Journal of Clinical Oncology, Vol 23, No 18 (June 20), 2005: pp. 4235-4236
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.00.8417
How Lymphotoxic Is Dose-Intensified Temozolomide? The Glioblastoma Experience
Wolfgang Wick,
Michael Weller
Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
To the Editor:
The moderate activity of temozolomide (TMZ) administered at 150 to 200 mg/m2 for 5 days every 4 weeks in chemoresistant cancers has provoked the clinical evaluation of a series of alternative dose-intensified TMZ schedules. In a recent issue of the Journal of Clinical Oncology, Su et al1 reported profound and selective CD4+ lymphopenia in malignant melanoma patients treated with TMZ at 75 mg/m2 for 6 weeks every 8 weeks, alone (n = 17) or in combination with thalidomide (n = 73) or  -interferon (n = 7). This lymphopenia evolved in the absence of significant neutropenia or thrombocytopenia and was associated with a high incidence of infection thought to be related to T-cell dysfunction. In contrast, our previous evaluation of a 1-week-on/1-week-off dose-intensified TMZ schedule had shown no such toxicity in 21 patients with recurrent glioblastoma.2 The alerting melanoma data1 prompted us to reassess our database for similar lymphotoxicity of prolonged TMZ chemotherapy in recurrent glioblastoma. Since our initial report,2 another 18 patients have received the same regimen, for a total of 39 patients with recurrent or progressive glioblastoma treated at our institution with the 1-week-on/1-week-off regimen of TMZ starting at 150 mg/m2 with dose adaptation in 25 mg/m2 steps according to leukocyte and platelet counts which were determined at weekly intervals.1
An analysis of the extended population confirmed the promising progression-free and overall survival rates achieved with 1-week-on/1-week-off TMZ in this group of patients (Table 1). Hematologic toxicity was overall low (Table 2). Thirty-two of 39 patients never experienced leukocyte counts below 3,000/µL or platelet counts below 100,000/µL. Thrombocytopenia necessitated platelet transfusions in five patients. Two patients experienced grade 3 to 4 hematologic toxicity according to the common terminology criteria for adverse events (CTCAE) later than 3 months after started on TMZ. All other patients suffered such toxicity within the first weeks of TMZ. None of the 13 patients receiving TMZ for more than 6 months experienced grade 3 to 4 hematologic toxicity. Weekly lymphocyte counts before and during therapy were available for re-evaluation for 15 patients. One patient experienced a drop in lymphocyte counts to 330 cells/µL with recovery after cessation of therapy and one patient to 380 cells/µL with prolonged lymphopenia (Table 2). Importantly, there were no opportunistic infections across the study population and no fatal toxicities.
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Table 2. Hematologic Toxicity in 39 Recurrent Glioblastoma Patients Receiving 382 Weeks of Dose-Intensified Temozolomide
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In summary, our present extended analysis of the continuous 1-week-on/1-week-off schedule of TMZ confirms the safety and efficacy of this regimen in recurrent or progressive glioblastoma (Tables 1 and 2). Possible explanations for the apparent discrepancy between the toxicity profile reported by Su et al and our experience, summarized in Table 2, include the different schedules of dose intensification (6 of 8 weeks at 75 mg/m2 v 1-week-on/1-week-off administered according to leukocyte and platelet counts), the different tumor entities (melanoma v glioblastoma) and a confounding effect of prior medication or co-medication. Both series analyzed lymphopenia retrospectively, but in contrast to the melanoma patients,1 our patients had fixed time intervals for blood analyses, probably excluding the possibility that lymphopenia was underestimated in our patients.
The encouraging results of the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) trial on concomitant and adjuvant TMZ for newly diagnosed glioblastoma will result in new interest in the development of still more effective TMZ regimens in glioblastoma.3 Although it is important to closely monitor lymphotoxicity in all future trials aiming at TMZ dose intensification, it is important not to dismiss this option for glioblastoma merely on the basis of alerting observations in malignant melanoma.1
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Wolfgang Wick, Schering-Plough. Michael Weller, Schering-Plough. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
REFERENCES
1. Su YB, Sohn S, Krown SE, et al: Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: A toxicity with therapeutic implications. J Clin Oncol 22:610-616, 2004[Abstract/Free Full Text]
2. Wick W, Steinbach JP, Küker WM, et al: One week on/one week off: A novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113-2115, 2004[Abstract/Free Full Text]
3. Stupp R, Mason WP, Van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005
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