A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse

Yung, W. K. Alfred; Albright, Robert E.; Olson, Jeffrey J.; Fredericks, Ruth K.; Fink, Karen; Prados, Michael D.; Brada, Michael; Spence, Alex M.; Hohl, Raymond J.; Shapiro, William R.; Glantz, Michael; Greenberg, Harry S.; Selker, Robert G.; Vick, Nicholas A.; Rampling, Roy; Friedman, Henry S.; Phillips, Peter C.B.; Bruner, Janet M.; Yue, Nancy Chang; Osoba, David; Zaknoen, Sara; Levin, Victor A.

doi:10.1054/bjoc.2000.1316

Cited by 871 publications

(559 citation statements)

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“…The latter analysis confirmed the importance of PFS-6 as a reliable endpoint for studies in recurrent gliomas. In the registration trial, temozolomide given at recurrence in a conventional treatment schedule induced a progression-free survival of 11 weeks and a PFS-6 of 21% [16].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

et al. 2008

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“…TMZ was superior to procarbazine in patients, 60% of which were pretreated with nitrosoureas, with a PFS-6 rate of 21% vs. 8% and median OS prolonged by 1.5 months [46]. A single-arm phase II trial in 126 patients led to a PFS-6 rate of 18% [45].…”

Section: Temozolomide Monotherapy and Combination Regimensmentioning

confidence: 96%

Therapeutic options in recurrent glioblastoma—An update

Seystahl

Wick

Weller

2016

Critical Reviews in Oncology/Hematology

171

134

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“…Most chemotherapeutic agents tested to date show only marginal, if any, clinical benefit. Temozolomide is a recent addition to the chemotherapeutic arsenal, and phase III clinical trials for temozolomide treatment of recurrent high-grade glioblastomas have shown responses to the drug, reflected in an increased progression-free survival (Bower et al, 1997;Paulsen et al, 1999;Janinis et al, 2000;Yung et al, 2000) The alkylating agent temozolomide is a second-generation imidazotetrazine prodrug. It can be administered orally and has a bioavailability of almost 100%.…”

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confidence: 99%

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

et al. 2003

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Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a threedimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment.

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A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse

Cited by 871 publications

References 20 publications

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

ACNU-based chemotherapy for recurrent glioma in the temozolomide era

Therapeutic options in recurrent glioblastoma—An update

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

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