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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 224-229

Optimal dose of bevacizumab in recurrent glioma: A retrospective study


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Submission15-Feb-2021
Date of Decision22-Apr-2021
Date of Acceptance28-May-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Vijay M Patil
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_41_21

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  Abstract 


Background: Recurrent gliomas have a dismal prognosis. They can be treated with re-surgery and re-irradiation. Bevacizumab as a single agent or in combination with chemotherapy is an alternative treatment option. However, in our country, a considerable proportion of patients cannot afford the approved 10 mg/kg dose.
Objective: This study was aimed at evaluating the efficacy of low-dose bevacizumab in recurrent gliomas.
Methods: Patients with recurrent gliomas presenting to our Neuro-Medical Oncology unit between July 1, 2015, and November 30, 2018, were retrospectively analyzed. The patients were divided into two groups, those treated with ≤5 mg/kg of bevacizumab (low dose) and those treated with >5–10 mg/kg (standard dose) of bevacizumab. The status of isocitrate dehydrogenase (IDH) and O[6]-methylguanine-DNA methyltransferase was recorded. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and adverse events.
Results: A total of 68 patients were treated with bevacizumab, of which 23 (33.8%) received the low-dose regimen. At a median follow-up of 26.2 months, there was no difference in the median PFS (low-dose group: 3.60 months; 95% confidence interval [CI], 2.5–7.47 vs. standard-dose group: 3.67 months; 95% CI, 2.17–4.53) (P = 0.18) and median OS (low-dose group: 7.33 months; 95% CI, 3.97–9.10 vs. standard-dose group: 5.47 months; 95% CI, 4.67–6.2) (P = 0.27). In addition, the adverse events were not significantly different between the two groups.
Conclusion: Low-dose bevacizumab may be effective in the treatment of recurrent gliomas and should be compared with standard dose in prospective randomized studies.

Keywords: Bevacizumab, glioblastoma, low.dose, recurrent glioma


How to cite this article:
Dsouza H, Singh GK, Menon N, Abhyankar A, Puranik A, Mahajan A, Janu A, Kalra D, Dale O, Varghese L, Epari S, Chatterjee A, Krishnatry R, Gupta T, Jalali R, Patil VM. Optimal dose of bevacizumab in recurrent glioma: A retrospective study. Cancer Res Stat Treat 2021;4:224-9

How to cite this URL:
Dsouza H, Singh GK, Menon N, Abhyankar A, Puranik A, Mahajan A, Janu A, Kalra D, Dale O, Varghese L, Epari S, Chatterjee A, Krishnatry R, Gupta T, Jalali R, Patil VM. Optimal dose of bevacizumab in recurrent glioma: A retrospective study. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Jul 27];4:224-9. Available from: https://www.crstonline.com/text.asp?2021/4/2/224/320137




  Introduction Top


Central nervous system (CNS) tumors constitute approximately 2% of all malignancies. In India, high-grade gliomas constitute about 59.5% of all CNS tumors, and comparable data have been reported from the Western and other Asian countries.[1]

The treatment of recurrent high-grade gliomas is challenging.[2] Even though re-surgery and re-irradiation have been reported to produce satisfactory survival, the applicability of these modalities is very limited.[3],[4],[5],[6],[7] Systemic salvage chemotherapy steps up in such situations. Bevacizumab alone or in combination with cytotoxic drugs is considered the standard treatment in this clinical scenario.[8] Several small studies have used bevacizumab at a dose of 10 mg/kg once in 2 weeks.[9],[10] The benefit of bevacizumab at this high dose is however questionable. In the recent European Organization for Research and Treatment of Cancer study, high-dose bevacizumab in combination with lomustine failed to show a survival benefit over lomustine alone.[11]

The mechanism of action of bevacizumab on the vasculature is an interesting phenomenon. In animal models, the dose of bevacizumab required for anatomical and physiological normalization of vasculature is 0.3–1 mg/kg.[12] This low dose leads to a reduction in the total vascular volume and decreases the immunosuppressive ability of the tumor microenvironment. Contrary to this, there are other experimental data suggesting that a high dose of bevacizumab (10 mg/kg) can cause destruction of the blood vessels, thus hampering the delivery of the chemotherapeutic agent.[12] However, whether low doses of bevacizumab can improve the patient outcomes is still unknown. In India, the access to bevacizumab is limited, and hence, we offer low-dose bevacizumab to economically underprivileged patients who cannot afford the standard dose of 10 mg/kg. We performed a retrospective analysis to assess the clinical outcomes with low-dose bevacizumab and compared them to those with standard-dose bevacizumab.


