Salvage therapy with bendamustine for temozolomide refractory recurrent anaplastic gliomas: a prospective phase II trial

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1 DOI /s CLINICAL STUDY Salvage therapy with bendamustine for temozolomide refractory recurrent anaplastic gliomas: a prospective phase II trial Marc C. Chamberlain 1 Howard Colman 2 Bryan T. Kim 3 Jeffrey Raizer 4 Received: 28 April 2016 / Accepted: 16 August 2016 Springer Science+Business Media New York 2017 Abstract There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy, re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration never previously evaluated in AG. Assess response and toxicity of bendamustine in recurrent AG in a phase II trial. Adults with radiation and temozolomide refractory recurrent AG were treated with bendamustine. A cycle of bendamustine was defined as two consecutive days of treatment (100 mg/m 2 /day) administered once every 4 weeks. Success of treatment was defined as progression free survival (PFS) at 6 months of 40 % or better. Twenty-six adults [16 males; 10 females: median age 40 years (range 30 65)] were treated, 12 at first recurrence and 17 at second recurrence. Prior salvage therapy included re-resection (14), chemotherapy (11) and re-radiation (2). Grade 3 treatmentrelated toxicities included lymphopenia (11 patients; Grade 4 in 3), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in one patient each. One patient discontinued therapy due to toxicity. There were * Marc C. Chamberlain chambemc@u.washington.edu 1 Division of Neuro Oncology, Department of Neurology and Neurological Surgery, Fred Hutchinson Cancer Research Center, University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Ave E, MS: G4 940, Seattle, WA 98109, USA Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA Department of Neurology, University of Washington, Seattle, WA, USA Department of Neurology, Northwestern University, Chicago, IL, USA five instances of bendamustine dose delays all due to lymphopenia. There were no dose reductions due to toxicity. The median number of of therapy was 3 (range 1 8). Best radiographic response was progressive disease in 12 (46 %), stable disease in 13 (50 %) and partial response in 1 (4 %). Median, 6- and 12-month PFS was 2.7 months (range 1 52), 27 and 8 % respectively. In patients with recurrent AG refractory to Z, bendamustine has manageable toxicity and modest single agent activity though not meeting prespecified study criteria. Keywords Bendamustine Anaplastic glioma (AG) Temozolomide refractory Introduction Anaplastic gliomas (AG), World Health Organization (WHO) grade III gliomas, are comprised of three histology subtypes including anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) [1]. Recent molecular pathology insights have revised this morphology-based classification with low (WHO Grade II) and intermediate (WHO Grade III) gliomas subdivided based on presence or absence of mutations in the isocitrate dehydrogenase genes (IDH1 or IDH2) [2 8]. Within intermediate grade gliomas with IDH mutations, tumors with a predominantly astrocytic histology and prognosis typically demonstrate ATRX (alpha thalassemia mental retardation X-linked) and p53 mutations and absence of the 1p/19q codeletion while tumors with a predominantly oligodendroglial histology and prognosis are characterized by presence of the 1p/19q codeletion [2 8]. Tumors without IDH mutation or 1p/19q codeletion typically have significantly worse prognosis, similar to WHO Vol.:( )

2 Grade IV (glioblastoma) tumors. The distinction between these biomarker defined subtypes is clinically germane as phase III studies have demonstrated a benefit on overall survival of chemotherapy in addition to radiation compared to radiation alone in both1p/19q codeleted AG as well as AG without codeletion that demonstrate mutations in IDH [9 12]. Currently newly diagnosed 1p/19q codeleted AG is treated with RT plus PCV (procarbazine, lomustine, vincristine) chemotherapy whereas uni- or nondeleted AG is treated with RT plus Z based upon early results of the CAT- NON trial. Uncertain is whether this distinction between IDH1 mutated versus wild type AG has treatment implications notwithstanding the clear prognostic importance [11]. Less well characterized is the management of recurrent AG following initial up-front therapy with RT and alkylator-based chemotherapy [12 18]. As with glioblastoma, recurrent AG may in appropriate patients, be considered for re-resection with or without instillation of carmustine (BCNU), biodegradable polymers (Gliadel), or re-rt (single fraction stereotactic or conformal multi-fraction RT) [19 21]. Notably repeat surgery or re-radiation for recurrent high-grade gliomas has never been systemically evaluated in prospective randomized trials and consequently evidenced-based data supporting these therapies in recurrent AG is meager. Further, most patients with recurrent AG are not candidates for reoperation or repeat RT and consequently are treated with systemic therapy either on a clinical trial or at physician discretion. The most frequently used and currently available systemic therapies at recurrence are re-challenge with Z, CCNU or PCV if not previously utilized, and bevacizumab [12 14, 18, 22 24]. Nonetheless, salvage treatment of recurrent AG with any current therapy remains unsatisfactory as reflected by comparatively short duration response and survival. Enrollment in clinical trials for recurrent disease is a proven method to test novel therapies and potentially improve upon current outcomes in patients with recurrent AG. Bendamustine (Treanda) is a purine analog/alkylator chemotherapy hybrid molecule [25 28]. Specifically, the drug was synthesized with a benzimidazole ring situated in the center of its structure where purine antimetabolite activity resides. A bifunctional mechlorethamine nitrogen mustard is attached to the benzimidazole ring which provides alkylating properties. The mechanism of action for bendamustine in humans has not been fully characterized though the alkylating properties of the agent have been established and bendamustine induces apoptosis via single and double strand deoxyribonucleic acid (DNA) breaks. In addition, studies have concluded that bendamustine causes more extensive and durable DNA strand breaks than those seen with conventional alkylating agents. In the NCI COM- PARE analysis, bendamustine showed limited cross correlation with other alkylating agents [28]. These results indicate that bendamustine has mechanism of action that goes beyond alkylation. Bendamustine also appears to induce a non-apoptotic process of cell death called mitotic catastrophe. Tissue distribution studies in a variety of nonprimate animals demonstrated wide distribution in all tissues including brain [25 28]. Clinical evidence of activity in brain was seen in two small studies of patients with either recurrent primary CNS lymphoma or recurrent glioblastoma [29, 30]. Both animal and human studies provide supportive evidence that bendamustine penetrates into the brain parenchyma. The primary objective of this prospective multicenter phase II study was to determine whether bendamustine given every 4 weeks at standard dose as established in hematologic cancers could significantly delay progression in patients with recurrent AG as determined by 6-month progression free survival (PFS-6). Twenty-six adult patients with recurrent AG previously treated with surgery, RT and Z chemotherapy were evaluated. Three additional patients treated similarly and progressing on salvage bevacizumab were also evaluated in a small exploratory sub-study. Study objective The primary endpoint of the study is the 6-month progression-free survival (PFS-6) i.e. the proportion of patients who remain alive and free of any progression at 6 months. Secondary objectives were to determine the safety of single agent bendamustine (Treanda) in the treatment of anaplastic gliomas and to assess quality of life using the FACT-Br instrument. Study design The study was a phase II open-label trial of bendamustine in patients with recurrent (first or second) anaplastic glioma. Treatment of bendamustine (100 mg/m 2 / day for two consecutive days) were repeated every 28 days, operationally defined as one cycle. Pretreatment anti-emetic medication included ondansetron and dexamethasone. A bendamustine dose reduction schedule was protocol prespecified. Use of growth factor support was not permitted. For patients responding to treatment or with stable disease, therapy continued for 6 months (six total ). Response parameters utilized the Macdonald criteria as these were in common use prior to introduction of the RANO criteria [31]. Repeated measures of tumor size were used to determine the duration of response and time to tumor progression. Magnetic resonance imaging (MRI) was performed every 2 months unless otherwise clinically indicated and a neurologic examination was performed prior to each cycle

