Research ArticleClinical Studies

Efficacy of Chemotherapy Plus Bevacizumab in Recurrent Glioblastoma Multiform: A Real-life Study

ALEXANDRE BEIGE, FRANÇOIS GHIRINGHELLI, JULIE LECUELLE, CAROLINE TRUNTZER, GILLES TRUC, JULIE VINCENT, WALID FARAH, FRANÇOIS BORSOTTI, IRINA MAZILU and SILVIA MIHAELA ILIE
Anticancer Research December 2022, 42 (12) 5847-5858; DOI: https://doi.org/10.21873/anticanres.16093

Abstract

Background/Aim: Bevacizumab and chemotherapy are used in glioblastoma multiforme (GBM) relapse. However, the choice of chemotherapeutic agent remains an open question and this study aimed to evaluate the efficacy and safety of different combinations. Patients and Methods: Between June 2005 and August 2020, all patients treated with chemotherapy plus bevacizumab (BVZ) for recurrent glioblastoma in the Georges-François Leclerc Cancer Center, Dijon, France were included in this retrospective comparative study. The primary objective was progression-free survival (PFS) and as secondary objectives, overall survival (OS), disease control rate (DCR), and safety were investigated. Factors associated with response were also analyzed. Results: A total of 160 patients were screened: 100 received fotemustine plus BVZ (62%) and 62 (38%) received another cytotoxic agent plus BVZ: 35 (22%) irinotecan (IRI), 18 (11%) temozolomide (TEM), and 7 (4%) lomustine (LOM). In the whole population, median PFS was 4.47 months, median OS was 9 months, and 3-month DCR was 51%. Regarding survival according to treatment, median OS was significantly lower in the fotemustine group compared to that in other cytotoxic agents: 7.3 vs. 19.9 months. In the fotemustine group, steroids use at baseline and low Karnofsky performance status were associated with poor median OS. Grade 3-4 adverse events were found in 21.9%, with no difference between groups, but 7 patients had grade 5 adverse events in the fotemustine group. Conclusion: Using real-life data, this study showed lower efficacy of fotemustine and bevacizumab, as compared to IRI or TEM or LOM-BVZ combinations.

Key Words:

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults worldwide and represents around 2,000 new cases per year in France (1, 2). The standard upfront strategy comprises surgical resection followed by concomitant chemoradiotherapy and adjuvant chemotherapy using temozolomide (TMZ), an alkylating agent (3). Prognosis of GBM remains poor, with a median survival of about 15 months (4).

There is currently no consensus on the optimal treatment at relapse, but strategy usually includes bevacizumab (BVZ), although it is not approved by the European Medicines Agency for this indication (5, 6). BVZ was approved by the FDA for recurrent high-grade glioma on the basis of two-phase II trials showing a 6-month progression-free survival (PFS) rate of 42.6% and a median overall survival (OS) of 9.2 months with BVZ alone, versus 50.3% and 8.7 months respectively with a combination of BVZ and irinotecan (IRI) (7). Consequently, the National Comprehensive Cancer Network (NCCN) Central Nervous System Cancer guidelines recommend BVZ among preferred regimens in GBM and anaplastic astrocytoma. Chemotherapy and BVZ are among recommended regimens by NCCN (8). The European Association of Neuro-Oncology (EANO) guidelines prefer lomustine (LOM) and BVZ in first intention, if available (9).

The rationale for recommending BVZ in GBM treatment is the dense neovascularization of this tumor, which is correlated to its aggressiveness (10, 11). The combination of BVZ with an alkylating agent yields response rates between 34% and 52%, a median PFS between 4.2 and 11 months, and an OS of 9.1 to 13.1 months (4). By decreasing interstitial pressure inside the tumor, cytotoxic delivery seems to be improved by the concomitant use of BVZ, which might influence its efficacy (12).

Therefore, in this retrospective study, we sought to investigate which of the classical companions of BVZ yields the best results in terms of PFS. Moreover, we assessed disease control rate, which is more closely correlated with a clinical benefit, as well as OS and tolerance.

Patients and Methods

Study population. Using our institution database, 454 files were screened and only 160 cases with GBM who met the eligibility criteria described below were retained. This study was approved by the CNIL (French national commission for data privacy) and the local ethics committee and performed in accordance with the Helsinki Declaration and European legislation. An informed consent was obtained from all subjects or their legal guardian.

Inclusion criteria for patient selection were age ≥18 years, first histologically confirmed diagnosis of glioblastoma between 2005 and 2020, confirmed first disease recurrence after chemoradiotherapy (RT) by TMZ followed by adjuvant TMZ, adequate hematological, renal, and liver function, and second-line treatment with at least one cycle of chemotherapy plus BVZ.

Exclusion criteria were unclear histological diagnosis (such as unspecified high-grade glioma) and patients treated in a randomized controlled study involving BVZ vs. placebo. We collected data regarding patient characteristics, disease presentation, and first line of treatment, namely: sex, age at diagnosis, date of diagnosis, tumor localization, O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status, Isocitrate dehydrogenase 1/2 (IDH) mutation status, Alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein expression, Karnofsky grade at diagnosis, type of upfront surgery, number of adjuvant TMZ cycles, and duration of first line treatment.

At recurrence, type of regimen, daily dose of corticosteroids, antiepileptic drug use, and absolute neutrophil count were recorded. Radiological response at 3 months, neurological deterioration at 3 months, daily dose of corticosteroids at 3 months, date of progression, date of death or last follow-up visit, and grade 3-4 adverse events were documented to assess study criteria. All patients underwent surgery for histological identification; either stereotactic biopsy or tumor resection.

Postoperative radiological assessment by MRI was performed to establish the quality of resection: partial resection R2 (residual disease >90% of the pre-operative tumor), R1 (residual disease 10-90%), or complete resection R0 (residual disease <10%).

