Long-term treatment with temozolomide in malignant glioma

Mannas, Jonathan P.; Lightner, Donita; DeFrates, Sean; Pittman, Thomas; Villanó, John L.

doi:10.1016/j.jocn.2013.03.039

Cited by 32 publications

(22 citation statements)

References 8 publications

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“…However, it is important to highlight that when the patient decided to stop the TMZ therapy because of a minor thrombocytopenia, he died 6 weeks later, having undergone 56 cycles of TMZ. 10 Such experience is similar to ours: 2 of our patients in Group B died 6 weeks after stopping TMZ.…”

Section: Long-term Tmz Therapy Versus a Standard Protocolsupporting

confidence: 85%

“…14 Reviewing the 4 published studies on long-term TMZ therapy, 6,8,10,16 we found that only Seiz et al reported that age had a role in their treatment paradigm, with those patients receiving more than 6 TMZ cycles younger than those receiving no more than 6 cycles, and the number of TMZ cycles did have a statistically significant correlation with improved PFS and OS in their study. 16 In the present study, age and KPS score were shown by univariate Cox proportional hazard regression analysis to be prognostic factors and to correlate with OS and PFS (p < 0.05).…”

Section: Predictors Of Response To Treatment and Survivalmentioning

confidence: 88%

“…6,8,10,16 Khasraw et al treated 3 patients with TMZ for 5, 7, and 8 years, respectively, but only 1 with a glioblastoma. Interestingly, 2 of their patients showed tumor recurrence following interruption of TMZ and responded well to reintroduction of TMZ.…”

Section: Long-term Tmz Therapy Versus a Standard Protocolmentioning

confidence: 99%

“…17 Despite anecdotal experiences with TMZ treatment longer than 6 cycles, very limited data are currently available in the literature, 6,8,10,16 and only 2 papers-even if with important bias-described the results of long-term TMZ treatment in cohorts of patients with glioblastoma. 6,16 In this paper we report our experience on the long-term administration of TMZ in a series of primary glioblastomas, analyzing its impact on patients' progression-free survival (PFS) and overall survival (OS), and compare these data with PFS and OS of a matched cohort of patients with primary glioblastoma treated according to the standard Stupp protocol.…”

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confidence: 99%

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Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

Barbagallo¹,

Paratore

Caltabiano

et al. 2014

FOC

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Object The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. Methods A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m2 starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30–72 years (mean 56.1 years), received 150 mg/m2 for 5 days every 28 days for more than 6 cycles (range 7–101 cycles). The 18 patients in Group B, aged 46–82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. Results All patients but 1 in Group A survived at least 18 months (range 18–101 months), and patients in Group B survived no more than 17 months (range 2–17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. Conclusions This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

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Section: Long-term Tmz Therapy Versus a Standard Protocolsupporting

confidence: 85%

Section: Predictors Of Response To Treatment and Survivalmentioning

confidence: 88%

Section: Long-term Tmz Therapy Versus a Standard Protocolmentioning

confidence: 99%

mentioning

confidence: 99%

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Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

Barbagallo¹,

Paratore

Caltabiano

et al. 2014

FOC

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“…Surgical resection with adjuvant radiotherapy and temozolomide-based chemotherapy are the mainstays of treatment [1]. Despite tremendous efforts in diagnosis and therapeutic strategies, the clinical outcome remains dismaying.…”

Section: Introductionmentioning

confidence: 99%

Norcantharidin induces growth inhibition and apoptosis of glioma cells by blocking the Raf/MEK/ERK pathway

Zheng

Song

et al. 2014

World J Surg Onc

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BackgroundMalignant gliomas represent the most common primary brain tumors. The prognosis of patients with malignant gliomas is poor in spite of current intensive therapy and novel therapeutic modalities are needed. Here we report that norcantharidin is effective in growth inhibition of glioma cell lines in vitro.MethodsGlioma cell lines (U87 and C6) were treated with norcantharidin. The effects of norcantharidin on the proliferation and apoptosis of glioma cells were measured by 3-[4,5-dimethylthiazol-2-thiazolyl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry. Western blotting was employed to determine the signaling pathway changes.ResultsThe results showed that norcantharidin effectively inhibited cell growth and induced apoptosis in glioma cells, which was concurrent with inhibition of the expression of phospho-MEK and phospho-ERK. Furthermore, the expression anti-apoptotic proteins Bcl-2 and Mcl-1 significantly reduced, but no changes in Bcl-xL and Bax.ConclusionsOur findings demonstrate that norcantharidin is effective for growth inhibition of glioma cell lines and suggest that norcantharidin may be a new therapeutic option for patients with glioma.

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Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

et al. 2015

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Malignant gliomas, including glioblastomas, are extremely difficult to treat. The median survival for glioblastoma patients with optimal therapeutic intervention is 15 months. We developed a novel MAO-B-selectively activated prodrug, N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propanamide (MP-MUS), for the treatment of gliomas based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The design of neutral MP-MUS involved the use of a seeker molecule capable of binding to mitochondrial MAO-B, which is up-regulated ≥fourfold in glioma cells. Once the binding occurs, MP-MUS is converted into a positively charged moiety, P(+) -MUS, which accumulates inside mitochondria at a theoretical maximal value of 1000:1 gradient. The LD50 of MP-MUS against glioma cells is 75 μM, which is two- to threefold more potent than temozolomide, a primary drug for gliomas. Importantly, MP-MUS was found to be selectively toxic toward glioma cells. In the concentration range of 150-180 μM MP-MUS killed 90-95 % of glioma cells, but stimulated the growth of normal human astrocytes. Moreover, maturation of MP-MUS is highly dependent on MAO-B, and inhibition of MAO-B activity with selegiline protected human glioma cells from apoptosis.

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Long-term treatment with temozolomide in malignant glioma

Cited by 32 publications

References 8 publications

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

Norcantharidin induces growth inhibition and apoptosis of glioma cells by blocking the Raf/MEK/ERK pathway

Design and Synthesis of a MAO‐B‐Selectively Activated Prodrug Based on MPTP: A Mitochondria‐Targeting Chemotherapeutic Agent for Treatment of Human Malignant Gliomas

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