Neurology -- Correspondence for Tosoni et al., 66 (3) 427-429

Correspondence published:

Is protracted low-dose temozolomide feasible in glioma patients?: Eric T. Wong (29 March 2006)

Reply from the authors: Alba A. Brandes, Alicia Tosoni (29 March 2006)

Is protracted low-dose temozolomide feasible in glioma patients? 29 March 2006

Eric T. Wong,
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Boston, MA 02215
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Re: Is protracted low-dose temozolomide feasible in glioma patients?

ewong{at}bidmc.harvard.edu Eric T. Wong

Tosoni et al [1] presented their findings on protracted low-dose temozolomide, at 75 mg/m2/day for 21 days in 28-day cycles. They found over 50% of patients had lymphopenia and more than 25% had at least grade 3 lymphopenia.
Although the rationale for continuous temozolomide and dose-dense temozolomide is to suppress O6-alkylguanine-DNA alkyltransferase (AGAT) activity, the toxicity profile of such regimens is still unclear. The various schedules of temozolomide used across different trials also add to the confusion [1-5].
However, if the trials were compared based on number of days of temozolomide exposure, dose intensity on a per month basis, and months on temozolomide, then a picture emerges that suggests that lymphopenia from chronic exposure to temozolomide is a function of days exposed to temozolomide, dose intensity, and number of months on temozolomide (Table 1).
Comparing to the standard dosing regimen (regimen 1), regimens 2 and 4 had at least 21 days of temozolomide exposure and the dose intensity is at least 50% greater than that of standard regimen. This is in contradistinction to regimens 5 and 6 without excessive lymphopenia in which there was shorter temozolomide exposure, about 3 or 7 days at a time per cycle, despite an increase in dose intensity of 1.8 to 2.1 times the standard regimen.
However, lymphopenia could still appear if temozolomide exposure was longer than 5.0 months. Likewise, regimen 3 did not report excessive lymphopenia, but the duration of exposure was very short at about 2.5 months. Clearly there was not enough time of exposure to temozolomide in regimen 3 to cause lymphopenia as the median time to lymphopenia was 101 days, or 3.6 months, in the largest trial. [5]
When future trials are planned using protracted or dose-dense temozolomide, consideration must be given to days of temozolomide exposure, dose intensity, and duration of exposure so that patients are not unnecessarily exposed to lymphopenia risk. Table
References
1. Tosoni A, Cavallo G, Ermani M, et al. Is protracted low-dose temozolomide feasible in glioma patients? Neurology 2006;66:427-429.
2. Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA, Abrey LE. A phase II study of extended low-dose temozolomide in recurrent malignant gliomas. Neurooncology 2002;4:39-43.
3. Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 2004;62:2113-2115.
4. Vera K, Djafari L, Faivre S, et al. Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors. Ann Oncol 2004;15:161-171.
5. 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 2004;22:610-161.
The author reports no conflicts of interest.

Reply from the authors 29 March 2006

Alba A. Brandes,
Department of Medical Oncology, Azienda USL Citt� di Bologna
Via Altura, 3 Bologna (Italy),
Alicia Tosoni
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Re: Reply from the authors

aa.brandes{at}yahoo.it Alba A. Brandes, et al.

We thank Dr. Wong for his interest in our manuscript. The correlation between lymphopenia and protracted temozolomide schedule represents an emerging concept. He analyzed the correlation between lymphopenia and the standard/protracted temozolomide schedules.
In patients treated with the standard schedule, lymphopenia seems to be uncommon. However, lymphopenia is not always registered as a toxicity in clinical trials, and it is possible that the real incidence of lymphopenia may be underreported. The EORTC trial [6] reported no lymphopenia among 287 patients treated with temozolomide concomitant with six weeks of radiotherapy, even if Pneumocystis Carinii prophylaxis was administered due to the risk of lymphopenia.
However, lymphopenia was not specifically recorded in the collection of data. In a like manner, Wick�s first study [3] did not report lymphopenia among 28 patients treated with temozolomide 1 week on/1 week off, and only in a subsequent database reassessment of 39 patients (7) Wick reported 33% of G2-3 lymphopenia. In almost all protracted temozolomide trials (2,8), a lymphopenia ranging from 13% to 83% has been reported.
Dr. Wong suggests that lymphopenia could be correlated to months on temozolomide exposure, dose intensity on a per month basis, and days of temozolomide exposure. We agree with the point regarding the duration of exposure: G3 lymphopenia was observed in 24.3-33% of patients if temozolomide exposure was > 4 months [1,4,5] but only in 6%-13% if the exposure was <3 months. [2,7]
In addition, our study demonstrates a clear trend toward an increase in cumulative lymphopenia with the increasing of number of cycles. [1] However, there is no consensus regarding lymphopenia and dose intensity. In phase I protracted temozolomide studies [4,8], lymphopenia does not increase, increasing the dosage. Furthermore, Wick et al. [7] reported G3 lymphopenia in 13% of patients even if he used a high dose intensity schedule.
Conflicting data exist on lymphopenia and days of temozolomide exposure: in one study [7] patients were treated for 7 days every 2 weeks with 13% of G3 lymphopenia but this may be due mainly to the shorter time (2.5 months) of TMZ exposure, in another [4], in which patients were treated for 3 days every 2 weeks, for a longer time (4.5 months), a high G3 lymphopenia rate (24.3%) was reported. Randomized trials with protracted temozolomide treatment should be conducted to establish if �more is better� in order to avoid unnecessary toxicity.
References
6. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996.
7. Wick W, Weller M. How lymphotoxic is dose-intensified temozolomide? The glioblastoma experience. J Clin Oncol 2005;23:4235-4236.
8. Brock CS, Newlands ES, Wedge SR, et al. Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 1998;58:4363-4367.
Author Disclosure: Dr. Brandes has had an advisory role with Schering-Plough. Dr. Tosoni reports no conflicts of interest.