Drug products: Alymsys, Avastin®, Aybintio, MVASI, Oyavas, Zirabev
ATC code: L01FG01
A study on non-small cell lung cancer patients treated with chemotherapy regimens including bevacizumab has shown a higher progression free survival in both men and women, however, the overall survival was only significantly prolonged in men. Also, one study showed that female sex was associated with improved progression-free survival and overall survival in bevacizumab treated Taiwanese patients with recurrent glioblastoma. Whether there are differences in adverse events between women and men remains unclear. Bevacizumab should be avoided in girls and women who may become pregnant unless an effective method of contraception is used. Bevacizumab can cause malformations in the children exposed during pregnancy. Due to this, bevacizumab is contraindicated during pregnancy.
Bevacizumab is a monoclonal antibody that inhibits the binding of vascular endothelial growth factor (VEGF) to its receptors. It is indicated, in combination with other antineoplastic therapies, for the treatment of metastatic and/or advanced colon cancer, breast cancer, non-small cell lung cancer, renal cell cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer . Due to its antiangiogenic action, it has also been studied and/or used off-label for the treatment of patients with diabetic macular edema, age-related macular degeneration, hereditary hemorrhagic telangiectasia, neurofibromatosis type 2 associated hearing loss, and aniridia, among others [2-8].
Pharmacokinetics and dosing
A pharmacokinetic study (949 men, 843 women) showed that, after correcting for body weight, men had a larger central volume (+ 20%) and a higher bevacizumab clearance (+ 17%) than women. The elimination half-life is 18 days for women and 20 days for men [1, 9]. However, no difference in dosing between men and women is recommended by the pharmaceutical company .
A clinical trial that compared carboplatin and paclitaxel with or without bevacizumab in patients with advanced-stage non-small cell lung cancer, showed that bevacizumab improved overall survival .
A retrospective analysis of this trial (463 men, 387 women) showed that the response rate in the bevacizumab treatment group was 34.9%, compared with 15,1% in the chemotherapy-alone arm . Both men and women had a higher response rate when treated with the regimen containing bevacizumab compared to paclitaxel and carboplatin alone (28.8% vs 15.7%, respectively, for men, and 41.1% vs 14.2%, respectively, for women).The addition of bevacizumab prolonged the progression-free survival for both women and men. Men had a median progression-free survival of 4.3 months with paclitaxel-carboplatin alone and 6.3 months with the regimen containing bevacizumab. Women had a median progression-free survival of 5.3 months with paclitaxel-carboplatin alone and 6.2 months with the addition of bevacizumab. The overall survival was prolonged for the entire group that received bevacizumab, however, the analysis showed that this effect was limited to men. The difference in overall survival in women receiving bevacizumab compared to women who received paclitaxel-carboplatin alone, was not significant .
A retrospective study (45 men, 31 women) showed that female sex, Eastern Cooperative Oncology Group (ECOG) performance status, and bevacizumab-induced hypertension were associated with improved clinical outcomes in progression-free survival and overall survival in Taiwanese patients with recurrent glioblastoma treated with bevacizumab . It was previously reported that among long-term glioblastoma survivors there is a slight preponderance of women [13, 14], and this finding was reproduced in this study. Some studies suggest that the difference might be due to biologic differences between men and women, such as sex hormones or tumor suppressor genes on the X chromosome [15, 16].
A study involving patients (19 men, 15 women) with metastatic colorectal cancer treated with FOLFIRIª-bevacizumab, found that this therapy had some changes in coagulation parameters, such as decreased D-dimer levels in men, increased fibrinogen levels in both women and men, and increased INR in women. However, none of these variables had an effect on overall survival or progression free survival .
In a clinical trial (463 men, 387 women), there were no differences in the incidence of fatal adverse events between women and men . Some other adverse events related to bevacizumab therapy were more common in women, including hypertension (women: 9.9%, men: 4.2%), constipation (women: 4.7%, men: 1.4%), and abdominal pain (women: 5.2%, men: 0.9%) . However, a pooled analysis of two trials (693 men, 494 women), showed that while women had a higher risk of grade 3 chemotherapy-related adverse events (FOLFIRI or FOLFOXªª) no sex difference in bevacizumab-related adverse events was observed .
Reproductive health issues
It has been reported that pre-menopausal women may notice that their periods become irregular or are missed and may experience impaired fertility . A clinical trial showed a higher incidence of new cases of ovarian failure among pre-menopausal women in the bevacizumab group compared with the control group . No reports have been made on infertility on male patients treated with bevacizumab.
