Induction versus no induction chemotherapy before neoadjuvant chemoradiotherapy and surgery in oesophageal adenocarcinoma: a multicentre randomised phase II trial (NCCTG N0849 [Alliance]).

AIM: report primary results from the first multicentre randomised trial evaluating induction chemotherapy prior to trimodality therapy in patients with oesophageal or gastro-oesophageal junction adenocarcinoma. Notably, recent data from a single-institution randomised trial reported that induction chemotherapy prolonged overall survival (OS) in patients with well/moderately differentiated tumours. METHODS: In this phase 2 trial (28 centres in the U.S. NCI-sponsored North Central Cancer Treatment Group [Alliance]), trimodality-eligible patients (T3-4N0, TanyN+) were randomised to receive induction (docetaxel, oxaliplatin, capecitabine; Arm A) or no induction chemotherapy (Arm B) followed by oxaliplatin/5-fluorouracil/radiation and subsequent surgery. The primary endpoint was the rate of pathologic complete response (pathCR). Secondary/exploratory endpoints were OS and disease-free survival (DFS). RESULTS: Of 55 patients evaluable for the primary endpoint, the pathCR rate was 28.6% (8/28) in A versus 40.7% (11/27) in B (P = .34). Given interim results indicating futility, accrual was terminated, but patients were followed. After a median follow-up of 60.4 months, a longer median OS in Arm A versus B was unexpectedly observed (3-year rates 57.1% versus 41.7%, respectively) driven by longer DFS after margin-free surgery. In posthoc analysis, induction (versus no induction) chemotherapy was associated with significantly longer OS and DFS among patients with well/moderately differentiated tumours, but not among patients with poorly/undifferentiated tumours (Pinteraction = 0.037). CONCLUSIONS: Adding induction chemotherapy prior to trimodality therapy did not improve the primary endpoint, pathCR. However, induction chemotherapy was associated with longer median OS, particularly among patients with well/moderately differentiated tumours. These findings may inform further development of curative-intent trials in this disease.

Linear accelerator-based single-fraction stereotactic body radiotherapy for symptomatic vertebral body hemangiomas: The Mayo Clinic experience.

Symptomatic vertebral hemangiomas (SVHs) are rare benign tumors that when symptomatic require procedural intervention or radiotherapy (RT). Although conventionally-fractionated RT has been an alternative to surgical resection, there is very little data on stereotactic body radiotherapy (SBRT) for SVHs. Six consecutively treated patients with SVHs underwent definitive single-fraction SBRT from 2010 to 2018 at our institution. The RT planning parameters, treatment, outcome, and toxicities are reported for 6 patients with 6 total SVHs treated with single-fraction SBRT. Each patient presented with back pain and received single-fraction SBRT to a thoracic vertebral body hemangioma. One patient had received radiofrequency ablation prior to SBRT. The median SBRT dose was 18 Gy (range, 13-20). Following SBRT, 4 (67%) patients reported improvement in presenting symptoms and 2 patients (33%) were refractory. There were no acute or chronic toxicities associated with SBRT including esophagitis, vertebral compression fractures, or myelopathy. To date, this is the largest series of single-fraction SBRT for SVHs. Single fraction SBRT appears to be a feasible option for SVHs. Further studies are needed to confirm our preliminary findings and optimize dose fractionation.

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Daily Lisinopril vs Placebo for Prevention of Chemoradiation-Induced Pulmonary Distress in Patients With Lung Cancer (Alliance MC1221): A Pilot Double-Blind Randomized Trial.

PURPOSE: Chemoradiation (CRT) is an integral treatment modality for patients with locally advanced lung cancer. It has been hypothesized that current use of an angiotensin-converting enzyme inhibitor during CRT may be protective for treatment-related lung damage and pneumonitis. METHODS AND MATERIALS: We conducted a pilot, double-blind, placebo-controlled, randomized trial. Study-eligible patients receiving curative thoracic radiation therapy (RT) were randomly assigned to 20 mg of lisinopril or placebo once daily during and up to 3 months after RT. All patients received concurrent chemotherapy. The primary endpoint was adverse event profiling. Multiple patient-reported outcome (PRO) surveys, including the Lung Cancer Symptom Scale, Function Assessment of Cancer Therapy-Lung, and the European Organisation for Research and Treatment of Cancer Lung Cancer Questionnaire, were applied with a symptom experience questionnaire. Exploratory comparative statistics were used to detect differences between arms with χ2 and Kruskal-Wallis testing. RESULTS: Five institutions enrolled 23 patients. However, accrual was less than expected. Eleven and 12 patients were in the placebo and lisinopril arms, respectively (mean age, 63.5 years; male, 62%). Baseline characteristics were balanced. Eighteen patients (86%) were former or current smokers. The primary endpoint was met; neither arm had grade 3 or higher hypotension, acute kidney injury, allergic reaction (medication-induced cough), or anaphylaxis (medication-related angioedema). Few PRO measures suggested that compared with the placebo arm, patients receiving lisinopril had less cough, less shortness of breath, fewer symptoms from lung cancer, less dyspnea with both walking and climbing stairs, and better overall quality of life (for all, P < .05). CONCLUSIONS: Although underpowered because of low accrual, our results suggest that there was a clinical signal for safety-and possibly beneficial by limited PRO measures-in concurrently administering lisinopril during thoracic CRT to mitigate or prevent RT-induced pulmonary distress. Our results showed that a definitive, larger-scale, randomized phase 3 trial is needed in the future.

Data collection of patient outcomes: one institution's experience.

Patient- and provider-reported outcomes are recognized as important in evaluating quality of care, guiding health care policy, comparative effectiveness research, and decision-making in radiation oncology. Combining patient and provider outcome data with a detailed description of disease and therapy is the basis for these analyses. We report on the combination of technical solutions and clinical process changes at our institution that were used in the collection and dissemination of this data. This initiative has resulted in the collection of treatment data for 23 541 patients, 20 465 patients with provider-based adverse event records, and patient-reported outcome surveys submitted by 5622 patients. All of the data is made accessible using a self-service web-based tool.

Alliance for clinical trials in oncology (ALLIANCE) trial A021501: preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas.

BACKGROUND: Borderline resectable pancreatic cancers infiltrate into adjacent vascular structures to an extent that makes an R0 resection unlikely when pancreatectomy is performed de novo. In a pilot study, Alliance for Clinical Trials in Oncology Trial A021101, the median survival of patients who received chemotherapy and radiation prior to anticipated pancreatectomy was 22 months, and 64% of operations achieved an R0 resection. However, the individual contributions of preoperative chemotherapy and radiation therapy to therapeutic outcome remain poorly defined. METHODS: In Alliance for Clinical Oncology Trial A021501, a recently activated randomized phase II trial, patients (N = 134) with a CT or MRI showing a biopsy-confirmed pancreatic ductal adenocarcinoma that meets centrally-reviewed anatomic criteria for borderline resectable disease will be randomized to receive either 8 cycles of modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles) or to 7 cycles of modified FOLFIRINOX followed by stereotactic body radiation therapy (33-40 Gy in 5 fractions). Patients without evidence of disease progression following preoperative therapy will undergo pancreatectomy and will subsequently receive 4 cycles of postoperative modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, bolus 5-fluorouracil 400 mg/m2, and infusional 5-fluorouracil 2400 mg/m2 over 2 days for 4 cycles). The primary endpoint is the 18-month overall survival rate of patients enrolled into each of the two treatment arms. An interim analysis of the R0 resection rate within each arm will be conducted to assess treatment futility after accrual of 30 patients. Secondary endpoints include rates of margin-negative resection and event-free survival. The primary analysis will compare the 18-month overall survival rate of each arm to a historical control rate of 50%. The trial is activated nationwide and eligible to be opened for accrual at any National Clinical Trials Network cooperative group member site. DISCUSSION: This study will help define standard preoperative treatment regimens for borderline resectable pancreatic cancer and position the superior arm for further evaluation in future phase III trials. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02839343 , registered July 14, 2016.

Doxepin rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy: a phase III, randomized, double-blind trial (NCCTG-N09C6 [Alliance]).

PURPOSE: Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain. PATIENTS AND METHODS: In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1. RESULTS: Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (-9.1) than for placebo (-4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and -2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study. CONCLUSION: A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.

Factors associated with endocrine deficits after stereotactic radiosurgery of pituitary adenomas.

