Esther Tahover* and Yakir Rottenberg
Department of Oncology Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Received date: July 11, 2013; Accepted date: August 06, 2013; Published date: August 09, 2013
Citation: Tahover E, Rottenberg Y (2013) Bevacizumab in Colorectal Cancer: Toxicity - Epidemiology, Management and Correlation with Response. J Gastroint Dig Syst 3:128. doi: 10.4172/2161-069X.1000128
Copyright: © 2013 Tahover E, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Gastrointestinal & Digestive System
During the recent years, the median survival of patients with metastatic colorectal cancer has improved dramatically. Gastroenterological interventions are frequently carried throughout the disease course, and familiarity with the various side effects of regimens which are commonly used in these patients is required. Bevacizumab, a humanized monoclonal antibody targeting VEGF, has a dominant role in the treatment of metastatic colon cancer. It has been shown in randomized trials to improve overall survival compared to standard treatment. Yet, this benefit is counterbalanced by a different safety profile compared to classic chemotherapy regimens, which is potentially serious and fatal. The side effects include impaired wound healing, bowel perforation, fistula formation, hemorrhage, thrombosis, proteinuria and hypertension. The current review focuses on the epidemiology, management and predictive value of bevacizumab’s toxicity.
Colorectal cancer; VEGF inhibitors; Toxicity; Tredictive factors
mCRC: Metastatic Colorectal Cancer; VEGF: Vascular Endothelial Growth Factor; PFS: Progression Free Survival; OS: Overall Survival; HTN: Hypertension; ATE: Arterial Thromboembolic Event; RCTs: Randomized Controlled Trails.
Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States (excluding skin cancers) . Overall, the lifetime risk of developing colorectal cancer is about five percent. Up to 20% of the patients are diagnosed at stage IV, with metastasic sites beyond the colon/rectum and regional lymph nodes . The majority of patients with metastatic colorectal cancer (mCRC) cannot be cured, and treatment is palliative and generally consists of systemic chemotherapy and biological therapy, including VEGF inhibitors.
Bevacizumab (Avastin®) is a humanized monoclonal antibody targeting Vascular endothelial growth factor (VEGF) . VEGF activates the major pathways involved in tumor angiogenesis. It causes endothelial cell survival, migration and permeability, and stimulates the growth of blood vessels that feed the tumor . Bevacizumab has been shown in randomized trials to improve progression free survival (PFS) and overall survival (OS) when combined with standard first [5-7] and second-line  chemotherapy protocols in mCRC. Bevacizumab has also been approved by the FDA for use in metastatic non-small cell lung cancer (based on improved OS ), kidney cancer (as it showed an improvement in PFS) , and glioblastoma multiforme (bevacizumab has improved response rate [11,12]). The drug has been previously approved by the FDA for breast cancer too, based on PFS improvement , but was later removed from this indication because the drug has not been shown to be safe and effective for that use . Bevacizumab is also being studied in phase II and III clinical trials for other neoplasms, such as ovarian cancer in which it has improved PFS [15,16]. However, the benefits of bevacizumab are counterbalanced by its side effect profile, which includes serious and potentially fatal adverse events.
Due to bevacizumab’s influence on blood vessels, it causes coagulative side effects and conversely also bleeding and wound repair problems, including GI perforation and fistulae [17-20]. Hypertension (HTN) is another effect bevacizumab has on peripheral blood vessels . Proteinuria is due to its effect on kidney blood vessels . A summary of bevacizumab’s side effects is shown in Table 1.
|Incidence||Relative risk||Hazard ratio|
|Arterial thromboembolic events||1.0-2.3%||1.82-2.0||[17-19, 22,26,27]|
|Wound healing complications||1.0-3.5%||[17-19, 29]|
|Hypertension||5.3-23.6%||2.98-5.28||[17-19, 23, 25]|
Table 1: Bevacizumab induced side effects (grade 3-5).
The toxicity of bevacizumab has been well studied in post marketing general population cohorts. Retrospective analyses of cohorts of mCRC assessing the safety of first line treatment of chemotherapy and bevacizumab have been published.(BEAT , BRiTE  and ARIES ).
They included thousands of patients and showed the main side effects (grade 3-5) in a general cohort included bleeding (2.2-3.0%), arterial thromboembolic event (ATE)  (1.0-2.3%), proteinuria (all grades) (1.0%) gastrointestinal perforation (2.0%), and woundhealing complications (1.0% in the general group and up to 3.5% postoperative).
HTN rates vary widely between these studies (5.3-22.0%) [17-19,23], due to different measuring protocols (before treatments, between treatments, at home or hospital), different rates of older patients in these trials and different rates of baseline HTN, although factors underlying the variation of high-grade hypertension have not been clearly defined. The risk of high grade HTN was evaluated in a recent meta-analysis  of randomized controlled trails (RCTs) to assess the risk of grade 3-4 HTN in cancer patients treated with bevacizumab. The study included 12,656 patients with a variety of tumors. The incidence of all-grade hypertension in patients receiving bevacizumab was 23.6%, with 7.9% being Grade 3 (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg; medical intervention indicated; more intensive therapy than previously used indicated) or grade 4 (lifethreatening consequences). Patients treated with bevacizumab had a significantly increased risk of developing high-grade HTN with a RR of 5.28 (p < 0.001) in comparison with controls. In another meta-analysis, the relative risk of bevacizumab associated HTN was 2.98 .
In order to further clarify the relative risks of the toxicity caused by adding bevacizumab to treatment, retrospective analyses of specific side effects comparing chemotherapy-treated patients versus chemotherapy–and-bevacizumab treated patients have also been published. A population-based cohort study  which assessed the 3 year cardiovascular risk among 6803 patients aged 65 years and above, from the SEER database, found that bevacizumab was associated with an elevated risk of ATEs (HR=1.82, P < 0.001). In another study , data were pooled from trials of different tumors including 1203 patients with mCRC, and bevacizumab added to chemotherapy increased the risk for an ATE with a HR of 2.0 (P=.031).
