Trial of a 5-day dosing regimen of temozolomide in patients with relapsed small cell lung cancers with assessment of methylguanine-DNA methyltransferase Journal Article

Authors: Zauderer, M. G.; Drilon, A.; Kadota, K.; Huberman, K.; Sima, C. S.; Bergagnini, I.; Sumner, D. K.; Travis, W. D.; Heguy, A.; Ginsberg, M. S.; Holodny, A. I.; Riely, G. J.; Kris, M. G.; Krug, L. M.; Pietanza, M. C.
Article 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: Objectives: Small cell lung cancers (SCLCs) are characterized by aberrantly methylated O6-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 75mg/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. Materials and methods: Patients with sensitive or refractory SCLCs and progression after one or two prior chemotherapy regimens received temozolomide 200mg/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. Conclusion: Temozolomide 200mg/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.
Keywords: immunohistochemistry; adult; cancer survival; clinical article; human tissue; treatment response; aged; overall survival; promoter region; clinical trial; constipation; fatigue; neutropenia; cancer recurrence; cancer combination chemotherapy; drug dose reduction; drug efficacy; cancer radiotherapy; chemotherapy; temozolomide; outcome assessment; polymerase chain reaction; anorexia; multiple cycle treatment; sensory neuropathy; gene expression; anemia; mucosa inflammation; thrombocytopenia; alkylating agent; radiation injury; tumor marker; dna methylation; lymphocytopenia; pneumonia; pruritus; rash; lung embolism; biomarker; brain metastasis; ondansetron; dna methyltransferase; radiation necrosis; small cell lung cancer; acute respiratory failure; sclc; mgmt; hypertransaminasemia; chemotherapy induced nausea and vomiting; human; male; female; article; patient history of chemotherapy
Journal Title: Lung Cancer
Volume: 86
Issue: 2
ISSN: 0169-5002
Publisher: Elsevier Ireland Ltd.  
Date Published: 2014-11-01
Start Page: 237
End Page: 240
Language: English
DOI: 10.1016/j.lungcan.2014.08.007
PROVIDER: scopus
PUBMED: 25194640
PMCID: PMC4497567
Notes: Export Date: 1 December 2014 -- Source: Scopus
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MSK Authors
  1. Camelia S Sima
    204 Sima
  2. Adriana Heguy
    85 Heguy
  3. Michelle S Ginsberg
    158 Ginsberg
  4. Lee M Krug
    211 Krug
  5. Maria C Pietanza
    115 Pietanza
  6. William D Travis
    548 Travis
  7. Gregory J Riely
    346 Riely
  8. Dyana K Sumner
    5 Sumner
  9. Andrei Holodny
    136 Holodny
  10. Kyuichi Kadota
    82 Kadota
  11. Mark Kris
    603 Kris
  12. Alexander Edward Drilon
    141 Drilon