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

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.

Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker.

PURPOSE: This phase II study was conducted to assess the efficacy of temozolomide in patients with relapsed small cell lung cancer (SCLC). EXPERIMENTAL DESIGN: Patients with disease progression after one or two prior chemotherapy regimens received temozolomide at 75 mg/m(2)/d for 21 days of a 28-day cycle. The primary endpoint was the overall response rate [ORR; complete response (CR) plus partial response (PR)], which was evaluated separately in sensitive and refractory cohorts. In the available tissue, we assessed O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status by PCR and MGMT expression by immunohistochemistry. RESULTS: Sixty-four patients were accrued: 48 patients in the sensitive cohort and 16 in the refractory group. One CR and 10 PRs were noted in sensitive patients [ORR, 23%; 95% confidence interval (CI), 12%-37%]. Two PRs were seen in the refractory cohort (ORR, 13%; 95% CI, 2%-38%). As second- and third-line treatment, the ORR was 22% (95% CI, 9%-40%) and 19% (95% CI, 7%-36%), respectively. Among patients with target brain lesions, 38% had a CR or PR (95% CI, 14%-68%). Grade ≥3 thrombocytopenia and neutropenia were observed in nine patients (14%). A greater number of cases with methylated MGMT had a response compared to those with unmethylated MGMT (38% vs. 7%; P = 0.08). CONCLUSION: Temozolomide has activity in relapsed SCLC, particularly for brain metastases. Response to temozolomide may correlate with MGMT methylation in SCLC.

Effect of age and tumor grade on BOLD functional MR imaging in preoperative assessment of patients with glioma.

PURPOSE: To retrospectively determine if there was a combined effect of advanced age and increased tumor grade on blood oxygen level-dependent (BOLD) functional magnetic resonance (MR) imaging signal intensity (SI) in patients with gliomas. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study, and the informed consent requirement was waived. Data from 39 patients (27 men, 12 women; age range, 19-78 years) who had histopathologically confirmed gliomas and who underwent surgery after preoperative functional MR imaging were analyzed. Fourteen patients had grade II or grade III gliomas, and 25 patients had grade IV gliomas. A change in BOLD SI was measured in motor cortices of tumor-containing and non-tumor-containing hemispheres. The effect of age and tumor grade, both individually and together, on BOLD functional MR SI was assessed with t tests and regression analysis. RESULTS: In patients with grade IV gliomas, SI change was lower in the tumor-containing hemisphere than in the non-tumor-containing hemisphere (P = .012). SI change decreased with increased age in the tumor-containing hemisphere in patients with grade II or III gliomas (P = .032) and in the non-tumor-containing hemisphere in patients with grade IV gliomas (P = .026). While advanced age and increased glioma grade reduced SI change, the combined effect of these factors was not additive. In patients with grade IV gliomas, tumor presence reduced SI change, but the level of reduction was uniform across all ages and did not correlate with age (P = .541). CONCLUSION: In older patients with grade IV gliomas, BOLD SI is equivalent to that measured in younger patients with grade IV gliomas. Advanced age and tumor grade do not have a combined effect for reduction of BOLD SI. Rather, in patients with grade IV gliomas, tumor grade played a dominant role in reduction of SI change, whereas in patients with grade II and III gliomas, reduction of SI change correlated with only advanced age.

The effect of prior surgery on blood oxygen level-dependent functional MR imaging in the preoperative assessment of brain tumors.

BACKGROUND AND PURPOSE: Blood oxygen level-dependent functional MR imaging (BOLD fMRI) is a clinically useful technique for preoperative mapping of eloquent cortices in patients with brain tumors. The purpose of this study was to determine the effect on BOLD fMRI accuracy of susceptibility artifacts caused by prior surgery by comparing volumes of activation in the primary motor cortex (PMC) of patients with and without prior brain surgery. METHODS: The volumes of fMRI activation of the PMC were measured for the tumor and nontumor sides in patients with (n = 13) and without (n = 30) prior neurosurgery. Statistical comparisons of the volumes were performed by using paired t tests and linear regression analysis. The location and degree of susceptibility artifact were subjectively assessed. RESULTS: No significant difference was found between the mean tumor and nontumor volumes of fMRI activations in patients without prior surgery (P = .51). In patients who had prior surgery, the volume of activation was significantly smaller on the side of the prior operation when compared with the contralateral side (P = .001). The volume of activation on the side of the tumor was also significantly smaller in the patients with prior surgery compared with those without prior surgery (P < .001). Nevertheless, the PMC was identified in all cases, and its location was confirmed intraoperatively. CONCLUSION: Prior surgery is associated with a decrease in the volume of fMRI activation in patients with prior surgery; however, by examining the T2 images, an astute radiologist can recognize this phenomenon, draw the appropriate conclusions, and correctly identify the PMC.