Expert pathologists performed histological confirmation of glioblastoma using the WHO 2007 or WHO 2016 classifications, depending on the year of diagnosis (13, 14). All patients received focal radiotherapy (RT) plus daily TMZ followed by adjuvant TMZ. RT consisted of fractionated irradiation, either at a dose of 60 Gy delivered in 30 fractions, or 40 Gy delivered in 15 fractions (3, 15). Concomitant chemotherapy consisted of daily TMZ at a dose of 75 mg/m2 from the first day of radiotherapy, seven days per week.

Adjuvant treatment was started after 4 weeks rest, using a Stupp surrogate regimen, with 6 cycles or more of TMZ. Initial daily TMZ dosage was 150 mg/m2 for five days every 4 weeks and increased to 200 mg/m2 if no major toxicities were observed. Patients with radiological confirmation of disease recurrence received a combined therapy consisting of chemotherapy and the anti-VEGF monoclonal antibody BVZ at 10 mg/kg, administered by infusion every two weeks until disease progression.

The associated cytotoxic agent was an alkylating agent among: fotemustine (FTM), TMZ, LOM, or the topoisomerase I inhibitor, IRI, according to national and international guidelines (8, 16, 17). The choice was made through neuro-oncology multidisciplinary staff according to institution guidelines, taking into account patient characteristics and results of clinical trials available at the time of the decision.

Intravenous FTM was adapted from Addeo’s schedule for fragile patients with an induction phase of 80 mg/m2 every two weeks for six weeks, followed by a maintenance phase of 80 mg/m2 every four weeks (18). IRI was administrated intravenously every two weeks at 125 mg/m2 or 340 mg/m2 for patients taking enzyme-inducing antiepileptic drugs (19). Other regimens included daily oral TMZ 200 mg/m2 for five days every 4 weeks and oral LOM 90-110 mg/m2 every 6 weeks (20). In case of discontinuation of either BVZ or chemotherapy due to grade 3 to 4 adverse events (AE), the treatment was resumed with a partial regimen until recovery or disease progression.

Response assessment. To assess response to second line treatment, a brain MRI was performed every 2 to 3 months and analyzed by an expert neuro-radiologist according to the Response Assessment in Neuro-Oncology (RANO) criteria (21).

The physician’s description of Karnofsky grade and neurological examination at the time of each MRI were collected from the medical records to assess neurological deterioration. The daily corticosteroid dose was recorded as a possible confounding factor for neurological evaluation.

Safety. AE were recorded from the medical records and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (22).

Statistical analysis. Patient characteristics are described as number and percentage for qualitative variables or median and interquartile range (IQR) for continuous variables. Comparisons between groups were performed using the Chi square or Fisher’s exact test (for qualitative variables) or the Wilcoxon test (for continuous variables).

PFS was defined as the time from the beginning of the second line treatment to the date of progressive disease, or the end of the study period, and was censored at 24 months. OS was defined as the time from the beginning of the second line treatment to the date of death or last follow-up visit and was censored at 24 months. Three- and 6-months disease control rates (DCR) were defined as the percentage of patients with partial or complete remission or stable disease according to an MRI evaluation after 3 and 6 months of the second line regimen, respectively.

Survival analysis was performed using the survival R library. The prognostic value of the different variables was tested using univariate and multivariate Cox regression models for OS and PFS. Survival probabilities were estimated using the Kaplan–Meier method and survival curves were compared using the log-rank test. p-Values <0.05 were considered statistically significant.

Results

Patient, tumor, and treatment characteristics. A total of 160 cases were analyzed. Table I summarizes the patient, tumor, and treatment characteristics. Median age was 60 years and 81% of patients had Karnofsky performance status ≥90%. Stereotactic biopsy or partial resection R2 were performed in 91 (57%) patients, whereas 69 (43%) had partial resection R1 or complete resection R0.

View this table:
Table I.

Summary of clinical characteristics of 160 patients with glioblastoma.

When evaluated, MGMT was methylated in 30 (38%) patients, whereas 48 (62%) had unmethylated status (p=0.17). IDH 1/2 were mutated in only 3 (3%) patients.

All patients received RT with concomitant TMZ, and the average duration of TMZ treatment was 6.7 months, with 37 (23%) patients having more than 6 adjuvant cycles.

The second line treatment consisted of FTM-BVZ in 100 (63%) patients, IRI-BVZ in 35 (22%) patients, TMZ-BVZ in 18 patients (11%), and LOM-BVZ in 7 (4%) patients.

Patients were divided into two groups according to the type of chemotherapy received, namely: FTM group and a second group comprising patients who received any other cytotoxic agent. The groups were well balanced in terms of sex, Karnofsky performance status, and type of surgery. However, patients in the FTM group were slightly older (p=0.02) and received longer adjuvant TMZ treatment after radiochemotherapy (p=0.02), whereas more patients received anti-epileptic drugs in the other cytotoxic agents’ group (p=0.001) (Table I).

At the beginning of the second line treatment, 82 (82%) and 46 (76%) patients were treated with corticosteroids in the FTM and other cytotoxic agents’ groups, respectively. The median dose was 60 mg of prednisone per day in both groups.

The median duration of treatment was 3.5 months in the whole population and did not differ between the FTM and the other chemotherapy groups: 3.2 (3.27) and 3.9 months (6.32) (p=0.26), respectively. When progressive disease was observed, 34 (22%) patients received another chemotherapy, with a median duration of 3.3 months.

Clinical outcomes.

DCR. At 3 months, DCR was 51% in the whole population, with a significant difference in favor of the other cytotoxic agents’ group compared to the FTM group (58% and 47% respectively, p=0.01). Moreover, clinical data showed a concordant benefit with less neurological deterioration at 3 months in the other cytotoxic agents’ group (p=0.02) (Table II).

View this table:
Table II.

Summary of clinical and response variables in treatment groups.

