Dose Modifications for Hematological Toxicity

Dose modifications for hematological toxicity: On days 21 and 28 of each TMZ cycle, hemograms were obtained. If platelet counts fell below 100,000 cell/ cm3, ANC fell below 1,000 cell/cm3, or a precipitous decline of >50% in either cell counts was observed, then doses were delayed for one week. This one week delay was followed by a dose reduction of 25% once the hematological toxicity resolved. Dose-limiting toxicities (grade III/IV toxicities) required a dose reduction for the subsequent week of treatment. Dose reduction by 25% was the initial step, then subsequent reduction was conducted in a stepwise manner to a maximum of three total reductions. If TMZ was held for longer than two consecutive weeks, it was discontinued.

After the first 27 patients were enrolled, a planned interim analysis of hematoxocity data was conducted. Due to the levels of grade III/IV thrombocytopenia, a decision was made to reduce the dose of TMZ for cycles 1 and ≥ 3 to 150 mg/m2/day.

Dose modifications for non-hematological toxicity: If the patient experienced a grade 2 non-hematologic toxicity, TMZ was withheld until the toxicity resolved to grade 1 or abated. If a grade 2 toxicity recurred, TMZ was withheld until the toxicity resolved to grade 1 or abated, then a dose reduction ensued. If the grade 2 toxicity recurred once again, TMZ was withheld permanently.

If the patient experienced grade 3 or 4 toxicity, TMZ was withheld until the toxicity resolved to grade 1 or abated. A dose reduction followed as per the initial protocol. If the grade 3 or 4 toxicity recurred, TMZ was withheld until toxicity resolved to grade 1 or abated. An additional dose reduction followed. With an additional recurrence of toxicity, TMZ was withheld permanently.

MGMT analysis: An assay for promoter methylation of O(6)-Methylguanine-DNA Methyltransferase (MGMT) was not readily available at the time this trial was written. However, an attempt was made to retrospectively analyze as many samples as possible when this became available. MGMT promoter analysis was conducted utilizing a quantitative methylation-specific polymerase chain reaction (PCR) using standard techniques [1]. An exploratory retrospective analysis of MGMT promoter status of available samples was conducted, with a total of 22 specimens being adequate for analysis.

A retrospective analysis of MGMT promoter analysis of available samples was conducted on 22 specimens. There did not appear to be a significant association observed between OS and MGMT promoter methylation status (n=22, supplemental table 2); however, this evaluation was limited due to sample size considerations. Of the 8 patients still alive at greater than 3 years after enrollment, 5 patients had tissue analyzed for MGMT status. 4 patients were noted to have unmethylated tumors, and 1 patient had a methylated tumor. 1. Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG, Belinsky SA (2000) Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer research 60: 5954-5958