A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

• Published in: British journal of cancer Vol. 116; no. 10; pp. 1279 - 1286
• Main Authors: Calegari, M A, Inno, A, Monterisi, S, Orlandi, A, Santini, D, Basso, M, Cassano, A, Martini, M, Cenci, T, de Pascalis, I, Camarda, F, Barbaro, B, Larocca, L M, Gori, S, Tonini, G, Barone, C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.05.2017
• Subjects: Aged; Aged, 80 and over; Anemia - chemically induced; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - therapeutic use; Cancer therapies; Chemotherapy; Clinical Study; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Disease-Free Survival; DNA Methylation; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Epigenetics; Female; GTP Phosphohydrolases - genetics; Humans; Medical prognosis; Medical research; Membrane Proteins - genetics; Metastasis; Middle Aged; Mutation; Nausea - chemically induced; Neoplasm Metastasis; Oncology; Promoter Regions, Genetic; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Response rates; Retreatment; Survival Rate; Temozolomide; Thrombocytopenia - chemically induced; Treatment Outcome; Tumor Suppressor Proteins - genetics; Tumors; Vomiting - chemically induced; Italy
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.109

Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m per day on days 1-5 every 28 days. From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.