3 of bendamustine. All tumor responses (partial or complete) by MRI were centrally reviewed at the University of Washington. There was no central pathology review as each institution determined pathology individually. A minimax two-stage design was used wherein the Type I error rate was set at 10 % (α= 0.10) and the Type II error rate is set at 20 % (β = 0.20) [power = 80 %]. Four prior studies in similar patients inform as to treatment efficacy [16, 17, 32, 33]. Based on these studies it was determined that for patients with recurrent AG, if the PFS-6 with bendamustine were less than 20 % there would be no interest in further study. If the PFS-6 were 40 % or more, further study would be warranted. Patients This was a prospective single arm phase II multicenter (University of Washington, Seattle, WA; University of Utah, Salt Lake City, UT; and Northwestern University, Chicago, IL) study for patients with recurrent AG treated with single agent bendamustine following prior treatment with surgery, RT and Z. The study opened in January 2009 and closed in January All patients consented to treatment after being apprised of alternative therapies and receiving disclosure of potential risks and benefits of bendamustine. No patient had been treated on an investigational trial prior to treatment with bendamustine; three patients were treated following progression on bevacizumab. The study was approved by the participating university institutional review boards and was funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program with general research support provided by Cephalon, Inc. d/b/a Teva Pharmaceuticals. All patients had a histologically proven intracranial AG [anaplastic astrocytoma (AA) in 16; anaplastic oligodendroglioma (AO) in 8; anaplastic oligoastrocytoma (AOA) in 5] that progressed following RT and Z (Table 1). Twelve patients (66 %) were treated at first recurrence and 17 patients (34 %) were treated at second recurrence. Twentyfive patients (86 %) had been treated with up-front chemotherapy (Table 1). Molecular pathology was inconsistently performed and revealed six patients with 1p/19q codeletion (4 AO, 1 AOA and 1 AA) (Table 1). IDH1 mutation status was established in only four patients wherein IDH1 was mutated in three patients (2 AA, 1 AO) and wild type in one patient (1 AA). Prior salvage therapy included re-resection in 14 (carmustine implant in 1), Z re-challenge in 11 and bevacizumab in three (Table 1). Amongst patients on antiepileptic drugs (n = 21), none were receiving an enzyme inducing agent. The interval between end of prior treatment and start of bendamustine ranged from 1 to 39 months (median 1.4). The median Karnofsky performance score at initiation of bendamustine treatment was 90 % (range %). All patients had recovered from prior chemotherapy with normal hematologic, renal and hepatic function. Radiographically measurable intracranial disease was required wherein recurrent tumor was bi-dimensionally measurable (at least 10 mm in one dimension) by cranial contrast-enhanced MRI. Histological confirmation of tumor recurrence was not required. To assess the quality of life, study participants were asked to complete the Functional Assessment of Cancer Therapy Brain version (FACT-Br) at the time of enrollment, and at the beginning of every other cycle. FACT-Br is a multidimensional self-administered rating scale consisting of 46 Likert-type questions, 27 of which are general questions, the remaining 19 being disease specific. Results Twenty-nine patients [17 males; 12 females: median age 41years (range 30 65)] were treated and evaluable for both toxicity (Common Toxicity Criteria version 3.0) and response. Grade 3 treatment-related toxicities included lymphopenia (17 patients; 20 instances), myalgia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in one patient each (Table 2). Five patients manifested one event each of Grade 4 lymphopenia. Five other episodes Grade 4 toxicities were seen (pneumonia in two patients, pulmonary embolus in one and seizure in one), of which none were considered to be treatment related. No Grade 5 toxicities were seen. Five serious adverse events were observed; three events were unrelated to treatment (pneumonia in two patients and seizure in one) and two were related (pneumonia in one and allergic reaction in one). A single patient discontinued therapy due to toxicity secondary to an allergic infusion reaction. There were no bendamustine dose reductions; five patients (one instance in each) required a brief delay (median 1-week) in treatment due to lymphopenia. A total of 98 of bendamustine were administered (median 3, range 1 8). Eight patients (28 %) completed the planned six of bendamustine. In the primary study cohort of patients that were bevacizumab naïve (n = 26), best radiographic response was progressive disease in 12 (46 %), stable disease in 13 (50 %) and partial response in 1 (4 %). In the single patient with a partial response, bendamustine treatment was continued for eight based on radiographic response seen at cycle six. Median, 6- and 12-month PFS was 2.7 months (95th CI months; range 1 52), 27 and 8 % respectively (Fig. 1). Response did not differ by AG histology. In the three patients treated following bevacizumab progression, best response was progressive disease in two and stable disease in one patient. Median PFS was 1.9 months

4 Table 1 Recurrent anaplastic glioma: survival after salvage bendamustine therapy Patient Sex/age (years) Histology/ tumor location/ molecular pathology Adjuvant therapy Salvage therapy Time before Benda Surgery Standard RT/TMZ Post-RT TMZ/ RT Surgery Chemo/ Pre-therapy KPS (%) Bendamustine therapy # Cycles Best response PFS Posttherapy survival OS 1 F/36 AOA/R unideletion 2 F/59 AO/R co-deletion 3 F/39 AA/R no-deletion 4 M/37 AOA/R no-deletion 5 F/37 AOA/L relative unideletion 6 M/31 AA/L unideletion 7 M/54 AO/L parietal/codeletion 8 M/45 AA/L parietal, occipital/ 9 M/49 AO/L relative co-deletion STR Yes TMZ/6 GTR TMZ/ PD GTR Yes TMZ/10 GTR TMZ/ SD STR Yes TMZ/1 TMZ/2 CBDCA/ SD STR Yes TMZ/6 GTR TMZ/ SD STR Yes TMZ/23 TMZ/ SD STR Yes TMZ/12 GTR PD Bx Yes TMZ/24 SRS PD Bx Yes TMZ/3 STR SD STR Yes TMZ/ SD

5 Table 1 (continued) Patient Sex/age (years) Histology/ tumor location/ molecular pathology 10 M/43 AA/R occipital/ 11 M/33 AA/R 12 M/33 AO/L nodeletion 13 M/49 AA/R 14 M/41 AO/L frontal, temporal/ co-deletion 15 F/38 AA/R 16 M/53 AA/L temporal/ nondeletion 17 M/35 AA/L temporal/ 18 M/37 AO/R co-deletion 19 F/30 AO/R parietal/ relative codeletion, IDH1 mut Adjuvant therapy Salvage therapy Time before Benda Surgery Standard RT/TMZ Post-RT TMZ/ RT Surgery Chemo/ Pre-therapy KPS (%) Bendamustine therapy # Cycles Best response PFS Posttherapy survival OS GTR Yes TMZ/ PD Bx Yes TMZ/12 CCNU/5 VCR/ PD GTR Yes TMZ/ SD GTR Yes TMZ/6 STR PD GTR Yes TMZ/10 RT + TMZ PD GTR Yes TMZ/19 STR SD Bx Yes TMZ/ PD STR No a None GTR TMZ/ PD Bx Yes TMZ/ PD GTR Yes TMZ/8 SRS GTR + Gliadel, GTR b SD

6 Table 1 (continued) Patient Sex/age (years) Histology/ tumor location/ molecular pathology 20 F/56 AA/L 21 M/35 AA/R codeletion, IDH1 mut 22 F/43 AA/L temporal/nodeletion 23 F/65 AA/L, IDH1 mut 24 M/57 AO/L nondeletion 25 F/39 AOA/L 26 M/61 AA/L frontal, parietal, temporal/, IDH1 wt 27 M/42 AA/R no-deletion 28 F/33 AOA/L parietal/ relative unideletion Adjuvant therapy Salvage therapy Time before Benda Surgery Standard RT/TMZ Post-RT TMZ/ RT Surgery Chemo/ Pre-therapy KPS (%) Bendamustine therapy # Cycles Best response PFS Posttherapy survival OS STR Yes TMZ/ PD Bx Yes None GTR GTR b TMZ/ SD STR Yes None STR TMZ/ SD GTR Yes TMZ/ SD GTR Yes TMZ/24 GTR TMZ/7 PCV/ukn SD STR No a None TMZ/ PD Bx Yes TMZ/ SD Bx Yes TMZ/6 BV/ SD Bx Yes TMZ/16 CBDCA/5 BV/ PD

7 Table 1 (continued) OS PFS Posttherapy survival Bendamustine therapy Pre-therapy KPS (%) Adjuvant therapy Salvage therapy Time before Benda Histology/ tumor location/ molecular pathology Patient Sex/age (years) # Cycles Best response RT Surgery Chemo/ Post-RT TMZ/ Surgery Standard RT/TMZ STR Yes TMZ/5 SRS BV/ PD F/55 AA/L frontal, splenium/ F female, M male, AOA anaplastic oligoastrocytoma, AO anaplastic oligodendroglioma, AA anaplastic astrocytoma, R right, L left,ukn nown, Mut mutation, WT wild type, STR subtotal resection, GTR gross total resection, Bx biopsy, Z temozolomide, CBDCA carboplatin, CCNU lomustine, PCV procarbazine, lomustine, vincristine, BV bevacizumab, PD progressive disease, SD stable disease, PR partial response, RT radiotherapy, SRS stereotactic radiosurgery, KPS Karnofsky performance status, PFS progression free survival, OS overall survival, Mns months a Radiation therapy only b Second re-operation (range 1 7 months). Twenty-one patients (72 %) discontinued treatment due to radiographic disease progression and one patient each due to neurologic decline, allergic infusion reaction and combined radiographic and neurologic progression. Seven patients (24 %) are alive and on alternative treatment; 21 patients (72 %) have died of disease progression. One patient was lost to follow-up. Median overall survival from initial diagnosis was 46.6 months (95th CI months; range months), median post-bendamustine survival was 16.2 months (95th CI months; range 1 59 months) (Fig. 2). In the three patients progressing on bevacizumab, the median post-bendamustine survival was 3.4 months (range ). There were no changes in the FACT-Br when comparing scores (both overall and subcategories) from study entry (26 completed) to study exit (18 completed) suggesting quality of life was not adversely affected by bendamustine therapy. Discussion Bendamustine is an attractive agent for the treatment of malignant gliomas for several reasons including the drugs bifunctional mechanism of anti-tumoral activity, non-cross resistance with other alkylator-based chemotherapy and apparent CNS penetration. Notwithstanding these rationalizations, bendamustine proved ineffective for recurrent AG previously treated with surgery, RT and temozolomide. Further and not dissimilar to other agents used to treat postbevacizumab progression, there was no evidence of activity admittedly in only three patients. There remains a significant challenge in treating recurrent AG as available salvage therapies are meager much as for recurrent glioblastoma [12, 13, 18, 22, 24]. Nearly half of all patients in the current study underwent a reoperation (all pathologically reconfirmed AG) however prospective data indicating re-resection provides a survival benefit is sparse. Whether re-radiation in recurrent AG is beneficial is similarly fraught with limited prospective data as prior studies are mostly single center and retrospective [20, 21]. The current study employed single fraction stereotactic radiotherapy (SRS) in three patients at time of first recurrence. Temozolomide was administered to 25 patients following initial surgery and again in 11 patients at first recurrence of which seven patients were re-challenged with Z following a disease free interval. The benefit of rechallenge with Z is presently unclear as there are conflicting studies regarding efficacy albeit the majority of data is in relationship to recurrent glioblastoma [14, 15]. Seven other patients were treated with salvage chemotherapy (three with bevacizumab, two with a nitrosourea and two with carboplatin) prior to bendamustine treatment. The lack of response stratified by histology (anaplastic astrocytoma

8 Table 2 Highest grade of toxicity observed Toxicity N total Grade I Grade II Grade III Grade IV Grade V Confusion Diarrhea a Dysarthria Dysphasia Pulmonary embolus Extravasation a Fatigue a Generalized muscle weakness Seizure Hyperglycemia Hypertension Bendamustine allergic reaction a Increased right sided weakness Lower extremity venous thrombosis Leukopenia a Lymphopenia a Myalgia a Nausea a Short term memory decline Pneumonia a Pneumonia Thrombocytopenia a Vomiting a Total a Bendamustine related toxicity Fig. 1 Progression free survival (PFS) after initiation of bendamustine. Mo. months, dashed lines 95th percentile confidence intervals

9 Fig. 2 Overall survival from initial surgery. Mo. months, dashed lines 95th percentile confidence intervals vs. anaplastic oligodendroglial gliomas) likely reflects the minimal activity of Bendamustine in either cohort and perhaps the failure to perform central pathology review prior to study initiation. Furthermore, the inability to segregate tumors based on molecular biomarkers may have confounded differences in response based upon histology. Novel therapies such as immunotherapies e.g. checkpoint inhibitors and CAR T-cells currently in early stage clinical trials may afford a more effective therapy for recurrent anaplastic gliomas. The pattern of treatment in the current study prior to enrollment in a clinical trial reflects common practice in the neuro-oncology community and was based on knowledge at that time of study implementation. Most notably molecular pathology was in evolution during the time period of the current study and was consequently sparsely collected. Importantly the significance of genotyping with respect to treatment allocation was incomplete. The final results of the RTOG 9402 and EORTC trials in anaplastic oligodendroglial tumors were nown and likely today a higher proportion of patients with 1p/19q codeleted AG (five patients in the present study as well as two additional relative codeleted patients) would be treated with RT followed by PCV chemotherapy (evidenced based) or the other commonly used alternative, RT with concurrent temozolomide followed by adjuvant temozolomide (not evidenced based but used as the experimental treatment arm in the CODEL trial) [9, 10]. Further and as recently demonstrated in the CATNON trial, non-codeleted AG would be treated with RT or RT-temozolomide followed by 6 12 of post-rt temozolomide, a pattern of treatment used in the majority of patients in the current study. The distinction between IDH1 mutant and wild type non-codeleted AG treatment remains unclear pending further data from the CATNON trial [11]. In summary, bendamustine though comparatively nontoxic and well tolerated demonstrated insufficient activity in the primary study cohort of recurrent AG having failed prior surgery, RT and temozolomide to warrant further study. Acknowledgments The authors want to thank Sandra Johnston and Alisa Clein for their organizational and administrative assistance in developing the study and manuscript. Disclosure MC Chamberlain and Bryan Kim collected and analyzed data. No personal communications cited in the manuscript. Compliance with ethical standards Conflict of interest The authors report no conflicts of interest. References 1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK et al (2007) WHO classification of tumors of the central nervous system. Acta Neuropathol. doi: /s Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A et al (2014) International Society of Neuropathology s. Brain Pathol Zurich Switz 24: Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:

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