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 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