A meta-analysis  was conducted to determine the overall risk of hemorrhage with bevacizumab. A total of 12,617 patients with a variety of solid tumors from 20 RCTs were included for analysis (7 were mCRC studies). Bevacizumab significantly increased the risk of bleeding with a RR of 2.48 (p< 0.001). In addition, bevacizumab significantly increased the risk of high-grade bleeding with a RR of 1.91 (p=0.003).
Fistula formation is another reason for caution when using bevacizumab, especially in patients who undergo surgical procedures. In a study  of 222 consecutive patients treated in one institution, who had undergone surgical excision for mCRC and subsequently received bevacizumab, 4.1% subsequently developed fistulas, most commonly anal or perineal and colovesicular. Nearly uniformly, cessation of bevacizumab led to fistula healing; however, 3 patients (33%) required fecal diversion. In that population, wound healing is another concern. Rates of wound healing abnormalities in pooled analysis have been reported . With cancer surgery 28-60 days before study treatment, wound healing complications occurred in 1.3% of bevacizumab-treated patients and 0.5% of control patients. With major surgery during study treatment, 13% of bevacizumab-treated patients and 3.4% of control patients had wound healing complications.
Some studies also report a high incidence of venous thromboembolic events. Yet, a pooled analysis  of individual patient data for 6,055 patients in 10 randomized studies of different cancers (including four mCRC trials) had suggested this is caused by the malignancy itself and bevacizumab does not increase this rate. The incidence of venous thromboembolic events in the chemotherapy only treated patients was 10.9% and in the chemotherapy with bevacizumab group the incidence was 9.8% (OR= 1.14, P=.13).
Fatal adverse events of all kinds have shown to be more common in bevacizumab treated patients. A meta-analysis  of prospective RCTs with a total of 10,217 patients with a variety of tumors (5 studies were of mCRC patients) showed that compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of a fatal adverse event, with a RR of 1.46 (P=.01; incidence, 2.5% vs 1.7%).
The FDA-approved manufacturer’s labeling for bevacizumab recommends intermittent monitoring for the development of proteinuria but does not provide specific recommendations, except temporary withholding of the drug if protein excretion if >2 g/24 hours, and permanent discontinuation for patients who develop the nephrotic syndrome. However, this complication is uncommon. In a report of 243 patients receiving bevacizumab for a metastatic solid tumor, the development of proteinuria affected treatment decisions in only two percent of cases .
Guidelines for pretreatment assessment, monitoring, and management of elevated blood pressure were defined by a National Cancer Institute panel . The recommendations include: 1) conducting a formal risk assessment for potential cardiovascular complications, 2) preexisting hypertension should be addressed before initiation of therapy, 3) blood pressure should be monitored throughout treatment, and 4) blood pressure should be managed with a goal of less than 140/90 mmHg for most patients (and to lower, prespecified goals in patients with specific preexisting cardiovascular risk factors).
Because of this risk of impaired surgical wound healing, GI perforation, and fistula formation, and considering the long half-line of bevacizumab (20 days), at least 28 days (preferably six to eight weeks) should elapse between surgery and last dose of bevacizumab, except in emergency situations.
Bevacizumab needs to be discontinued in the setting of a severe bleeding and supportive transfusions should be instituted. Minor bleeding (eg, epistaxis) may be managed symptomatically with no discontinuation or only temporary cessation of the agent.
Several studies have shown in the last years that developing HTN during treatment with bevacizumab is a biomarker for efficacy of VEGF signal inhibition. These studies have reported better response rates (75 vs. 32 %, p=0.04 ) and higher rate of complete or partial response  (84.6 vs. 42.6 %, p=0.006). They also showed better PFS (14.5 months versus 3.1 months, p=0.04 ; 15.1 versus 8.3 months, p=0.04 ; 10.5 vs. 5.3 months, p =0.008  in those who did and did not develop HTN, respectively) and OS (25.8 vs. 11.7 months, p<0.001  in those who did and did not develop HTN, respectively) among patients who developed HTN compared to those who did not developed HTN. One study  reported on 119 non-small cell lung, colorectal, or ovarian cancer patients who had home-based as well as in-clinic measurements and found that very early HTN, within 42 days, was predictive of response. We  also found that HTN was associated with better OS in mCRC patients who developed HTN during bevacizumab treatment (median not reached vs. 36.8 months, p=0.029) as well as PFS (29.9 vs. 17.2 months, p=0.024, respectively).
Of note, the median onset of hypertension is at least 2 months from first bevacizumab dose . Patients would have taken several cycles before the emergence of hypertension, which in principle is not ideal for a predictive biomarker.
Although no association was reported between other toxicities and response to bevacizumab, gene expression profiles are being studied to predict response. For example, analyzing specimens from 25 mCRC patients, the genes for vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase-3 predicted response to bevacizumab therapy with an accuracy of 96%, sensitivity of 90.9%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 93.3% .
Bevacizumab improves overall survival in mCRC patients and is widely used in the oncology practice. Physicians need to be aware of the common side effects (bleeding, arterial thromboembolic events, proteinuria, and hypertension), their incidence and management.
On the other hand, patients who develop HTN during treatment may survive longer and this is not a reason to discontinue treatment but to medically treat the HTN and reassure the patient it is a good prognostic marker. We recommend carrying out a large cohort study among patients who developed toxicity versus patients who did not developed toxicity, with pharmacokinetic properties and gene analysis to better define the risks and benefits of bevacizumab treatment.
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals