Evaluation of hypofractionated adaptive radiotherapy using the MR Linac in localised pancreatic cancer: protocol summary of the Emerald-Pancreas phase 1/expansion study located at Oxford University Hospital, UK.

INTRODUCTION: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas. METHODS AND ANALYSIS: This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED10)=100 Gy), 39 Gy in three (BED10=90 Gy) or 25 Gy in a single fraction (BED10=87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in. ETHICS AND DISSEMINATION: The trial is approved by the West Midlands-Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement. TRIAL REGISTRATION NUMBER: ISRCTN10557832.

Prospective randomised phase II trial evaluating adjuvant pelvic radiotherapy using either IMRT or 3-Dimensional planning for endometrial cancer.

OBJECTIVE: To compare the incidence of grade ≥2 gastrointestinal (GI) or genitourinary (GU) toxicity for patients undergoing 3DRT versus IMRT in the postoperative setting for endometrial cancer. METHODS: Eligible patients were post-operatively randomly assigned to one of two parallel groups in a 1:1 ratio, to have their RT delivered using either a 3DRT technique or using IMRT. The prescription dose was 45 Gy in 25 fractions over 5 weeks followed by vaginal vault brachytherapy. Toxicity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0. Fisher's exact tests were used to test for associations between toxicity and arm. Differences in dosimetric parameters for patients with or without toxicity were tested using Mann-Whitney U-tests. RESULTS: 84 patients with a median age of 62 were evaluable for primary outcome. The median follow-up was 52 months. 14 (35%) participants from the 3DRT arm and 15 (34%) from the IMRT arm experienced acute grade ≥2 GI toxicity with older patients having a statistically higher risk of grade ≥2 acute GI toxicity. 20 (50%) participants from the 3DRT arm and 25 (57%) from the IMRT arm experienced acute grade ≥2 GI or GU toxicity (p = .662). 12 (30%) patients from the 3DRT arm and 17 (39%) from the IMRT arm experienced acute grade ≥2 GU toxicity (p = .493). CONCLUSION: Although IMRT can reduce dose to normal tissue, in this study no benefit in acute GI or GU toxicity outcome was seen.

The oligometastatic paradigm and the role of radiotherapy.

Most cancer-related deaths are due to metastatic disease. There is now an emerging evidence base suggesting that a subgroup of metastatic patients benefit significantly from local resection (surgery) or ablation (stereotactic ablative body radiation, SABR) of their metastatic sites. These patients are in what has been termed the 'oligometastatic state', a transitional window between local and disseminated disease where locally ablative, metastasis-directed therapy prolongs progression-free survival, improves overall survival and sometimes achieves cure. Appropriately selecting those who fit this oligometastatic phenotype, while integrating advances in ablative technologies such as SABR with modern systemic treatments, is an evolving challenge for oncologists.

Quantification of Organ Motion in Male and Female Patients Undergoing Long-Course Radiation Therapy for Rectal Cancer in the Supine Position.

Purpose: Previous studies have reported data on the internal rectal motion of patients with rectal cancer treated in the prone position. With the introduction of intensity modulated techniques, more patients are treated in the more reproducible supine position. Data informing specific margins for this treatment position are sparse, as are data comparing rectal motion characteristics and factors in male and female patients. The purpose of this retrospective study was to quantify and compare the interfractional rectal movement characteristics of male and female patients with rectal cancer treated with long-course chemoradiation therapy in the supine position. The data will aid the generation of internal target volume margins accounting for this organ's internal physiological movements. Methods and Materials: Cone beam computed tomography (CBCT) images were acquired from 19 male and 16 female patients with rectal cancer on the first 3 days of treatment and weekly thereafter. The rectum, bladder, and femoral heads were delineated on the planning CT (PCT) and 6 CBCT for each patient. Overall, 245 images were analyzed. All patients were treated with a full bladder. The rectum was divided into three 5-cm segments (upper, mid, and lower). The motion of the rectum was quantified by documenting the anteroposterior and lateral distances as measured using fixed anatomic landmarks, namely from the anterior aspect of the sacrum and mid-left femoral head, respectively. These measurements were taken at 1-cm intervals from the inferior border of L5 vertebrae. The sigmoid was excluded from these measurements. Estimations of systematic and random physiological movement error were determined and margins were calculated. Results: Two hundred forty-five image sets (19 PCT + 114 CBCT for male, 16 PCT + 96 CBCT for female) on patients who had undergone long-course radiation therapy were analyzed. Rectal tumor location was 31% in the inferior rectum, 46% in the mid rectum, and 23% in the superior rectum. Random rectal motion (mean of the per-patient standard deviation [σ]) was largest for the upper and mid rectum in the anterior direction. There were statistically significant differences in σ between male and female patients in the left lateral motion of the mid and inferior rectum as well as the anterior, posterior, and right motion of the inferior rectum (mid left: P < .0005; lower left: P < .0005; lower posterior: P = .001; lower anterior: P = .032; lower right: P = .001). Suggested internal target volume margin guidelines are therefore nonisotropic and vary per segment of rectum and sex. Conclusions: In our present study, interfractional rectal motion is shown to be significantly different between male and female patients. Our data suggest that the use of asymmetrical sex-specific margins in patients with rectal cancer treated in the supine position should be considered.

Anal squamous cell carcinoma: a retrospective case series.

BACKGROUND: Anal cancer is a relatively rare cancer with 660 cases diagnosed in 2000-2015 in Ireland (1). The current standard treatment is radical chemoradiotherapy (CRT). The aim of our study was to review the treatment and outcomes of patients with localised anal squamous cell carcinoma (SCC), who received radical treatment in our radiation oncology network between 2008 and 2014 inclusive. METHODS: Data were collected retrospectively from ARIA® oncology information system and patient charts. Statistical analyses were performed using IBM® SPSS® statistical software version 25.0. RESULTS: Seventy-nine cases of anal SCC were identified. Mean age of patients at commencement of radiotherapy (RT) was 60.2 years (standard deviation: 13.1 years). The most common total RT dose was 50.4 Gy in 28 fractions (N = 58; 73.4%). Median follow-up was 5.6 years. Two (2.6%) patients had persistent disease, seventeen (21.8%) patients developed loco-regional recurrence and nine (11.5%) patients developed solid organ metastases, four of whom had complete treatment response at the primary site. Eight patients underwent salvage anal surgery following completion of RT. Median overall survival was 10.5 years (95% confidence interval (CI) 5.1-15.8 years), median loco-regional relapse-free survival was 10.4 years (95% CI 4.4-16.3 years) and median disease-free survival was 9.3 years (95% CI 6.3-12.2 years). CONCLUSION: Our study demonstrates that treatment for anal SCC and outcomes following definitive CRT in Ireland during the study period were comparable to international standards.

Competing mortality risks: predicted cardiovascular disease risk versus predicted risk of breast cancer mortality in patients receiving adjuvant chemotherapy in a single Irish center.

BACKGROUND: Due to advances in care, most women diagnosed with breast cancer do not die from the disease itself. Instead, cardiovascular disease (CVD) remains the most frequent cause of death. Many breast cancer patients are older and have established CVD risk factors. They are at further risk due to exposure to anthracyclines, HER2 targeted agents, endocrine therapy and radiotherapy. In this study, we compared the 10-year predicted risk of breast cancer mortality versus that of cardiovascular (CV) morbidity/mortality in breast cancer patients receiving adjuvant chemotherapy using online predictive risk calculators. Furthermore, we evaluated the predicted outcome of CV risk factor optimisation on their overall CV risk. METHODS: This was a cross sectional study. All patients with resected Stage I-III breast cancer who received adjuvant chemotherapy at our centre from September 2015 to November 2016 were identified. Data recorded included demographics, tumor characteristics, treatments and CV risk factors. To calculate predicted 10-year risk of CVD and impact of lifestyle changes, we used the JBS3 (Joint British Society) online risk calculator. To calculate the predicted 10-year risk of breast cancer mortality, we used the PREDICT calculator. Biostatistical methods included Wilcoxon signed rank test for predicted CVD risk pre and post cardiovascular risk optimization. RESULTS: We identified 102 patients. Of this cohort, 76 patients were ≥ 50 years & 26 were < 50 years of age. The group had significant baseline cardiovascular risk factors: increased BMI (68 %, n = 70), ex-smoking (34 %, n = 35), current smoking (13 %, n = 13), hypertension (47 %, n = 47) and dyslipidemia (57 %). Of the total group, 48 % had a high (> 20 %) and 37 % had a moderate (10-20 %) 10-year predicted breast cancer mortality risk. Regarding 10-year predicted risk of CVD, 11 % and 22 % fell into the high (> 20 %) and moderate (10-20 %) risk categories, respectively. Assuming CV risk factor optimisation, there was a predicted improvement in median 10-year CV risk from 26.5 to 9.9 % (p = .005) in the high CVD risk group and from 14.0 to 6.6 % (p < .001) in the moderate CVD risk group. CONCLUSIONS: Benefits predicted with a CVD risk intervention model indicates that this should be incorporated into routine breast oncology care.

Stereotactic radiosurgery to surgical cavity post resection of brain metastases: Local recurrence and overall survival rates. A single-centre experience.

INTRODUCTION: We reviewed local control (LC) and overall survival (OS) post intracranial SRS to cavity post resection of brain metastases at one institution, and factors affecting LC. METHODS: A retrospective review was conducted of adjuvant SRS at one institution from 2013 to 2016. Patient records, treatment plans and diagnostic images were reviewed. Local failure was MRI defined. Categorical variables were analysed using chi-square and Fisher's exact tests. Continuous variables were analysed using Mann-Whitney tests. The Kaplan-Meier method was used to estimate survival times and the log-rank test was used to compare differences in survival. RESULTS: Forty-seven patients with 48 cavities were treated with SRS post operatively. LC rate was 69%, and the distant intracranial failure rate was 47% for entirety of the follow-up period. The 12-month freedom from local recurrence (FFLR) was 77% (63-91%). Median OS (95% CI) was 22.7 (14.6-30.8) months. Patients with a single metastasis had longer FFLR (30.1 vs 14.4 months; P = 0.014). Median interval from surgery to SRS was 6.3 weeks. Patients with interval >7 weeks had increased local recurrence (LR) (62%) than <7 weeks (37%), P = 0.025. Patients with a margin < 2 mm were more likely to experience LR (48%) than those with margin equal to 2 mm (20%); this approached statistical significance (P = 0.063). The median follow-up for all patients was 15.4 months (2-41). CONCLUSIONS: We determined LC and OS post adjuvant SRS at our institution. Based on the findings of this retrospective review SRS should be given promptly post operatively with a 2 mm PTV margin.