Controlled disease at 3 months was related to MGMT status, with 18 (19%) patients with methylated MGMT status and 4 (12%) patients with unmethylated status showing progressive disease (p=0.03).

At 6 months, DCR in the whole population was 34%, with no significant difference between groups (17% in FTM treated patients and 28.3% for other chemotherapeutics, p=0.28).

PFS and OS. The median follow-up duration was 23.5 months (95%CI=21-30.1) in this study.

In the overall population, median PFS was 4.47 months (95%CI=3.9-5.5) and there was no significant difference between treatment groups, with a median PFS of 4.4 months (95%CI=3.6-5.5) in the FTM treated patients and 5.5 months (95%CI=3.7-8.5) in the patients receiving other cytotoxic agents (HR=1.24, 95%CI=0.86-1.81, p=0.25) (Figure 1). By univariate survival analysis, anti-epileptic usage was associated with better PFS (HR=0.84, 95%CI=0.8-0.88, p<0.001, respectively) (Figure 2A). In the FTM group, corticosteroid intake at 3 months was significantly associated with poorer PFS (HR=1.97, 95%CI=1.06-3.64, p=0.03) (Figure 2B). In the other cytotoxic agents’ group, MGMT unmethylated status was significantly associated with poorer PFS (HR=11, 95%CI=1.18-100, p=0.04) (Figure 2C). MGMT unmethylated status was significantly associated with poorer PFS; with a median PFS of 3.9 months (95%CI=3-5.4) in patients with MGMT unmethylated status, and 4.9 months (95%CI=3.5-14.4) in patients with MGMT methylated status (HR=0.57, 95%CI=0.34-0.99, p=0.05) (Figure 3).

Figure 1.
Figure 1.

Kaplan–Meier curves according to two therapeutic groups for progression-free survival.

Figure 2.
Figure 2.

Univariate Cox models for progression-free survival. Forest plots representing the hazard ratio and confidence interval using univariate Cox models for progression-free survival for in whole population (A), in fotemustine group (B) and in other cytotoxic agents, group (C). p-Values were adjusted using Benjamini-Hochberg FDR correction. The arrow means the limit of the confidence interval is greater than the limit of the axis.

Figure 3.
Figure 3.

Kaplan–Meier curves for progression-free survival according to O6-methylguanine-DNA methyltransferase (MGMT) methylation status in all patients.

Median OS in the whole population was 9 months (95%CI=8-15.7) with a significantly lower median OS in the FTM group (7.3 months (95%CI=5.9-11) compared to that in patients treated with other chemotherapeutic agents (19.9 months (95%CI=10.5-NR), HR=2.13, 95%CI=1.23-3.7, p=0.007 (Figure 4A and Figure 5). In the FTM group, corticosteroid use at baseline was associated with poor survival: median OS was 6.7 months (95%CI=5.4-8.6) for patients taking steroids and was not reached (95%CI=10.4-not reached) for patients treated with other cytotoxic agents (HR=2.9, 95%CI=1.1-7.3, p=0.03) (Figure 4B, C and Figure 6A).

Figure 4.
Figure 4.

Univariate Cox models for overall survival. Forest plots representing the hazard ratio and confidence interval using univariate Cox models for overall survival in whole population (A), in fotemustine group (B) and in other cytotoxic agents, group (C). p-Values were adjusted using Benjamini-Hochberg FDR correction. The arrow means the limit of the confidence interval is greater than the limit of the axis.

Figure 5.
Figure 5.

Kaplan–Meier curves according to two therapeutic groups for overall survival.

Figure 6.
Figure 6.

Kaplan–Meier curves for overall survival according corticosteroid intake (A) and Karnofsky grade (B) inside each group.

Similarly, subgroup analysis according to Karnofsky status showed that patients with low performance status who received FTM had poorer survival compared to those treated with other cytotoxic agents: median OS 4.4 months (95%CI=3.6-NR) vs. NR (95%CI=10.5-NR) respectively (HR=4.5, 95%CI=1.3-16.7, p=0.02) (Figure 4B, C and Figure 6B).

Subgroup analysis showed that IRI-BVZ and TMZ-BVZ or LOM-BVZ were both associated with better OS compared to FTM-BVZ: 61.5, 11.4, and 7.3 months, respectively (HR=0.45, 95%CI=0.2-0.98, p=0.05 and HR=0.49, 95%CI=0.25-0.97, p=0.04, respectively) (Figure 7A). However, no significant difference was found in terms of PFS: 4.9, 6.5 and 4.4 months, respectively (HR=0.92, 95%CI=0.59-1.44, p=0.72 and HR=0.68, 95%CI=0.4-0.13, p=0.14, respectively) (Figure 7B).

Figure 7.
Figure 7.

Kaplan–Meier curves for overall survival (A) and progression-free survival (B) according to treatment combination (Fotemustine vs. Irinotecan vs. Temozolomide or Lomustine).

Similarly, 3-month DCR was higher with both IRI and TMZ or LOM combinations compared to FTM-BVZ: 47% of patients treated by fotemustine showed remission or stable disease after 3 months of relapse treatment vs. 54% in the IRI subgroup and 64% in the TMZ or LOM subgroup, p=0.02) (Table II).

Safety. Grade 3 and 4 AE were observed in 35 patients (21.9%), with no significant difference between groups. AE frequently associated with BVZ, such as high blood pressure (HBP), proteinuria, thrombo-embolic events, and hemorrhage were observed in 7%, 8%, 11%, and 2% respectively, with no significant difference between treatment groups (Table III).

View this table:
Table III.

Summary of adverse events.

However, grade 5 AE occurred in 7 patients (4%), possibly related to BVZ: 4 patients died from gastrointestinal perforation, 1 from necrotizing dermohypodermitis, 1 from uncontrolled muscular hemorrhage, and 1 from subarachnoid hemorrhage. All of them received concomitant administration of BVZ and FTM. There was no grade 5 AE observed in patients receiving an association of BVZ with TMZ, LOM, or IRI.

In the FTM group, the rate of thrombopenia was significantly higher with 21 (21%) patients showing grade 3 or 4 thrombopenia, compared to 4 (7%) in the other cytotoxic agents’ group. In addition, 53 patients (53%) died while on treatment in the FTM group vs. 18 patients (30%) in the other treatment group (p=0.005).

Discussion

There is no standard for systemic treatment of progressive GMB after upfront treatment, with re-irradiation or surgical re-intervention being among the multimodal therapeutic options (9). Several studies have addressed the question of the efficacy of BVZ alone and reported an objective response rate from 6 to 38%, 6-month PFS rate between 18 and 43%, median PFS between 2.8 and 4.2 months, and median OS of 7 to 10.5 months (23).

Fotemustine-Bevacizumab. In this study, FTM-BVZ was the most frequently administered regimen. Three-month radiological response rate (partial or complete) under FTM-BVZ was 33%, which is lower than that reported in other studies (12, 23), probably due to selection bias. Median (m)PFS and mOS were 4.4 and 7.3 months, respectively, which is also slightly lower than that previously reported (12, 24). As regards toxicity, the grade 3-4 AE rate was 21%, with 7% of grade 5 AE, mostly due to thrombopenia (21%), as expected.

In a phase II study, 6-month OS rate was 73.3% with FTM, compared to 62.1% with BVZ, with higher rates in MGMT promoter methylated tumors (87.5% and 50%, respectively) (25). Soffietti et al. conducted a phase II study in grade IV glioma, which found a 6-month PFS rate of 42.6%, mPFS of 5.2 months (95%CI=3.8-6.6), and mOS of 9.1 months (95%CI=7.3-10.3). AE were mostly grade 3 neutropenia (13%) and thrombocytopenia (9%) and the rate of discontinuation was 22% (12).

Vaccaro et al. found that responders had better mPFS and mOS: 6 months (95%CI=2.4-9.6) and 8 months (95%CI=5.1-10.9) versus 1 month (95% non-estimable) and 3 months (95%CI=1.4-4.5) in non-responders. Forty-eight % had grade 3-4 AE, namely 6 hematologic and 5 non-hematologic, leading to 25% FTM dose reduction (24). In the literature, the most common FTM schedule is 100 mg/m2 every week for 3 consecutive weeks followed by a 5-week rest period, and then infusion every 3 weeks (24).

Lately, the regimen has been adapted for better hematological tolerance: 80 mg/m2 every 2 weeks for 5 cycles followed by a 5-week rest period, and then 80 mg/m2 every 4 weeks or 60 mg/m2 weekly for 3 cycles followed by a 5-week rest period, and then 75 mg/m2 every 4 weeks (25, 26).

In single arm analyses, the objective response rates attained with BVZ-FTM, in second or third line, vary between 46.5% (27) and 52% (12).

IRI-BVZ was the second most prescribed regimen, and it yielded the best 3-months disease control rate, at 54%, as well as the longest median OS, at 61.4 months, albeit with modest PFS of 4.9 months (IQ=1.9-11). IRI alone has been evaluated in GBM in several studies, with reported mPFS ranging between 1 and 7.6 months and mOS from 5.8 to 17.9 months (28). It was approved in the USA following a phase II study comparing IRI-BVZ to BVZ alone (7). The combination yielded a 6-month PFS rate of 50.3% vs. 42.6% with BVZ, and an objective response rate of 37.8 % vs. 28.2% with BVZ (p<0.0001), albeit with 65.8% grade 3 or higher AE with the combination, versus 46.4% with BVZ (7).

A meta-analysis of 477 patients found a better objective response rate with IRI-BVZ compared to BVZ alone (45.8% vs. 33.9% respectively, p=0.013) and improved 6-month PFS (48.3% vs. 38.8% respectively, p=0.046), but no difference in OS (8.91 vs. 8.63 months respectively, p=0.487 (29).

Vredenburgh et al. studied the IRI-BVZ combination with BVZ at 15 mg/kg every 22 days and found a radiological response rate of 62% and 6-month OS of 72% with 12.5% thrombotic complication and 2 toxic deaths (brain hemorrhage and gastrointestinal perforation) (19). Bokstein et al. evaluated the same association with BVZ 5 mg/kg every 15 days: response rate and mOS were similar but there were only 2 grade 3 AE (1 fatigue and 1 paranoid psychosis) (30).

In our analysis, this regimen was used in only 4.4% (7 patients). For this reason, we assessed its efficacy as part of a subgroup comprising patients treated with LOM or TMZ. In these patients, we found better efficacy compared to the association of FTM-BVZ: HR for OS was 0.49, 95%CI=0.25-0.97, p=0.04 but with no individual difference for mPFS and OS (4.2 months, 95%CI=3.7-4.3; 9.1 months, 95%CI=8.1-10.1). The BELOB phase II trial validated LOM-BVZ, showing better results than either agent alone. Accordingly, 9-month OS was 63% (95%CI=49-75) for the combined group compared to 43% (95%CI=29-57) for the LOM group and 38% (95%CI=25-51) for the BVZ group, although there was no difference in terms of mPFS (31).

A phase II study tested BVZ at 10 mg/kg every 2 weeks, 5 mg/kg/week or at a low dose 5 mg/kg every 3 weeks, and 1.66 mg/kg/week plus LOM (90 mg/m2) in 6-week cycles. mPFS was not significantly longer in the low dose LOM-BVZ arm (4.34 months (95%CI=2.96-8.34) compared to the BVZ arm (4.11 months, 95%CI=2.69-5.55, p=0.19) (32).

In a retrospective study in patients with recurrent GBM, BEV-LOM (N=18) vs. BEV alone (N=17) yielded better a PFS (6.11 months, 95%CI=3.41-12.98; p=0.00241) and OS [6.59 months (95%CI=5.51-16.3; p=0.0238) versus 2 months] (33).

