1. A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation.
- Author
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Calegari MA, Inno A, Monterisi S, Orlandi A, Santini D, Basso M, Cassano A, Martini M, Cenci T, de Pascalis I, Camarda F, Barbaro B, Larocca LM, Gori S, Tonini G, and Barone C
- Subjects
- Aged, Aged, 80 and over, Anemia chemically induced, Antineoplastic Agents, Alkylating adverse effects, Colorectal Neoplasms pathology, DNA Methylation, Dacarbazine adverse effects, Dacarbazine therapeutic use, Disease-Free Survival, Female, GTP Phosphohydrolases genetics, Humans, Membrane Proteins genetics, Middle Aged, Mutation, Nausea chemically induced, Neoplasm Metastasis, Promoter Regions, Genetic, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, Retreatment, Survival Rate, Temozolomide, Thrombocytopenia chemically induced, Treatment Outcome, Vomiting chemically induced, Antineoplastic Agents, Alkylating therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, DNA Modification Methylases genetics, DNA Repair Enzymes genetics, Dacarbazine analogs & derivatives, Tumor Suppressor Proteins genetics
- Abstract
Background: 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., Methods: 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
-2 per day on days 1-5 every 28 days., Results: 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., Conclusions: 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.- Published
- 2017
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