  Methods Top


General study details

This retrospective study was conducted in the Neuro-Medical Oncology unit of the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary care and oncology-only teaching center in Mumbai, India. A prospective database of all the patients receiving systemic therapy from July 1, 2015, to November 30, 2018, was used for the current analysis. The study (protocol 900650) was approved on July 28, 2020, by the Institutional Ethics Committee-III, Advanced Centre for Treatment, Research, and Education in Cancer, Mumbai-410210, India [Supplementary Appendix 1]. The need for obtaining a written informed consent was waived. The study was performed in accordance with the principles of Good Clinical Practice and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. All patients provided written informed consent prior to receiving chemotherapy. No funding was obtained for this study.

Participants

Patients with relapsed or progressive glioblastoma aged more than 18 years and treated with bevacizumab who visited the Neuro-Medical Oncology unit of our tertiary care center between July 1, 2015, and November 30, 2018, were identified from the database and included in the analysis.

Variables

The primary endpoint of the study was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and adverse events.

Study methodology

All the patients were discussed in a joint neuro-oncology meeting and were ineligible for re-surgery or re-irradiation and offered bevacizumab alone or in combination with cytotoxic therapy. The choice of single-agent therapy or combination was based on the Eastern Cooperative Oncology Group performance status and comorbidities of the patients. Bevacizumab was administered once every 2–3 weeks. The first dose of bevacizumab was administered with adequate supportive medications over 90 minutes, and the subsequent doses were administered over 30 minutes. The dose of bevacizumab was determined based on the financial condition of the patient. The drug was discontinued in case of disease progression or intolerable side effects. In addition, it was discontinued if the patient could not afford it. The details of the baseline characteristics, previous treatments, histopathology, molecular features, date of treatment initiation with bevacizumab, dose of bevacizumab, date of disease progression, and date of death or date of last follow-up were obtained from the database and entered into an Excel sheet. The patients were divided into two groups depending on the dose of bevacizumab they received. The standard dose (STD-B) group included patients who received >5–10 mg/kg of bevacizumab, while the low-dose (LD-B) group included patients who received ≤5 mg/kg of bevacizumab.

Statistics

No formal sample size calculation was performed for this study, and all consecutive patients fulfilling the eligibility criteria were enrolled. The Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY, USA: IBM Corp.) and RStudio version 3.5.2 were used for data analysis. The time-to-event variables were estimated using the Kaplan–Meier method.[13] OS was defined as the time in months from the start of treatment with bevacizumab to death. In patients who were alive at the time of data censoring, OS was defined as the time in months from the start of treatment with bevacizumab to the date of last follow-up. PFS was defined as the time in months from the start of treatment with bevacizumab to disease progression or death. In patients who were alive and did not show disease progression at the time of data censoring, PFS was defined as the time in months from the start of treatment with bevacizumab to the date of last follow-up. The adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.02.

Median with 95% confidence interval (CI) was calculated using the Brookmeyer and Crowley method. The estimates were compared between the STD-B and LD-B groups using the log-rank test. P < 0.05 was considered statistically significant. The hazard ratio with its 95% CI was calculated using the COX regression analysis with the Efron method of tie handling.[14] The assumption of proportionality was tested before performing the COX regression analysis and it were met.[15] Continuous variables were expressed as median with 95% CI and compared between the two groups using the median test.[16] Normal distribution of the continuous variables was confirmed using the Shapiro–Wilk test. The ordinal and nominal variables were expressed as percentages with 95% CI and were compared between the two groups using the Fisher's test.


