title: Activity of temozolomide in patients with advanced chemorefractory colorectal cancer and MGMT promoter methylation.
abstract: BACKGROUND
  No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments.
  
  
  METHODS
  Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease.
  
  
  RESULTS
  Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P=0.004). TP53 status had no influence on the primary end point.
  
  
  CONCLUSIONS
  Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.
authors.affiliation: Department of Medical Oncology.
authors.forename: F
authors.initials: F
authors.lastname: Pietrantonio
authors.forename: F
authors.initials: F
authors.lastname: Perrone
authors.forename: F
authors.initials: F
authors.lastname: de Braud
authors.forename: A
authors.initials: A
authors.lastname: Castano
authors.forename: C
authors.initials: C
authors.lastname: Maggi
authors.forename: I
authors.initials: I
authors.lastname: Bossi
authors.forename: A
authors.initials: A
authors.lastname: Gevorgyan
authors.forename: P
authors.initials: P
authors.lastname: Biondani
authors.forename: M
authors.initials: M
authors.lastname: Pacifici
authors.forename: A
authors.initials: A
authors.lastname: Busico
authors.forename: M
authors.initials: M
authors.lastname: Gariboldi
authors.forename: F
authors.initials: F
authors.lastname: Festinese
authors.forename: E
authors.initials: E
authors.lastname: Tamborini
authors.forename: M
authors.initials: M
authors.lastname: Di Bartolomeo
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: MGMT; clinical trial; colorectal cancer; temozolomide