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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 7  |  Page : 95-98
 

A meta-analysis of bevacizumab combined with chemotherapy in the treatment of ovarian cancer


1 Department of Pharmacy, Women and Infants Hospital of Zhengzhou, Zhengzhou Henan Province 450000, China
2 Department of Gynaecology and Obstetrics, Women and Infants Hospital of Zhengzhou, Zhengzhou Henan Province 450000, China
3 Department of Pharmacy, People's Hospital of Zhengzhou, Zhengzhou Henan Province 450000, China
4 Department of Clinical Pharmacy, The Center Hospital of Jinhua City, Jinhua 321000, China

Date of Web Publication27-Mar-2015

Correspondence Address:
Y L Zhu
Department of Clinical Pharmacy, The Center Hospital of Jinhua City, Jinhua 321000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.154084

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 » Abstract 

Introduction: Angiogenesis plays an important role in the biology of ovarian cancer. The clinical efficacy and side effects of bevacizumab, the vascular endothelial growth factor inhibitor, on survival and toxicity in women with this ovarian cancer, was not conclusive. We performed this systematic review and meta-analysis in order to clarify the efficacy of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. Materials and Methods: We searched the electronic database of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CNKI for clinical controlled trials of comparing bevacizumab combined with chemotherapy and chemotherapy alone in the treatment of ovarian cancer. The primary outcomes of eligible studies included median progression-free survival (PFS), overall survival (OS), and toxicities such as enterobrosis, hypertension, albuminuria, congestive heart failure (CHF), neutrophils, thrombosis, and bleeding. The Hazard ratio (HR) and relative risk were used for the meta-analysis and were expressed with 95% confidence intervals (CIs). All the statistical analyses were carried out by  Stata 11.0 software (http://www.stata.com; Stata Corporation, College Station, TX, USA). Results: We included 5 studies with 1798 cases in the bevacizumab combined with the chemotherapy group and 1810 subjects in the chemotherapy alone group. The pooled results showed that bevacizumab + chemotherapy compared with chemotherapy alone can significant prolong the median PFS (HR, 0.64; 95% CI, 0.46-0.82; P < 0.05) but not the OS (HR, 0.84; 95% CI, 0.59-10.9; P > 0.05); the toxicity analysis showed that the enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding were significantly increased in the bevacizumab + chemotherapy group compared with chemotherapy alone (Pall < 0.05). But the CHF risk between the two groups was not statistical different (P > 0.05). Conclusion: Bevacizumab combined with chemotherapy prolonged the median PFS in patients with ovarian cancer but also increase the risk of developing enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding.


Keywords: Bevacizumab, chemotherapy, meta-analysis, ovarian cancer, prognosis, toxicity


How to cite this article:
Wang T S, Lei W, Cui W, Wen P, Guo H F, Ding S G, Yang Y P, Xu Y Q, Lv S W, Zhu Y L. A meta-analysis of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. Indian J Cancer 2014;51, Suppl S3:95-8

How to cite this URL:
Wang T S, Lei W, Cui W, Wen P, Guo H F, Ding S G, Yang Y P, Xu Y Q, Lv S W, Zhu Y L. A meta-analysis of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. Indian J Cancer [serial online] 2014 [cited 2020 Aug 12];51, Suppl S3:95-8. Available from: http://www.indianjcancer.com/text.asp?2014/51/7/95/154084



 » Introduction Top


Ovarian cancer is one of the most diagnosed carcinomas for human beings. [1] The expected incidence of epithelial ovarian cancer in women in the United States in 2012 is approximately 22,280 (15,500 deaths) and in Europe in 2008 was estimated at 69,565 patient cases (44,280 deaths). [2] At most of the time, the patients with epithelial ovarian cancer were diagnosed with advanced stage, who was need for systematic chemotherapy. The standard chemotherapy regimen was platinum-based chemotherapy for epithelial ovarian cancer. Although good initial response to standard chemotherapy strategy, most cases would suffer from disease progression and require further treatment.

Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF-A), has demonstrated clinical efficacy for the treatment of epithelial ovarian in several clinical trials. [3],[4] We searched all the clinical studies reporting bevacizumab combined with chemotherapy regimen in the treatment of epithelial ovarian cancer and made a meta-analysis in order to evaluate the clinical effects and toxicity for bevacizumab combined with chemotherapy in the treatment of epithelial ovarian cancer.


 » Materials and Methods Top


Literature search

A literature search was carried to find the randomized controlled trials and clinical control studies evaluating bevacizumab in the treatment of epithelial ovarian cancer. We searched Medline (1996-September 2014), Embase (1996-September 2014), and the Cochrane Central Register of Controlled Trials (issue 4, 2014) and CNKI (1996-September 2014). The language was restricted to English and Chinese. The searching items were as follows: Ovarian cancer, ovarian carcinoma, ovarian neoplasm, bevacizumab, and Avastin. Clinical studies, that met the following criteria, were included: (1) Prospective randomized trials; (2) the treatment strategy was bevacizumab combined with chemotherapy and standard chemotherapy; (3) the patients were restricted to epithelial ovarian cancer with pathology confirmation.

Data extraction

The general information and exact data were extracted by two reviews (Taoxing WANG and Wei CUI) independently and checked by another reviewer (Wei LEI). Disagreements were solved by a third reviewer (Wei LEI) after referring to the original articles. The end points of interest included overall survival (OS), progression-free survival (PFS), and adverse events like toxicities such as enterobrosis, hypertension, albuminuria, congestive heart failure (CHF), neutrophils, thrombosis, and bleeding were extracted from each included studies. And the general information of the first author, year of publication, chemotherapy regimen, and follow-up years were also extracted.

Statistical analyses

The Hazard ratio (HR) and its 95% confidence interval (CI) were deemed as the effects size and pooled by random or fixed effects model using a general variance-based method. For toxicities, the relative risk (RR) was used as the effect size. The number of toxicity events reported in each arm was combined using the random or fixed effect model. The statistical heterogeneity was evaluated by Chi-square test, and I2 statistic was employed to assess variability across studies attributable to heterogeneity beyond chance. [5] P > 0.10 for the Chi-square test and an I2 value <25% were interpreted as signifying low-level heterogeneity and deemed no statistical heterogeneity. The fixed effect pooled method was used in the above situations otherwise random effect mode was employed.


 » Results Top


General characteristics of the five studies

We finally included 5 clinical trials in this meta-analysis with 1798 cases in the bevacizumab combined with the chemotherapy group and 1810 subjects in the chemotherapy alone group. Of the included 5 studies, 4 trials were prospective randomized controlled trials and 1 was retrospective clinical controlled study. The patients included in the 5 studies range from 64 to 1528. 4 studies compared the Bevacizumab + paclitaxel and carboplatin (PC) with PC chemotherapy regimen and 1 study compared Bevacizumab + gemcitabine and carboplatin with gemcitabine and carboplatin chemotherapy regimen. The detailed information of the included 5 studies is shown in [Table 1].
Table 1: The detailed characteristics of the five studies

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Progression-free survival and overall survival analysis

For PFS, 4 studies reported their HR and 95% CI. We evaluate the statistical heterogeneity for HR of the included 4 studies. The I2 = 91.5%, P = 0.00 indicating significant heterogeneity was existed amongs the studies. The random effect mode was used to calculate the pooled HR. The pooled HR for median PFS was 0.64 (95% CI: 0.46-0.82) indicating that bevacizumab + chemotherapy compared with chemotherapy alone can significant prolonged the median PFS. For OS, 3 studies reported their HR and 95% CI. The statistical heterogeneity for HR of the included 4 studies was I2 = 67.7%, P = 0.045 indicating significant heterogeneity among the included 3 articles. The random effect model was used with the pooled HR for median PFS of 0.84 (95% CI: 0.59-1.09) indicating no statistical difference between bevacizumab + chemotherapy and chemotherapy alone [Figure 1].
Figure 1: The forest plot evaluating the Hazard ratio for progression-free survival and overall survival

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Toxicity

Three articles reported the enterobrosis, the pooled RR was 3.58 with it 95% CI of 1.10-11.71 (P < 0.05). It indicated that the bevacizumab + chemotherapy regimen significant increased the risk of developing enterobrosis. Five studies reported the hypertension with the pooled RR of 5.10 (P < 0.05). Bevacizumab + chemotherapy regimens increased 5 times risk of developing hypertension than chemotherapy alone. For albuminuria, the synthesized RR was 3.63 (95% CI: 1.42-9.25) showing bevacizumab significant increased the risk of developing albuminuria. For neutrophils, thrombosis, and bleeding, the pooled results also indicated that the significant increased the risk of above side effects (Pall < 0.05). But the risk of developing CHF was not statistical different between bevacizumab + chemotherapy and chemotherapy regimen alone (P > 0.05), [Figure 2].
Figure 2: The forest plot for evaluating the toxicity between bevacizumab + chemotherapy and chemotherapy regimen alone

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Publication bias

The publication bias was assessed by Begg's funnel plot. The funnel plot showed symmetrical indicating no significant publication bias [Figure 3].
Figure 3: Funnel plot for evaluation the publication bias

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 » Discussion Top


Ovarian carcinoma consists of several pathology types with the different treatment modality according to its own histopathological type. The epithelial ovarian cancer comprises 80% of all the types ovarian cancers. [9] According to the epidemiology data, epithelial ovarian cancer was leading cause of gynecologic cancer-related death in the United States and the 5 th most common cause of cancer death in women. And it was reported that nearly 60% of the diagnosed epithelial ovarian cancer cannot be cured with recurrence finally.

At present, the platinum-based combination chemotherapy regimen was recommended for ovarian cancer. Such as the paclitaxel plus carboplatin regimen and gemcitabine combined with carboplatin chemotherapy regimens. Although good initial response to standard platinum-based combination chemotherapy strategy, most cases would suffer from disease progression and require further treatment. According to the National Comprehensive Cancer Network, humanized anti-VEGF monoclonal antibody-Bevacizumab is also active in both platinum-sensitive and platinum-resistant ovarian cancer patients. [10],[11],[12] But bevacizumab can also increase the risk of developing arterial thrombosis or intestinal performation.

Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. [6] Bevacizumab, a humanized anti-VEGF monoclonal antibody, which blocks angiogenesis by inhibiting VEGF, has shown single-agent activity in women with recurrent tumors. [6] Combination treatment modality with bevacizumab can be considered base on the published trials documenting the activity and toxicity of the combination. [13],[14] The standard chemotherapy delayed progression and improved survival for newly diagnosed ovarian cancer after initial surgery, and that the addition of bevacizumab delayed progression for recurrent ovarian cancer after platinum-based chemotherapy.

Here, we performed a meta-analysis based on published clinical studies reporting the clinical efficacy and side effects for combination treatment regimen with bevacizumab. 5 clinical studies were included and pooled in this meta-analysis with 1798 cases in the bevacizumab combined with the chemotherapy group and 1810 subjects in the chemotherapy alone group. The pooled results showed that bevacizumab + chemotherapy compared with chemotherapy alone can significantly prolong the median PFS but not the OS. The toxicity analysis showed that the enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding were significantly increased in the bevacizumab + chemotherapy group compared with chemotherapy alone. But the CHF risk between the two groups was not statistical different. Thereafter, bevacizumab combined with chemotherapy prolonged the median PFS in patients with ovarian cancer but also increased the risk of developing enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding according to the published data. There were only 5 clinical studies included in this meta-analysis, the evidence was weak. Hence, well-designed prospective randomized controlled trials were needed for further evaluation; the exact activity for bevacizumab combined with chemotherapy regimen in the treatment of ovarian cancer.

 
 » References Top

1.
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29.  Back to cited text no. 1
    
2.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.  Back to cited text no. 2
    
3.
Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012;30:2039-45.  Back to cited text no. 3
    
4.
Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, et al. AVEREL: A randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 2013;31:1719-25.  Back to cited text no. 4
    
5.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 5
    
6.
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-83.  Back to cited text no. 6
    
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Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011;365:2484-96.  Back to cited text no. 7
    
8.
Akers SN, Riebandt G, Miller A, Groman A, Odunsi K, Lele S. Bevacizumab for the treatment of recurrent ovarian cancer: A retrospective cohort study. Eur J Gynaecol Oncol 2013;34:113-9.  Back to cited text no. 8
    
9.
Chan JK, Cheung MK, Husain A, Teng NN, West D, Whittemore AS, et al. Patterns and progress in ovarian cancer over 14 years. Obstet Gynecol 2006;108:521-8.  Back to cited text no. 9
    
10.
Bidus MA, Webb JC, Seidman JD, Rose GS, Boice CR, Elkas JC. Sustained response to bevacizumab in refractory well-differentiated ovarian neoplasms. Gynecol Oncol 2006;102:5-7.  Back to cited text no. 10
    
11.
Wright JD, Hagemann A, Rader JS, Viviano D, Gibb RK, Norris L, et al. Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis. Cancer 2006;107:83-9.  Back to cited text no. 11
    
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Simpkins F, Belinson JL, Rose PG. Avoiding bevacizumab related gastrointestinal toxicity for recurrent ovarian cancer by careful patient screening. Gynecol Oncol 2007;107:118-23.  Back to cited text no. 12
    
13.
Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008;26:76-82.  Back to cited text no. 13
    
14.
Richardson DL, Backes FJ, Seamon LG, Zanagnolo V, O′Malley DM, Cohn DE, et al. Combination gemcitabine, platinum, and bevacizumab for the treatment of recurrent ovarian cancer. Gynecol Oncol 2008;111:461-6.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]



 

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