Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848.

PURPOSE: NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions. METHODS AND MATERIALS: In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan. RESULTS: From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%). CONCLUSION: One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

Phase II Trial of Five-Fraction Accelerated Partial Breast Irradiation (APBI) Using Noninvasive Image-Guided Breast Brachytherapy (NIBB).

PURPOSE/OBJECTIVE(S): NIBB has potential advantages over other APBI techniques by delivering highly conformal radiation with minimal collateral dose to the heart and lung compared with external beam techniques, but unlike other brachytherapy techniques NIBB is non-invasive. Previous data has shown encouraging outcomes using a 10-fraction regimen. To improve efficiency, convenience, and cost, reduction in the fraction number is desirable. Final results of a prospective phase II trial are reported. MATERIALS/METHODS: NIBB APBI was delivered using 28.5Gy in 5 fractions daily over 1 week. Patient eligibility criteria required: invasive carcinoma ≤2.0 cm or DCIS ≤3.0 cm, ER positive (if invasive), lymph node negative, LVI absent, and lumpectomy with margins negative by 2mm. The primary endpoint was grade ≥ 2 subcutaneous fibrosis/induration <30%. Secondary endpoints included any late toxicity, cosmetic outcome, and local control. RESULTS: 40 patients were treated with a median follow-up of 59.7 months. The mean age was 67 years (50-89 years) and tumor size was 1.0cm (0.3-2.0cm). 80% had invasive carcinoma. The mean breast separation with compression was 6.7cm (3.5-8.9cm). The 5-year actuarial local control was 96.6% and overall survival was 96.9%. Grade 2 and 3 late toxicities were 15% and 0%, respectively. The rate of grade 2 subcutaneous fibrosis/induration was 2.5% (+/-2.5%) meeting the study's primary endpoint. The most common late toxicity of any grade was skin telangiectasia; 22.5% grade 1 and 15% grade 2. Only breast separation was associated with telangiectasia risk, p=0.002. Overall cosmetic outcome was excellent, good, and fair/poor in 75%, 25%, and 0%, respectively. CONCLUSIONS: NIBB APBI delivered in 5 fractions results in a low rate of late toxicity and a high rate of good/excellent cosmetic outcomes. Telangiectasia risk can be minimized by keeping breast separation ≤7.0cm. The local failure rate was appropriately low. Further investigation of this technique is warranted.

Predictors of Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation Followed by Consolidative Durvalumab.

Purpose: In patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab. Methods and Materials: Patients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival. Results: Sixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% (P = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy (P = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively. Conclusions: The modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed.

The Brown University Oncology Group Experience With FOLFOX + Nab-paclitaxel [FOLFOX-A] for Metastatic and Locally Advanced Pancreatic, BrUOG-292 and BrUOG-318.

OBJECTIVES: To evaluate response rate, toxicity, and efficacy of the novel combination of nab-paclitaxel, oxaliplatin, 5-fluorouracil, and leucovorin [FOLFOX-A] in patients with advanced pancreatic ductal adenocarcinoma [PDAC]. METHODS: BrUOG-292 and BrUOG-318 were two concurrently run, prospective, single-arm phase II studies evaluating FOLFOX-A as first-line therapy in patients with metastatic and locally advanced/borderline resectable PDAC respectively. The FOLFOX-A regimen consisted of 5-fluorouracil, 1200 mg/m 2 /d as a continuous intravenous (IV) infusion over 46 hours, leucovorin 400 mg/m 2 IV, oxaliplatin 85 mg/m 2 IV, and nab-paclitaxel 150 mg/m 2 IV on day 1 every 14 days up to a maximum of 12 cycles. Patients with locally advanced or borderline resectable disease were permitted to stop treatment after 6 cycles and receive radiation therapy and/or surgical exploration if feasible. The primary end point was overall response rate [ORR]. Secondary end points were median progression-free survival [PFS], median overall survival [OS], and safety. RESULTS: Seventy-eight patients with previously untreated PDAC were enrolled between June 2014 and November 2019; 76 patients were evaluable. The median follow-up was 40 months and 32 months, respectively. overall response rate was 34%. Among the patients enrolled on BrUOG-292 [48 patients], the PFS was 5 months and OS was 11 months, respectively. For those enrolled on BrUOG 318 [28 patients], the PFS was 11 months and OS was 22 months. Treatment-related toxicities included grade 3 fatigue [40%], diarrhea [14%], and neuropathy [2%]. CONCLUSIONS: The combination of FOLFOX-A has promising activity in PDAC and may represent an alternative to FOLFIRINOX when reduction of gastrointestinal toxicity is required.

Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.

BACKGROUND: Trastuzumab is a monoclonal antibody against HER2 (also known as ERBB2). The primary objective of the NRG Oncology/RTOG-1010 trial was to establish whether trastuzumab improves disease-free survival when combined with trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) for patients with untreated HER2-overexpressing oesophageal adenocarcinoma. METHODS: NRG Oncology/RTOG-1010 was an open label, randomised, phase 3 trial for which patients were accrued from 111 NRG-affiliated institutions in the USA. Eligible patients were adults (aged ≥18 years) with newly diagnosed pathologically confirmed oesophageal adenocarcinoma, American Joint Committee on Cancer 7th edition T1N1-2 or T2-3N0-2 stage disease, and a Zubrod performance status of 0-2. Patients were stratified by adenopathy (no vs yes [coeliac absent] vs yes [coeliac present ≤2 cm]) and randomly assigned (1:1) to receive weekly intravenous paclitaxel (50 mg/m2 intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30-60 min) for 6 weeks with radiotherapy 50·4 Gy in 28 fractions (chemoradiotherapy) followed by surgery, with or without intravenous trastuzumab (4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21-56 days after surgery). The primary endpoint, disease-free survival, was defined as the time from randomisation to death or first of locoregional disease persistence or recurrence, distant metastases, or second primary malignancy. Analyses were done by modified intention to treat. This study is registered with Clinicaltrials.gov, NCT01196390; it is now closed and in follow-up. FINDINGS: 606 patients were entered for HER2 assessment from Dec 30, 2010 to Nov 10, 2015, and 203 eligible patients who were HER2-positive were enrolled and randomly assigned to chemoradiotherapy plus trastuzumab (n=102) or chemoradiotherapy alone (n=101). Median duration of follow-up was 2·8 years (IQR 1·4-5·7). Median disease-free survival was 19·6 months (95% CI 13·5-26·2) with chemoradiotherapy plus trastuzumab compared with 14·2 months (10·5-23·0) for chemoradiotherapy alone (hazard ratio 0·99 [95% CI 0·71-1·39], log-rank p=0·97). Grade 3 treatment-related adverse events occurred in 41 (43%) of 95 patients in the chemoradiotherapy plus trastuzumab group versus 52 (54%) of 96 in the chemoradiotherapy group and grade 4 events occurred in 20 (21%) versus 21 (22%). The most common grade 3 or worse treatment-related adverse events for both groups were haematological (53 [56%] of 95 patients in the chemoradiotherapy plus trastuzumab group vs 55 [57%] of 96 patients in the chemotherapy group) or gastrointestinal disorders (28 [29%] vs 20 [21 %]). 34 (36%) of 95 patients in the chemoradiotherapy plus trastuzumab group and 27 (28%) of 96 patients in the chemoradiotherapy only group had treatment-related serious adverse events. There were eight treatment-related deaths: five (5%) of 95 patients in the chemoradiotherapy plus trastuzumab group (bronchopleural fistula, oesophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three (3%) of 96 in the chemoradiotherapy group (two multiorgan failure and one sepsis). INTERPRETATION: The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing oesophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in oesophageal cancer are warranted. FUNDING: National Cancer Institute and Genentech.

Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer.

OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

Impact of Diabetes and Insulin Use on Prognosis in Patients With Resected Pancreatic Cancer: An Ancillary Analysis of NRG Oncology RTOG 9704.

PURPOSE: Diabetes mellitus (DM) has been proposed to be tumorigenic; however, prior studies of the association between DM and survival are conflicting. The goal of this ancillary analysis of RTOG 9704, a randomized controlled trial of adjuvant chemotherapy in pancreatic cancer, was to determine the prognostic effects of DM and insulin use on survival. METHODS AND MATERIALS: Eligible patients from RTOG 9704 with available data on DM and insulin use were included. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and variable levels were compared using log-rank test. Cox proportional hazards models were created to assess the associations among DM, insulin use, and body mass index phenotypes on outcomes. RESULTS: Of 538 patients enrolled from 1998 to 2002, 238 patients were eligible with analyzable DM and insulin use data. Overall 34% of patients had DM and 66% did not. Of patients with DM, 64% had insulin-dependent DM, and 36% had non-insulin-dependent DM. On univariable analysis, neither DM nor insulin dependence were associated with OS or DFS (P > .05 for all). On multivariable analysis, neither DM, insulin use, nor body mass index were independently associated with OS or DFS. Nonwhite race (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.35-3.50; P = .0014), nodal involvement (HR, 1.74; 95% CI, 1.24-2.45; P = .0015), and carbohydrate antigen 19-9 (CA19-9) ≥90 U/mL (HR, 3.61; 95% CI, 2.32-5.63; P < .001) were associated with decreased OS. Nonwhite race (HR, 1.67; 95% CI, 1.05-2.63; P = .029) and CA19-9 ≥90 U/mL (HR, 2.86; 95% CI, 1.85-4.40; P < .001) were associated with decreased DFS. CONCLUSIONS: DM and insulin use were not associated with OS or DFS in patients with pancreatic cancer in this study. Race, nodal involvement, and increased CA19-9 were significant predictors of outcomes. These data might apply to the more modern use of neoadjuvant therapies for potentially resectable pancreatic cancer.

Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704.

BACKGROUND: Several registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial. MATERIALS AND METHODS: This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients. CONCLUSION: Ancillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216. IMPLICATIONS FOR PRACTICE: Several population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.

Results of the NRG Oncology/RTOG 0848 Adjuvant Chemotherapy Question-Erlotinib+Gemcitabine for Resected Cancer of the Pancreatic Head: A Phase II Randomized Clinical Trial.

PURPOSE: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. METHODS: Eligibility-within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm-6 cycles of gemcitabine. Gemcitabine+erlotinib arm-gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. RESULTS: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, (P=0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P=0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). CONCLUSIONS: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation.

PURPOSE: Iododeoxyuridine (IUdR) is a potent radiosensitizer; however, its clinical utility is limited by dose-limiting systemic toxicities and the need for prolonged continuous infusion. 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is an oral prodrug of IUdR that, compared with IUdR, is easier to administer and less toxic, with a more favorable therapeutic index in preclinical studies. Here, we report the clinical and pharmacologic results of a first-in-human phase I dose escalation study of IPdR + concurrent radiation therapy (RT) in patients with advanced metastatic gastrointestinal (GI) cancers. PATIENTS AND METHODS: Adult patients with metastatic GI cancers referred for palliative RT to the chest, abdomen, or pelvis were eligible for study. Patients received IPdR orally once every day × 28 days beginning 7 days before the initiation of RT (37.5 Gy in 2.5 Gy × 15 fractions). A 2-part dose escalation scheme was used, pharmacokinetic studies were performed at multiple time points, and all patients were assessed for toxicity and response to Day 56. RESULTS: Nineteen patients were entered on study. Dose-limiting toxicity was encountered at 1,800 mg every day, and the recommended phase II dose is 1,200 mg every day. Pharmacokinetic analyses demonstrated achievable and sustainable levels of plasma IUdR ≥1 µmol/L (levels previously shown to mediate radiosensitization). Two complete, 3 partial, and 9 stable responses were achieved in target lesions. CONCLUSIONS: Administration of IPdR orally every day × 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels ≥1 µmol/L. These results support the investigation of IPdR + RT in phase II studies.

Postresection CA19-9 and margin status as predictors of recurrence after adjuvant treatment for pancreatic carcinoma: Analysis of NRG oncology RTOG trial 9704.

PURPOSE: NRG Oncology RTOG 9704 was the first adjuvant trial to validate the prognostic value of postresection CA19-9 levels for survival in patients with pancreatic carcinoma. The data resulting from this study also provide information about predictors of recurrence that may be used to tailor individualized management in this disease setting. This secondary analysis assessed the prognostic value of postresection CA19-9 and surgical margin status (SMS) in predicting patterns of disease recurrence. METHODS AND MATERIALS: This multicenter cooperative trial included participants who were enrolled as patients at oncology treatment sites in the United States and Canada. The study included 451 patients analyzable for SMS, of whom 385 were eligible for postresection CA19-9 analysis. Postresection CA19-9 was analyzed at cut points of 90, 180, and continuously. Patterns of disease recurrence included local/regional recurrence (LRR) and distant failure (DF). Multivariable analyses included treatment, tumor size, and nodal status. To adjust for multiple comparisons, a P value of ≤ .01 was considered statistically significant and > .01 to ≤ .05 to be a trend. RESULTS: For CA19-9, 132 (34%) patients were Lewis antigen-negative (no CA19-9 expression), 200 (52%) had levels <90, and 220 (57%) had levels <180. A total of 188 patients (42%) had negative margins, 152 (34%) positive, and 111 (25%) unknown. On univariate analysis, CA19-9 cut at 90 was associated with increases in LRR (trend) and DF. Results were similar at the 180 cut point. SMS was not associated with an increase in LRR on univariate or multivariate analyses. On multivariable analysis, CA19-9 ≥ 90 was associated with increased LRR and DF. Results were similar at the 180 cut point. CONCLUSIONS: In this prospective evaluation, postresection CA19-9 was a significant predictor of both LRR and DF, whereas SMS was not. These findings support consideration of adjuvant radiation therapy dose intensification in patients with elevated postresection CA19-9.

