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Purpose: Technological advances in radiation therapy (RT) delivery have the potential to reduce errors via increased automation and built-in quality assurance (QA) safeguards, yet may also introduce new types of errors. Intensity-modulated RT (IMRT) is an increasingly used technology that is more technically complex than three-dimensional (3D)-conformal RT and conventional RT. We determined the rate of reported errors in RT delivery among IMRT and 3D/conventional RT treatments and characterized the errors associated with the respective techniques to improve existing QA processes., Methods and Materials: All errors in external beam RT delivery were prospectively recorded via a nonpunitive error-reporting system at Brigham & Women's Hospital/Dana Farber Cancer Institute. Errors are defined as any unplanned deviation from the intended RT treatment and are reviewed during monthly departmental quality improvement meetings. We analyzed all reported errors since the routine use of IMRT in our department, from January 2004 to July 2009. Fisher's exact test was used to determine the association between treatment technique (IMRT vs. 3D/conventional) and specific error types. Effect estimates were computed using logistic regression., Results: There were 155 errors in RT delivery among 241,546 fractions (0.06%), and none were clinically significant. IMRT was commonly associated with errors in machine parameters (nine of 19 errors) and data entry and interpretation (six of 19 errors). IMRT was associated with a lower rate of reported errors compared with 3D/conventional RT (0.03% vs. 0.07%, p = 0.001) and specifically fewer accessory errors (odds ratio, 0.11; 95% confidence interval, 0.01-0.78) and setup errors (odds ratio, 0.24; 95% confidence interval, 0.08-0.79)., Conclusions: The rate of errors in RT delivery is low. The types of errors differ significantly between IMRT and 3D/conventional RT, suggesting that QA processes must be uniquely adapted for each technique. There was a lower error rate with IMRT compared with 3D/conventional RT, highlighting the need for sustained vigilance against errors common to more traditional treatment techniques., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Prior literature has suggested synergy between immune checkpoint therapy (ICT) and radiotherapy (RT) for the treatment of brain metastases (BrM), but to the authors' knowledge the optimal timing of therapy to maximize this synergy is unclear. Methods: A total of 199 patients with melanoma and non–small cell lung cancer with BrM received ICT and RT between 2007 and 2016 at the study institution. To reduce selection biases, individual metastases were included only if they were treated with RT within 90 days of ICT. Concurrent treatment was defined as RT delivered on the same day as or in between doses of an ICT course; all other treatment was considered to be nonconcurrent. Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per‐metastasis basis, using a sandwich estimator to account for intrapatient correlation. Results: The final cohort included 110 patients with 340 BrM, with 102 BrM treated concurrently and 238 BrM treated nonconcurrently. Response rates were higher with the use of concurrent treatment (70% vs 47%; P <.001), with correspondingly lower rates of progressive disease (5% vs 26%; P <.001). On multivariable analysis, concurrent treatment was found to be associated with improved time to response (hazard ratio, 1.76; 95% CI, 1.18‐2.63 [P =.006]) and decreased local recurrence (hazard ratio, 0.42; 95% CI, 0.23‐0.78 [P =.006]). This effect appeared to be greater for melanoma than for non–small cell lung cancer, although interaction tests were not statistically significant. Only 1 of 103 metastases which had a complete response later developed disease progression. Conclusions: Concurrent RT and ICT may improve response rates and decrease local recurrence of brain metastases compared with treatment that was nonconcurrent but delivered within 90 days. Further study of this combination in prospective, randomized trials is warranted. There is significant interest in potential synergy between radiotherapy and immune checkpoint therapy, but the optimal timing of each therapy remains unclear. The current study examines a cohort of patients with melanoma and non–small cell lung cancer with brain metastases who were managed with immune checkpoint therapy and brain‐directed radiotherapy within a 90‐day period. Compared with nonconcurrent therapy, concurrent therapy is associated with an improved brain metastasis response rate and decreased local recurrence. [ABSTRACT FROM AUTHOR]

Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field. [ABSTRACT FROM AUTHOR]

