rapidly addresses dysphagia, and allows for CRT based on accurate pathologic staging, but delays systemic treatment. Randomized studies that compare preoperative with postoperative CRT in treating esophageal cancer are needed to identify conclusively the best standard of care. Based on the study information currently available, we conclude that treatment options should be tailored to the individual patient.

Downstream Effect of a Proton Treatment Center on an Academic Medical Center.

PURPOSE: To quantify the effects of opening a proton center (PC) on an academic medical center (AMC)/radiation oncology department. METHODS AND MATERIALS: Radiation treatment volume and relative value units from fiscal year 2015 (FY15) to FY17 were retrospectively analyzed at the AMC and 2 community-based centers. To quantify new patient referrals to the AMC, we reviewed the electronic medical record for all patients seen at the PC since consults were initiated in November 2015 (n = 1173). Patients were excluded if the date of entry into the AMC electronic medical record predated their PC consultation. Hospital resource use and professional and technical charges were obtained for these patients. Academic growth, philanthropy, and resident education were evaluated based on grant submissions, clinical trial enrollment, philanthropy, and pediatric case exposure, respectively, from PC opening through FY17. RESULTS: From FY15 to FY17, radiation fractions at the AMC and the 2 community sites decreased by 14% (95% confidence interval [CI], 12%-16%, P < .001) and increased by 19% (95% CI, 16%-23%, P < .001) and 2% (95% CI, -1.1 to 4.3%, P = NS), respectively; the number of new starts decreased by 3% (95% CI, -13% to 7%, P = NS) and 2% (95% CI, -20% to 16%, P = NS) and increased by 13% (95% CI -2% to 27%, P = NS), respectively. At the AMC, technical and professional relative value units decreased by 5% and 14%, respectively. The PC made 561 external referrals to the AMC, which resulted in $2.38 million technical and $2.13 million professional charges at the AMC. Fifteen grant submissions ($12.83 million) resulted in 6 awards ($3.26 million). Twenty-two clinical trials involving proton therapy were opened, on which a total of 5% (n = 54) of patients enrolled during calendar years 2017 and 2018. The PC was involved in gift donations of $1.6 million. There was a nonsignificant 37% increase in number of pediatric cases. CONCLUSIONS: Despite a slight decline in AMC photon patient volumes and relative value units, a positive downstream effect was associated with the addition of a PC, which benefited the AMC.

Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non-Small Cell Lung Cancer: A Long-term Update of the NRG Oncology/RTOG 0214 Phase 3 Randomized Clinical Trial.

IMPORTANCE: Brain metastasis (BM) rates are high in locally advanced non-small cell lung cancer (LA-NSCLC), approaching rates seen in small cell lung cancer, where prophylactic cranial irradiation (PCI) is standard of care. Although PCI decreases the incidence of BM in LA-NSCLC, a survival advantage has not yet been shown. OBJECTIVE: To determine if PCI improves survival in LA-NSCLC. DESIGN, SETTING, AND PARTICIPANTS: Radiation Therapy Oncology Group (RTOG) 0214 was a randomized phase 3 clinical trial in stage III NSCLC stratified by stage (IIIA vs IIIB), histologic characteristics (nonsquamous vs squamous) and therapy (no surgery vs surgery). The study took place at 291 institutions in the United States, Canada, and internationally. Of 356 patients with stage III NSCLC entered onto this study, 16 were ineligible; therefore, 340 patients were randomized. INTERVENTION FOR CLINICAL TRIALS: Observation vs PCI. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS). The secondary end points were disease-free survival (DFS) and incidence of BM. RESULTS: Of the 340 total participants, mean (SD) age was 61 years; 213 of the participants were men and 127 were women. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The OS for PCI was not significantly better than observation (hazard ratio [HR], 0.82; 95% CI, 0.63-1.06; P = .12; 5- and 10-year rates, 24.7% and 17.6% vs 26.0% and 13.3%, respectively), while the DFS (HR, 0.76; 95% CI, 0.59-0.97; P = .03; 5- and 10-year rates, 19.0% and 12.6% vs 16.1% and 7.5% for PCI vs observation) and BM (HR, 0.43; 95% CI, 0.24-0.77; P = .003; 5- and 10-year rates, 16.7% vs 28.3% for PCI vs observation) were significantly different. Patients in the PCI arm were 57% less likely to develop BM than those in the observation arm. Younger patients (<60 years) and patients with nonsquamous disease developed more BM. On multivariable analysis, PCI was associated with decreased BM and improved DFS, but not improved OS. Multivariable analysis within the nonsurgical arm suggests that PCI effectively prolongs OS, DFS, and BM. CONCLUSIONS AND RELEVANCE: In patients with stage III LA-NSCLC without progression of disease after therapy, PCI decreased the 5- and 10-year rate of BM and improved 5- and 10-year DFS, but did not improve OS. Although this study did not meet its primary end point, the long-term results reveal many important findings that will benefit future trials. Identifying the appropriate patient population and a safe intervention is critical. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00048997.

