The Adverse Effects and Use of Bevacizumab in Patients with Glioblastoma: A Systematic Review and Meta-Analysis
Abstract
:1. Introduction
2. Results
2.1. Study Selection
2.2. Study Characteristics
2.3. Risk of Bias Assessment in Individual Studies and Heterogeneity
2.4. BV with Another Drug vs. BV//BV with Another Drug vs. Another Drug
2.5. BV with Another Drug vs. Placebo
2.6. BV with Radiotherapy and Another Modality
2.7. Adverse Effects in GBM
2.8. Adverse Event Statistics in GBM
2.9. Adverse Event Statistics Total
2.9.1. General Adverse Effects of Bevacizumab (In Other Types of Cancers)
2.9.2. Arterial Hypertension
2.9.3. Diarrhea
2.9.4. Headache
2.9.5. Fatigue
2.9.6. Constipation
2.9.7. Thrombocytopenia
2.9.8. Neutropenia
2.9.9. Lymphopenia
2.9.10. Nausea and Vomiting
2.9.11. Anemia
2.9.12. Anorexia
2.9.13. Thrombosis
2.9.14. Leukopenia
2.9.15. Proteinuria
3. Discussion
4. Materials and Methods
4.1. Protocol and Registration
4.2. Literature Search
4.3. Study Selection
4.4. Data Extraction and Quality Assessment
4.5. Statistical Methods
5. Conclusions
Limitations
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Author | Country | Population | Intervention | Outcomes | Follow-Up | Results | ||
---|---|---|---|---|---|---|---|---|
Sample Size (n) | Patients’ Mean Age (SD) | Intervention | Characteristics/Dose | |||||
Friedman et al., 2009 [11] | USA | CG: 82 EG: 85 | CG: 57 EG: 54 | CG: BV + CP-11 EG: BV |
|
| 2 months |
|
Nayak et al., 2021 [12] | USA | CG: 30 EG: 50 | CG: Not mentioned EG: Not mentioned | CG: pembrolizumab EG: pembrolizumab + BV |
|
|
| |
Tsien et al., 2023 [13] | USA | CG: 86 EG: 84 | CG: 60 EG: 57 | CG: BV + RT EG: BV |
| Not mentioned | Not mentioned | |
Lee et al., 2020 [14] | USA | CG: 58 EG: 57 | CG: No average mentioned EG: No average mentioned | CG: BV + trebananib EG: BV + placebo |
| 6 months |
| |
Puduvalli et al., 2020 [15] | USA | CG: 44 EG: 30 | CG: No average is mentioned EG: No average is mentioned | CG: BV + Vor EG: BV |
|
| 19.84 months average |
|
Reardon et al., 2020 [16] | USA | CG: 182 EG: 165 | CG: 55.2 EG: 55 | CG: Nivolumab EG: BV |
| 9.5 months |
| |
Weathers et al., 2016 [17] | USA | CG: 33 EG: 36 | CG: No average is mentioned EG: No average is mentioned | CG: BV + lomustine EG: BV |
| 6 months |
| |
Wirsching et al., 2018 [18] | Suiza | CG: 25 EG: 50 | CG: 70 EG: 70 | CG: B (only radiotherapy) EG: A (radiotherapy + BV) See radiotherapy |
| Not mentioned |
| |
Field et al., 2015 [19] | Australia | BV + ICE: 58. BV: 62. | BV + Carboplatin: 55. BV: 55. | BV + carboplatin BV |
| None | 32 months |
|
Kelly et al., 2023 [20] | USA | EG: 60 | EG: 59 | A1: TVB-2640 + BV. A2: BV. |
| None | Not mentioned |
|
Ellingson et al., 2018 [21] | USA | CG: 459 EG: 458 | CG: 56. EG: 55. | CG: Chemoradiation + placebo. EG: Chemoradiation + BV See radiotherapy |
|
| Not mentioned |
|
Wirsching et al., 2021 [22] | Switzerland | BV + RTH: 44 RTH: 23 | BV + RTH: 70 RTH: 69 | BV + RTH RTH |
|
| 4 months |
|
Kickingereder et al., 2020 [23] | Germany | CG: 93 EG: 161 | CG: 60 EG: 58 | BV groups: BV/BV + lomustina NO-BV group: Lomustina |
|
| Not mentioned |
|
Herrlinger et al., 2016 [24] | Germany | CG: 54 EG: 116 | CG: 56 EG: 56 | CG: TMZ + RT EG: BV + RT + IRI |
|
| 12 weeks |
|
Gilbert et al., 2014 [25] | USA | CG: 309. EG: 312. | None | CG: Placebo EG: BV |
|
| Patients evaluated weekly for adverse events had weekly complete blood counts and monthly blood chemical analyses during radiotherapy During maintenance phase of treatment, patients underwent hemograms and blood chemical analyses on days 21 and 28 of each cycle Imaging studies of tumors |
|
Author | Confounding | Selection | Measurement of Intervention | Missing Data | Measurement of Outcomes | Reported Result | Overall |
---|---|---|---|---|---|---|---|
Friedman et al., 2009 [11] | Low | Serious | Serious | Moderate | Low | Low | Moderate |
Gilbert et al., 2014 [25] | Low | Low | Low | Low | Low | Low | Low |
Field et al., 2015 [19] | Low | Serious | Serious | Moderate | Low | Low | Moderate |
Herrlinger et al., 2016 [24] | Low | Low | Low | Low | Low | Low | Low |
Weathers et al., 2016 [17] | Moderate | Low | Low | Low | Low | Low | Low |
Ellingson et al., 2018 [21] | Low | Serious | Serious | Moderate | Low | Low | Moderate |
Wirsching et al., 2018 [18] | Low | Low | Low | Low | Low | Low | Moderate |
Kickingereder et al., 2020 [23] | Moderate | Serious | Moderate | Low | Serious | Moderate | Serious |
Lee et al., 2020 [14] | Moderate | Serious | Serious | Moderate | Low | Low | Moderate |
Puduvalli et al., 2020 [15] | Serious | Serious | Serious | Moderate | Low | Low | Serious |
Reardon et al., 2020 [16] | Low | Low | Low | Low | Low | Low | Low |
Wirsching et al., 2021 [22] | Low | Serious | Moderate | Low | Serious | Moderate | Moderate |
Nayak et al., 2021 [12] | Low | Serious | Serious | Moderate | Low | Low | Moderate |
Kelly et al., 2023 [20] | Low | Low | Low | Low | Low | Low | Low |
Tsien et al., 2023 [13] | Low | Serious | Moderate | Low | Serious | Moderate | Moderate |
Author | Diarrhea | Hypophosphatemia | Nausea and Vomiting | Headache | Fatigue | Constipation | Thrombocytopenia | Neutropenia | Lymphopenia | Anemia | High Blood Pressure |
---|---|---|---|---|---|---|---|---|---|---|---|
Field et al., 2015 [19] | 24% (15/62) | Not reported | 39% (24/62) | Not reported | 84% (52/62) | 29% (18/62) | 23% (14/62) | 6% (4/62) | Not reported | 10% (6/62) | Not reported |
Kelly et al., 2023 [20] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Ellingson et al., 2018 [21] | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used |
Wirsching et al., 2021 [22] | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used |
Kickingereder et al., 2020 [23] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Herrlinger et al., 2016 [24] | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used |
Gilbert et al., 2014 [25] | Not reported | Not reported | 0.66% (2/303) | Not reported | 2.3% (7/303) | Not reported | 10.2% (31/303) | 7.3% (22/303) | 10.5% (32/303) | 0.66% (2/303) | Not reported |
Tsien et al., 2023 [13] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | 42.2% (24/57) |
Friedman et al., 2009 [11] | 1.2% (1/84) | Not reported | Not reported | 36.9% (31/84) | 45.2% (38/84) | Not reported | Not reported | 1.2% (1/84) | 2.4% (2/84) | Not reported | 29.8% (30/84) |
Nayak et al., 2021 [12] | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used |
Puduvalli et al., 2020 [15] | Not reported | Not reported | 5.2% (2/38) | 5.2% (2/38) | 2.6% (1/38) | 0% 0/38 | Not reported | Not reported | 2.6% (1/38) | Not reported | 23.7 (9/38) |
Weathers et al., 2016 [17] | Not reported | Not reported | Not reported | Not reported | 11.1% (4/36) | Not reported | 0% (0/36) | 2.8% (1/36) | 22.2% (8/36) | Not reported | 5.6% (2/36) |
Wirsching et al., 2018 [18] | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used | BV alone was not used |
Lee et al., 2020 [14] | Not reported | 14% (8/57) | 24.6% (14/57) * | 57.9% (33/57) | 66.7% (38/57) | Not reported | Not reported | Not reported | Not reported | Not reported | 42.1% (24/57) |
Reardon et al., 2020 [16] | 1.2% (2/165) | not reported | 5.5% (9/165) * | 4.8% (8/165) | 13.9% (23/165) | not reported | not reported | not reported | not reported | not reported | 22.4% (37/165) |
Total percentage in the articles that reported the effects | 5.8% | 14% | 9.2% | 36.87% | 24.1% | 29% | 12.32% | 5.77% | 9.32% | 2.19% | 32.72% |
Author | BV + X | Diarrhea | Hypophosphatemia | Nausea and Vomiting | Headache | Fatigue | Constipation | Thrombocytopenia | Neutropenia | Lymphopenia | Anemia | High Blood Pressure |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Field et al., 2015 [19] | BV + Carboplatin | 26% (15/58) | Not reported | 50% (29/58) | Not reported | 86% (50/58) | 45% (26/58) | 55% (32/58) | 24% (14/58) | Not reported | 28% (16/58) | Not reported |
Kelly et al., 2023 [20] | BV + Denifanstat | 8% (2/25) | Not reported | 8% (2/25) (only vomiting) | 12% (3/25) | 0.28% (7/25) | 0.12% (3/25) | 4% (1/25) | Not reported | Not reported | Not reported | 52% (13/25) |
Ellingson et al., 2018 [21] | BV + Radiotherapy + Temozolomide | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Wirsching et al., 2021 [22] | BV + Hypofractionated Radiotherapy | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Kickingereder et al., 2020 [23] | BV + Lomustina | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Herrlinger et al., 2016 [24] | BV + Radiotherapy + Irinotecan | Not reported | Not reported | 4.2% | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Gilbert et al., 2014 [25] | BV + Radiotherapy + Temozolomide | Not reported | Not reported | 0.66% (2/303 during chemotherapy) 4% (11/260 during adjuvant treatment) | Not reported | 2% (7/303 during chemotherapy) 13% (34/260 during adjuvant treatment) | Not reported | 10% (31/303 during chemotherapy) 11% (29/260 during adjuvant treatment) | 7% (22/303 during chemotherapy) 10% (26/250 during adjuvant treatment) | 11% (32/303 during chemotherapy) 13% (34/260 during adjuvant treatment) | 0.66% (2/303 during chemotherapy) 2% (6/260 during adjuvant treatment). | 1.32% (4/303 during chemotherapy) 4% (11/260 during adjuvant treatment) |
Tsien et al., 2023 [13] | BV + Radiotherapy | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Friedman et al., 2009 [11] | BV + Irinotecan | 74.7% (59/79) | Not reported | 67.1% * (53/79) | Not reported | 75.9% (60/79) | Not reported | Not reported | 8.9% (7/79) | 7.6% (6/79) | Not reported | 26.6% (21/79) |
Nayak et al., 2021 [12] | BV + Pembrolizumab | 6% (3/50) | Not reported | Not reported | 16% (8/50) | 18% (9/50) | Not reported | Not reported | Not reported | 4% (2/50) | Not reported | 50% (25/50) |
Puduvalli et al., 2020 [15] | BV + Vorinostat (Suberoylanidized Acid) | Not reported | Not reported | 0.0% (0/47) nausea and 0.0% (0/47) vomiting | 2.1% (1/47) | 4% (2/47) | 2.1% (1/47) | Not reported | Not reported | 4% (2/47) | Not reported | 13% (6/47) |
Weathers et al., 2016 [17] | BV + Lomustina | Not reported | Not reported | Not reported | Not reported | 3% (1/35) | Not reported | 23% (8/35) | 14% (5/35) | 46% (16/35) | Not reported | 0.03% (1/35) |
Wirsching et al., 2018 [18] | BV + Radiotherapy | Not reported | Not reported | Not reported | 8% (4/50) | 20% (10/50) | Not reported | Not reported | Not reported | Not reported | Not reported | 26% (13/50) |
Lee et al., 2020 [14] | BV + Trebananib | Not reported | 8.6% (5/58) | 13.8% (8/58) | 34.5% (20/58) | 63.8% (37/58) | Not reported | Not reported | Not reported | Not reported | Not reported | 44.8% (26/58) |
Reardon et al., 2020 [16] | - | - | - | - | - | - | - | - | - | - | - | - |
Total percentage in the articles that reported the effects | - | 15 | 8.6 | 13.37 | 15.65 | 22.48 | 23 | 14.83 | 10.2 | 11.88 | 3.86 | 13.2 |
Author | Diarrhea | Anorexia | Nausea and Vomiting | Headache | Fatigue | Thrombosis | Thrombocytopenia | Neutropenia | Lymphopenia | Leukopenia | Anemia | High Blood Pressure | Proteinuria | Constipation |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Denda et al., 2016 [29] | 12/48 25% | 28/48 58% | 24/48 50%, only nausea 10/48 21%, vomiting | Not reported | 34/48 71% | 2/48 4% | 27/48 56% | 32/48 67 | Not reported | Not reported | 44/48 92% | 11/48 23% | 4/48 8% | Not reported |
Garcia et al., 2008 [30] | Not reported | Not reported | 2/70 2.9%, only nausea 3/70 4.3%, vomiting | Not reported | 6/70 8.6% | 3/70 4.3% | Not reported | Not reported | 14/70 20% | 2/70 2.9% | Not reported | 11/70 15.7% | 3/70 4.3% | 3/70 4.3% |
Dellapasqua et al., 2008 [31] | 16/46 34.8% | 2/46 4.3% | 24/46 52.2%, only nausea 8/46 17.4%, vomiting | Not reported | Not reported | Not reported | 7/46 15.2% | 15/46 32.6% | Not reported | 27/46 58.7% | 8/46 17.4% | 22/46 47.8% | 15/46 32.6% | 17/46 37% |
Kim et al., 2008 [32] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Dashti et al., 2022 [33] | Not reported | Not reported | 2/10 20% | 5/10 50% | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Spitzer et al., 2008 [34] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Kudoh et al., 2011 [35] | 4/30 13.3% | Not reported | 12/30 40%, only nausea 5/30 16.7%, vomiting | Not reported | 5/30 16.7% | Not reported | 1/30 3.3% | 7/30 23.3% | Not reported | 13/30 43.3% | Not reported | 7/30 23.3% | Not reported | 10/30 33.3% |
Tewari et al., 2023 [36] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Dupuis-Girod et al., 2014 [37] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Kennedy et al., 2018 [38] | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported | Not reported |
Takemura et al., 2018 [39] | 1/18 5.5% | Not reported | 4/18 22.2%, only nausea | Not reported | Not reported | Not reported | 1/18 5.5% | 11/18 61.1% | Not reported | 10/18 55.5% | Not reported | Not reported | Not reported | Not reported |
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Bruna-Mejías, A.; Silva-Bravo, V.; Moyano Valarezo, L.; Delgado-Retamal, M.F.; Nazar-Izquierdo, D.; Aguilar-Aguirre, I.; Nova-Baeza, P.; Orellana-Donoso, M.; Suazo-Santibáñez, A.; Gutiérrez-Espinoza, H.; et al. The Adverse Effects and Use of Bevacizumab in Patients with Glioblastoma: A Systematic Review and Meta-Analysis. Pharmaceuticals 2025, 18, 795. https://doi.org/10.3390/ph18060795
Bruna-Mejías A, Silva-Bravo V, Moyano Valarezo L, Delgado-Retamal MF, Nazar-Izquierdo D, Aguilar-Aguirre I, Nova-Baeza P, Orellana-Donoso M, Suazo-Santibáñez A, Gutiérrez-Espinoza H, et al. The Adverse Effects and Use of Bevacizumab in Patients with Glioblastoma: A Systematic Review and Meta-Analysis. Pharmaceuticals. 2025; 18(6):795. https://doi.org/10.3390/ph18060795
Chicago/Turabian StyleBruna-Mejías, Alejandro, Vicente Silva-Bravo, Laura Moyano Valarezo, María Fernanda Delgado-Retamal, Diego Nazar-Izquierdo, Isidora Aguilar-Aguirre, Pablo Nova-Baeza, Mathias Orellana-Donoso, Alejandra Suazo-Santibáñez, Héctor Gutiérrez-Espinoza, and et al. 2025. "The Adverse Effects and Use of Bevacizumab in Patients with Glioblastoma: A Systematic Review and Meta-Analysis" Pharmaceuticals 18, no. 6: 795. https://doi.org/10.3390/ph18060795
APA StyleBruna-Mejías, A., Silva-Bravo, V., Moyano Valarezo, L., Delgado-Retamal, M. F., Nazar-Izquierdo, D., Aguilar-Aguirre, I., Nova-Baeza, P., Orellana-Donoso, M., Suazo-Santibáñez, A., Gutiérrez-Espinoza, H., Sanchis Gimeno, J., Bastidas-Caldes, C., & Valenzuela Fuenzalida, J. J. (2025). The Adverse Effects and Use of Bevacizumab in Patients with Glioblastoma: A Systematic Review and Meta-Analysis. Pharmaceuticals, 18(6), 795. https://doi.org/10.3390/ph18060795