A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol.
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.



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.



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.



ISRCTN14138956 . Funded by CRUK.
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Daniel L P
DL
Holyoake
Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Elizabeth
E
Ward
The Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow, G12 0YN, UK.
Derek
D
Grose
The Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow, G12 0YN, UK.
David
D
McIntosh
The University of Leeds, Cancer Research UK Leeds Centre,14 Leeds Institute of Cancer and Pathology, Cancer Genetics Building, St James's University Hospital, 15 Beckett Street, Leeds, West Yorkshire, LS9 7TF, UK.|Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Bexley Wing, Beckett Street, Leeds, LS9 7TF, UK.
David
D
Sebag-Montefiore
Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Bexley Wing, Beckett Street, Leeds, LS9 7TF, UK.
Ganesh
G
Radhakrishna
Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford, OX3 7LE, UK.
Neel
N
Patel
Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford, OX3 7LE, UK.
Michael
M
Silva
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.|Oxford University Hospitals NHS Foundation Trust, Old Road, Headington, Oxford, OX3 7LE, UK.
Somnath
S
Mukherjee
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD, UK.
Victoria Y
VY
Strauss
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford, OX3 7LD, UK.
Lang'o
L
Odondi
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Emmanouil
E
Fokas
The Institute of Cancer Research, Chester Beatty Laboratories, 237, Fulham Rd, London, SW3 6JB, UK.
Alan
A
Melcher
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK. maria.hawkins@oncology.ox.ac.uk.
Maria A
MA
Hawkins
D005260:Female; D006801:Humans; D008297:Male; D019583:Dose Fractionation, Radiation; D010190:Pancreatic Neoplasms / Q000532:radiotherapy; D011446:Prospective Studies; D016634:Radiosurgery / Q000009:adverse effects / Q000379:methods; D011880:Radiotherapy Planning, Computer-Assisted; D016019:Survival Analysis; D016896:Treatment Outcome
Borderline-resectable; Pancreatic cancer; Stereotactic body radiation therapy (SBRT)