The EORTC 26101 phase III trial (N=437) compared LOM 90 mg/m2 + BVZ 10 mg/kg to LOM 110 mg/m2. Grade 3-5 AE occurred in 38.1% in the monotherapy group and in 63.6% in the combination group. mPFS was 4.2 months with the combination (95%CI=3.7-4.3) vs. 1.5 months for LOM alone (95%CI=1.5-2.5), but with no benefit in terms of OS [9.1 months (95%CI=8.1-10.1) vs. 8.6 months (95%=7.6-10.4] for the combination and monotherapy respectively (p=0.65) (20).

In our analysis, the rechallenge regimen of TMZ was 150 mg-200 mg/m2 on days 1-5, every 28 days and was prescribed in 11.2% (18 patients). There was no association with MGMT status (p=0.17), and tolerance was better than that in the FTM-BVZ group. Regarding efficacy, there was no difference compared to other non-FTM agents: mPFS 6.5 months, mOS 11.4 months; however, a slightly better 3-month DCR was reported. Most published data have investigated TMZ-BVZ at relapse with TMZ metronomic at lower doses.

In Reardon et al.’s phase II trial, daily TMZ or etoposide at 50 mg/m2 for 21 consecutive days each month combined with BVZ 10 mg/kg every 2 weeks was tested in 33 patients. Fifty-two % achieved stable disease, 6-month PFS was 4.4%, and median PFS was 7.3 weeks, while the only grade 4 AE was reversible neutropenia (34). Verhoeff et al. evaluated BVZ 10 mg/kg i.v. every 3 weeks with daily TMZ 50 mg/m2 in 23 patients with high grade glioma: overall response rate (20%), mPFS (13.9 weeks) and mOS (17.1 weeks) were all considerably lower compared with most other studies with TMZ-BVZ regimen (35).

Similar results were found in a phase II study with combined protracted daily TMZ and biweekly BVZ in 32 patients with recurrent GBM, reporting a 6-month PFS rate of 18.8% (95%CI=7.6-33.7), mPFS of 15.8 weeks, and mOS of 37 weeks with a 6-month OS rate of 62.5% (95%CI=43.5-76.7). As regards tolerance, two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis) and one patient experienced grade 5 pneumonia (36).

A Spanish phase II study tested another schedule at first relapse of GBM: BVZ 10 mg/kg day every 2 weeks and TMZ 150 mg/m2 on days 1-7 and 15-21, every 28 days. The estimated 6-month PFS rate was 21.9% (95%CI=9.3-40), mPFS and mOS were 4.2 months (95%CI=3.6-5.4) and 7.3 months (95%CI=5.8-8.8), respectively. Nineteen % were long-term survivors, with mPFS and mOS of 9.5 months (95%CI=7.9-23.6) and 15.4 months (95%CI=8.9-NA), respectively. Three grade 3-4 hemorrhages and six cases of thrombopenia occurred (37).

In the literature, to the best of our knowledge, there is no direct comparison of any of the regimens presented here. The only available comparisons were between the combination therapy and anti-angiogenic alone. Furthermore, the association of LOM-BVZ was mainly assessed at first relapse, whereas FTM and IRI were tested mostly at any relapse, rendering comparisons between clinical trials difficult.

Our study is one of the largest analyses of different associations of cytotoxic-antiangiogenic agents, especially FTM-BVZ; however, because of the retrospective design and the long period of inclusion, there is some potential for bias.

Conclusion

In this large retrospective study assessing several combinations of BVZ with cytotoxic agents in GBM patients at relapse, one of the largest studies to date assessing the combination of FTM-BEV, we found no difference in terms of PFS between treatments, but we report lower OS in the FTM group. Moreover, there were more grade 4-5 AE in this group.

In both cohorts, PFS was better in patients with MGMT methylated status, and the disease control rate was better in patients treated with other cytotoxic agents. The best disease control and objective response rates were observed in patients who received IRI.

However, these data suggest that the risk/benefit ratio could favor the use of irinotecan instead of alkylating agents, especially in case of MGMT unmethylated status and in patients at risk of hemorrhagic syndrome.

Footnotes

  • Authors’ Contributions

    All Authors contributed substantially to the conception and design of the study, acquisition of data and analysis and interpretation of data, drafting the article and revising it critically for important intellectual content. All Authors approved the version to be submitted.

  • Conflicts of Interest

    The Authors have no relevant financial or non-financial relationships or activities or any conflict of interest to disclose. The abstract of this paper was presented at the ESMO Congress 2021 as poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in Annals of Oncology: https://doi.org/10.1016/j.annonc.2021.08.025

  • Received September 25, 2022.
  • Revision received October 31, 2022.
  • Accepted November 1, 2022.

