A randomized phase 2/3 trial of rosuvastatin with neoadjuvant chemo-radiation in patients with locally advanced rectal cancer

Prachi S Patil ^1* Avanish P Saklani ² Naveena Kumar AN ³ Ashwin De Souza ² Rahul Krishnatry ⁴ Snehal Khanvilkar ⁵ Mufaddal Kazi ² Reena Engineer ⁴ Vikas Ostwal ⁶ Anant Ramaswamy ⁶ Munita Bal ⁷ Priya Ranganathan ⁸ Sanjeev Galande ⁹

• ¹ Department of Digestive Diseases & Clinical Nutrition, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ² Department of surgical oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ³ Department of Surgical oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
• ⁴ Homi Bhabha National Institute, Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ⁵ Project Associate II, , Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ⁶ Homi Bhabha national Institute, Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ⁷ Department of Pathology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ⁸ Department of Anaesthesiology, Tata Memorial Hospital, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
• ⁹ Laboratory of Chromatin Biology & Epigenetics, Indian Institute of Science Education and Research, Pune, Pune, Maharashtra, India

Aim: Statins have shown to improve the possibility of a pathologic complete response (pCR) in patients with locally advanced rectal cancer when given in combination with neoadjuvant chemoradiotherapy (NACTRT) in observational studies. The primary objective of this phase II randomized controlled trial (RCT) is to determine the impact of rosuvastatin in improving pCR rates in patients with locally advanced rectal cancer, who are undergoing NACTRT. The secondary objectives are to compare adverse events, postoperative morbidity and mortality and disease free survival (DFS) and overall survival in the two arms and to identify potential prognostic and predictive factors determining outcomes. If the study is positive, we plan to proceed to a phase III RCT with 3 year DFS as the primary end point.Methods: This is a prospective, randomized, open label phase II/III study. The phase II study has a sample size of 316 patients (158 in each arm) to be accrued over 3 years to have 288 evaluable patients. The standard arm will receive NACTRT while the intervention group will receive 20 mg Rosuvastatin orally once daily along with NACTRT for 6 weeks followed by rosuvastatin alone for 6-10 weeks till surgery. All patients will be reviewed after repeat imaging in a multidisciplinary tumor board at 12-16 weeks after starting NACTRT and operable patients will be planed for surgery . The pathological response rate and tumor regression grade (TRG) as well as post-surgical complications will be recorded.The addition of rosuvastatin to NACTRT may improve the oncological outcomes by increasing the likelihood of pCR in patients with locally advanced rectal cancer undergoing NACTRT. This would be a low cost, low risk intervention which could potentially lead to refinement of strategies like 'watch and wait' subsequently in a select subgroup of patients.