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 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.

MATERIALS AND 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.

CONCLUSION:

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: Marjorie G Zauderer, Alex Drilon, Kyuichi Kadota, Kety Huberman, Camelia S Sima, Isabella Bergagnini, Dyana K Sumner, William D Travis, Adriana Heguy, Michelle S Ginsberg, Andrei I Holodny, Gregory J Riely, Mark G Kris, Lee M Krug, M Catherine Pietanza
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 86 Issue 2 Pg. 237-40 (Nov 2014) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 25194640 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Alkylating
• Dacarbazine
• O(6)-Methylguanine-DNA Methyltransferase
• Temozolomide

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Alkylating (administration & dosage, adverse effects)
• Dacarbazine (administration & dosage, adverse effects, analogs & derivatives)
• Drug Administration Schedule
• Female
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Neoplasm Staging
• O(6)-Methylguanine-DNA Methyltransferase (metabolism)
• Small Cell Lung Carcinoma (drug therapy, metabolism, pathology)
• Temozolomide
• Treatment Outcome