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Background and Purpose: Margin-directed neoadjuvant radiotherapy for borderline-resectable pancreatic cancer (BRPC) aims to facilitate clear surgical margins. A systematic method was developed for definition of a boost target volume prior to a formal phase-I study., Material and Methods: Reference structures were defined by two oncologists and one radiologist, target structures were submitted by eight oncologist investigators and compared using conformity indices. Resultant risk of duodenal bleed (NTCP) was modelled., Results: For GTV, reference volume was 2.1cm 3 and investigator mean was 6.03cm 3 (95% CI 3.92-8.13cm 3 ), for boost volume 1.1cm 3 and 1.25cm 3 (1.02-1.48cm 3 ). Mean Dice conformity coefficient for GTV was 0.47 (0.38-0.56), and for boost volume was significantly higher at 0.61 (0.52-0.70, p=0.01). Discordance index (DI) for GTV was 0.65 (0.56-0.75) and for boost volume was significantly lower at 0.39 (0.28-0.49, p=0.001). NTCP using reference contours was 2.95%, with mean for investigator contour plans 3.93% (3.63-4.22%). Correlations were seen between NTCP and GTV volume (p=0.02) and NTCP and DI (correlation coefficient 0.83 (0.29-0.97), p=0.01)., Conclusions: Better conformity with reference was shown for boost volume compared with GTV. Investigator GTV volumes were larger than reference, had higher DI scores and modelled toxicity risk. A consistent method of target structure definition for margin-directed pancreatic radiotherapy is demonstrated., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control., Methods/design: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015., Discussion: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options., Trial Registration: ISRCTN14138956 . Funded by CRUK.