A Multicenter Cohort Study of Dose-Dense Temozolomide (21 of 28 Days) for the Treatment of Recurrent Anaplastic Astrocytoma or Oligoastrocytoma

Neyns, Bart; Chaskis, Cristo; Joosens, E.; Menten, Johan; D’Hondt, Lionel; Branle, Fabrice; Sadones, Jan; Michotte, Alex

doi:10.1080/07357900701708393

Cited by 37 publications

(36 citation statements)

References 21 publications

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“…Notably, long-term responses of 15 and 19 months were even achieved in patients with unmethylated MGMT promoter, pointing towards the efficacy of this MGMT-depleting strategy. The long-term response of all patients with grade III tumors indicates that the regimen is also effective in patients with anaplastic gliomas, an observation that supports recentlypublished promising results (13). Also of note is that objective responses and a favorable long-term outcome were observed even though, in a considerable number of patients, the regimen was switched, directly or within less than 3 months, from the conventional 5/28-day to the dose-dense 21/28-day regimen.…”

Section: Discussionsupporting

confidence: 69%

“…Tosoni et al reported a considerable rate of pneumonia during a 21/28-day regimen for relapsed malignant glioma (14). However, a similar rate of infection was not observed by Neyns et al (13), who treated patients using the same regimen. In our series, 1 patient developed severe pneumonia 3 weeks after permanent discontinuation of chemotherapy for progression, without isolation of Pneumocystis carinii.…”

Section: Discussionmentioning

confidence: 81%

“…We therefore decided to use the 21/28-day regimen, but increased the daily dose for two reasons: i) previous results indicated that the 7/14 regimen, which added up to a dose of 2100 mg/m 2 per cycle, was associated with an acceptable toxicity, while the 21 day schedule with 75 mg/m 2 only added up to 1575 mg/m 2 per cycle; ii) in vitro studies indicate that temozolomide can induce apoptosis in GBM cells in a dose-dependent manner requiring the equivalent of at least 100 mg/m 2 (11). This dosage has been shown to be tolerable in patients with renal cell carcinoma (12), and has shown promising results in patients with recurrent anaplastic gliomas (13).…”

Section: Discussionmentioning

confidence: 99%

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Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas

Jh²,

Wrede³

et al. 2008

Mol Med Rep

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Abstract. Treatment of recurrent malignant glioma, which has a poor patient prognosis, has not been standardised. Moreover, it is unclear whether repeated treatment with temozolomide is effective in patients who received previous temozolomide treatment before developing a recurrence. Here, we present the results of a high-dose individually adapted 21-day regimen demonstrating that rechallenge is effective even in patients expressing O 6 -methylguanine-DNA methyltransferase (MGMT) in the tumor. Twenty-one patients with recurrent malignant gliomas pre-treated with temozolomide, 18 WHO IV glioblastoma (GBM) and 3 WHO III patients, received 100 mg/m 2 temozolomide on days 1-21/28. The GBM patients had a median Karnofsky performance status of 60% and a median age of 54.8 years. Blood counts decreased continuously, enabling a gradual dose adaptation. When blood counts dropped below normal values, temozolomide was applied on days 1-5/7. Dosage was reduced to 50-75 mg/m 2 in 11 patients and gradually increased up to 130 mg/m 2 in 3 patients. WHO grade 3/4 toxicity was hematological in 3 patients and non-hematological in 3 patients. In GBM patients (n=18), response after >3 months was complete in 3 patients, partial in 1 (22%), stable disease in 7 (39%) and progressive disease in 7 (39%). Progression-free survival at 6 months (PFS-6M) was 39%. Median survival was 9.1 months from relapse and 17.9 months overall. Of the patients with unmethylated MGMT promoter, 2/7 were progression-free for >6 (15 and 19) months. The data indicate that rechallenge with near-continuous, higher-dose temozolomide (100 mg/m 2 on days 1-21/28 or days 1-5/7 with individual dose adaptation) is also feasible in patients with critical blood counts. Objective responses can be achieved even after relapse during a conventional 5/28-day regimen. The resistance of tumors characterized by unmethylated MGMT promoter may be overcome by near continuous temozolomide administration, which is probably most effective with a 5/7-day schedule. In spite of the relatively poor clinical prognosis, the data indicate that rechallenge with temozolomide with a dose-dense and long-lasting administration protocol is tolerable and comparable with other reported treatment protocols involving temozolomide.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas

Jh²,

Wrede³

et al. 2008

Mol Med Rep

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“…[67][68][69][70][71][72][73][74] One particularly relevant question is whether concomitant RT plus temozolomide is sufficient to confer a survival benefit in patients with newly diagnosed GBM. This question is the object of an ongoing international Intergroup trial designed to establish the optimal sequence and relative contribution of the concomitant and adjuvant chemotherapy compared with RT alone in patients with anaplastic astrocytoma.…”

Section: Brain Tumor Trials With Novel Schedules Of Temozolomidementioning

confidence: 99%

Correlation of O⁶-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

Hegi

Liu

Herman

et al. 2008

JCO

725

523

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Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity AbstractResistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies. is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all glioblastoma patients with MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies. Correlation of MGMT Promoter Methylation With Clinical Outcomes in Glioblastoma and

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“…The MGMT promoter methylation status was not associated with a difference in survival [9]. Profound lymphopenia was also reported in another trial looking at this treatment schedule, with a dose of 100 mg/m 2 , in the setting of recurrent disease [10]. A phase II trial of 90 patients with recurrent gliomas using the dose-dense schedule was feasible and safe and showed similar activity in patients with and without MGMT gene promoter methylation [11].…”

Section: Tmz Dose and Schedulementioning

confidence: 92%

Controversies in the Adjuvant Therapy of High-Grade Gliomas

Holdhoff

Grossman

2011

The Oncologist

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The 2-year survival rate of patients with glioblastoma accrued to research studies increased from 10% to nearly 40% from 2000 to 2010. These improvements began with the demonstration of a survival benefit when daily temozolomide was administered with 6 weeks of standard radiation and for 6 months thereafter. This treatment regimen is often associated with significant lymphopenia, thrombocytopenia, and progressive blood-brain barrier dysfunction that can result in clinical and radiologic deterioration without true tumor progression ("pseudoprogression"). With new evidence that combining this cytotoxic agent with radiation improves survival in this malignancy, many investigators have modified the regimen to further improve patient outcomes. These largely uncontrolled studies highlight controversies regarding the optimal therapy of this disease. This review focuses on the following selected controversies: (a) What is the appropriate temozolomide dose, schedule, and duration in the postradiation period? (b) How should other U.S. Food and Drug Administration-approved therapies (such as carmustine wafers and bevacizumab) be incorporated into this treatment regimen? (c) Should the results in glioblastoma be extrapolated to patients aged >70 and to patients with lower grade gliomas? and (d) How should novel therapeutic approaches be added to radiation and temozolomide in clinical trials for patients with newly diagnosed glioblastoma? The Oncologist 2011;16:351-358

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A Multicenter Cohort Study of Dose-Dense Temozolomide (21 of 28 Days) for the Treatment of Recurrent Anaplastic Astrocytoma or Oligoastrocytoma

Cited by 37 publications

References 21 publications

Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas

Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas

Correlation of O⁶-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

Controversies in the Adjuvant Therapy of High-Grade Gliomas

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A Multicenter Cohort Study of Dose-Dense Temozolomide (21 of 28 Days) for the Treatment of Recurrent Anaplastic Astrocytoma or Oligoastrocytoma

Cited by 37 publications

References 21 publications

Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas

Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas

Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

Controversies in the Adjuvant Therapy of High-Grade Gliomas

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Product

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Correlation of O⁶-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity