Slow Accrual

A phase II, randomized study of placebo versus metformin in association to chemotherapy with capecitabine and radiation in the neoadjuvant treatment of locally advanced (T3-4N0M0 or TxN1-2M0) rectal carcinomas.

NEOMETRE is a randomized, double blind trial aiming to evaluate the efficacy and tolerability of metformin in association to chemoradiotherapy for the preoperative treatment of locally advanced (T3-4N0M0 or TxN1-2M0) rectal carcinomas.

Patients eligible for this study will be submitted to neoadjuvant 3D radiotherapy with 50,4 Gray (Gy) divided in 25 applications, in association to capecitabine, 825mg/m2 bid for five days every week. The participants will be randomized to daily metformin or placebo during the chemoradiotherapy period. The primary end-point is pathological complete response. The secondary end-points are recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), local recurrence rate, overall response rate, sphincter preservation rate, quality of life (QoL) and toxicity.

Inclusion Criteria:

• 18 years or older;
• biopsy proven poorly differentiated carcinoma or adenocarcinoma of the rectum;
• lesions located within 12 cm of the anal verge (from colonoscopy assessment);
• ability to tolerate oral treatment;
• locally advanced tumor, classified by the presence of positive regional lymph nodes or primary tumor invasion beyond the serosa (T3 or T4), assessed by MRI;
• eligibility for curative surgery (no distant metastasis or invasion of bony structures of the pelvis);
• Performance Status (PS) Eastern Cooperative Oncology Group (ECOG) 0-2;
• adequate hematologic functions (hemoglobin ≥ 10 g / dL [5.6 mmol / L]; neutrophil count ≥ 1,500 / mm3 and platelet count ≥ 100,000 / mm3), adequate renal function (serum creatinine less than 1.5 times the UNL) and adequate hepatic function (bilirubin less than 1.5 times the UNL; aspartate aminotransferase and alanine aminotransferase less than 2.5 times the UNL);

Exclusion Criteria:

• known hypersensitivity to metformin or its excipients;
• squamous carcinomas of the rectum or anal canal;
• chronic treatment with corticosteroids or other immunosuppressive agents;
• treatment with oral antidiabetic products;
• distant metastasis at diagnosis or tumor invasion of pelvic bone structures that may proscribe curative intent surgery;
• chronic or acute infections;
• use of drugs under study up to four weeks prior to randomization;
• pregnant or nursing patients;
• prior radiotherapy to the pelvic region;
• myocardial infarction up to six months prior to randomization, or uncontrolled ischemic heart disease;
• congestive heart insufficiency New York Heart Association (NYHA) III-IV.