June 2016 Vol 9, No 4 - Clinical
Abdullah K. Alahmari, BPharm, PhD candidate
Graduate student
University of Cincinnati
College of Pharmacy, OH
Ziyad S. Almalki, BPharm, PhD candidate
Graduate student
University of Cincinnati
College of Pharmacy, OH
Ahmed K. Alahmari,, Medical Student
Student
King Khalid University
College of Medicine
Abha, Kingdom of Saudi Arabia
Jeff J. Guo, BPharm, PhD
Professor
Pharmacoepidemiology & Pharmacoeconomics
College of Pharmacy
University of Cincinnati
OH
Download PDF
Abstract

BACKGROUND: Bevacizumab is a recombinant, humanized monoclonal antibody that hinders the proliferation of new blood vessels required for malignant progression. The drug is considered safe and tolerable; however, some controversy remains about whether it is linked to venous and arterial thromboembolic events (TEEs).

OBJECTIVE: To evaluate the risk for overall, venous, and arterial TEEs in patients with colorectal cancer (CRC) who are administered bevacizumab plus chemotherapy in randomized controlled trials (RCTs).

METHODS: We searched PubMed and CENTRAL databases to extract reports of relevant trials that were published in English between January 1, 2003, and December 31, 2014. All RCTs in which bevacizumab plus chemotherapy was compared with standard chemotherapy or with placebo plus chemotherapy for the treatment of CRC, and TEEs were reported, were included in a meta-analysis. Risk ratios (RRs) with 95% confidence intervals (CIs) of TEEs were calculated for each RCT. Because the between-study heterogeneities (I2) were insignificant, a fixed-effect model was used to determine the effect size of each TEE. A funnel plot was created to assess publication bias, and 2 forms of sensitivity analyses were performed for each outcome.

RESULTS: This meta-analysis included 22 RCTs with a total of 13,185 patients. Overall, compared with the control groups, patients with CRC who received bevacizumab were at significant risk for overall TEEs (RR, 1.334; 95% CI, 1.191-1.494; P <.001; I2 = 1.37%). Regarding venous TEEs, a significant risk was observed for patients who received bevacizumab versus control patients (RR, 1.244; 95% CI, 1.091-1.415; P = .001; I2 = 0.0%). Similarly, the risk for arterial TEEs was significant in bevacizumab-treated patients (RR, 1.627; 95% CI, 1.162-2.279; P = .005; I2 = 0.0%). Sensitivity analyses did not affect the level of significance of the effect size for each outcome, and no significant publication bias was observed.

CONCLUSION: In all the studies reviewed in this meta-analysis, the risk for venous or arterial TEEs was associated with bevacizumab use in patients with CRC. Healthcare providers are encouraged to consider thromboprophylaxis agents, periodically monitor their patients who receive bevacizumab, and carefully manage patients who are at increased risk for those complications.

KEY WORDS: arterial thromboembolic events, bevacizumab, colorectal cancer, meta-analysis, randomized controlled trials, TEEs, venous thromboembolic events

Am Health Drug Benefits.
2016;9(4):221-232
www.AHDBonline.com
Supplemental materials online

Received January 19, 2016
Accepted in final form April 29, 2016

Disclosures are at end of text

Bevacizumab (Avastin) is a recombinant, humanized monoclonal antibody known as antiangiogenic or anti–vascular endothelial growth factor (anti­VEGF), which has a unique mechanism of action. It works through blocking the angiogenesis process, a physiologic process leading to the generation of new blood vessels, by targeting the VEGF.1-5 Those blood vessels are the source of oxygen, blood, and nutrition needed for the progression of most malignant cells; by hindering their proliferation, a progression-free state is ensured.4

In 2004, the US Food and Drug Administration granted the first approval of bevacizumab for use in multiple metastatic cancers. In the same year, bevacizumab was approved as first-line treatment in combination with other chemotherapies for metastatic colorectal cancer (CRC).6,7 Currently, bevacizumab is one of the most used antiangiogenic drugs for patients with CRC.

A study by Hess and colleagues indicated that more than 68% of patients with metastatic CRC in the United States were exposed to bevacizumab from 2004 to 2008.8 More precisely, bevacizumab was prescribed for 901 (54%) of 1655 patients with metastatic CRC as initial first-line treatment, for 58% of those who needed a continued second-line regimen, and for 50% of those who were administered third-line therapy.8 In addition, bevacizumab was prescribed for 57% of geriatric patients with newly diagnosed CRC and for 44% of geriatric patients with relapsed CRC.9

Previous clinical trials have proved that adding bevacizumab to the traditional chemotherapy regimens for metastatic CRC, as either a first- or second-line drug, has led to significant improvement in the rates of response,10-13 overall survival,12-14 and progression-free survival15-18 compared with chemotherapy alone. However, the majority of those reports show that bevacizumab has been associated with an increased risk for serious adverse events. Most of those adverse events ranged from mild to moderate in severity and were common (eg, high blood pressure, bleeding, constipation, thrombocytopenia, proteinuria, bowel perforation).11-32 Thromboembolic events (TEEs) were generally rare in the bevacizumab-treated population, yet were life-threatening and warrant careful monitoring and management.11-32

Bevacizumab has shown superiority in improving overall survival for patients with cancer, but because the increased risk for TEEs leads to higher mortality, such superiority may be affected.3,33-38 In previous meta-analyses, the incidence of arterial and venous TEEs among patients with different types of cancer treated with bevacizumab ranged from 0.6% to 5.6%34,35,37,38 and from 6.8% to 19.9%,33 respectively; among patients with CRC, the incidence of these events ranged from 0.5% to 8.5%34,35,37,38 and from 16.1% to 22.6%,33 respectively.

Complications such as thrombosis have been linked to cancer for many years, and thrombosis was ranked second in the list of causes of death among patients with cancer.39 By contrast, cancer is one of the main risk factors leading to venous TEEs, and it had been estimated that approximately 20% of all venous TEEs were cancer­ related.40,41 Along with medications, the risk for TEEs is influenced by many cofactors, such as age, trauma, smoking status, surgery, immobility, blood abnormalities, cancer and its type, hormonal therapy, and pregnancy.41,42 Previous epidemiologic studies demonstrated that the risk for TEEs varied by type of cancer. Compared with cancer-free patients, individuals with brain cancer and those with colon cancer are at an increased relative risk for TEEs, >25% and >17%, respectively.41,43

Previous meta-analyses have tried to determine the risk for either arterial or venous TEEs associated with bevacizumab use in patients with cancer.33-38 Scappaticci and colleagues analyzed 5 randomized controlled trials (RCTs) and found a significantly greater risk for arterial but not for venous TEEs among various cancers.34 A pooled analysis of 15 RCTs showed a significant risk for venous TEEs among all patients with cancer but a nonsignificant risk for patients with CRC.33 In contrast, the analysis of 10 RCTs by Hurwitz and colleagues showed a nonsignificant risk for venous TEEs among all patients with cancer, including those with CRC.36

Other studies indicated that the risk for arterial TEEs is significant for patients with all types of cancer, including CRC.35,37,38 However, those studies have some limitations. First, the goal of those studies was to investigate the risk for TEEs by analyzing RCTs of various types of cancers rather than just one type. It would be more reliable to examine the association between each cancer and TEEs, which would minimize the confounding effects of cancer type and site. Furthermore, those studies were limited to few RCTs and a small sample size for each type of cancer, which might have led to underestimation of the true risk for TEEs.

Other studies investigated the safety of bevacizumab in patients with CRC.44-49 Although 5 studies showed that bevacizumab use was associated with a significant risk for thrombosis, no detailed results for arterial or venous TEEs were presented.44-48 In contrast, a study by Galfrascoli and colleagues shows a significant risk for arterial TEEs but a nonsignificant risk for venous thrombosis in the bevacizumab group.49

Given the association between chemotherapy and TEEs, the high mortality rate caused by cancer-related thrombosis, and the conflicting results of published studies, a meta-analysis to address the risk for TEEs in patients with CRC is needed to enhance healthcare providers’ awareness and inform careful patient management. In previous meta-analyses, the risk for thrombosis associated with bevacizumab use was examined among patients with different types of cancer, including CRC. However, there is no recent and large meta-analysis in which this association was analyzed solely for patients with CRC. Therefore, the objective of the current meta-analysis was to determine the risk for overall, venous, and arterial TEEs associated with bevacizumab plus chemotherapy in patients with CRC.

Methods
Search Strategy

To identify and extract relevant clinical trials, we performed a comprehensive literature search using the databases of PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL).

In PubMed, this search was limited to RCTs whose title and abstract contained all the following key words—“bevacizumab” and “colorectal cancer,” “beva­cizumab” and “colon cancer,” “bevacizumab” and “rectal cancer,” “Avastin” and “colorectal cancer,” “Avastin” and “colon cancer,” “Avastin” and “rectal cancer,” “antiangiogenic” and “colorectal cancer,” “antiangiogenic” and “colon cancer,” “antiangiogenic” and “rectal cancer,” “anti-VEGF” and “colorectal cancer,” “anti-VEGF” and “colon cancer,” and “anti-VEGF” and “rectal cancer.” In addition, we conducted a PubMed search limited to abstracts only, using pairs of the key words, “bevacizumab” and “thrombosis,” “bevacizumab” and “thromboembolism,” “bevacizumab” and “thrombotic,” “bevacizumab” and “embolism,” “bevacizumab” and “infarction,” and “bevacizumab” and “ischemia.”

For the CENTRAL database, the search was limited to title, abstract, and the key word combinations of “beva­cizumab,” “colorectal cancer,” and “clinical trials”; “bevacizumab,” “colon cancer,” and “clinical trials”; “bevacizu­mab,” “rectal cancer,” and “clinical trials”; “Avastin,” “colorectal cancer,” and “clinical trials”; “Avastin,” “colon cancer,” and “clinical trials”; and “Avastin,” “rectal cancer,” and “clinical trials.”

These searches were restricted to clinical trials in humans that were published between January 1, 2003, and December 31, 2014, and were written in English. We searched the references cited in the retrieved studies, but have not contacted any of the authors of those studies.

Inclusion/Exclusion Criteria

To achieve our objective, only RCTs that involved humans and comparisons of bevacizumab with a standard or placebo chemotherapy regimen for the treatment of CRC were retrieved. To be included, a study was required to have clear clinical data for any TEE (ie, venous thrombosis, arterial thrombosis, thrombosis, pulmonary embolism, cardiac ischemia, cerebral ischemia, cardiac infarction, or cerebral infarction) for the 2 chemotherapy groups. Thus, single-arm or phase 1 RCTs, or review articles were excluded. Also excluded were non-English publications, studies of safety or pharmacokinetics, replies to authors, nonrandomized studies, publications in which TEEs were not reported, and studies in which both arms received bevacizumab therapy.

Quality Assessment

To assess the quality of reporting completeness of each RCT included in our study, we incorporated the Jadad quality assessment criteria.50 Briefly, this is a test of 5 yes or no questions, in which each question answered “yes” is worth 1 point and no in-between answers are permitted. The answers to the first 3 questions are scored as 1 point if the study was randomized, 1 point if double-blinded, and 1 point if it addressed dropouts; each of these 3 questions is scored as zero points if the answer is “no.”

The answers to the last 2 questions are scored as an extra point if the study was randomized and the randomization method was appropriate, and an extra point if the study was double-blinded and the blinding method was appropriate, but 1 point is deducted for each “no” response. Quality scores yielded from these criteria range from zero (very poor quality) to 5 (excellent quality). We conducted a sensitivity analysis by removing studies with poor quality scores (≤2) and recalculated the effect size for each outcome to examine the influence of studies with poor quality scores on our results.

Data Extraction

Relevant data (the number or percentage of TEEs and the sample size used for safety analysis in the bevacizumab and the control arms) were extracted from each study individually. Using all these data and a 2 × 2 contingency table, we calculated the risk ratio (RR) of TEEs for each study, along with 95% confidence intervals (CIs). Two blinded reviewers performed all data extraction, as well as the calculation of effect sizes for the 22 RCTs included.

Outcome Definitions Used in This Report

In our study, TEEs were classified into 3 groups. First, overall TEEs were defined as the sum of arterial and venous TEEs reported in each study. Second, venous TEEs were defined as any events involving venous thrombosis, venous thromboembolism, vein occlusion, thrombophlebitis, or pulmonary embolism. Arterial TEEs were defined as any events including arterial thrombosis, cardiac ischemia, cerebral ischemia, cardiac infarction, or cerebral infarction.

Statistical Methods

The RR, 95% CI, and P value were calculated for each study. For each outcome, the RR for TEEs was calculated using the fixed-effect model, because the between-study statistical heterogeneity measured by the Higgins I2 test was <50% and was insignificant. (If the I2 value is <50%, then a fixed-effect model is considered appropriate; otherwise, a random-effect model should be used.) In addition, we performed 2 forms of sensitivity analysis for each outcome by removing 1 study at a time, as well as studies with poor quality scores (≤2), then we recalculated the fixed-effect estimates.

The presence of publication bias was evaluated visually using a funnel plot of the logarithm of effect size against the standard error for each trial, and statistically using the 2-tailed P value results for the Egger’s and Begg’s tests. If a P value showed significance, it would indicate significant publication bias.

The analyses were made using Microsoft Excel 2010 and the Comprehensive Meta-Analysis software (Biostat, Englewood, NJ).

Results

According to our search criteria, 506 potentially relevant clinical trial publications were identified. Of these, 387 articles were excluded, because they were single-arm studies, review articles, abstracts only, or were counted twice (Figure 1). A total of 22 RCTs, representing a total of 13,185 patients, were included in our meta-analysis (Table).

Figure 1

Table
Tableb

The numbers of TEEs quantified in this analysis were taken from 7 phase 2, 13 phase 3, 1 phase 2/3, and 1 phase-undetermined RCTs. Of the 22 RCTs, only 4 were placebo-controlled and blinded. The follow-up duration of the studies included ranged from 12 months to 60 months.

The dose of bevacizumab varied between studies—either 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks. The quality score for each RCT was calculated (see Appendix, Table 1), and the majority of studies received a score of 2 or 3. Furthermore, 3 studies had a quality score of 1; 5 studies had a score of 2; 12 studies had a score of 3; 1 study had a score of 4; and 1 study had a score of 5. No study yielded a quality score of zero. (Detailed baseline characteristics of all patients included in each study are presented in the Appendix, Table 2.)

Results of Individual Studies

Overall thromboembolic events. We combined the number of arterial and venous events from each trial to analyze the overall risk for TEEs in the bevacizumab and the control groups. All 22 RCTs were included for this outcome assessment, and the events of overall TEEs were developed in 9.9% of bevacizumab-treated patients compared with 7.5% of the control patients. Compared with patients in the control arm, patients receiving bevaciz­umab plus chemotherapy had a significant risk for TEEs (RR, 1.334; 95% CI, 1.191-1.494; P <.001; I2 = 1.37%; Figure 2).

Figure 2

Sensitivity analysis, by removing 1 study at a time, showed effect sizes ranging from an RR of 1.305 (95% CI, 1.163-1.464; P <.001) to an RR of 1.374 (95% CI, 1.219-1.549; P <.001). In addition, an effect size of RR of 1.305 (95% CI, 1.141-1.493; P <.001) was yielded by removing studies with a poor quality score (≤2).

For overall TEEs, visual evaluation of the funnel plot (Figure 3) of logarithm of effect sizes versus standard error for each trial indicated some publication bias. However, the P values of Egger’s and Begg’s tests were 0.968 and 0.967, respectively. Thus, there was no significant evidence of publication bias for studies included in the assessment of overall TEEs.

Figure 3

Venous TEEs. For patients with CRC included in this analysis, venous TEEs were observed in 8% of patients receiving bevacizumab plus chemotherapy compared with 6.5% of the control group. According to our results, the RR for venous TEEs in the bevacizumab group versus the control group was 1.244 (95% CI, 1.091-1.415; P = .001; I2 = 0.0%; Figure 4). Significant risk for venous TEEs was observed even after removing (a) all studies with quality score ≤2 (RR, 1.258; 95% CI, 1.079-1466; P = .003) and (b) 1 study at a time (ie, range of RR of 1.202 [95% CI, 1.043-1.384; P = .011] to 1.280 [95% CI, 1.115-1.470; P <.001]).

Figure 4

For publication bias, Figure 5 shows the funnel plot of the logarithm of effect sizes against the standard error for each study included in this outcome, except for 1 missing study; however, the results of Egger’s and Begg’s tests were 0.877 and 0.855, respectively. Therefore, no significant publication bias was present.

Figure 5

Arterial TEEs. Among the RCTs in which any arterial TEE was reported for patients with CRC, the percentage of arterial TEEs was 2.3% for bevacizumab chemotherapy and 1.1% for the control therapy. The estimated RR of having an arterial TEE for bevacizumab versus the control therapy was 1.627 (95% CI, 1.162-2.279; P = .005; I2 = 0.0%; Figure 6). Sensitivity analysis, by deleting a single study at a time, showed that RR point estimates ranged from 1.561 (95% CI, 1.112-2.192; P = .010) to 1.772 (95% CI, 1.177-2.666; P = .006). Similarly, a significant RR of 1.631 (95% CI, 1.057-2516; P = .027) was observed after deleting poor­quality studies.

Figure 6

Figure 7 shows the funnel plot of the logarithm of effect sizes versus standard error for studies that included arterial TEEs, which indicates some bias. However, the 2-tailed P values for Egger’s and Begg’s tests (0.702 and 0.207, respectively) showed no significant evidence of publication bias for this outcome.

Figure 7

Discussion

In this meta-analysis we considered the risk for overall, arterial, and venous TEEs associated with the use of bevacizumab chemotherapy in patients with CRC based on 22 RCTs comparing bevacizumab therapy and a controlled group.7,11-14,16-32 Our findings indicate a significant increase in risk for TEEs in this particular population. Patients with CRC who received bevacizumab had a >33% risk for any type of thrombosis. More precisely, bevacizumab therapy was associated with a 24% increased risk for venous TEEs and a 62% increased risk for arterial TEEs.

We believe that our study is unique, because it focused on comprehensively addressing the risk for TEEs in bevaciz­umab-treated patients with CRC using more recent and a larger number of RCTs than in a previous pooled meta-analysis. Our results are in agreement with those of previous pooled analyses that included patients with CRC in terms of significant overall risk for TEEs,44-48 significant arterial risk,35,37,38,49 and significant risk for grade ≥3 venous TEEs.33 However, our findings for venous TEEs conflict with results of previous studies. The RR estimated by Nalluri and colleagues for all grades of venous TEEs in patients with CRC was 1.19 (95% CI, 0.92-1.55).33 By contrast, Scappaticci and colleagues34 reported a lower hazard ratio (HR) of venous TEE risk (HR, 0.89; 95% CI, 0.66-1.20; P = .44). The results of Hurwitz and colleagues regarding venous TEEs in CRC indicated a nonsignificant unadjusted odds ratio (OR) of 1.22 (95% CI, 0.93-1.58).36 Similarly, Galfrascoli and colleagues found a nonsignificant RR of 1.23 (95% CI, 0.93-1.62; P = .15) for venous TEEs in patients with CRC.49

Some reasons can explain these conflicts. First, the number of CRC clinical trials included in previous reports was smaller (3,33 4,36 and 649) than in our analysis (22 RCTs). Therefore, the pooled sample size of those studies was also small, ranging from 1096 to 2813 patients. It has been proved that a negative correlation exists between sample size and CI limits; thus, the smaller the sample size, the wider the “certain” level of confidence, and vice versa.51 Furthermore, the focus of the studies by Scappaticci and colleagues34 and Galfrascoli and colleagues49 was limited to grade ≥3 TEEs (other grades were omitted), which would explain the difference between their findings and ours.

Although the previous pooled studies did not have the power to generate statistical significance, an increased risk (ie, 9%-19%) for venous TEEs was reported for patients with CRC.33,36,49 Similarly, for bevacizu­mab-treated patients with CRC in our analysis, the risk for venous or arterial thrombosis was more than 24% and 62% higher, respectively, than in control patients. Because cancer-related thrombosis is the second leading cause of death among patients with cancer, and is associated with substantial mortality risk (OR, 8.1; 95% CI, 3.6-18.1),40,41,52 we believe that the increased risk observed in previous and current studies indicates the presence of a clinical issue that warrants greater awareness to help control its consequences.