Lymph Node Size Predicts for Asymptomatic Brain Metastases in Patients With Non-small-cell Lung Cancer at Diagnosis.

BACKGROUND: We questioned whether the National Comprehensive Cancer Network recommendations for brain magnetic resonance imaging (MRI) for patients with stage ≥ IB non-small-cell lung cancer (NSCLC) was high-yield compared with American College of Clinical Pharmacy and National Institute for Health and Care Excellence guidelines recommending stage III and above NSCLC. We present the prevalence and factors predictive of asymptomatic brain metastases at diagnosis in patients with NSCLC without extracranial metastases. MATERIALS AND METHODS: A retrospective analysis of 193 consecutive, treatment-naïve patients with NSCLC diagnosed between January 2010 and August 2015 was performed. Exclusion criteria included no brain MRI staging, symptomatic brain metastases, or stage IV based on extracranial disease. Univariate and multivariate logistic regression was performed. RESULTS: The patient characteristics include median age of 65 years (range, 36-90 years), 51% adenocarcinoma/36% squamous carcinoma, and pre-MRI stage grouping of 31% I, 22% II, 34% IIIA, and 13% IIIB. The overall prevalence of brain metastases was 5.7% (n = 11). One (2.4%) stage IA and 1 (5.6%) stage IB patient had asymptomatic brain metastases at diagnosis, both were adenocarcinomas. On univariate analysis, increasing lymph nodal stage (P = .02), lymph nodal size > 2 cm (P = .009), multi-lymph nodal N1/N2 station involvement (P = .027), and overall stage (P = .005) were associated with asymptomatic brain metastases. On multivariate analysis, increasing lymph nodal size remained significant (odds ratio, 1.545; P = .009). CONCLUSION: Our series shows a 5.7% rate of asymptomatic brain metastasis for patients with stage I to III NSCLC. Increasing lymph nodal size was the only predictor of asymptomatic brain metastases, suggesting over-utilization of MRI in early-stage disease, especially in lymph node-negative patients with NSCLC. Future efforts will explore the utility of baseline MRI in lymph node-positive stage II and all stage IIIA patients.

Long-term survival in patients with synchronous, solitary brain metastasis from non-small-cell lung cancer treated with radiosurgery.

PURPOSE: To report the outcome of patients with synchronous, solitary brain metastasis from non-small-cell lung cancer (NSCLC) treated with gamma knife stereotactic radiosurgery (GKSRS). PATIENTS AND METHODS: Forty-two patients diagnosed with synchronous, solitary brain metastasis from NSCLC were treated with GKSRS between 1993 and 2006. The median Karnofsky performance status (KPS) was 90. Patients had thoracic Stage I-III disease (American Joint Committee on Cancer 2002 guidelines). Definitive thoracic therapy was delivered to 26/42 (62%) patients; 9 patients underwent chemotherapy and radiation, 12 patients had surgical resection, and 5 patients underwent preoperative chemoradiation and surgical resection. RESULTS: The median overall survival (OS) was 18 months. The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively. For patients who underwent definitive thoracic therapy, the median OS was 26.4 months compared with 13.1 months for those who had nondefinitive therapy, and the 5-year actuarial OS was 34.6% vs. 0% (p < 0.0001). Median OS was significantly longer for patients with a KPS >or=90 vs. KPS < 90 (27.8 months vs. 13.1 months, p < 0.0001). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (p = 0.020) and KPS (p = 0.001). CONCLUSIONS: This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with GKSRS. Definitive thoracic therapy and KPS significantly impacted OS. The 5-year OS of 21% demonstrates the potential for long-term survival in patients treated with GKSRS; therefore, patients with good KPS should be considered for definitive thoracic therapy.

Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity.

PURPOSE: To determine the feasibility and toxicity of the addition of cetuximab with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer on a Phase II study. METHODS AND MATERIALS: Patients with locoregional esophageal and proximal gastric cancer without distant organ metastases were eligible. All patients received cetuximab, paclitaxel, and carboplatin weekly for 6 weeks with 50.4 Gy radiation. RESULTS: Sixty patients were enrolled, 57 with esophageal cancer and 3 with gastric cancer. Forty-eight had adenocarcinoma and 12 had squamous cell cancer. Fourteen of 60 patients (23%) had Grade 3 dermatologic toxicity consisting of a painful, pruritic acneiform rash on the face outside of the radiation field. The rates of Grades 3 and 4 esophagitis were 12% and 3%, respectively. Three patients had Grade 3/4 cetuximab hypersensitivity reactions and were not assessable for response. Forty of 57 patients (70%) had a complete clinical response after chemoradiation. CONCLUSION: Cetuximab can be safely administered with chemoradiation for esophageal cancer. Dermatologic toxicity and hypersensitivity reactions were associated with the addition of cetuximab. There was no increase in esophagitis or other radiation-enhanced toxicity.

