title: Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase.
abstract: OBJECTIVE
  Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O(6)-methyl-guanine-DNA methyltransferase (MGMT). Epigenetic silencing of MGMT is associated with loss of MGMT activity and improved sensitivity to alkylating agents in glioblastomas. We have reported the activity of temozolomide, a non-classical alkylating agent, in patients with relapsed sensitive or refractory SCLCs, given at 75 mg/m2/day for 21 of 28 days. However, prolonged myelosuppression was noted. We therefore evaluated a 5-day dosing schedule of temozolomide and examined MGMT as a predictive biomarker for temozolomide treatment in SCLC.
  
  
  METHODS
  Patients with sensitive or refractory SCLCs and progression after one or two prior chemotherapy regimens received temozolomide 200 mg/m2/day for 5 consecutive days in 28-day cycles. The primary endpoint was tolerability. We also assessed MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry in tumor specimens.
  
  
  RESULTS
  Of 25 patients enrolled, 5 experienced grade 3 or 4 toxicity (anemia, thrombocytopenia, neutropenia, and constipation). The partial response rate was 12% [95% CI: 3-31%], with partial responses in 2 refractory patients. We were able to obtain tumor samples for more than half of patients for MGMT testing.
  
  
  CONCLUSIONS
  Temozolomide 200 mg/m2/day for 5 days in 28-day cycles is tolerable and active in patients with relapsed SCLCs. No treatment-limiting prolonged cytopenias were observed, making this our preferred schedule for further studies. Acquisition of archived biospecimens is feasible and necessary in order to continue evaluating the role of MGMT as a predictive biomarker in SCLCs.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States. Electronic address: zauderem@mskcc.org.
authors.forename: Marjorie G
authors.initials: MG
authors.lastname: Zauderer
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Geoffrey Beene Translational Oncology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Kety
authors.initials: K
authors.lastname: Huberman
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: Isabella
authors.initials: I
authors.lastname: Bergagnini
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: Dyana K
authors.initials: DK
authors.lastname: Sumner
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.affiliation: Geoffrey Beene Translational Oncology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Ginsberg
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Holodny
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, United States.
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Pietanza
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide
keywords: Alkylating agent; Biomarker; Chemotherapy; MGMT; SCLC; Temozolomide