SPAR: A randomized placebo-controlled phase 2 trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: An AGITG clinical trial.

Abstract

TPS3646 Background: In retrospective studies statin use during preoperative chemo-radiation (pCRT) for rectal cancer is associated with improved overall survival, pathological tumor response and treatment toxicity. In vivo preclinical studies show that statins radiosensitize cancer cells, with improved tumor control and reduced radiation-induced gastrointestinal (GI) and skin toxicities. A prospective randomized trial is justified to confirm these clinically important benefits. Tumor regression following pCRT has strong prognostic significance, as assessed radiologically (MRI-based tumor regression grading [mrTRG]) prior to, or pathologically (pathTRG) following, surgery. Using mrTRG after each treatment phase in total neoadjuvant therapy (TNT) programs could assess incremental tumor regression and optimize patient management including surgery. Methods: Design: This double-blind phase 2 trial is recruiting 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 17 sites in New Zealand and Australia. Patients are randomized to simvastatin 40mg or placebo daily for 90 days, starting 1 week prior to pCRT, with minimization for major prognostic variables. Pelvic MRI at baseline and 6-8 weeks after pCRT will assess mrTRG. A protocol amendment allows TNT using consolidation chemotherapy after pCRT; MRI timing is unchanged. Primary objective: comparison of rates of grades 1-2 mrTRG following pCRT with simvastatin or placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives: comparison of rates of grades 1-2 pathTRG in resected tumors; incidence of > grade 2 acute GI and non-GI adverse events (AE); incidence of late GI AE; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection post-pCRT; 3-year local recurrence rate, disease-free and cancer-specific survival; and pathological scores for radiation colitis. Tertiary and correlative objectives: association between mrTRG and pathTRG grouping; inter-observer scoring agreement on mrTRG and pathTRG; comparison of the association between tumor CD3+ and/or CD8+ T-cell infiltrates in diagnostic biopsies and pathTRG; intensity and distribution of subsets of infiltrating T-cells in 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). Eligibility criteria exclude statin use within 6 weeks prior to trial entry, patients intolerant of statins, and planned use of oxaliplatin or biological agents during pCRT. Trial recruitment commenced April 2018 and 95 of 222 patients have been recruited as at 21 January 2022. Clinical trial information: ACTRN12617001087347.