Metformin with neoadjuvant chemoradiation to improve pathologic response in rectal cancer: A pilot phase I/II trial

C S Wong; W Chu; S Ashamalla; D Fenech; S Berry; A Kiss; M Koritzinsky

doi:10.1016/j.ctro.2021.07.001

Metformin with neoadjuvant chemoradiation to improve pathologic response in rectal cancer: A pilot phase I/II trial

Clin Transl Radiat Oncol. 2021 Jul 22:30:60-64. doi: 10.1016/j.ctro.2021.07.001. eCollection 2021 Sep.

Authors

C S Wong¹, W Chu¹, S Ashamalla², D Fenech², S Berry³, A Kiss⁴, M Koritzinsky⁵

Affiliations

¹ Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada.
² Division of Surgical Oncology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada.
³ Department of Oncology, Queen's University, Ontario, Canada.
⁴ Institute for Clinical Evaluative Sciences, Institute of Health Policy, Management and Evaluation, University of Toronto, Ontario, Canada.
⁵ Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Ontario, Canada.

Abstract

Purpose: Neoadjuvant radiotherapy with or without chemotherapy decreases the risk of local recurrence after surgery for rectal cancer. Emerging data suggest that diabetic patients on metformin may have improved cancer outcome after radiotherapy. A single institutional pilot study was performed to determine if metformin given concurrently with long course chemoradiation (CRT) may improve pathologic complete response (pCR) in non-diabetic rectal cancer patients. The study was designed to construct a confidence interval (CI) for the pCR rate to determine the sample size for a phase 2 trial.

Methods: Non-diabetic patients with biopsy confirmed rectal cancer deemed candidates for long course neoadjuvant CRT were invited to participate. Radiation consisted of 50.4 Gy in 28 daily fractions with concurrent daily capecitabine (825 mg/m² twice daily). Participants self-administered metformin (500 mg of twice daily) 2 weeks prior to, during and for 4 weeks after CRT.

Results: A total of 16 patients were accrued. One patient withdrew from the study. Only grade 1 or 2 adverse events were observed. Three patients had a clinical complete response (cCR) and did not undergo surgery. Of the 12 patients who underwent surgery, there were two pCRs. For the combined pCR/cCR rate of 33% (95% CI 19-47%), a total of 85 patients will be required to yield a 95% CI with a 10% margin of error.

Conclusions: Adding metformin to neoadjuvant CRT for rectal cancer does not appear to enhance toxicities. These results will be used to refine the design and conduct of a future phase 2 trial to determine whether adding metformin to CRT improves pCR/cCR rates.

Keywords: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood counts; CI, confidence interval; CRT, chemoradiation; CT, computerized tomography; CTCAE, Common Terminology Criteria for Adverse Events; ICF, Informed Consent Form; IHC-GCP, International Conference on Harmonization Good Clinical Practice; MRI, magnetic resonance imaging; Metformin; Neoadjuvant chemoradiation; Pathologic response; REB, Research Ethics Board; Rectal cancer; TME, total mesorectal excision; cCR, clinical complete response; pCR, pathological complete response.