The mechanism by which bevacizumab causes thrombosis is still unknown, but several theories have been proposed. Those theories are based on the pathologic impact of VEGF inhibition accomplished by bevacizu­mab.33,37 One theory proposed that hindering the physiologic anti-inflammatory effect of VEGF would increase vascular inflammation and cause thrombus development eventually.33,35,37 In addition, the inhibition of VEGF would decrease the production of nitric oxide and prostacyclin, leading to increased blood viscosity and platelet aggregation.33,35,37 Others have suggested that bevacizumab interaction with malignant cells produces toxic substances that increase blood coagulation.33 Some investigators have connected the anti-VEGF activity of bevacizumab to damaging the endothelial walls of blood vessels and exposing subendothelial lipids by thrombosis formulation.33,38

Our findings are of considerable importance for CRC management and cautious prescribing of bevacizumab for patients with CRC, because cancer is already a risk factor for TEEs. Therefore, taking into account how much prescribing bevacizumab for patients with CRC can induce TEEs, and suitable prophylaxis are advised.41,43,52 In a large study, patients with CRC had a 3.1% incidence of venous TEEs over the 2-year follow-up.53

In addition, patients with metastatic cancer who receive chemotherapy have been proved to have a more than 6-fold increased risk for thrombosis compared with patients with cancer who do not receive chemotherapy.54 Therefore, we believe that identifying drugs linked to TEEs is the first step in preventing such adverse effects and will lead to better outcomes. The significant risk presented in our study will increase the awareness of this issue, which may lead to better diagnosis and management of TEEs in patients with CRC who receive this drug.

Patients with cancer who have a history of thrombosis52 or previous exposure to chemotherapy,41,55 and patients who are undergoing major surgery,56 hospitalized,55 or newly diagnosed54 have an increased risk for TEEs and should receive thromboprophylaxis appropriately. However, the 2014 updated guideline of the American Society of Clinical Oncology does not recommend prescribing thromboprophylaxis for outpatients. Interestingly, this guideline mandates low-molecular-weight heparin or low-dose aspirin as prophylaxis for patients with multiple myeloma who receive antiangiogenesis treatment, such as bevacizumab.57 We found that patients with metastatic CRC who receive bevacizumab plus chemotherapy are at increased risk for TEEs and, similar to multiple myeloma, our results may support the need to consider thromboprophylaxis for patients with CRC.

Thromboprophylaxis is recommended by the American College of Chest Physicians guidelines for acutely admitted patients with any type of cancer58; however, some survey studies have proved that thromboprophylaxis is underutilized by most oncologists because of unawareness of these guidelines, omitted risk factors, and caution of associated adverse events.58,59 To better minimize the mortality risk associated with cancer-related thrombosis, primary prophylaxis therapy should be considered for all patients at risk.60 Bevacizumab is known to cause bleeding and thrombocytopenia,11-14,16-32 and the potential benefit of using aspirin or other anticoagulants in clinical trials has not been proved to outweigh the risk.49,60 Therefore, a careful and patient-tailored thromboprophylaxis guideline for bevacizumab use in CRC is greatly needed.

Our analysis has some strengths over previous studies. This is the first analysis of the risk for overall, venous, and arterial TEEs associated with bevacizumab that is focused solely on patients with CRC. Our specific focus on patients with CRC eliminated the confounding effect of cancer type, an important factor contributing to the associated risk. Moreover, we analyzed 22 RCTs, including the most recent trials. This produced a larger pooled sample size than in previous meta-analyses, thereby providing adequate power to detect potentially modest effects.

Limitations

Although our study has many strengths, it has several limitations as well. First, we did not analyze the impact of different bevacizumab doses and heterogeneous chemotherapy regimens on the development of TEEs. Therefore, we do not know if a subgroup analysis of those regimens would alter the significance of our findings.

Second, because we did not have access to all patient characteristics and confounding factors, it is possible that some TEEs in the RCTs analyzed might be attributable to factors other than bevacizumab itself. Although our study included RCTs analyzed in previous meta-analyses,33-38,44-49 those meta-analyses reported event and sample numbers that are different from our findings. Possible reasons for this discrepancy include that those analyses might have had different definitions for TEEs, or they might have contacted the authors of the original RCTs for clarification and/or supplemental data.

Therefore, based on our definition of TEEs, and because we did not contact the authors of the RCTs for clarification, our numbers are not the same as those presented in previous meta-analyses.

Conclusion

The findings of our study indicate that the risk for thrombotic events, either venous or arterial, is associated with the combination of bevacizumab and chemotherapy in patients with CRC. To better understand this association and improve patient outcomes, additional studies are needed. The evaluation of bevacizumab and TEEs should consider the grade of TEEs and the impact of different bevacizumab doses, and it should stratify the results by chemotherapy regimens. Further investigation to understand the mechanism by which bevacizumab leads to TEEs in patients with CRC, and to identify the best prophylaxis, is recommended. Prolonged observational studies that can control confounding factors, identify patients at risk, determine higher-risk chemotherapy combinations, and provide evaluation based on real-world data are also needed. Healthcare providers are encouraged to consider the use of a thrombosis prophylactic regimen, including periodic monitoring of their patients and careful management of those at higher risk for thrombosis.

