Salvage therapy with single agent bendamustine for recurrent glioblastoma
ABSTRACT The treatment of recurrent glioblastoma (GBM) remains challenging notwithstanding the recent approval of bevacizumab for this indication. Bendamustine has a bifunctional mechanism of action including alkylation, penetrates the CNS and does not show cross resistance to other alkylator chemotherapies. In a single institution phase 2 trial, patients with recurrent GBM were treated with bendamustine (100 mg/m(2)/day administered intravenously for two consecutive days every 4 weeks). The primary study endpoint was 6-month progression free survival (PFS-6). An interim analysis for futility was conducted according to a Simon two-stage minimax design. Complete blood counts were obtained bimonthly, clinical evaluations and brain imaging every month for the first cycle and bimonthly thereafter. Treatment responses were based upon MacDonald criteria. Sixteen patients were enrolled (nine men; seven women), with a median age of 53 years (range 36-68) and a median Karnofsky performance status of 90 (range 70-100). Nine patients were treated at first relapse and seven at second relapse (five patients were bevacizumab failures). A total of 25 cycles of bendamustine were administered with a median of 1 (range 1-6). Bendamustine-related toxicity was seen in eight patients; lymphopenia in seven (5 grade 3; 2 Grade 4), thrombocytopenia in two (1 Grade 3; 1 Grade 4), and neutropenia in one (1 Grade 3). Fourteen patients have died due to disease progression, two patients are alive and on alternative therapies. Only one patient was progression-free at 6 months, triggering the stopping rule for futility. Bendamustine was reasonably well tolerated but failed to meet the study criteria for activity in adults with recurrent GBM.
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- "Fotemustine is an alkylator that has been popular in France and Italy . Bendamustine has shown major success in lymphoma and penetrates the BBB, making its lack of efficacy in glioblastoma a disappointment ; additional dose escalation may represent a residual investigative approach. VAL-083 is a first-in-class bifunctional N7 DNA alkylating agent that crosses the BBB and accumulates in brain tissue. "
ABSTRACT: Medical treatments for glioblastoma face several challenges. Lipophilic alkylators remain the mainstay of treatment, emphasising the primacy of good blood–brain barrier penetration. Temozolomide has emerged as a major contributor to improved patient survival. The roles of procarbazine and vincristine in the procarbazine, lomustine and vincristine (PCV) schedule have attracted scrutiny and several lines of evidence now support the use of lomustine as effective single-agent therapy. Bevacizumab has had a convoluted development history, but clearly now has no major role in first-line treatment, and may even be detrimental to quality of life in this setting. In later disease, clinically meaningful benefits are achievable in some patients, but more impressively the combination of bevacizumab and lomustine shows early promise. Over the last decade, investigational strategies in glioblastoma have largely subscribed to the targeted kinase inhibitor paradigm and have mostly failed. Low prevalence dominant driver lesions such as the FGFR-TACC fusion may represent a niche role for this agent class. Immunological, metabolic and radiosensitising approaches are being pursued and offer more generalised efficacy. Finally, trial design is a crucial consideration. Progress in clinical glioblastoma research would be greatly facilitated by improved methodologies incorporating: (i) routine pharmacokinetic and pharmacodynamic assessments by preoperative dosing; and (ii) multi-stage, multi-arm protocols incorporating new therapy approaches and high-resolution biology in order to guide necessary improvements in science.
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ABSTRACT: New drugs are constantly sought after to improve the survival of patients with malignant gliomas. The ideal substance would selectively target tumor cells without eliciting toxic side effects. Here, we report on the anti-proliferative, anti-migratory, and anti-invasive properties of the natural, nontoxic compound Curcumin observed in five human glioblastoma (GBM) cell lines in vitro. We used monolayer wound healing assays, modified Boyden chamber trans-well assays, and cell growth assays to quantify cell migration, invasion, and proliferation in the absence or presence of Curcumin at various concentrations. Levels of the transcription factor phospho-STAT3, a potential target of Curcumin, were determined by sandwich-ELISA. Subsequent effects on transcription of genes regulating the cell cycle were analyzed by quantitative real-time PCR. Effects on apoptosis were determined by caspase assays. Curcumin potently inhibited GBM cell proliferation as well as migration and invasion in all cell lines contingent on dose. Simultaneously, levels of the biologically active phospho-STAT3 were decreased and correlated with reduced transcription of the cell cycle regulating gene c-Myc and proliferation marking Ki-67, pointing to a potential mechanism by which Curcumin slows tumor growth. Curcumin is part of the diet of millions of people every day and is without known toxic side effects. Our data show that Curcumin bears anti-proliferative, anti-migratory, and anti-invasive properties against GBM cells in vitro. These results warrant further in vivo analyses and indicate a potential role of Curcumin in the treatment of malignant gliomas.BMC Cancer 09/2010; 10(1):491. DOI:10.1186/1471-2407-10-491 · 3.36 Impact Factor
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ABSTRACT: Novel therapeutic options for patients with recurrent primary central nervous system lymphoma (RPCNSL) are needed. Bendamustine, a bifunctional purine analog/alkylating agent, is approved for use in patients with progressive systemic indolent non-Hodgkin's B-cell lymphomas. Limited data suggests that bendamustine may partition into the brain in the setting of a disrupted blood-brain barrier. This report describes the first known experience of patients with RPCNSL treated with bendamustine. Therapy was well-tolerated and best response was noted as stable disease after eight cycles of bendamustine followed by a subsequent local systemic recurrence found at five months follow-up. CNS involvement in this patient remained stable 20 + months post-bendamustine treatment. Based on our observations, further neuropharmacokinetic and efficacy studies with bendamustine may be warranted in this patient population.Journal of Neuro-Oncology 01/2012; 107(3):659-63. DOI:10.1007/s11060-011-0788-x · 3.07 Impact Factor