Recurrent glioblastoma treatment

Recurrent glioblastoma treatment

Less than 10% of recurrent gliomas recur away from the original tumor site 1).

Reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 2) 3) (duration of high quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 4). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely


The standard of care management for newly diagnosed GBM includes surgery, radiation, temozolomide (TMZ) chemotherapy, and tumor treating fields 5).

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for recurrent glioblastomas (GBMs) 6) 7).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogression, pseudoresponse, or radionecrosis.

Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a recurrent glioblastoma can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserve the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 8).

Options

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma.

Given the lack of consensus on optimal management of recurrent GBM, knowledge of care patterns used for these patients and the criteria used to determine therapeutic strategy is germane to clinicians who care for these patients.


In a study, Hundsberger et al investigated which treatments are currently being used for recurrent GBM within a single nation (Switzerland) and how clinicians are deciding to use them 9)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent GBM. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent GBM were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high performance status were usually managed with temozolomide.The findings of this study underscore the lack of effective first- and second-line treatments for GBM, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for GBM stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision making.The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent GBM. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dodes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 10).

Figure. A through F, clinical decision-making tree for recurrent glioblastoma multiforme (GBM) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGBM, recurrent glioblastoma multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in recurrent glioblastoma in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

Resection

Temozolomide

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 11).

Bevacizumab

Intraarterial chemotharapy

Intrarterial chemotherapy is a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 12).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 13).

Second surgery plus carmustine wafers followed by intravenous fotemustine

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions 14).

Immunotherapy

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 15).

Laser induced interstitial thermotherapy

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 16).

Outcome

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 17) 18).

Reviews

Optimal treatment for recurrent high grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

In a analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 19).

Case series

2018

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 20).

References

2016

Quick-Weller et al. performed tumour resections in seven patients with rGBM, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGBM. However, not all rGBMs exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGBM 21).

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Lombardi G, Della Puppa A, Zustovich F, Pambuku A, Farina P, Fiduccia P, Roma A, Zagonel V. The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: a monoinstitutional experience. Biomed Res Int. 2014;2014:678191. doi: 10.1155/2014/678191. Epub 2014 Apr 9. PubMed PMID: 24812626.
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Glioblastoma Genetics

Glioblastoma Genetics

The understanding of molecular subtypes of gliomas led to the World Health Organization Classification of Tumors of the Central Nervous System 2016 classification criteria for these tumors, introducing the concept of primary glioblastoma and secondary glioblastomas based on genetic alterations and gene or protein expression profiles. Some of these genetic alterations are currently believed to have clinical significance and are more related to secondary GBMs: TP53 mutations, detectable in the early stages of secondary GBM (found in 65%), isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 mutations (50% of secondary GBMs), and also O6 methylguanine DNA methyltransferase (75% of secondary GBMs) 1).

Glioblastoma (GBM) genetic analysis has become integral for classification and determination of prognosis 2) 3) 4).

Genetic mapping of the GBM genome has unveiled countless significantly mutated genes; although many of these mutations contribute to glioma progression, therapeutic-specific modalities require further investigation 5) 6) 7).

Several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer 8).


Genomewide mutational analysis of glioblastomas revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas).

Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas 9).

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Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013 Oct 10;155(2):462-77. doi: 10.1016/j.cell.2013.09.034. Erratum in: Cell. 2014 Apr 24;157(3):753. PubMed PMID: 24120142; PubMed Central PMCID: PMC3910500.
9)

Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19;360(8):765-73. doi: 10.1056/NEJMoa0808710. PubMed PMID: 19228619; PubMed Central PMCID: PMC2820383.

Bevacizumab for recurrent glioblastoma

Bevacizumab for recurrent glioblastoma

Bevacizumab(Avastin®)– a monoclonal antibody against VEGFFDA approved in May 2009 for progressive glioblastoma following prior treatment based on two trials: the BRAIN study, AVF3708g 1) and NCI 06-C-0064E 2).

Given as 10 mg/kg every 2 weeks until disease progression. The reported 6-month PFS rate was 36.0%. The median response durations were 3.9 months and 4.2 months from the two trials. The median OS was 9.3 months 3).

Side effects: gastrointestinal perforations, wound healing complications, hemorrhage, fistula formation, arterial thromboembolic events, hypertension.


Faltings et al. first reported the effect of rechallenging a patient with super-selective intra-arterial cerebral infusion (SIACI) of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus IV bevacizumab for GBM, further exploring theories of bevacizumab resistance 4).


Some phase 2 trials had reported encouraging progression free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma 5)

There was interest in the role of bevacizumab, alone or in combination with cytotoxic drugs, but the results were conflicting 6) 7) 8) 9).

Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular endothelial growth factor monoclonal antibody, for treatment of recurrent GBM. Phase 2 studies demonstrated the efficacy and safety of bevacizumab therapy for recurrent GBM, which led to its approval by the US Food and Drug Administration in 2009 for use in recurrent GBM. Since then, several new Phase 2 studies and retrospective series have demonstrated that bevacizumab significantly increased six-month progression-free survival in patients with recurrent GBM and may do so in new-onset GBM 10).

Further studies in recurrent disease are being conducted; preliminary results of a randomized trial showed favorable results with the combination with CCNU, and final results are awaited. Meanwhile, outside the realm of clinical trials, the current trend appears to be to reserve bevacizumab for use in recurrent disease, or for patients with moderate or severe neurologic symptoms, either in the newly diagnosed or recurrent setting. Further research efforts are needed to determine optimal candidates for this treatment from a molecular standpoint, as well as to develop imaging tools capable of accurately identifying response and progression, and to establish new drug combinations that could result in unquestionable clinical benefit and improved survival in these patients 11).

Monitoring response

In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response.

Standardized relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI is predictive of overall survival (OS) and progression free survival (PFS) in patients with recurrent high-grade brain tumor treated with bevacizumab 12).

Overall survival

Trials on recurrent glioblastoma have shown that bevacizumab alone is able to increase response rate on MRI, median and 6-month progression-free survival (PFS), and modestly overall survival, allowing an improvement of neurological function and a reduction of steroids.

Any drug combination was not superior over bevacizumab alone. A synergistic effect of CCNU has been suggested when added to bevacizumab (BELOB trial), but excluded when added to cediranib (REGAL trial). Phase III trials on bevacizumab in newly diagnosed glioblastoma have shown an improvement of PFS of 3-4 months, but failed to prolong overall survival.

In a randomized trial of bevacizumab for newly diagnosed glioblastoma, the first-line use of bevacizumab did not improve overall survival. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.) 13).

Unexplained is the observation that females had longer overall survival (OS) with BEV than males in patients with progressive glioblastoma 14).

Case series

Case reports

References

1)

Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31. PubMed PMID: 19720927.
2)

Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009; 27:740–745
3)

Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009; 14:1131–1138
4)

Faltings L, Kulason KO, Patel NV, Wong T, Fralin S, Li M, Schneider JR, Filippi CG, Langer DJ, Ortiz R, Boockvar JA. Rechallenging Recurrent Glioblastoma with Intra-Arterial Bevacizumab with Blood Brain Barrier Disruption Results in Radiographic Response: a Case Report. World Neurosurg. 2019 Jul 24. pii: S1878-8750(19)32043-1. doi: 10.1016/j.wneu.2019.07.137. [Epub ahead of print] PubMed PMID: 31351210.
5)

Manneh Kopp RA, Sepúlveda-Sánchez JM, Ruano Y, Toldos O, Pérez Núñez A, Cantero D, Hilario A, Ramos A, de Velasco G, Sánchez-Gómez P, Hernández-Laín A. Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab. Clin Transl Oncol. 2019 Mar 15. doi: 10.1007/s12094-019-02070-6. [Epub ahead of print] PubMed PMID: 30877636.
6)

Lombardi G, Zustovich F, Farina P, et al. Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature. Anticancer Drugs. 2012;24(1):90–97.
7)

Reardon DA, Desjardins A, Peters KB, et al. Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer. 2011;117(23):5351–5358.
8)

Zustovich F, Lombardi G, Pastorelli D, et al. Bevacizumab and glioblastomas, a single-centre experience: how disease history and characteristics may affect clinical outcome. Anticancer Research. 2010;30(12):5213–5216.
9)

Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Journal of Clinical Oncology. 2009;27(28):4733–4740.
10)

Hanson JA, Hsu FP, Jacob AT, Bota DA, Alexandru D. Antivascular endothelial growth factor antibody for treatment of glioblastoma multiforme. Perm J. 2013 Fall;17(4):68-74. doi: 10.7812/TPP/13-081. PubMed PMID: 24361023; PubMed Central PMCID: PMC3854812.
11)

Thomas AA, Omuro A. Current Role of Anti-Angiogenic Strategies for Glioblastoma. Curr Treat Options Oncol. 2014 Aug 31. [Epub ahead of print] PubMed PMID: 25173555.
12)

Schmainda KM, Prah M, Connelly J, Rand SD, Hoffman RG, Mueller W, Malkin MG. Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma. Neuro Oncol. 2014 Jan 15. [Epub ahead of print] PubMed PMID: 24431219.
13)

Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PubMed PMID: 24552317.
14)

Levin VA, Mendelssohn ND, Chan J, Stovall MC, Peak SJ, Yee JL, Hui RL, Chen DM. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neurooncol. 2015 Jan 11. [Epub ahead of print] PubMed PMID: 25575937.
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