Temozolomide-related idiosyncratic and other uncommon toxicities: a systematic review.

Temozolomide (TMZ)-related idiosyncratic and other uncommon toxicities have been reported. To better characterize these toxicities and to identify any associated risk factors, we performed a systematic review. We searched the PubMed database, limited to the English language, published between 1999 and December 2011. We selected only those articles in which TMZ was temporally related and was the sole or main contributing chemotherapeutic drug to idiosyncratic drug reactions (IDRs) and other uncommon toxicities. Hematological IDRs are biopsy-proven aplastic anemia or grade V toxicity or grade IV toxicity with slow and incomplete hematological recovery. Seventy-three cases were identified, including 21 hematological IDRs, 31 nonhematological IDRs and uncommon infections, and 21 second primary cancers. With a caveat of publication and reporting bias, the following observations could be made. The hematological IDRs predominantly occurred in female patients (exact binomial two-tailed, P=0.0041) and most patients were receiving TMZ concomitantly with radiotherapy for glioma. The median duration of exposure to TMZ was 30 days and the median cumulative TMZ exposure was 2250 mg/m (range, 500-6900 mg/m). The sex predilection was not evident in nonhematological IDRs and other uncommon toxicities. TMZ-induced pneumonitis and cholestatic hepatitis are emerging as a nonhematological hypersensitive reaction and IDR, respectively. For TMZ-related myelodysplasia or leukemia, the cumulative dose of TMZ ranged from 1400 to 30 000 mg/m. The cumulative dose of TMZ was lower and latency was shorter with a previous exposure to other leukemogenic drugs, suggesting that TMZ may have augmented the leukemogenic potential of other drugs. Early appearance of profound myelosuppression during the course of TMZ and concurrent radiotherapy could be a hematological IDR, which warrants prompt investigations to exclude aplastic anemia. Myelodysplasia or leukemia developed after a median TMZ exposure of 15 g/m.