An evaluation of planning techniques for stereotactic body radiation therapy in lung tumors.

PURPOSE: To evaluate four planning techniques for stereotactic body radiation therapy (SBRT) in lung tumors. METHODS AND MATERIALS: Four SBRT plans were performed for 12 patients with stage I/II non-small-cell lung cancer under the following conditions: (1) conventional margins on free-breathing CT (plan 1), (2) generation of an internal target volume (ITV) using 4DCT with beam delivery under free-breathing conditions (plan 2), (3) gating at end-exhale (plan 3), and (4) gating at end-inhale (plan 4). Planning was performed following the RTOG 0236 protocol with a prescription dose of 54 Gy (3 fractions). For each plan 4D dose was calculated using deformable-image registration. RESULTS: There was no significant difference in tumor dose delivered by the 4 plans. However, compared with plan 1, plans 2-4 reduced total lung BED by 1.9+/-1.2, 3.1+/-1.6 and 3.5+/-2.1 Gy, reduced mean lung dose by 0.8+/-0.5, 1.5+/-0.8, and 1.6+/-1.0 Gy, reduced V20 by 1.5+/-1.0%, 2.7+/-1.4%, and 2.8+/-1.8%, respectively, with p<0.01. Compared with plan 2, plans 3-4 reduced lung BED by 1.2+/-1.0 and 1.6+/-1.5 Gy, reduced mean lung dose by 0.6+/-0.5 and 0.8+/-0.7 Gy, reduced V20 by 1.2+/-1.1% and 1.3+/-1.5%, respectively, with p<0.01. The differences in lung BED, mean dose and V20 of plan 4 compared with plan 3 were insignificant. CONCLUSIONS: Tumor dose coverage was statistically insignificant between all plans. However, compared with plan 1, plans 2-4 significantly reduced lung doses. Compared with plan 2, plan 3-4 also reduced lung toxicity. The difference in lung doses between plan 3 and plan 4 was not significant.

Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123.

OBJECTIVES: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. MATERIALS AND METHODS: Eligible patients included stage II-IIIB non-small cell lung cancer, stage I central non-small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. RESULTS: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. CONCLUSIONS: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

Implications of Pathologic Complete Response Beyond Mediastinal Nodal Clearance With High-Dose Neoadjuvant Chemoradiation Therapy in Locally Advanced, Non-Small Cell Lung Cancer.

PURPOSE: To determine, in a retrospective analysis of a large cohort of stage III non-small cell lung cancer patients treated with curative intent at our institution, whether having a pathologic complete response (pCR) influenced overall survival (OS) or freedom from recurrence (FFR) in patients who underwent definitive (≥60 Gy) neoadjuvant doses of chemoradiation (CRT). METHODS AND MATERIALS: At our institution, 355 patients with locally advanced non-small cell lung cancer were treated with curative intent with definitive CRT (January 2000-December 2013), of whom 111 underwent mediastinal reassessment for possible surgical resection. Ultimately 88 patients received trimodality therapy. Chi-squared analysis was used to compare categorical variables. The Kaplan-Meier analysis was performed to estimate OS and FFR, with Cox regression used to determine the absolute hazards. RESULTS: Using high-dose neoadjuvant CRT, we observed a mediastinal nodal clearance (MNC) rate of 74% (82 of 111 patients) and pCR rate of 48% (37 of 77 patients). With a median follow-up of 34.2 months (range, 3-177 months), MNC resulted in improved OS and FFR on both univariate (OS: hazard ratio [HR] 0.455, 95% confidence interval [CI] 0.272-0.763, P = .004; FFR: HR 0.426, 95% CI 0.250-0.726, P = .002) and multivariate analysis (OS: HR 0.460, 95% CI 0.239-0.699, P = .001; FFR: HR 0.455, 95% CI 0.266-0.778, P = .004). However, pCR did not independently impact OS (P = .918) or FFR (P = .474). CONCLUSIONS: Mediastinal nodal clearance after CRT continues to be predictive of improved survival for patients undergoing trimodality therapy. However, a pCR at both the primary and mediastinum did not further improve survival outcomes. Future therapies should focus on improving MNC to encourage more frequent use of surgery and might justify use of preoperative CRT over chemotherapy alone.