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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 356-359

Bevacizumab in progressive or recurrent glioblastoma: A quest for the optimal dosage

Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission31-May-2021
Date of Decision12-Jun-2021
Date of Acceptance13-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Ahitagni Biswas
Department of Radiotherapy and Oncology, All India Institute of Medical Sciences, Ansarinagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_128_21

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How to cite this article:
Biswas A. Bevacizumab in progressive or recurrent glioblastoma: A quest for the optimal dosage. Cancer Res Stat Treat 2021;4:356-9

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Biswas A. Bevacizumab in progressive or recurrent glioblastoma: A quest for the optimal dosage. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Oct 22];4:356-9. Available from: https://www.crstonline.com/text.asp?2021/4/2/356/320172

Glioblastoma is the commonest and most aggressive primary malignant brain tumor in adults. The mainstay of treatment for patients with newly diagnosed glioblastoma is maximal safe resection of tumor followed by postoperative radiotherapy (60 Gray in conventional fractionation) with concurrent and adjuvant temozolomide (TMZ).[1] However, the clinical outcome with this approach is unsatisfactory, with a median overall survival (OS) of 12–16 months and a 5-year OS rate of approximately 10%.[2] The therapeutic options at tumor progression are limited, and historically, the OS in such patients is 3–6 months. Therefore, re-surgery and re-irradiation should be considered, whenever feasible. In patients who are not suitable for these treatment modalities, systemic chemotherapy with irinotecan, lomustine, or TMZ may be considered. The response rate with these agents is less than 15%, and the 6-month progression-free survival (PFS) rate is less than 20%. Hence, progressive or recurrent glioblastoma remains a medical conundrum, and more novel and effective therapies are clearly required.

Glioblastoma is a highly vascularized tumor, characterized by microvascular proliferation due to the upregulation of the vascular endothelial growth factor (VEGF) signaling pathway. Bevacizumab, a humanized monoclonal antibody, selectively binds the circulating VEGF and is approved for use in metastatic colorectal, ovarian, cervical, renal, breast, and non-squamous non-small-cell lung cancers. In a Phase II trial, the combination of bevacizumab with irinotecan led to an impressive objective response rate (ORR) of 57%, 6-month PFS rate of 46%, and median OS of 10.5 months in 35 patients with recurrent glioblastoma.[3] In the randomized, multicenter Phase II study, BRAIN, conducted in 167 patients with recurrent glioblastoma, the ORR, 6-month PFS rate, and median OS were 28.2%, 42.6%, and 9.2 months, respectively, in the bevacizumab-alone arm, and 37.8%, 50.3%, and 8.7 months, respectively, in the bevacizumab plus irinotecan arm.[4] Grade 3–5 adverse events occurred in 46.4% of patients in the bevacizumab-alone arm and 65.8% of patients in the bevacizumab plus irinotecan arm, suggesting that bevacizumab alone is also a worthwhile treatment option in patients with recurrent glioblastoma. A drawback of these Phase II studies is that they did not include control groups of patients who did not receive bevacizumab. In addition, it is unclear whether the high ORR with bevacizumab actually translated into an OS benefit. In the randomized multicenter, Phase II study, BELOB, conducted in 153 patients with recurrent glioblastoma, the ORRs were 38%, 5%, and 34%, the 6-month PFS rates were 16%, 13%, and 41%, and the median OS rates were 8, 8, and 11 months in the bevacizumab-alone, lomustine-alone, and bevacizumab plus lomustine arms, respectively, suggesting the need for further assessment of the combination of bevacizumab plus lomustine regimen in Phase III trials.[5] In the randomized, multicenter Phase III study, EORTC 26101, conducted in 437 patients with progressive glioblastoma, the ORRs were 13.9% and 41.5%, median PFS were 1.5 months and 4.2 months (hazard ratio 0.49; P < 0.001), and median OS were 8.6 months and 9.1 months (hazard ratio 0.95; P = 0.65) in the lomustine-alone and bevacizumab plus lomustine arms, respectively.[6] The incidences of grade 3–5 adverse events were 38.1% and 63.6% in the monotherapy and combination groups, respectively. This trial demonstrated that in patients with progressive glioblastoma, the increase in ORR and PFS did not translate into a meaningful OS benefit with the addition of bevacizumab to lomustine. However, a 35.5% crossover rate to off-label use of bevacizumab after progression on the trial treatment in the lomustine-alone arm should be noted in this context.