Author Disclosure Statement
Mr Abdullah Alahmari, Mr Almalki, and Mr Ahmed Alahmari reported no conflicts of interest. Dr Guo has received research grants or unrestricted grant funding from Ohio Department of Job and Family Services (a state Medicaid agency), Ortho-McNeil Janssen Scientific Affairs, Eli Lilly, Roche-Genentech, and Novartis. No financial support was received for this article.

References

1. Suenaga M, Mizunuma N, Kobayashi K, et al. Management of venous thromboembolism in colorectal cancer patients treated with bevacizumab. Med Oncol. 2010;27:807-814.
2. Kabbinavar FF, Wallace JF, Holmgren E, et al. Health-related quality of life impact of bevacizumab when combined with irinotecan, 5-fluorouracil, and leucovorin or 5-fluorouracil and leucovorin for metastatic colorectal cancer. Oncologist. 2008;13:1021-1029.
3. Tebbutt NC, Murphy F, Zannino D, et al; for the Australasian Gastro-Intestinal Trials Group. Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab. Ann Oncol. 2011;22:1834-1838.
4. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011-1027.
5. Tsavaris N, Voutsas IF, Kosmas C, et al. Combined treatment with bevaciz­umab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients. Invest New Drugs. 2012;30:395-402.
6. Hurwitz H. New combinations in metastatic colorectal cancer: what are our expectations? Oncologist. 2005;10:320-322.
7. Madajewicz S, Waterhouse DM, Ritch PS, et al. Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer. Invest New Drugs. 2012;30:772-778.
8. Hess GP, Wang PF, Quach D, et al. Systemic therapy for metastatic colorectal cancer: patterns of chemotherapy and biologic therapy use in US medical oncology practice. J Oncol Pract. 2010;6:301-307.
9. Fu AZ, Tsai H-T, Marshall JL, et al. Utilization of bevacizumab in US elderly patients with colorectal cancer receiving chemotherapy. J Oncol Pharm Pract. 2014;20:332-340.
10. Lee E-K, Revil C, Ngoh CA, et al. Clinical and cost effectiveness of bevacizumab + FOLFIRI combination versus FOLFIRI alone as first-line treatment of metastatic colorectal cancer in South Korea. Clin Ther. 2012;34:1408-1419.
11. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60-65.
12. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinote­can, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.
13. Giantonio BJ, Catalano PJ, Meropol NJ, et al; for the Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colo­rectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539-1544.
14. Allegra CJ, Yothers G, O’Connell MJ, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol. 2009;27:3385-3390.
15. Lee K-D, Chen H-H, Wang H-M, et al. An open-label safety study of first-line bevacizumab in combination with standard chemotherapy in Chinese patients with metastatic colorectal cancer treated in an expanded access program in Taiwan. Oncology. 2013;84:299-304.
16. Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol. 2010;28:3191-3198.
17. Price TJ, Zannino D, Wilson K, et al. Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of capecitabine, bevacizumab and mitomycin C. Ann Oncol. 2012;23:1531-1536.
18. Cunningham D, Lang I, Marcuello E, et al; for the AVEX Study Investigators. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077-1085.
19. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697-3705.
20. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019. Errata in: J Clin Oncol. 2008;26:3110; J Clin Oncol. 2009;27:653.
21. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE study. J Clin Oncol. 2008;26:3523-3529. Erratum in: J Clin Oncol. 2008;26:4697.
22. Jackson NA, Barrueco J, Soufi-Mahjoubi R, et al. Comparing safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in elderly versus nonelderly patients with metastatic colorectal cancer: findings from the bolus, infusional, or capecitabine with camptostar-celecoxib study. Cancer. 2009;115:2617-2629.
23. Sharma S, Abhyankar V, Burgess RE, et al. A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol. 2010;21:297-304.
24. Kemeny NE, Jarnagin WR, Capanu M, et al. Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer. J Clin Oncol. 2011;29:884-889.
25. Guan Z-Z, Xu J-M, Luo R-C, et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011;30:682-689.
26. Stintzing S, Fischer von Weikersthal L, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306. Ann Oncol. 2012;23:1693-1699.
27. Bennouna J, Sastre J, Arnold D, et al; for the ML18147 Study Investigators. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29-37.
28. de Gramont A, Van Cutsem E, Schmoll H-J, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 2012;13:1225-1233.
29. Dotan E, Meropol NJ, Burtness B, et al. A phase II study of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as frontline therapy for metastatic colorectal cancer. A Fox Chase extramural research study. J Gastrointest Cancer. 2012;43:562-569.
30. Schmoll H-J, Cunningham D, Sobrero A, et al. Cediranib with mFOL­FOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012;30:3588-3595.
31. Cunningham D, Wong RPW, D’Haens G, et al; for the HORIZON I Study Group. Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer. Br J Cancer. 2013;108:493-502.
32. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1065-1075.
33. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277-2285.
34. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232-1239. Errata in: J Natl Cancer Inst. 2008;100:156; J Natl Cancer Inst. 2008;100:685.
35. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010;49:287-297.
36. Hurwitz HI, Saltz LB, Van Cutsem E, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol. 2011;29:1757-1764.
37. Chen X-L, Lei Y-H, Liu C-F, et al. Angiogenesis inhibitor bevacizumab increases the risk of ischemic heart disease associated with chemotherapy: a meta-analysis. PLoS One. 2013;8:e66721.
38. Schutz FAB, Je Y, Azzi GR, et al. Bevacizumab increases the risk of arterial ischemia: a large study in cancer patients with a focus on different subgroup outcomes. Ann Oncol. 2011;22:1404-1412.
39. Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res. 2010;125:490-493.
40. Caine GJ, Stonelake PS, Lip GYH, Kehoe ST. The hypercoagulable state of malignancy: pathogenesis and current debate. Neoplasia. 2002;4:465-473.
41. Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus. 2011;9:120-138.
42. Martinelli I, Bucciarelli P, Mannucci PM. Thrombotic risk factors: basic pathophysiology. Crit Care Med. 2010;38(2 suppl):S3-S9.
43. Heit JA. Cancer and venous thromboembolism: scope of the problem. Cancer Control. 2005;12(suppl 1):5-10.
44. Cao Y, Tan A, Gao F, et al. A meta-analysis of randomized controlled trials comparing chemotherapy plus bevacizumab with chemotherapy alone in metastatic colorectal cancer. Int J Colorectal Dis. 2009;24:677-685.
45. Macedo LT, da Costa Lima AB, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer. 2012;12:89.
46. Dai F, Shu L, Bian Y, et al. Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials. Clin Drug Investig. 2013;33:779-788.
47. Lv C, Wu S, Zheng D, et al. The efficacy of additional bevacizumab to cytotoxic chemotherapy regimens for the treatment of colorectal cancer: an updated meta-analysis for randomized trials. Cancer Biother Radiopharm. 2013;28:501-509.
48. Qu C-Y, Zheng Y, Zhou M, et al. Value of bevacizumab in treatment of colorectal cancer: a meta-analysis. World J Gastroenterol. 2015;21:5072-5080.
49. Galfrascoli E, Piva S, Cinquini M, et al; for the ORION Collaborative Group. Risk/benefit profile of bevacizumab in metastatic colon cancer: a systematic review and meta-analysis. Dig Liver Dis. 2011;43:286-294.
50. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.
51. du Prel J-B, Hommel G, Röhrig B, Blettner M. Confidence interval or P-value? Part 4 of a series on evaluation of scientific publications. Dtsch Arztebl Int. 2009;106:335-339.
52. Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7.
53. Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2006;24:1112-1118.
54. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815.
55. Lyman GH, Khorana AA, Falanga A, et al; for the American Society of Clinical Oncology. American Society of Clinical Oncology guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505.
56. Falanga A, Russo L, Verzeroli C. Mechanisms of thrombosis in cancer. Thromb Res. 2013;131(suppl 1):S59-S62.
57. Lyman GH, Bohlke K, Khorana AA, et al; for the American Society of Clinical Oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33:654-656.
58. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S-400S.
59. Kakkar AK, Levine M, Pinedo HM, et al. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8:381-388.
60. Brose KMJ, Lee AYY. Cancer-associated thrombosis: prevention and treatment. Curr Oncol. 2008;15(suppl 1):S58-S67.

 


 

APPENDIX: Supplement Materials

Thromboembolic Events Associated with Bevacizumab plus Chemotherapy for Patients with Colorectal Cancer: A Meta-Analysis of Randomized Controlled Trials

Abdullah K. Alahmari, BPharm, PhD candidate; Ziyad S. Almalki, BPharm, PhD candidate; Ahmed K. Alahmari, MD student; Jeff J. Guo, BPharm, PhD

This Appendix has not been edited and is provided as supplemental materials for this article, which was published in American Health & Drug Benefits in June 2016.

Table 1

Table 2

Stakeholder Perspective
Better Patient Education Needed Regarding Thromboembolic Events Risk in Patients with Cancer
Jeffrey A. Bourret, PharmD, MS, BCPS, FASHP
Senior Director
North America Medical Affairs
Medical Lead
Specialty Payer & Channel Customer Strategy
Pfizer Inc
Collegeville, PA

Educating patients on the risks of their treatments in the context of their medical condition is challenging. Physicians need data from randomized, real-­world, observational clinical trials to effectively assess a drug’s benefits and risks for specific patient subgroups based on age, concomitant medications, and specific cancers.

Meta-analyses provide healthcare professionals information that can be used to assess the risks and benefits of current treatments for specific conditions. Alahmari and colleagues present a meta-analysis of randomized controlled trials (RCTs) on thromboembolic events associated with bevacizumab plus chemotherapy in patients with colorectal cancer (CRC).1 Their meta-analysis is a great resource for healthcare professionals and for associations that generate treatment guidelines and prophylaxis recommendations to avoid adverse events. This is a valuable resource for clinicians. Similar evidence for other cancers is needed to guide clinical practice and reduce adverse events.

PATIENTS: Patients with cancer are at an increased risk for thromboembolic events.2 A patient’s age, sex, ethnicity, and treatments, and the impact of cancer on blood coagulation affect the risk for such events.2 Patients can struggle to understand the risks and benefits of a treatment, especially in complex medical conditions such as CRC. They need to know their risk for thromboembolic events, especially with metastatic CRC, and the potential risks of various CRC treatments, which include combination regimens. Alahmari and colleagues found a significant risk for thromboembolic events in patients with CRC who receive bevacizumab.1 This implies an increased need for thromboprophylaxis agents and for recognizing the signs and symptoms of venous thromboembolism (VTE). To add to the complexity, patients with cancer are also at risk for bleeding, so they need to know the risks for bleeding associated with anticoagulant treatment.2

Physicians are beginning to use icon arrays to depict clinical risks for educating patients, and this needs to be more common: many patients with cancer receive limited information on deep-vein thrombosis (DVT) or pulmonary embolism (PE) risks. Aggarwal and colleagues surveyed 500 patients with cancer about DVT/PE risks.3 Only 24% and 15% of patients had heard of DVT and PE, respectively; only 19% and 17% could list the symptoms; and only 3% knew that cancer treatments carry a risk for DVT/PE.3 Most alarming: only 25% of patients had received education about DVT/PE prevention, and <50% had received VTE prophylaxis.3

MANUFACTURERS/PAYERS: The pharmaceutical industry provides safety information from RCTs as part of a drug label through postmarketing pharmacovigilance and long-term extension safety trials. However, RCT data are captured in controlled settings and may not reflect patients in real-world settings who may receive additional treatments for their comorbidities. Data from various registries are critical for providing real-world data. Payers can play a critical role in leveraging their claims data to supplement RCTs data for further insights into the incidence of VTE events. Electronic medical records could be used to detect whether at-risk patients have received VTE prophylaxis and have been educated on VTE and bleeding risks. Payers’ increased capability in predictive analytics further offers an opportunity to identify patients at risk.

PROVIDERS: Explaining risks to patients is difficult, and takes time. Patients require ongoing education on their prescribed treatment, emphasizing the need for continuing education beyond office visits. For many cancer treatments, specialty pharmacy call center clinicians play an important role in patient education through monthly outbound telephonic support. Interactive multimedia education and icon arrays that graphically explain treatment risks offer opportunities to improve the process. Providers can assist by conducting studies to add to the literature. Quick online access to updated guidelines would be a great improvement. Representation from the cardiology and vascular communities to assist oncologists in developing guidelines for VTE prevention in specific cancers, along with patient recommendations, would further enhance outcomes.

1. Alahmari AK, Almalki ZS, Alahmari AK, Guo JJ. Thromboembolic events associated with bevacizumab plus chemotherapy for patients with colorectal cancer: a meta-analysis of randomized controlled trials. Am Health Drug Benefits. 2016;9(4):221-232.
2. Wilts IT, Bleker SM, Van Es N, et al. Safety of anticoagulant treatment in cancer patients. Expert Opin Drug Saf. 2015;14:1227-1236.
3. Aggarwal A, Fullam L, Brownstein AP, et al. Deep vein thrombosis (DVT) and pulmonary embolism (PE): awareness and prophylaxis practices reported by patients with cancer. Cancer Invest. 2015;33:405-410.

Related Items
Major Cardiovascular Events in Patients with Gout and Associated Cardiovascular Disease or Heart Failure and Chronic Kidney Disease Initiating a Xanthine Oxidase Inhibitor
JoAnne Foody, MD;, Robin S. Turpin, PhD, Beni A. Tidwell, BS, Debra Lawrence, PhD, Kathy L. Schulman, MS
November 2017 Vol 10, No 8 published on November 21, 2017 in Clinical, Original Research
Medication Adherence, Treatment Patterns, and Dose Reduction in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Abiraterone Acetate or Enzalutamide
Ajay S. Behl, PhD, Lorie A. Ellis, PhD, Dominic Pilon, MA, Yongling Xiao, PhD
September 2017 Vol 10, No 6 published on September 20, 2017 in Clinical, Original Research
The Relative Burden of Menopausal and Postmenopausal Symptoms versus Other Major Conditions: A Retrospective Analysis of the Medical Expenditure Panel Survey Data
Annlouise R. Assaf, PhD, Andrew G. Bushmakin, MS, Nina Joyce, PhD, Michael J. Louie, MD, MPH, MSc, Michael Flores, MPH, Margaret Moffatt, MPH
September 2017 Vol 10, No 6 published on September 20, 2017 in Clinical, Original Research
The Medical and Economic Burden of Narcolepsy: Implications for Managed Care
Michael J. Thorpy, MB, ChB, George Hiller, RPh, James T. Kenney, RPh, MBA
July 2017 Vol 10, No 5 published on July 24, 2017 in Clinical
Comparing Medication Adherence and Persistence Among Patients with Type 2 Diabetes Using Sodium-Glucose Cotransporter 2 Inhibitors or Sulfonylureas
Kelly F. Bell, PharmD, MSPhr, MS, Katherine Cappell, PhD, Michael Liang, MS, Amanda M. Kong, MPH
June 2017 Vol 10, No 4 published on June 22, 2017 in Clinical, Original Research
Last modified: June 27, 2016
  •  Association for Value-Based Cancer Care
  • Value-Based Cancer Care
  • Value-Based Care in Rheumatology
  • Oncology Practice Management
  • Rheumatology Practice Management
  • Urology Practice Management
  • Inside Patient Care: Pharmacy & Clinic
  • Lynx CME