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Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Rectal Cancer | Study protocol

SPAR – a randomised, placebo-controlled phase II trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: an AGITG clinical trial

Authors: Michael B. Jameson, Kirsten Gormly, David Espinoza, Wendy Hague, Gholamreza Asghari, Grahame Mark Jeffery, Timothy Jay Price, Christos Stelios Karapetis, Michael Arendse, James Armstrong, John Childs, Frank A. Frizelle, Sam Ngan, Andrew Stevenson, Martinus Oostendorp, Stephen P. Ackland

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG).

Methods

A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours; incidence of toxicity; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection; cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping; inter-observer agreement on mrTRG scoring and pathTRG scoring; studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018.

Discussion

When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations.

Trial registration

ANZ Clinical Trials Register ACTRN12617001087​347.
(www.​anzctr.​org.​au, registered 26/7/2017)
Protocol Version: 1.1 (June 2017).
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Metadata
Title
SPAR – a randomised, placebo-controlled phase II trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: an AGITG clinical trial
Authors
Michael B. Jameson
Kirsten Gormly
David Espinoza
Wendy Hague
Gholamreza Asghari
Grahame Mark Jeffery
Timothy Jay Price
Christos Stelios Karapetis
Michael Arendse
James Armstrong
John Childs
Frank A. Frizelle
Sam Ngan
Andrew Stevenson
Martinus Oostendorp
Stephen P. Ackland
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6405-7

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