Objective: Lower extremity lymphedema adversely affects quality of life by causing discomfort, impaired mobility and increased risk of infection. The goal of this study is to investigate factors that influence the likelihood of lymphedema in patients with endometrial cancer who undergo adjuvant radiation with or without chemotherapy. Methods: A retrospective chart review identified all stage I-III endometrial cancer patients who had a hysterectomy with or without complete staging lymphadenectomy and adjuvant radiation therapy between January 2006 and February 2013. Patients with new-onset lymphedema after treatment were identified. Logistic regression was used to find factors that influenced lymphedema risk. Results: Of 212 patients who met inclusion criteria, 15 patients (7.1%) developed new-onset lymphedema. Lymphedema was associated with lymph-node dissection (odds ratio [OR], 5.6; 95% CI, 1.01 to 105.5; p=0.048) and with the presence of pathologically positive lymph nodes (OR, 4.1; 95% CI, 1.4 to 12.3; p=0.01). Multivariate logistic regression confirmed the association with lymph-node positivity (OR, 3.2; 95% CI, 1.0007 to 10.7; p=0.0499) when controlled for lymph-node dissection. Median time to lymphedema onset was 8 months (range, 1 to 58 months) with resolution or improvement in eight patients (53.3%) after a median of 10 months. Conclusion: Lymph-node positivity was associated with an increased risk of lymphedema in endometrial cancer patients who received adjuvant radiation. Future studies are needed to explore whether node-positive patients may benefit from early lymphedema-controlling interventions. [ABSTRACT FROM AUTHOR]

Purpose: Postorchiectomy adjuvant radiotherapy (RT) for Stage I seminoma can be associated with long-term toxicity, and management strategies with a lower treatment burden achieve the same excellent cure rate. Because studies suggest that radiation oncologists in the United States continue to recommend RT for these patients, we sought to identify factors associated with management recommendations. Methods and Materials: We conducted a one-time internet-based survey among 491 randomly selected American radiation oncologists self-described as specializing in genitourinary oncology. Results: Response rate was 53% (n = 261). Forty-nine percent of respondents worked in university-affiliated practices. Sixty-two percent of respondents always/usually recommended adjuvant RT for patients with Stage I seminoma, whereas 21% always/usually recommended surveillance and 3% always/usually recommended chemotherapy. One third (33%) expressed concerns that patients who experienced relapse during surveillance could not be salvaged. Although 88% of physicians were aware of an increased risk of second malignant neoplasms (SMN) after adjuvant RT, 85% underestimated its magnitude. Compared with physicians not typically recommending RT, physicians who always/usually recommended RT were more likely to believe that patients might not be salvaged at relapse during surveillance (p = 0.008) and were less aware of the association between RT and SMN (p = 0.04). Conclusions: Respondents who always/usually recommend postorchiectomy RT for patients with Stage I seminoma are more likely to underestimate late RT morbidity and to believe that surveillance is associated with increased mortality. Given the equivalent efficacy and reduced morbidity of surveillance compared with RT, our findings underscore the need for ongoing physician education to increase appropriate clinical implementation of surveillance strategies. [Copyright &y& Elsevier]

Purpose: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. Methods and Materials: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. Results: Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). Conclusions: Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising. [Copyright &y& Elsevier]

Neurologic death is the most serious consequence of intracranial disease among patients with brain metastases. Identifying patients with brain metastases at increased risk of neurologic death can improve care and guide further research. We sought to delineate factors predictive of neurologic death among patients with brain metastases. We identified 1218 patients with newly diagnosed brain metastases managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2008–2015. Factors predictive of neurologic death were assessed via univariable and multivariable Fine and Gray competing risks regression. On multivariable analysis, neurologic death was associated with number of brain metastases (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% confidence interval [CI] 1.01–1.02, P < 0.001) and 3 primary tumor sites (reference=non-small cell lung cancer): melanoma (HR 4.67, 95% CI 3.27–6.68, P < 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47–3.68, P < 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28–3.82, P = 0.005). Conversely, a reduction in neurologic death was found in patients with good Karnofsky performance status (90–100 vs. 30-80, HR 0.67, 95% CI 0.48–0.95, P = 0.03) and progressive extracranial metastases at diagnosis of intracranial disease (HR 0.50, 95% CI 0.38–0.67, P = 0.001). Among patients with breast primaries, HER2+ patients displayed increased neurologic death relative to the reference of HR+/HER2– (univariable analysis only: HR 2.41, 95% CI 1.00–5.84, P = 0.05). Patients with melanoma, small cell lung cancer, gastrointestinal cancer, and HER2+ breast cancer primaries, as well as greater intracranial versus extracranial disease burden, harbor significant risk of neurologic death. Future research investigating novel intracranial approaches should focus on these populations. [ABSTRACT FROM AUTHOR]

Myxopapillary ependymoma (MPE) is a rare, typically slow-growing subtype of spinal ependymomas. There are no standard guidelines for radiotherapy and long-term outcomes after radiation, particularly patterns of relapse, for pediatric and young adult (YA) patients with MPE remain under-characterized. This is an Institutional Review Board-approved multi-institutional retrospective cohort study of 60 pediatric and YA patients diagnosed with MPE and received radiotherapy between 2000-2020. Clinical and treatment characteristics, and long-term outcomes were recorded. Site(s) of progression was compared to radiation fields. Survival outcomes were analyzed using Kaplan-Meier method. Cumulative incidence of local in-field progression (CILP) after initial radiotherapy was analyzed using Gray's method with out-of-field-only progression as a competing risk. Univariate analyses were performed using Cox proportional hazard's model. The median age at radiation was 14.8 years (range: 7.1-26.5). At time of radiotherapy, 45 (75.0%) and 35 (58.3%) patients had gross residual and multifocal disease, respectively. Forty-eight (80.0%), seven (11.7%) and five (8.3%) patients received involved field radiotherapy, craniospinal irradiation, and whole spine radiation, respectively. Median follow-up from end of radiotherapy was 6.2 years (range: 0.6-21.0). Five-year overall survival, progression-free survival, and CILP were 100%, 60.8% and 4.1%, respectively. Both local recurrences were at sites of gross residual disease. Of the eighteen out-of-field first recurrences after radiotherapy, all were superior to the initial treatment field and nine had intracranial relapse. On univariate analyses, distant-only recurrence before radiation (HR: 4.00, 95% CI: 1.54-10.43, p = 0.005) was significantly associated with shorter time to progression. While the risk of recurrence within the radiation field is low, pediatric and YA patients with high-risk MPE remain at risk for recurrences in the spine above the radiation field and intracranially after radiotherapy. Future prospective studies are needed to investigate the appropriate radiation field and dose based on the extent of metastases. [ABSTRACT FROM AUTHOR]

Purpose: To describe patterns of failure (POF) after reirradiation (reRT) with intensity modulated radiation therapy (IMRT) for recurrent/second primary squamous cell carcinoma of the head and neck.Methods: From 08/2004-02/2013, 75 consecutive patients received reRT with IMRT. Gross tumor was generally treated with a 5mm planning target volume (PTV) margin. For postoperative cases, a 5mm PTV was added to the clinical target volume which included the postoperative bed. Elective neck coverage was not standard. POF were characterized by correlating the recurrent tumor location on CT-imaging with the reRT IMRT plan.Results: Patients received definitive reRT (55%) or postoperative reRT (45%) to a median 60Gy (range, 59.4-70Gy). Most patients (88%) received concurrent chemotherapy including induction (16%). The median overall survival was 1.8years. Isolated local-regional recurrence (LRR) was the most common failure-type (2-year cumulative incidence [CI] 22.5% [95% C.I. 13.6-32.7%]), but concurrent LRR and distant-failure occurred frequently (2-year CI LRR+distant-failure 19.6% [95% C.I. 11.3-29.5%]); isolated distant-failure was rare (2-year CI 5.7% [95% C.I. 1.8-12.8%]). The 2-year in-field control was 65% (95% C.I. 52-81%) reflecting encouraging control within the irradiated target. Patients with gross disease were more likely to recur in-field (p=0.02), whereas postoperative patients were more likely to recur out-of-field/marginally than in-field (p=0.02).Conclusions: POF after reRT differ when treating gross disease or postoperatively and should be considered when delineating reRT targets. Aggressive local therapy resulted in favorable in-field control, yet there remains a high competing risk of regional and distant micrometastatic disease. Better systemic agents are needed to control clinically occult local-regional and distant disease. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this cross-sectional study was to characterize long-term breast pain in patients undergoing breast-conserving surgery and radiation (BCT) and to identify predictors of this pain.Methods and Materials: We identified 355 eligible patients with Tis-T2N0M0 breast cancer who underwent BCT in 2007 to 2011, without recurrent disease. A questionnaire derived from the Late Effects Normal Tissue Task Force (LENT) Subjective, Objective, Management, Analytic (SOMA) scale was mailed with 7 items detailing the severity, frequency, duration, and impact of ipsilateral breast pain over the previous 2 weeks. A logistic regression model identified predictors of long-term breast pain based on questionnaire responses and patient, disease, and treatment characteristics.Results: The questionnaire response rate was 80% (n=285). One hundred thirty-five patients (47%) reported pain in the treated breast, with 19 (14%) having pain constantly or at least daily; 15 (11%) had intense pain. The pain interfered with daily activities in 11 patients (8%). Six patients (4%) took analgesics for breast pain. Fourteen (10%) thought that the pain affected their quality of life. On univariable analysis, volume of breast tissue treated to ≥105% of the prescribed dose (odds ratio [OR] 1.001 per cc, 95% confidence interval [CI] 1.000-1.002; P=.045), volume treated to ≥110% (OR 1.009 per cc, 95% CI 1.002-1.016; P=.012), hormone therapy use (OR 1.95, 95% CI 1.12-3.39; P=.02), and other sites of pain (OR 1.79, 95% CI 1.05-3.07; P=.03) predicted for long-term breast pain. On multivariable analysis, volume ≥110% (OR 1.01 per cc, 95% CI 1.003-1.017; P=.007), shorter time since treatment (OR 0.98 per month, 95% CI 0.96-0.998; P=.03), and hormone therapy (OR 1.84, 95% CI 1.05-3.25; P=.03) were independent predictors of pain.Conclusion: Long-term breast pain was common after BCT. Although nearly half of patients had pain, most considered it tolerable. Dosimetric inhomogeneity independently predicted for pain and should be minimized to the greatest extent possible. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. Methods and Materials A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treated with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. Results Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P =.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P =.007) but not dose ( P =.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. Conclusions Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter TTLR, suggesting that radiation dose escalation, addition of radiosensitizers, or a combination of both may be indicated in these patients. [ABSTRACT FROM AUTHOR]

Purpose: To determine the maximum tolerated dose and tolerability of (1) afatinib in combination with postoperative radiation therapy (PORT) for patients with intermediate-risk squamous cell carcinoma of the head and neck (SCCHN) and (2) afatinib in combination with PORT and weekly docetaxel for high-risk SCCHN.Methods and Materials: An open-label, multicenter, 2-cohort, phase 1 dose-escalation trial was conducted using a 3 + 3 design. Eligible patients had definitive surgery for SCCHN, including the oral cavity, oropharynx, larynx, or hypopharynx and had intermediate- or high-risk pathologic features. Afatinib was given for a 1-week lead in before PORT and daily during 6 to 6.5 weeks of PORT with or without weekly docetaxel. The starting dose was 30 mg and could be escalated to 40 mg or de-escalated to 20 mg. The primary objective was to determine the maximum tolerated dose of afatinib with PORT or PORT + docetaxel.Results: Between April 2013 and November 2017, 27 patients were enrolled and started study treatment, including 16 intermediate-risk patients and 11 high-risk patients, all with Eastern Cooperative Oncology Group performance status of 0 to 1. Most patients (n = 25) had oral cavity cancer and were treated to a median total dose of 60 Gy in the intermediate-risk arm and 65 Gy in the high-risk arm. There was 1 grade 4 event, but no deaths. The maximum tolerated dose was not established owing to dose-limiting toxicities (DLTs) in both arms. In the high-risk arm, DLTs were grade 3 mucositis (n = 3) and grade 3 diarrhea/hypokalemia (n = 1). In the intermediate-risk arm, DLTs were grade 3 mucositis (n = 4) and grade 3 diarrhea (n = 2).Conclusions: Afatinib in combination with PORT for mucosal SCCHN was difficult to tolerate because of grade 3 toxicity, mostly mucositis, in a cohort of patients requiring high-dose PORT to the oral cavity. This regimen may be better tolerated for a non-oral cavity site or if given in a different schedule. [ABSTRACT FROM AUTHOR]