  Results Top


Baseline characteristics

Of a total of 90 patients, 68 fulfilled the eligibility criteria. There were 45 and 23 patients in the STD-B and LD-B groups, respectively [Figure 1]. The baseline characteristics of the patients are shown in [Table 1]. All patients at baseline underwent maximal safe surgical resection. Radiation was received at baseline by 63 (92.6%) patients and at relapse by 5 (7.3%) patients. Temozolomide was received at baseline by 52 (76.5%) patients. At the time of planning bevacizumab, all patients in the study had received radiation and temozolomide.
Figure 1: Flowchart for patient selection for the study evaluating the optimal dose of bevacizumab in recurrent glioma

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Table 1: Patient demographics and tumor characteristics in the study evaluating the optimal dose of bevacizumab in recurrent glioma

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Treatment delivery and compliance

The details of the treatment regimen, delivery, and reasons for stopping bevacizumab are presented in [Table 2].
Table 2: Treatment delivery and compliance in the study evaluating the optimal dose of bevacizumab in recurrent glioma

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Adverse events

Adverse events were recorded in all the patients [Table 3]. Any grade adverse events were seen in 5 (21.7%) patients in the LD-B group and 17 (37.8%) in the STD-B group (P = 0.274). Grade 3–5 adverse events were seen in 5 (11.1%) and 2 (8.6%) patients in the LD-B and STD-B groups, respectively (P = 0.844).
Table 3: Adverse events between the two groups of patients in the study evaluating the optimal dose of bevacizumab in recurrent glioma

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Outcomes

Symptoms were present in 20 patients in the LD-B group and 40 in the STD-B group. Symptomatic benefit was noted in 11 (55%, n = 20) and 22 (55%, n = 40) patients in the LD-B and STD-B groups, respectively (P = 1). A subjective improvement in headache was reported by 2 (15.4%, n = 13) and 5 (21.7%, n = 23) patients in the LD-B and STD-B groups, respectively (P = 1). Subjective and objective increase in the motor functions was reported by 2 (15.4%, n = 13) and 5 (21.7%, n = 23) patients in the LD-B and STD-B groups, respectively (P = 1). Subjective improvement in sensory functions was not reported by any of the patients in either group.

At the time of data censoring, the median follow-up was 26.2 months (range, 14.5–37.89 months). Disease progression was observed in 22 (95.65%) patients in the LD-B group and 44 (97.77%) in the STD-B group. The median PFS was 3.60 (95% CI, 2.5–7.47) for the LD-B and 3.67 (95% CI, 2.17–4.53) months for STD-B group of patients (hazard ratio: 1.00; 95% CI, 0.54–1.84; P = 0.18) [Figure 2]. The results of COX regression analysis for PFS and OS are presented in [Table 4]. A total of 22 (32.35%) patients had died at the time of data censoring. The median OS was 7.33 (95% CI, 3.97–9.10) and 5.47 (95% CI, 4.67–6.2) months for the LD-B and STD-B groups, respectively (hazard ratio: 1.00; 95% CI, 0.55–1.79; P = 0.27) [Figure 3].
Figure 2: Progression-free survival of patients receiving low.dose and standard-dose bevacizumab

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Figure 3: Overall survival of patients receiving low-dose and standard-dose bevacizumab

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Table 4: Cox regression analysis for progression free and overall survival in the study evaluating the optimal dose of bevacizumab in recurrent glioma

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  Discussion Top


We observed that bevacizumab at doses lower than the standard dose can be effective in clinical practice. Concomitant chemotherapy or the duration of treatment did not alter the outcomes in our study. The rates of adverse events such as hypertension, proteinuria, and intracranial bleed were similar between the patients who received low-dose bevacizumab and standard-dose bevacizumab. Paradoxically, financial toxicity as a reason for treatment discontinuation was reported more often in the low-dose arm. This could be due to the preexisting financial status of these patients.[17]

A literature search in the PubMed database was performed using the MeSH terms “low dose,” “bevacizumab,” and “glioma” in various permutations and combinations and without any filters to identify any additional literature on this topic. We identified two more clinical datasets dealing with a similar analysis. A retrospective analysis conducted by Lorgis et al. in 110 patients compared low-dose bevacizumab (below 5 mg/kg) with the standard dose. As compared to patients who were treated with standard-dose bevacizumab, those who received the low-dose regimen showed better PFS (12 vs. 2 months, P < 0.0001) and OS (16 vs. 6 months, P = 0.0002).[18] In a prospective, randomized study conducted by Weathers et al., there was no difference in the outcomes between low-dose (5 mg/kg) and standard-dose bevacizumab. The median PFS was 4.34 months (95% CI, 2.96–8.34) in the low-dose bevacizumab plus lomustine arm and 4.11 months (95% CI, 2.69–5.55) in the single-agent bevacizumab arm.[19]

Other than in patients with brain tumors, low-dose bevacizumab has also been used in patients with other malignancies such as colon cancer. The first study that compared 5 mg/kg bevacizumab with 10 mg/kg along with fluorouracil (5-FU)/leucovorin (LV) reported a median time to progression of 9.0 months and 7.2 months for the two groups, respectively (hazard ratio: 0.54; P = 0.13).[20] In the pivotal AVF2107 phase III trial, irinotecan, 5-FU, and LV (IFL) with either placebo or bevacizumab 5 mg/kg were used once every 2 weeks. The median survival was 15.6 months with IFL and 20.3 months with IFL plus bevacizumab (hazard ratio: 0.66; P < 0.001).[21] In light of these data, bevacizumab dosed at 5 mg/kg was approved for colorectal cancer.

A limitation of our current study is its retrospective nature. In addition, the two groups were not well matched. A higher proportion of patients in the LD-B group had Grade 2/3 histology and hence a high rate of isocitrate dehydrogenase-mutated disease. However, despite this imbalance, the results of the multivariate COX regression analysis suggested that there was no difference in outcomes between the two groups. The hazard ratio between the 2 groups was 1 (95% CI; 0.55–1.79) for PFS and 1 (95% CI; 0.54–1.84) for OS. The advantage of the low-dose regimen is that it is likely to decrease the risk of adverse events as well as the cost of treatment. Although we did not find a difference in the rate of adverse events between the two groups, this needs to be verified in a well-designed prospective study.

Thus, overall our study suggests that a low dose of bevacizumab is at least as effective as the standard dose of bevacizumab in patients with recurrent gliomas.


  Conclusion Top


Low-dose bevacizumab is effective in patients with relapsed-recurrent gliomas and its potential needs to be studied further in prospective randomized studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


Supplementary Appendix 1: Study protocol

A retrospective study on the patterns of care in recurrent high-grade gliomas in a tertiary care center in India


  Introduction Top


Relapse or progression in high-grade gliomas is common.[1] There is no standard of care for those who progress after first-line therapy.[2],[3] Options available include local therapy such as re-surgery, re-radiation, and systemic therapy (bevacizumab, CCNU) or a clinical trial.[3] No treatment has shown definitive improvement in outcomes.[3] Patients with longer progression-free interval (>2 years), smaller volume of disease, and disease in noneloquent areas are preferably selected for local therapy, while others receive systemic therapy.[4]

There is a paucity of studies on the resection of recurrent high-grade gliomas and do not provide clear conclusions. Most studies describe only relatively low number of patients and provide conflicting results with respect to the survival benefit of a surgical resection. More recent data suggest an improved survival in patients after repeat surgery.[5]

Multiple systemic agents have been used for the treatment of relapsed high-grade glioma including the anti-vascular endothelial growth factor agent, bevacizumab. However, none of them conferred a survival advantage. The use of irinotecan with bevacizumab improved the estimated 6-month progression-free survival (PFS) rate when compared to bevacizumab alone (50.3% versus 42.6%) but did not improve overall survival (OS) (9.2 vs. 8.7 months).[6] In the EORTC 26101 trial, the use of bevacizumab with lomustine (CCNU) in patients with recurrent glioblastoma showed an improvement in PFS but no improvement the OS (9.1 months for the combination versus 8.6 months for CCNU alone).[7] Even in the trial setting, improvement in the survival outcomes is modest. In the real world, not all patients are able to receive treatment for recurrent/relapsed high-grade gliomas.

Real-world data on the patterns of care in relapsed/recurrent high-grade gliomas are sparse. A retrospective population-based study from Australia studied the patterns of care in patients with recurrent glioblastoma (rGBM). The study reported that only 49% of received treatment at first progression and 51% received best supportive care (BSC).[3] A multicenter retrospective study from the Netherlands reported that 60.5% of patients with rGBM received treatment at progression and 39.5% received BSC.[8] This highlights the fact that a large proportion of patients often do not receive treatment at progression even in the developed world.

In patients who received treatment, Parakh et al. reported that 76% underwent re-resection and 48% of patients who underwent re-resection subsequently received systemic therapy. 3 Patients who received treatment had a higher OS compared to those who did not receive any treatment (7 vs. 3 months, P < 0.0001). At first progression, those who received chemotherapy had the highest survival followed by patients who had chemotherapy after surgery (10 vs. 8.0 months). Patients who underwent re-resection alone had a survival of 5.0 months (95% confidence interval: 3.1–6.9). None of these differences were statistically significant.[3] In the study by Linde et al., 34.8% received systemic therapy, 18.7% underwent re-resection, and only 7% received re-irradiation. Patients who received systemic therapy (7.3 months) and surgery (11 months) had longer survival than those who received BSC (3.1 months, hazard ratio 0.46, P < 0.001).[8] In a study of patients with rGBM treated at the Cleveland Clinic, at first recurrence, only 24% had surgery and 10% received re-irradiation. Patients who underwent surgical resection had a longer OS (14 vs. 10.8 months, P = 0.046), and those who received chemotherapy had longer PFS (5.2 vs. 3.2 months, P < 0.001).[9] These studies show that patients with recurrent high-grade gliomas who receive treatment at progression have better overall survival. Some studies suggest that patients who underwent re-resection had a better survival, while others suggest that those who received systemic therapy did better; however, this is not consistent across studies.

There are no data on the pattern of care in the Indian setting. It is important to note that the data available come from countries of the developed world with better health-care systems. The pattern of care in India may differ from developed countries due to racial, socioeconomic, and other factors that impact the pattern of care. Hence, we would like to conduct this study to determine the pattern of care in the Indian setting.

Aim

This was to study the pattern of care in relapsed high-grade gliomas, factors which influence the pattern of care and outcomes in the Indian setting.


  Methods Top


Setting

The study will be conducted by the neuro-oncology disease management group and Department of Medical Oncology at Tata Memorial Hospital.

Study design

This was a retrospective study.

Selection of cases

All patients with recurrent/relapsed high-grade glioma who were seen in the medical oncology outpatient department (OPD) (neuro-oncology disease management group) from 2015 to 2018 will be included.

Data collection

A prospective database of all patients attending the neuro-oncology OPD has been maintained from June 2015 onward by the neuro-oncology DMG at Tata Memorial Hospital. Data will be collected from this database and electronic medical records. No patients will be contacted (in person/telephonically) for data collection.

The following data will be collected from the database:

  • Demography-age gender, Eastern Cooperative Oncology Group performance status, comorbidities, and family income
  • Tumor characteristics – Grade and previous treatment
  • Treatment offered at relapse – Type of therapy
  • Outcomes – Overall survival and relapse-free interval
  • Quality of life (QoL) data if available.


The data collected will be entered into an Excel sheet and cross-checked by two independent individuals.

Statistics

Descriptive statistics will be used for demographics, which will be presented as absolute numbers and percentages. Overall survival will be calculated using the Kaplan–Meier method. COX regression analysis will be used to determine the factors impacting the pattern of care at recurrence/relapse and outcomes. The following factors will be analyzed to see if they impact outcome to age, gender, PS, family income, grade at relapse, molecular classification, and treatment received. If data are available, we will perform a cross-sectional and longitudinal analysis of the FACT QOL.

Ethical considerations

Since this is an observational study of patients who have already received standard therapy, there are no ethical considerations. Since no patients will be contacted in the study, we request a waiver of consent. At the time of analysis and publication, the patient data will be anonymized, and no form of patient identity will be revealed.


  References Top


  1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.
  2. Gallego O. Nonsurgical treatment of recurrent glioblastoma. Curr Oncol 2015;22:e273-81.
  3. Parakh S, Thursfield V, Cher L, Dally M, Drummond K, Murphy M, et al. Recurrent glioblastoma: Current patterns of care in an Australian population. J Clin Neurosci 2016;24:78-82.
  4. Kirkpatrick JP, Sampson JH. Recurrent malignant gliomas. Semin Radiat Oncol 2014;24:289-98.
  5. Ringel F, Pape H, Sabel M, Krex D, Bock HC, Misch M, et al. Clinical benefit from resection of recurrent glioblastomas: Results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neurooncology 2016;18:96-104.
  6. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40.
  7. Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 2017;377:1954-63.
  8. Van Linde ME, Brahm CG, de Witt Hamer PC, Reijneveld JC, Bruynzeel AM, Vandertop WP, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: A retrospective multicenter analysis. J Neurooncol 2017;135:183-92.
  9. Migdady I, Dai L, Thapa B, Bellamkonda S, Ahluwalia M. Patterns of care in recurrent glioblastoma in the era of molecular diagnosis (P6.129). Neurology 2018; 90 (15 Supplement)




 
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