Bevacizumab can cause fetal harm and is therefore contraindicated during pregnancy. It is recommended that women of childbearing potential treated with bevacizumab use effective contraception during and for six months after the treatment . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
ª FOLFIRI is a drug combination that includes folinic acid (FOL), fluorouracil (F), and irinotecan hydrochloride (IRI).ªª FOLFOX is a drug combination that includes folinic acid (FOL), fluorouracil (F), and oxaliplatin (OX).
Date of litterature search: 2019-10-25
- Avastin (bevacizumab). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-09-25, cited 2019-10-25].
- Huang V, Bergner AL, Halpin C, Merker VL, Sheridan MR, Widemann BC et al. Improvement in Patient-reported Hearing After Treatment With Bevacizumab in People With Neurofibromatosis Type 2. Otol Neurotol. 2018;39(5):632-638. PubMed
- van Asten F, Michels CTJ, Hoyng CB, van der Wilt GJ, Klevering BJ, Rovers MM et al. The cost-effectiveness of bevacizumab, ranibizumab and aflibercept for the treatment of age-related macular degeneration-A cost-effectiveness analysis from a societal perspective. PLoS One. 2018;13(5):e0197670. PubMed
- Buscarini E, Botella LM, Geisthoff U, Kjeldsen AD, Mager HJ, Pagella F et al. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2019;14(1):28. PubMed
- Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. Cochrane Database Syst Rev. 2017;6(1):CD007419. PubMed
- Lapid-Gortzak R, Santana NTY, Nieuwendaal CP, Mourits MP, van der Meulen IJE. Topical bevacizumab treatment in aniridia. Int Ophthalmol. 2018;38(4):1741-1746. PubMed
- Zur KB, Fox E. Bevacizumab chemotherapy for management of pulmonary and laryngotracheal papillomatosis in a child. Laryngoscope. 2017;127(7):1538-1542. PubMed
- Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Awh CC et al. Effect of Bevacizumab vs Aflibercept on Visual Acuity Among Patients With Macular Edema Due to Central Retinal Vein Occlusion: The SCORE2 Randomized Clinical Trial. JAMA. 2017;317(20):2072-2087. PubMed
- Han K, Peyret T, Marchand M, Quartino A, Gosselin NH, Girish S et al. Population pharmacokinetics of bevacizumab in cancer patients with external validation. Cancer Chemother Pharmacol. 2016;78(2):341-51. PubMed
- Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-50. PubMed
- Brahmer JR, Dahlberg SE, Gray RJ, Schiller JH, Perry MC, Sandler A et al. Sex differences in outcome with bevacizumab therapy: analysis of patients with advanced-stage non-small cell lung cancer treated with or without bevacizumab in combination with paclitaxel and carboplatin in the Eastern Cooperative Oncology Group Trial 4599. J Thorac Oncol. 2011;6(1):103-8. PubMed
- Liau CT, Chou WC, Wei KC, Chang CN, Toh CH, Jung SM. Female sex, good performance status, and bevacizumab-induced hypertension associated with survival benefit in Asian patients with recurrent glioblastoma treated with bevacizumab. Asia Pac J Clin Oncol. 2018;14(2):e8-e14. PubMed
- Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130(1):2596-606. PubMed
- Shinojima N, Kochi M, Hamada J, Nakamura H, Yano S, Makino K et al. The influence of sex and the presence of giant cells on postoperative long-term survival in adult patients with supratentorial glioblastoma multiforme. J Neurosurg. 2004;101(2):219-26. PubMed
- Plunkett RJ, Lis A, Barone TA, Fronckowiak MD, Greenberg SJ. Hormonal effects on glioblastoma multiforme in the nude rat model. J Neurosurg. 1999;90(6):1072-7. PubMed
- Seki Y, Suico MA, Uto A, Hisatsune A, Shuto T, Isohama Y et al. The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome. Cancer Res. 2002;62(22):6579-86. PubMed
- Bilir C, Engin H, Temi YB. Effect of gender on coagulation functions: a study in metastatic colorectal cancer patients treated with bevacizumab, irinotecan, 5-Fluorouracil, and leucovorin. Adv Hematol. 2014;2014(1):473482. PubMed
- Marmorino F, Rossini D, Lonardi S, Moretto R, Zucchelli G, Aprile G et al. Impact of age and gender on the safety and efficacy of chemotherapy plus bevacizumab in metastatic colorectal cancer: a pooled analysis of TRIBE and TRIBE2 studies. Ann Oncol. 2019;1(1):1. PubMed
- Concise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2019-03-14.] länk
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson