Efficacy and Tolerability of Temozolomide in an Alternating Weekly Regimen in Patients With Recurrent Glioma

Wick, Antje; Felsberg, Jörg; Steinbach, Joachim P.; Herrlinger, Ulrich; Platten, Michael; Blaschke, Britta; Meyermann, Richard; Reifenberger, Guido; Weller, Michael; Wick, Wolfgang

doi:10.1200/jco.2007.10.7722

Cited by 235 publications

(158 citation statements)

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“…Thus, the relatively poor results in this study could be due to the fact that the combination partners in the PBV and PCV regimens contribute to this efficacy or that temozolomide pre-treated patients are less likely to respond to nitrosoureas at recurrence. Altogether, treatment results with ACNU are inferior compared with the recent studies with bevacizumab/irinotecan [18,19] or doseintensified temozolomide [17] and also showed considerable hematotoxicity. We do not propose that our data exclude a role of ACNU in certain subgroups of patients or within combined treatments in recurrent glioblastoma.…”

Section: Discussionmentioning

confidence: 73%

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ACNU-based chemotherapy for recurrent glioma in the temozolomide era

et al. 2008

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No standard of care for patients with recurrent glioblastoma has been defined since temozolomide has become the treatment of choice for patients with newly diagnosed glioblastoma. This has renewed interest in the use of nitrosourea-based regimens for patients with progressive or recurrent disease. The most commonly used regimens are carmustine (BCNU) monotherapy or lomustine (CCNU) combined with procarbazine and vincristine (PCV). Here we report our institutional experience with nimustine (ACNU) alone (n = 14) or in combination with other agents (n = 18) in 32 patients with glioblastoma treated previously with temozolomide. There were no complete and two partial responses. The progression-free survival (PFS) rate at 6 months was 20% and the survival rate at 12 months 26%. Grade III or IV hematological toxicity was observed in 50% of all patients and led to interruption of treatment in 13% of patients. Non-hematological toxicity was moderate to severe and led to interruption of treatment in 9% of patients. Thus, in this cohort of patients pretreated with temozolomide, ACNU failed to induce a substantial stabilization of disease in recurrent glioblastoma, but caused a notable hematotoxicity. This study does not commend ACNU as a therapy of first choice for patients with recurrent glioblastomas pretreated with temozolomide. (PCV). Here we report our institutional experience with nimustine (ACNU) alone (n=14) or in combination with other agents (n=18) in 32 patients with glioblastoma treated previously with temozolomide. There were no complete and two partial responses. The progression-free survival (PFS) rate at 6 months was 20% and the survival rate at 12 months 26%. Grade III or IV hematological toxicity was observed in 50% of all patients and led to interruption of treatment in 13% of patients. Non-hematological toxicity was moderate to severe and led to interruption of treatment in 9% of patients. Thus, in this cohort of patients pretreated with temozolomide, ACNU failed to induce a substantial stabilization of disease in recurrent glioblastoma, but caused a notable hematotoxicity. This study does not commend ACNU as a therapy of first choice for patients with recurrent glioblastomas pretreated with temozolomide.

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Section: Discussionmentioning

confidence: 73%

“…A recent phase II study using a weekly alternating schedule of dose-intensified temozolomide (one week on/one week off) led to a median survival of 24 weeks and a PFS-6 of 44% [17]. In the latter study, patients who had received temozolomide as a first-line therapy benefited from a dose-intensified re-exposure, too.…”

Section: Discussionmentioning

confidence: 99%

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

et al. 2008

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“…The In contrast to newly diagnosed glioblastoma, the predictive value of MGMT promoter methylation has remained controversial in recurrent glioblastoma. The absence of a strong predictive effect on tumor response or outcome with various temozolomide administration schedules [47][48][49] suggests that MGMT-independent mechanisms of resistance have a predominant role in the setting of recurrent Gelöscht: , a clinically interesting finding that will need prospective validation glioblastoma. Nevertheless, patients with MGMT-methylated tumors still showed improved survival in these series, although no such effect was seen in a recent study from Belgium.…”

Section: The Role Of Mgmt In Glioma Subtypes Glioblastomamentioning

confidence: 99%

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

et al. 2009

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The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile.Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

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“…As unlimited dose escalations of adjuvant TMZ were allowed in the UKT-05 trial protocol, the grade 4 lymphotoxicity rate per cycle was higher (10.3%) than observed in the recurrent glioma trial conducted at the same institutions (0.7%) (6). Notably, grade 3/4 lymphopenia per patient did not exceed markedly grade 3/4 lymphopenia reported with a phase II trial that investigated the combined concomitant and adjuvant therapy with the integrin inhibitor cilengitide and six courses of conventionally-dosed TMZ in addition to radiotherapy in patients with newly diagnosed glioblastoma (55.8%) (18).…”

Section: Discussionmentioning

confidence: 83%

“…However, depletion of MGMT by prolonged exposure to TMZ not only affects tumor cells but also normal cells, particularly hematopoietic precursor cells, potentially enhancing hematologic toxicity (5). Other dose-dense TMZ regimens did not show an unusual incidence of toxicities and also demonstrated promising efficacy data at recurrence (6).…”

Section: Introductionmentioning

confidence: 99%