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

Alessandra Cassano, Brunella Barbaro, Maria Alessandra Calegari, Armando Orlandi, Tonia Cenci, Ivana De Pascalis, Floriana Camarda, Luigi Maria Larocca, Stelvio Gori, Gerolamo Tonini, Carlo Antonio Barone, A. Inno, D. Santini, S. Gori, G. Tonini

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1279-1286
Number of pages8
JournalBritish Journal of Cancer
Volume116
DOIs
Publication statusPublished - 2017

Keywords

  • Aged
  • Aged, 80 and over
  • Anemia
  • Antineoplastic Agents, Alkylating
  • Colorectal Neoplasms
  • DNA Methylation
  • DNA Modification Methylases
  • DNA Repair Enzymes
  • Dacarbazine
  • Disease-Free Survival
  • Female
  • GTP Phosphohydrolases
  • Humans
  • MGMT
  • Membrane Proteins
  • Middle Aged
  • Mutation
  • Nausea
  • Neoplasm Metastasis
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • Retreatment
  • Survival Rate
  • Temozolomide
  • Thrombocytopenia
  • Treatment Outcome
  • Tumor Suppressor Proteins
  • Vomiting
  • colorectal cancer
  • metastatic
  • temozolomide

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