OBJECTIVE: To analyze the factors associated with anterior pituitary deficits after pituitary adenoma stereotactic radiosurgery (SRS). METHODS: The tumor, pituitary stalk, and pituitary gland were segmented on the dose plans of 82 patients (secreting tumors, n = 53; nonsecreting tumors, n=29) for dose-volume analysis. No patient had undergone prior radiation therapy and all patients had at least 12 months of endocrinological follow-up (median, 63 months; mean, 69 months; range, 13-134). RESULTS: Thirty-four patients (41%) developed new anterior pituitary deficits at a median of 32 months (range, 2-118) after SRS. The risk of developing new anterior pituitary deficits was 16% and 45% at 2 and 5 years, respectively. Multivariate analysis of the entire group showed that poor visualization of the pituitary gland (hazard ratio [HR]=2.63, 95% confidence interval [CI]=1.10-6.25, P=.03) was associated with a higher rate of new anterior pituitary deficits. Dosimetric analysis of 60 patients whose pituitary gland could be clearly identified showed that increasing mean pituitary gland radiation dose correlated with new anterior pituitary deficits (HR=1.11, 95% CI=1.02-1.20, P=.02). New anterior pituitary deficits stratified by mean pituitary gland radiation dose: 19.1 Gy, 83% (5/6). CONCLUSION: New endocrine deficits after pituitary adenoma radiosurgery were correlated with increasing radiation dose to the pituitary gland. Methods that limit the radiation dose to the pituitary gland during SRS may increase the probability of preserving pituitary function.

Validation of a method for assessing resident physicians' quality improvement proposals.

BACKGROUND: Residency programs involve trainees in quality improvement (QI) projects to evaluate competency in systems-based practice and practice-based learning and improvement. Valid approaches to assess QI proposals are lacking. OBJECTIVE: We developed an instrument for assessing resident QI proposals--the Quality Improvement Proposal Assessment Tool (QIPAT-7)-and determined its validity and reliability. DESIGN: QIPAT-7 content was initially obtained from a national panel of QI experts. Through an iterative process, the instrument was refined, pilot-tested, and revised. PARTICIPANTS: Seven raters used the instrument to assess 45 resident QI proposals. MEASUREMENTS: Principal factor analysis was used to explore the dimensionality of instrument scores. Cronbach's alpha and intraclass correlations were calculated to determine internal consistency and interrater reliability, respectively. RESULTS: QIPAT-7 items comprised a single factor (eigenvalue = 3.4) suggesting a single assessment dimension. Interrater reliability for each item (range 0.79 to 0.93) and internal consistency reliability among the items (Cronbach's alpha = 0.87) were high. CONCLUSIONS: This method for assessing resident physician QI proposals is supported by content and internal structure validity evidence. QIPAT-7 is a useful tool for assessing resident QI proposals. Future research should determine the reliability of QIPAT-7 scores in other residency and fellowship training programs. Correlations should also be made between assessment scores and criteria for QI proposal success such as implementation of QI proposals, resident scholarly productivity, and improved patient outcomes.

Central neurocytoma: management recommendations based on a 35-year experience.

PURPOSE: To examine the outcomes of patients with histologically confirmed central neurocytomas. METHODS AND MATERIALS: The data from 45 patients with central neurocytomas diagnosed between 1971 and 2003 were retrospectively evaluated. Various combinations of surgery, radiotherapy (RT), and chemotherapy had been used for treatment. RESULTS: The median follow-up was 10.0 years. The 10-year overall survival and local control rate was 83% and 60%, respectively. Patients whose tumor had a mitotic index of <3 (per 10 high-power fields) experienced a 10-year survival and local control rate of 89% and 74%, respectively, compared with 57% (p = 0.040) and 46% (p = 0.14) for patients with a tumor mitotic index of > or =3. The 10-year survival and local control rate was 90% and 74% for patients with typical tumors compared with 63% (p = 0.055) and 46% (p = 0.41) for those with atypical tumors. A comparison of gross total resection with subtotal resection showed no significant difference in survival or local control. Postoperative RT improved local control at 10 years (75% with RT vs. 51% without RT, p = 0.045); however, this did not translate into a survival benefit. No 1p19q deletions were found in the 19 tumors tested. CONCLUSION: Although the overall prognosis is quite favorable, one-third of patients experienced tumor recurrence or progression at 10 years, regardless of the extent of the initial resection. Postoperative RT significantly improved local control but not survival, most likely because of the effectiveness of salvage RT. For incompletely resected atypical tumors and/or those with a high mitotic index, consideration should be given to adjuvant RT because of the more aggressive nature.