Objectives: To characterize specific serious toxicities of reRT with intensity modulated radiation therapy (IMRT) for squamous cell carcinoma of the head and neck (SCCHN) and identify treatment-related predictors of toxicity for patient counseling and decision-making.Materials/methods: 75 consecutive patients with recurrent or 2nd primary SCCHN received reRT from 8/2004-02/2013. All patients had prior definitive or postoperative RT. Objective endpoints of "serious toxicity" were defined as: hospitalization during reRT, tracheotomy after reRT, hemorrhage, soft tissue complication requiring operative intervention, or other CTCAE grade ≥4 toxicity.Results: Patients received definitive (n=41,55%) or postoperative (n=34,45%) reRT (median dose 60Gy, range 59.4-70Gy). Most patients (88%) had concurrent chemotherapy. With a median follow-up of 1.4years, 39 (52%) patients had at least one serious toxicity: hospitalization during reRT (24%), surgically-managed soft tissue complication (19%), and/or urgent tracheotomy (18%). There were no grade 5 acute toxicities but there were 4 fatal hemorrhages (median 8.3months) including 2 attributed to local-regional recurrence (LRR). Most patients (69%) had a percutaneous endoscopic gastrostomy (PEG) tube at last follow-up; those with a LRR had higher PEG tube-dependence rates (86% vs. 53%, p=0.001). LRR, site of reRT, and laryngeal RT dose, were marginally associated with toxicity-risk.Conclusions: Patients considering reRT should be counseled on the high rate of PEG tube-dependence, and events of urgent tracheotomy, hospitalization, hemorrhage, and operative intervention, which typically occur months after reRT completion. Further study of baseline patient function and cumulative radiation dose to the larynx and other organs-at-risk may improve estimates of serious toxicity-risk after reRT. [ABSTRACT FROM AUTHOR]

Purpose: The median survival time of patients with locally advanced adenocarcinoma of the pancreas is 8–10 months. Radiation therapy has been used to improve local control and palliate symptoms. This randomized study was undertaken to determine whether the addition of 5-fluorouracil (5-FU) and mitomycin-C (MMC) to radiation therapy improves outcome in this patient population. Patients and Methods: One hundred fourteen patients were randomized to receive 59.4 Gy external beam radiotherapy in 1.8 Gy fractions alone or in combination with 5-FU (1,000 mg/m2/day for 4 days by continuous infusion Days 2–5 and 28–31) and MMC (10 mg/m2 on Day 2). Results: One hundred four patients were evaluable for efficacy. Hematologic and nonhematologic toxicities were more common in the combination arm. The response rates were 6% in the radiation therapy arm and 9% in the combination arm. There were no differences in median disease-free survival time (DFS) or overall survival time (OS) between the combination and radiation therapy alone arms: 5.1 vs. 5.0 months, respectively, for DFS (p = 0.19) and 8.4 vs. 7.1 months, respectively, for OS (p = 0.16). Conclusion: The addition of 5-FU and MMC to radiotherapy increased toxicity without improving DFS or OS in patients with locally advanced pancreatic cancer. Alternative drugs for radiosensitization may improve outcome. [Copyright &y& Elsevier]