AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma

Brandes, Alba Ariela; Finocchiaro, Gaetano; Zagonel, Vittorina; Reni, Michele; Caserta, Claudia; Fabi, Alessandra; Clavarezza, Matteo; Maiello, Evaristo; Eoli, Marica; Lombardi, Giuseppe; Monteforte, Marta; Proietti, Elena; Agati, R.; Eusebi, Vincenzo; Franceschi, Enrico

doi:10.1093/neuonc/now035

Cited by 74 publications

(48 citation statements)

References 24 publications

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“…The incidence of AEs in second and third lines of treatment was generally similar between the treatment groups, although the incidence of SAEs in second‐line treatment was higher with CCNU + BEV than with CCNU + placebo (18% vs. 7%). The higher rate of thrombocytopenia observed in the CCNU + BEV group than in the CCNU + placebo group is in line with data from the BELOB and AVAREG studies . The high rates of study treatment discontinuation in second and third lines of treatment observed in this study reflect the hastened clinical deterioration upon progression and the difficulty in managing these patients in clinical practice.…”

Section: Discussionsupporting

confidence: 85%

“…Despite first‐line treatment with surgical resection followed by radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) , the prognosis remains poor, with 1‐ and 5‐year glioblastoma survival rates of 39.3% and 5.5%, respectively . In the recurrent setting, chemotherapy remains the main treatment option ; nitrosourea‐based regimens, such as lomustine (CCNU), are the preferred choice . The efficacy of chemotherapeutic agents is limited, and there remains a high unmet medical need to establish effective glioblastoma treatments; anti‐VEGF agents, such as bevacizumab (BEV), have been investigated.…”

Section: Introductionmentioning

confidence: 99%

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A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Brandes¹,

Gil-Gil

Saran

et al. 2018

The Oncologist

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Background. We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. Patients and Methods. TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Brandes¹,

Gil-Gil

Saran

et al. 2018

The Oncologist

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“…Response rate was 42.6% and 14.3%, in BEV and FTM arms. Median survival was 7.4 (95%CI 6.0-8.9) and 8.6 (95%CI 6.6-10.8) months, respectively, similarly to the entire population of the study [ 3 ]. After progression, 59.6% and 67.9% of patients in the BEV and FTM arm, respectively, received a third line treatment.…”

Section: Resultsmentioning

confidence: 94%

“…In the multicentric noncomparative, randomized phase II AVAREG trial (EudraCT: 2011-001363-46) [ 3 ], that evaluated the role of bevacizumab (BEV) or fotemustine (FTM) in recurrent GBM, we obtained similar survival with the two compounds.…”

Section: Introductionmentioning

confidence: 99%

Early tumour shrinkage as a survival predictor in patients with recurrent glioblastoma treated with bevacizumab in the AVAREG randomized phase II study

et al. 2017

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BACKGROUNDDisease assessment for recurrent glioblastoma (GBM) represents a challenge, especially with the use of antiangiogenic agents. Moreover, validated neuroradiological predictors of outcome are lacking. Recently, the concept of early tumor shrinkage (ETS) has been developed to better assess the ability of treatments in determining a rapid and remarkable tumor response.The aim of the study was to evaluate the role of ETS in predicting survival of GBM patients treated with BEVMETHODSWe examined the radiological data of patients with recurrent GBM treated with bevacizumab (BEV) or fotemustine (FTM) in the randomized phase II AVAREG trial (EudraCT: 2011-001363-46).Radiologic assessments at first disease assessment (day 46) were used to calculate the relative change in the sum of the products of perpendicular diameters of all measurable lesions determined by either T1 contrast and T2/FLAIR.RESULTSIn patients treated with BEV, the best ETS cut-off was reduction of 15% with T1 contrast and of 40% with T2/FLAIR. Adopting this cut-off for T1 contrast radiological changes, ETS was a significant predictor of OS for patients treated with BEV (HR = 0.511, 95%CI:0.269-0.971, p = 0.040). The cut-off obtained for T2/FLAIR was not significantly correlated with OS (p = 0.102), but we found a trend for correlation with survival when considering the variable as continuous (p = 0.058).CONCLUSIONSETS evaluating T1 contrast reduction is a helpful predictor of survival in patients with recurrent GBM treated with BEV, and if validated in a larger prospective trial could be a helpful surrogate endpoint.

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“…Some studies indicated that it was associated with better outcome in methylated patients receiving TMZ-containing therapy ( 18 , 19 ). But some studies also showed that it conferred survival benefit in methylated patients receiving TMZ-free therapy ( 21 , 22 ). So it is necessary to review whether the survival benefit from MGMT methylation is therapy dependent or independent, which will define MGMT promoter methylation as a predictive or prognostic biomarker.…”

Section: Introductionmentioning

confidence: 99%

The Clinical Significance of O6-Methylguanine-DNA Methyltransferase Promoter Methylation Status in Adult Patients With Glioblastoma: A Meta-analysis

et al. 2018

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Background and objectivePromoter status of O6-methylguanine-DNA methyltransferase (MGMT) has been widely established as a clinically relevant factor in glioblastoma (GBM) patients. However, in addition to varied therapy schedule, the prognosis of GBM patients is also affected by variations of age, race, primary or recurrent tumor. This study comprehensively investigated the association between MGMT promoter status and prognosis in overall GBM patients and in different GBM subtype including new diagnosed patients, recurrent patients and elderly patients.MethodsA comprehensive search was performed using PubMed, EMBASE, Cochrane databases to identify literatures (published from January 1, 2005 to April 1, 2017) that evaluated the associations between MGMT promoter methylation and prognosis of GBM patients.ResultsTotally, 66 studies including 7,886 patients met the inclusion criteria. Overall GBM patients with a methylated status of MGMT receiving temozolomide (TMZ)-containing treatment had better overall survival (OS) and progression-free survival (PFS) [OS: hazard ratio (HR) = 0.46, 95% confidence interval (CI): 0.41–0.52, p < 0.001, Bon = 0.017; PFS: HR = 0.48, 95% CI 0.40–0.57, p < 0.001, Bon = 0.014], but no significant advantage on OS or PFS in GBM patients with TMZ-free treatment was observed (OS: HR = 0.97, 95% CI 0.91–1.03, p = 0.08, Bon = 1; PFS: HR = 0.76, 95% CI 0.57–1.02, p = 0.068, Bon = 0.748). These different impacts of MGMT status on OS were similar in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM. Among patients receiving TMZ-free treatment, survival benefit in Asian patients was not observed anymore after Bonferroni correction (Asian OS: HR = 0.78, 95% CI 0.64–0.95, p = 0.02, Bon = 0.24, I2 = 0%; PFS: HR = 0.69, 95% CI 0.50–0.94, p = 0.02, Bon = 0.24). No benefit was observed in Caucasian receiving TMZ-free therapy regardless of Bonferroni adjustment.ConclusionThe meta-analysis highlights the universal predictive value of MGMT methylation in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM patients. For elderly methylated GBM patients, TMZ alone therapy might be a more suitable option than radiotherapy alone therapy. Future clinical trials should be designed in order to optimize therapeutics in different GBM subpopulation.

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AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma

Abstract: Single-agent bevacizumab may have a role in patients with recurrent glioblastoma.

Cited by 74 publications

References 24 publications

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Early tumour shrinkage as a survival predictor in patients with recurrent glioblastoma treated with bevacizumab in the AVAREG randomized phase II study

The Clinical Significance of O6-Methylguanine-DNA Methyltransferase Promoter Methylation Status in Adult Patients With Glioblastoma: A Meta-analysis

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