Five fraction accelerated partial breast irradiation using noninvasive image-guided breast brachytherapy: Feasibility and acute toxicity.

PURPOSE: To improve efficiency, convenience, and cost, a prospective phase II trial was initiated to evaluate accelerated partial breast irradiation delivered with noninvasive image-guided breast brachytherapy (NIBB) via five once-daily fractions. METHODS AND MATERIALS: Women ≥50 years old with early-stage breast cancer undergoing breast conserving surgery were enrolled. Eligibility criteria included invasive carcinoma ≤2.0 cm or ductal carcinoma in situ ≤3.0 cm, ER positive (if invasive), lymph node negative, LVI absent, and margins negative by 2 mm. Patients received a total dose of 28.5 Gy in five daily fractions. NIBB was delivered using two orthogonal axes for each fraction. Applicators were selected to encompass the lumpectomy cavity with a 1.0 cm clinical target volume margin and 0 to 0.5 cm planning target volume margin. Acute and late toxicity was assessed based on CTCAE v3.0. RESULTS: Forty patients with a mean age of 67 years underwent protocol treatment. Mean tumor size was 1.0 cm (0.3-2.0 cm). Eighty percent had invasive carcinoma and the remainder had ductal carcinoma in situ. Mean tumor bed volume was 21 cc (5-79 cc) and mean breast volume was 1319 cc (499-3044 cc). Mean breast separation with compression was 6.7 cm (3.5-8.9 cm). All patients tolerated well. Median discomfort with compression was 1 (range: 0-7) on a 10-point pain scale. Acute skin reaction was Grade 0-1 in 70%, Grade 2 in 28%, and Grade 3 in 3%. Acute skin toxicity was not associated with breast size but was associated with larger breast separation with compression (p < 0.01) and larger applicator size (p < 0.01). No Grade 3+ late toxicity or local recurrences have been observed at a median followup of 14 months. CONCLUSIONS: Accelerated partial breast irradiation delivered using NIBB over five daily fractions is a convenient treatment option that is feasible and well tolerated.

Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer.

PURPOSE: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer. PATIENTS AND METHODS: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 × 109 colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation. RESULTS: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months. CONCLUSIONS: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted.

PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.

PURPOSE: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation. MATERIALS AND METHODS: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation. CONCLUSIONS: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.

Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704.

BACKGROUND: The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS: Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS: Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P < .0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95% confidence interval, 0.27-0.63; P < .0001). CONCLUSIONS: In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment. Cancer 2018;124:491-8. © 2017 American Cancer Society.

Analysis of Outcomes Using Hypofractionated Tumor Bed Boost Combined With Hypofractionated Whole Breast Irradiation for Early-stage Breast Cancer.

INTRODUCTION: Tumor bed boost improves local control and is an important part of breast-conserving therapy. Data on the use of a hypofractioned tumor bed boost are needed. We performed a retrospective analysis of patients treated with hypofractionated whole breast irradiation (WBI) and hypofractionated boost to examine acute and delayed outcomes. MATERIALS AND METHODS: We examined the records of patients treated with hypofractionated WBI and tumor bed boost after lumpectomy for Stage 0 to II breast cancer. Local control, toxicity, and cosmetic outcome were evaluated. Patient, tumor, and treatment characteristics were evaluated including excision volume, surgical technique, surgical complications, chemotherapy, endocrine therapy administration, radiation dose, fractionation, and technique. RESULTS: A total of 143 patients received hypofractionated WBI with hypofractionated boost between 2010 and 2015. The median follow-up was 16.8 months. The median patient age was 65 years. Patient stage was 0, I, and II in 25%, 68%, and 7%, respectively. All patients received hypofractionated WBI with 42.5 Gy in 16 fractions. Sixty-one percent of women received a boost regimen of 2.66 Gy/fraction for 3 fractions. Boost techniques included noninvasive breast brachytherapy, electrons, 3-dimensional conformal radiation therapy, or a combination of techniques. Acute skin reaction was grade 1 in 65% and grade 2 in 32%. Good or excellent cosmetic outcome was achieved in 94% of patients. Subcutaneous fibrosis was the most common delayed toxicity in 19%, of which 86% was grade 1. There were no local recurrences. CONCLUSIONS: Hypofractionated tumor bed boost is well-tolerated with a low rate of toxicity and high rate of good-to-excellent cosmetic outcome.

Patients with Long-Term Control of Systemic Disease Are a Favorable Prognostic Group for Treatment of Brain Metastases with Stereotactic Radiosurgery Alone.

BACKGROUND: Stereotactic radiosurgery (SRS) alone is an attractive option for treatment of brain metastases. SRS avoids whole-brain radiotherapy (WBRT)-associated morbidity, but is limited by regional central nervous system (CNS) failures and short survival in some patients. We evaluated a subgroup of patients with controlled systemic disease that could represent a favorable patient population for SRS alone. METHODS: All patients with brain metastases treated with SRS without WBRT at our institution between 2004 and 2014 were grouped into two cohorts: those with controlled systemic disease (CSD) for 1 year or longer before prior to presentation with brain metastases and those without (i.e., uncontrolled systemic disease [USD]). Rates of local and regional CNS failure, and overall survival were assessed with χ2 and Student t tests. Cox regression analysis was performed to evaluate independent predictors of regional control and overall survival. RESULTS: Two hundred ninety-four patients underwent SRS to 697 lesions, of which 65 patients had CSD. Median follow-up was 9.7 months. There was no difference in local control between the two cohorts (P = 0.795). Regional CNS control was significantly better for patients with CSD (68% vs. 48%; P = 0.001). Overall survival at 1 and 5 years for CSD were 65% and 13% with USD yielding 41% and 7%, respectively (P < 0.001). Multivariate analysis demonstrated that USD (relative CSD) independently predicts regional failure (hazard ratio [HR], 1.75; P = 0.008) and shorter overall survival (HR, 1.55; P = 0.007). CONCLUSIONS: Patients with brain metastases after 1 year or longer of primary and systemic disease control represent a particularly favorable cohort, with lower regional CNS failure and prolonged survival, for an approach of SRS alone.

Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study.

PURPOSE: Following preoperative chemoradiation and surgery, many patients with stage II to III rectal cancer are unable to tolerate full-dose adjuvant chemotherapy. BrUOG R-224 was designed to assess the impact of COmplete Neoadjuvant Treatment for REctal cancer (CONTRE), primary chemotherapy followed by chemoradiation and surgery, on treatment delivery, toxicities, and pathologic response at surgery. METHODS: Patients with clinical stage II to III (T3 to T4 and/or N1 to N2) rectal cancer received 8 cycles of modified FOLFOX6 followed by capecitabine 825 mg/m bid concurrent with 50.4 Gy intensity-modulated radiation therapy. Surgery was performed 6 to 10 weeks after chemoradiation. RESULTS: Thirty-nine patients were enrolled between August 2010 and June 2013. Median age was 61 years (30 to 79 y); 7 patients (18%) were clinical stage II and 32 (82%) stage III. Thirty-six patients (92%) received all 8 cycles of mFOLFOX6, of whom 35 completed subsequent chemoradiation; thus 89% of patients received CONTRE as planned. No unexpected toxicities were reported. All patients had resolution of bleeding and improvement of obstructive symptoms, with no complications requiring surgical intervention. Pathologic complete response (ypT0N0) was demonstrated in 13 patients (33%; 95% CI, 18.24%-47.76%). CONCLUSIONS: CONTRE seems to be a well-tolerated alternative to the current standard treatment sequence. Evaluating its impact on long-term outcomes would require a large randomized trial, but using pathologic response as an endpoint, it could serve as a platform for assessing the addition of novel agents to preoperative treatment in stage II to III rectal cancer.

Stereotactic Body Radiation Therapy Boost After Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Dose Escalation Study.

PURPOSE: Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD). METHODS AND MATERIALS: Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cc and <60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients per cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated. RESULTS: Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at <24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P<.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively. CONCLUSIONS: SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24 Gy in 2 fractions. Toxicity at the PBV is a concern but potentially can be avoided with strict dose-volume constraints.