Bevacizumab

Additional information

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 [1]. 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 [1].

Effects

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 [10].

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 [11]. 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 [11].

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 [12]. 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 [17].

Adverse effects

In a clinical trial (463 men, 387 women), there were no differences in the incidence of fatal adverse events between women and men [11].  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%) [11]. 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 [18].

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 [1]. 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 [1]. 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 [1]. 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).