The recommended dose of bevacizumab in the various systemic cancer protocols is 5–15 mg/kg once every 2–3 weeks. The most commonly used dose of bevacizumab in patients with recurrent glioblastomas is 10 mg/kg once every 2 weeks till disease progression or emergence of unacceptable toxicities.[3],[4],[5],[6] However, this treatment option is cost-prohibitive to the majority of the patients in the Indian subcontinent.[7] Besides, some retrospective studies involving patients with recurrent glioblastomas have shown no statistically significant difference in the OS and PFS between the groups treated with 5 mg/kg of bevacizumab once every 2 weeks and 10 mg/kg of bevacizumab once every 2 weeks.[8] Moreover, the toxicity profile was more favorable in the low-dose bevacizumab group.[8] In this context, the study by D'Souza et al., published in the current issue of the journal, provides valuable insights into the issue of the optimal bevacizumab dosage in patients with recurrent glioblastomas.[9]

In D'Souza et al.'s retrospective study on 68 patients with recurrent or progressive glioblastoma, unsuitable for re-surgery or re-irradiation, 45 (66.2%) received standard-dose bevacizumab (>5–10 mg/kg once every 2–3 weeks) and 23 (33.8%) received low-dose bevacizumab (≤5 mg/kg once every 2–3 weeks).[9] Systemic chemotherapy (irinotecan/lomustine) was added depending on the performance status and the medical comorbidities of the patients. The primary and secondary endpoints of the study were OS and PFS, respectively. At a median follow-up of 26.2 months, the median OS was 7.33 versus 5.47 months (P = 0.27) and the median PFS was 3.60 versus 3.67 months (P = 0.18) in the low-dose and standard-dose arms, respectively. The proportion of patients attaining symptomatic relief was 55% in each group. The incidence of any grade adverse event was 21.7% versus 37.8% (P = 0.274) and grade 3–5 adverse events was 8.6% versus 11.1% (P = 0.844) in the low-dose and standard-dose groups, respectively.

We would like to congratulate D'Souza et al.[9] for conducting this study comparing low-dose with standard-dose bevacizumab in patients with progressive or recurrent glioblastoma, which is particularly relevant in the low- and middle-income countries (LMICs). The authors concluded that low-dose bevacizumab may be as effective as standard-dose bevacizumab (pertaining to survival and disease control), with an identical toxicity profile in this group of patients. Besides, it may be the more cost-effective option in LMICs, where health-care resources are scarce and socioeconomic challenges are formidable.[10],[11]

However, it is necessary to interpret the results of this study with caution. This is a retrospective analysis of outcomes of patients with recurrent or progressive glioblastoma, who received either standard-dose or low-dose bevacizumab, depending solely on their financial reserves. The two groups were not well balanced pertaining to the various tumor-and treatment-related factors. The incidence of glioblastoma at baseline was 34.8% versus 75.6% (P = 0.002) in the low-dose versus standard-dose bevacizumab groups, respectively. Quite predictably, the incidence of isocitrate dehydrogenase (IDH) gene mutations at the time of initial diagnosis was 43.5% versus 17.8% (P = 0.04) in the low-dose versus standard-dose bevacizumab groups, respectively. In the multivariate analysis of OS and PFS, IDH mutation was the only significant prognostic factor predicting favorable outcomes. In addition, a higher proportion of patients received concurrent systemic chemotherapy in the low-dose arm (47.9%) compared to the standard-dose arm (37.8%) (P = 0.524). Numerically, the median number of cycles of bevacizumab was also higher in the low-dose arm (6 cycles) compared to the standard-dose arm (4 cycles) (P = 0.6082). The cycle frequency of bevacizumab was also variable (every 2–3 weeks), and hence, the dose intensity of bevacizumab (mg/kg/week) should have been statistically compared between the 2 study groups. Notably, there was no mention about the performance status of the patients, a powerful prognostic factor in primary as well as progressive or recurrent glioblastoma, in the two study groups. Moreover, it is unclear as to why the authors reported the tumor O[6]-methylguanine-DNA methyltransferase (MGMT) status glioblastoma, reporting the mutated) instead of the MGMT promoter methylation status (methylated versus unmethylated). As there may be a difference in the tumor biology in primary versus progressive or recurrent glioblastoma, reporting the proportion of patients in this study who underwent a repeat biopsy or surgery on progression could provide more insight to the readers. In addition, the authors have not mentioned about the response assessment protocol in patients receiving bevacizumab with or without chemotherapy. It would be pertinent to note the response and pseudoresponse rates in the two study groups. The incidence of Grade 3–5 adverse events was only 10.3% in this study. In contrast, the incidence of grade 3–5 adverse events in the bevacizumab-alone arm in the BRAIN trial was 46.4%.[4] Arterial hypertension is the most common toxicity of bevacizumab, and the incidence of Grade-3 or worse hypertension was 26% in the bevacizumab-alone arm in the BELOB trial.[5] These data raise the possibility of underreporting of the treatment-related toxicities in D'souza et al.'s study. It is also surprising to note that bevacizumab was not discontinued in any patient due to treatment-related toxicity. Moreover, the information regarding salvage/palliative treatment modalities offered to the patients in this study after progression on bevacizumab is lacking, and the same is critical, particularly with respect to the OS.

An objective cost-effectiveness analysis could enhance the strength of this study and will help the readers ascertain whether low-dose bevacizumab is indeed the more cost-effective option in patients with progressive glioblastoma in LMICs. In addition, the effect of low-dose versus standard-dose bevacizumab on the health-related quality of life and neurocognitive function of the patients should be assessed meticulously. Finally, to precisely answer the question whether low-dose bevacizumab is as effective as standard-dose bevacizumab with a more favorable toxicity profile in the context of progressive or recurrent glioblastoma, we require a well-designed prospective randomized controlled trial in the future. While awaiting a definitive answer to this question, bevacizumab at a standard dose of 10 mg/kg once every 2 weeks should be considered in appropriate patients with recurrent glioblastoma. Despite several limitations, the current study by D'Souza et al. raises the possibility that low-dose bevacizumab could also be a pragmatic option in this cohort of patients in LMICs.[9]

Thus, the management of patients with progressive or recurrent glioblastoma is extremely challenging and is tailored based on various factors, including the age, performance status, comorbidities, time to progression, response and toxicities of antecedent treatment, corticosteroid requirement, and types of antiepileptic drugs. Re-surgery is feasible in roughly one out of every four patients with recurrent glioblastoma.[12] Re-irradiation should be considered in suitable patients with small margins and ultraprecise conformal techniques such as intensity-modulated radiation therapy, fractionated stereotactic radiotherapy, and stereotactic radiosurgery.[12] Systemic chemotherapeutic options, such as lomustine, irinotecan, and TMZ, though frequently used in patients with progressive or recurrent glioblastoma, are associated with poor and short-lived responses. Glioblastomas are characterized by chaotic vascular architecture, and bevacizumab decreases the vascular permeability, brain edema, and interstitial pressure and improves drug delivery to the intracranial tumor. Some studies have demonstrated that bevacizumab may decrease the requirement of corticosteroids by inducing vascular normalization.[4] Bevacizumab, alone or in combination with chemotherapy, usually leads to reasonable response rates (35%–50%) and PFS (around 4 months), but a tangible OS benefit remains elusive. In spite of an initial response, there is eventual tumor progression, probably due to the activation of alternative proangiogenic signal transduction pathways. This opens a window of opportunity for oral, multitargeted small-molecule inhibitors of angiogenesis, but the Phase II clinical trials of sunitinib, pazopanib, imatinib, and tandutinib have been largely disappointing. In the Phase III trial, REGAL, on 325 patients with recurrent glioblastoma, cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, given either alone or in combination with lomustine, failed to significantly improve the PFS, when compared with lomustine alone.[13] In the Phase III trial, CENTRIC, on 545 patients with MGMT-promoter-methylated newly diagnosed glioblastoma, the addition of cilengitide, a selective αvβ3 and αvβ5 integrin inhibitor, to standard TMZ -based chemoradiotherapy failed to improve the OS.[14] Bevacizumab negates VEGF-mediated immunosuppression, and therefore, may be an attractive candidate for combination with immune checkpoint inhibitors. However, pembrolizumab alone or in combination with bevacizumab was found to be ineffective in patients with recurrent glioblastoma in a recently published randomized Phase II study.[15] These studies underscore the necessity of predictive tumor tissue, circulating, and neuroimaging biomarkers, which can help us select the right subset of patients with recurrent glioblastoma, who may benefit from antiangiogenic therapy. To cut a long story short, bevacizumab remains the sole antiangiogenic agent, approved for use in recurrent glioblastoma by the United States Food and Drug Administration (in 2009). From a practical viewpoint, it is particularly suitable for patients with large tumors, significant brain edema, and moderate-to-severe neurological symptoms. Although the recommended dose of bevacizumab for patients with recurrent glioblastoma is 10 mg/kg once every 2 weeks, low-dose bevacizumab (5 mg/kg once every 2 weeks) may be explored in LMICs under the umbrella of a clinical trial.

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