References

  1. ↵
    1. Ostrom QT,
    2. Bauchet L,
    3. Davis FG,
    4. Deltour I,
    5. Fisher JL,
    6. Langer CE,
    7. Pekmezci M,
    8. Schwartzbaum JA,
    9. Turner MC,
    10. Walsh KM,
    11. Wrensch MR and
    12. Barnholtz-Sloan JS
    : The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol 16(7): 896-913, 2014. PMID: 24842956. DOI: 10.1093/neuonc/nou087
    OpenUrlCrossRefPubMed
  2. ↵
    1. Fabbro-Peray P,
    2. Zouaoui S,
    3. Darlix A,
    4. Fabbro M,
    5. Pallud J,
    6. Rigau V,
    7. Mathieu-Daude H,
    8. Bessaoud F,
    9. Bauchet F,
    10. Riondel A,
    11. Sorbets E,
    12. Charissoux M,
    13. Amelot A,
    14. Mandonnet E,
    15. Figarella-Branger D,
    16. Duffau H,
    17. Tretarre B,
    18. Taillandier L and
    19. Bauchet L
    : Association of patterns of care, prognostic factors, and use of radiotherapy-temozolomide therapy with survival in patients with newly diagnosed glioblastoma: a French national population-based study. J Neurooncol 142(1): 91-101, 2019. PMID: 30523606. DOI: 10.1007/s11060-018-03065-z
    OpenUrlCrossRefPubMed
  3. ↵
    1. Stupp R,
    2. Mason WP,
    3. van den Bent MJ,
    4. Weller M,
    5. Fisher B,
    6. Taphoorn MJ,
    7. Belanger K,
    8. Brandes AA,
    9. Marosi C,
    10. Bogdahn U,
    11. Curschmann J,
    12. Janzer RC,
    13. Ludwin SK,
    14. Gorlia T,
    15. Allgeier A,
    16. Lacombe D,
    17. Cairncross JG,
    18. Eisenhauer E,
    19. Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and National Cancer Institute of Canada Clinical Trials Group
    : Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10): 987-996, 2005. PMID: 15758009. DOI: 10.1056/NEJMoa043330
    OpenUrlCrossRefPubMed
  4. ↵
    1. Yang SB,
    2. Gao KD,
    3. Jiang T,
    4. Cheng SJ and
    5. Li WB
    : Bevacizumab combined with chemotherapy for glioblastoma: a meta-analysis of randomized controlled trials. Oncotarget 8(34): 57337-57344, 2017. PMID: 28915674. DOI: 10.18632/oncotarget.16924
    OpenUrlCrossRefPubMed
  5. ↵
    1. Khasraw M,
    2. Ameratunga MS,
    3. Grant R,
    4. Wheeler H and
    5. Pavlakis N
    : Antiangiogenic therapy for high-grade glioma. Cochrane Database Syst Rev (9): CD008218, 2014. PMID: 25242542. DOI: 10.1002/14651858.CD008218.pub3
    OpenUrlCrossRefPubMed
  6. ↵
    1. Kreisl TN,
    2. Kim L,
    3. Moore K,
    4. Duic P,
    5. Royce C,
    6. Stroud I,
    7. Garren N,
    8. Mackey M,
    9. Butman JA,
    10. Camphausen K,
    11. Park J,
    12. Albert PS and
    13. Fine HA
    : Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5): 740-745, 2009. PMID: 19114704. DOI: 10.1200/JCO.2008.16.3055
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Friedman HS,
    2. Prados MD,
    3. Wen PY,
    4. Mikkelsen T,
    5. Schiff D,
    6. Abrey LE,
    7. Yung WK,
    8. Paleologos N,
    9. Nicholas MK,
    10. Jensen R,
    11. Vredenburgh J,
    12. Huang J,
    13. Zheng M and
    14. Cloughesy T
    : Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28): 4733-4740, 2009. PMID: 19720927. DOI: 10.1200/JCO.2008.19.8721
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Nabors LB,
    2. Portnow J,
    3. Ahluwalia M,
    4. Baehring J,
    5. Brem H,
    6. Brem S,
    7. Butowski N,
    8. Campian JL,
    9. Clark SW,
    10. Fabiano AJ,
    11. Forsyth P,
    12. Hattangadi-Gluth J,
    13. Holdhoff M,
    14. Horbinski C,
    15. Junck L,
    16. Kaley T,
    17. Kumthekar P,
    18. Loeffler JS,
    19. Mrugala MM,
    20. Nagpal S,
    21. Pandey M,
    22. Parney I,
    23. Peters K,
    24. Puduvalli VK,
    25. Robins I,
    26. Rockhill J,
    27. Rusthoven C,
    28. Shonka N,
    29. Shrieve DC,
    30. Swinnen LJ,
    31. Weiss S,
    32. Wen PY,
    33. Willmarth NE,
    34. Bergman MA and
    35. Darlow SD
    : Central nervous system cancers, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 18(11): 1537-1570, 2020. PMID: 33152694. DOI: 10.6004/jnccn.2020.0052
    OpenUrlCrossRefPubMed
  9. ↵
    1. Weller M,
    2. van den Bent M,
    3. Preusser M,
    4. Le Rhun E,
    5. Tonn JC,
    6. Minniti G,
    7. Bendszus M,
    8. Balana C,
    9. Chinot O,
    10. Dirven L,
    11. French P,
    12. Hegi ME,
    13. Jakola AS,
    14. Platten M,
    15. Roth P,
    16. Rudà R,
    17. Short S,
    18. Smits M,
    19. Taphoorn MJB,
    20. von Deimling A,
    21. Westphal M,
    22. Soffietti R,
    23. Reifenberger G and
    24. Wick W
    : EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol 18(3): 170-186, 2021. PMID: 33293629. DOI: 10.1038/s41571-020-00447-z
    OpenUrlCrossRefPubMed
  10. ↵
    1. Das S and
    2. Marsden PA
    : Angiogenesis in glioblastoma. N Engl J Med 369(16): 1561-1563, 2013. PMID: 24131182. DOI: 10.1056/NEJMcibr1309402
    OpenUrlCrossRefPubMed
  11. ↵
    1. Plate KH,
    2. Breier G,
    3. Weich HA and
    4. Risau W
    : Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359(6398): 845-848, 1992. PMID: 1279432. DOI: 10.1038/359845a0
    OpenUrlCrossRefPubMed
  12. ↵
    1. Soffietti R,
    2. Trevisan E,
    3. Bertero L,
    4. Cassoni P,
    5. Morra I,
    6. Fabrini MG,
    7. Pasqualetti F,
    8. Lolli I,
    9. Castiglione A,
    10. Ciccone G and
    11. Rudà R
    : Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol 116(3): 533-541, 2014. PMID: 24293233. DOI: 10.1007/s11060-013-1317-x
    OpenUrlCrossRefPubMed
  13. ↵
    1. Louis DN,
    2. Ohgaki H,
    3. Wiestler OD,
    4. Cavenee WK,
    5. Burger PC,
    6. Jouvet A,
    7. Scheithauer BW and
    8. Kleihues P
    : The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2): 97-109, 2007. PMID: 17618441. DOI: 10.1007/s00401-007-0243-4
    OpenUrlCrossRefPubMed
  14. ↵
    1. Louis DN,
    2. Perry A,
    3. Reifenberger G,
    4. von Deimling A,
    5. Figarella-Branger D,
    6. Cavenee WK,
    7. Ohgaki H,
    8. Wiestler OD,
    9. Kleihues P and
    10. Ellison DW
    : The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6): 803-820, 2016. PMID: 27157931. DOI: 10.1007/s00401-016-1545-1
    OpenUrlCrossRefPubMed
  15. ↵
    1. Lapointe S,
    2. Florescu M,
    3. Simonyan D and
    4. Michaud K
    : Impact of standard care on elderly glioblastoma patients. Neurooncol Pract 4(1): 4-14, 2017. PMID: 31385982. DOI: 10.1093/nop/npw011
    OpenUrlCrossRefPubMed
  16. ↵
    1. Association des neuro-oncologues d’expression française
    : Référentiel Glioblastome (Grade IV OMS). Available at: https://www.onco-grandest.fr/wp-content/uploads/2020/07/anocef_referentiel_glioblastome2018.pdf [Last accessed on November 1, 2022]
  17. ↵
    1. Stupp R,
    2. Brada M,
    3. van den Bent MJ,
    4. Tonn JC,
    5. Pentheroudakis G and ESMO Guidelines Working Group
    : High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25 Suppl 3: iii93-ii101, 2014. PMID: 24782454. DOI: 10.1093/annonc/mdu050
    OpenUrlCrossRefPubMed
  18. ↵
    1. Addeo R,
    2. Lamberti G,
    3. Simonetti G,
    4. Iodice P,
    5. Marinelli A,
    6. Montella L,
    7. Cappabianca S,
    8. Gaviani P,
    9. Caraglia M,
    10. Prete SD and
    11. Silvani A
    : Biweekly fotemustine schedule for recurrent glioblastoma in the elderly: activity and toxicity assessment of a multicenter study. CNS Oncol 8(2): CNS32, 2019. PMID: 31290692. DOI: 10.2217/cns-2019-0004
    OpenUrlCrossRefPubMed
  19. ↵
    1. Vredenburgh JJ,
    2. Desjardins A,
    3. Herndon JE 2nd.,
    4. Marcello J,
    5. Reardon DA,
    6. Quinn JA,
    7. Rich JN,
    8. Sathornsumetee S,
    9. Gururangan S,
    10. Sampson J,
    11. Wagner M,
    12. Bailey L,
    13. Bigner DD,
    14. Friedman AH and
    15. Friedman HS
    : Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30): 4722-4729, 2007. PMID: 17947719. DOI: 10.1200/JCO.2007.12.2440
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Wick W,
    2. Gorlia T,
    3. Bendszus M,
    4. Taphoorn M,
    5. Sahm F,
    6. Harting I,
    7. Brandes AA,
    8. Taal W,
    9. Domont J,
    10. Idbaih A,
    11. Campone M,
    12. Clement PM,
    13. Stupp R,
    14. Fabbro M,
    15. Le Rhun E,
    16. Dubois F,
    17. Weller M,
    18. von Deimling A,
    19. Golfinopoulos V,
    20. Bromberg JC,
    21. Platten M,
    22. Klein M and
    23. van den Bent MJ
    : Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 377(20): 1954-1963, 2017. PMID: 29141164. DOI: 10.1056/NEJMoa1707358
    OpenUrlCrossRefPubMed
  21. ↵
    1. Ellingson BM,
    2. Wen PY and
    3. Cloughesy TF
    : Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurotherapeutics 14(2): 307-320, 2017. PMID: 28108885. DOI: 10.1007/s13311-016-0507-6
    OpenUrlCrossRefPubMed
  22. ↵
    Common Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm [Last accessed on October 25, 2022]
  23. ↵
    1. Seystahl K,
    2. Wick W and
    3. Weller M
    : Therapeutic options in recurrent glioblastoma – An update. Crit Rev Oncol Hematol 99: 389-408, 2016. PMID: 26830009. DOI: 10.1016/j.critrevonc.2016.01.018
    OpenUrlCrossRefPubMed
  24. ↵
    1. Vaccaro V,
    2. Fabi A,
    3. Vidiri A,
    4. Giannarelli D,
    5. Metro G,
    6. Telera S,
    7. Vari S,
    8. Piludu F,
    9. Carosi MA,
    10. Villani V,
    11. Cognetti F,
    12. Pompili A,
    13. Marucci L,
    14. Carapella CM and
    15. Pace A
    : Activity and safety of bevacizumab plus fotemustine for recurrent malignant gliomas. Biomed Res Int 2014: 351252, 2014. PMID: 24877084. DOI: 10.1155/2014/351252
    OpenUrlCrossRefPubMed
  25. ↵
    1. Addeo R,
    2. Caraglia M,
    3. De Santi MS,
    4. Montella L,
    5. Abbruzzese A,
    6. Parlato C,
    7. Vincenzi B,
    8. Carraturo M,
    9. Faiola V,
    10. Genovese M,
    11. Cennamo G and
    12. Del Prete S
    : A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma. J Neurooncol 102(3): 417-424, 2011. PMID: 20694830. DOI: 10.1007/s11060-010-0329-z
    OpenUrlCrossRefPubMed
  26. ↵
    1. Fabi A,
    2. Metro G,
    3. Vidiri A,
    4. Lanzetta G,
    5. Carosi M,
    6. Telera S,
    7. Maschio M,
    8. Russillo M,
    9. Sperduti I,
    10. Carapella CM,
    11. Cognetti F and
    12. Pace A
    : Low-dose fotemustine for recurrent malignant glioma: a multicenter phase II study. J Neurooncol 100(2): 209-215, 2010. PMID: 20352471. DOI: 10.1007/s11060-010-0163-3
    OpenUrlCrossRefPubMed
  27. ↵
    1. Liu Z,
    2. Zhang G,
    3. Zhu L,
    4. Wang J,
    5. Liu D,
    6. Lian L,
    7. Liu J,
    8. Lai T and
    9. Zhuang X
    : Retrospective analysis of bevacizumab in combination with fotemustine in chinese patients with recurrent glioblastoma multiforme. Biomed Res Int 2015: 723612, 2015. PMID: 25789324. DOI: 10.1155/2015/723612
    OpenUrlCrossRefPubMed
  28. ↵
    1. Abdel-Rahman O and
    2. Fouad M
    : Irinotecan-based regimens for recurrent glioblastoma multiforme: [corrected] a systematic review. Expert Rev Neurother 15(11): 1255-1270, 2015. PMID: 26469869. DOI: 10.1586/14737175.2015.1101346
    OpenUrlCrossRefPubMed
  29. ↵
    1. Zhang G,
    2. Huang S and
    3. Wang Z
    : A meta-analysis of bevacizumab alone and in combination with irinotecan in the treatment of patients with recurrent glioblastoma multiforme. J Clin Neurosci 19(12): 1636-1640, 2012. PMID: 23047061. DOI: 10.1016/j.jocn.2011.12.028
    OpenUrlCrossRefPubMed
  30. ↵
    1. Bokstein F,
    2. Shpigel S and
    3. Blumenthal DT
    : Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 112(10): 2267-2273, 2008. PMID: 18327820. DOI: 10.1002/cncr.23401
    OpenUrlCrossRefPubMed
  31. ↵
    1. Taal W,
    2. Oosterkamp HM,
    3. Walenkamp AM,
    4. Dubbink HJ,
    5. Beerepoot LV,
    6. Hanse MC,
    7. Buter J,
    8. Honkoop AH,
    9. Boerman D,
    10. de Vos FY,
    11. Dinjens WN,
    12. Enting RH,
    13. Taphoorn MJ,
    14. van den Berkmortel FW,
    15. Jansen RL,
    16. Brandsma D,
    17. Bromberg JE,
    18. van Heuvel I,
    19. Vernhout RM,
    20. van der Holt B and
    21. van den Bent MJ
    : Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15(9): 943-953, 2014. PMID: 25035291. DOI: 10.1016/S1470-2045(14)70314-6
    OpenUrlCrossRefPubMed
  32. ↵
    1. Weathers SP,
    2. Han X,
    3. Liu DD,
    4. Conrad CA,
    5. Gilbert MR,
    6. Loghin ME,
    7. O’Brien BJ,
    8. Penas-Prado M,
    9. Puduvalli VK,
    10. Tremont-Lukats I,
    11. Colen RR,
    12. Yung WKA and
    13. de Groot JF
    : A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. J Neurooncol 129(3): 487-494, 2016. PMID: 27406589. DOI: 10.1007/s11060-016-2195-9
    OpenUrlCrossRefPubMed
  33. ↵
    1. Heiland DH,
    2. Masalha W,
    3. Franco P,
    4. Machein MR and
    5. Weyerbrock A
    : Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine. J Neurooncol 126(3): 567-575, 2016. PMID: 26614518. DOI: 10.1007/s11060-015-2002-z
    OpenUrlCrossRefPubMed
  34. ↵
    1. Reardon DA,
    2. Desjardins A,
    3. Peters K,
    4. Gururangan S,
    5. Sampson J,
    6. Rich JN,
    7. McLendon R,
    8. Herndon JE 2nd.,
    9. Marcello J,
    10. Threatt S,
    11. Friedman AH,
    12. Vredenburgh JJ and
    13. Friedman HS
    : Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol 103(2): 371-379, 2011. PMID: 20853132. DOI: 10.1007/s11060-010-0403-6
    OpenUrlCrossRefPubMed
  35. ↵
    1. Verhoeff JJC,
    2. Lavini C,
    3. van Linde ME,
    4. Stalpers LJA,
    5. Majoie CBLM,
    6. Reijneveld JC,
    7. van Furth WR and
    8. Richel DJ
    : Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 21(8): 1723-1727, 2010. PMID: 20064829. DOI: 10.1093/annonc/mdp591
    OpenUrlCrossRefPubMed
  36. ↵
    1. Desjardins A,
    2. Reardon DA,
    3. Coan A,
    4. Marcello J,
    5. Herndon JE 2nd.,
    6. Bailey L,
    7. Peters KB,
    8. Friedman HS and
    9. Vredenburgh JJ
    : Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 118(5): 1302-1312, 2012. PMID: 21792866. DOI: 10.1002/cncr.26381
    OpenUrlCrossRefPubMed
  37. ↵
    1. Sepúlveda JM,
    2. Belda-Iniesta C,
    3. Gil-Gil M,
    4. Pérez-Segura P,
    5. Berrocal A,
    6. Reynés G,
    7. Gallego O,
    8. Capellades J,
    9. Ordoñez JM,
    10. La Orden B and
    11. Balañá C
    : A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma. Clin Transl Oncol 17(9): 743-750, 2015. PMID: 26033428. DOI: 10.1007/s12094-015-1304-0
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Efficacy of Chemotherapy Plus Bevacizumab in Recurrent Glioblastoma Multiform: A Real-life Study
ALEXANDRE BEIGE, FRANÇOIS GHIRINGHELLI, JULIE LECUELLE, CAROLINE TRUNTZER, GILLES TRUC, JULIE VINCENT, WALID FARAH, FRANÇOIS BORSOTTI, IRINA MAZILU, SILVIA MIHAELA ILIE
Anticancer Research Dec 2022, 42 (12) 5847-5858; DOI: 10.21873/anticanres.16093
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords