Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 13  |  Issue : 5  |  Page : 869--877

Efficacy and safety of bevacizumab in elderly patients with advanced colorectal cancer: A meta-analysis


Xiuxing Chen1, Yanfeng Chen2, Xiuyu Cai1, Dongsheng Zhang3, Lei Fan4, Huijuan Qiu1, Bei Zhang1, Guifang Guo1,  
1 VIP Inpatient Department, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
2 Department of Head and Neck Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
3 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
4 Department of Orthopaedics, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P. R. China

Correspondence Address:
Guifang Guo
Cancer Center, Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060
P. R. China

Abstract

Aims: Bevacizumab plus chemotherapy (CT) has been the standard treatment for advanced colorectal cancer (ACRC) in the last decade. However, whether geriatric patients treated with this combination achieved more benefits or suffered severer toxicities than CT alone remained controversial. This meta-analysis was aimed to provide more convincing evidence. Subjects and Methods: Randomized control trials (RCTs) and retrospective comparative studies on the comparison between bevacizumab plus CT and CT for geriatric ACRC patients were retrieved in PubMed, Web of Science, EMBASE, and Ovid until June 2016. One RCT, five subgroup analyses of RCTs, and two retrospective studies with efficacy and safety data were identified, involving a total of 2813 cases. The included primary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Results: For geriatric ACRC, both OS (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.74–0.94, P = 0.003) and PFS (HR 0.55, 95% CI 0.48–0.63, P < 0.001) have been improved after the addition of bevacizumab to CT. The odds ratios (ORs) for total grade and grade 3–5 AEs were 1.85 (95% CI 1.12–3.04, P = 0.02) and 2.09 (95% CI 1.69–2.58, P < 0.001), respectively. For overall grade toxicities, proteinuria (OR 10.89, 95% CI 1.37–86.28, P = 0.02), hypertension (OR 4.44, 95% CI 1.85–10.62, P < 0.05), and fistulae/abscess (OR 12.07, 95% CI 1.54–94.88, P < 0.05) were significantly higher in the bevacizumab arm. For grades 3–5, increased risk of hypertension (OR 3.91, 95% CI 2.48–6.16, P < 0.001), arterial thromboembolism (OR 3.25, 95% CI 1.70–6.19, P < 0.001), and venous thromboembolism (OR 2.17, 95% CI 1.11–4.25, P = 0.02) was observed in the bevacizumab group. Conclusions: After the addition of bevacizumab to CT in geriatric ACRC, both PFS and OS could be significantly improved, while it would also lead to some high-grade AEs, hypertension, and arterial and venous thromboembolism.



How to cite this article:
Chen X, Chen Y, Cai X, Zhang D, Fan L, Qiu H, Zhang B, Guo G. Efficacy and safety of bevacizumab in elderly patients with advanced colorectal cancer: A meta-analysis.J Can Res Ther 2017;13:869-877


How to cite this URL:
Chen X, Chen Y, Cai X, Zhang D, Fan L, Qiu H, Zhang B, Guo G. Efficacy and safety of bevacizumab in elderly patients with advanced colorectal cancer: A meta-analysis. J Can Res Ther [serial online] 2017 [cited 2019 Dec 11 ];13:869-877
Available from: http://www.cancerjournal.net/text.asp?2017/13/5/869/220486


Full Text



 Introduction



Most studies have revealed the efficacy and safety of bevacizumab, a humanized antibody targeting vascular growth factor receptor, in the whole population.[1] Many epidemiological studies showed that increasing age was a vital risk factor for developing colorectal cancer (CRC). Elderly patients accounted for approximately two-third of all newly emerging CRC cases and all deaths according to the latest data.[2] Old patients were generally underrepresented and excluded from clinical trials because of their limited regenerative ability, reduced resistance to diseases, and increased comorbidities.[3],[4],[5] However, combination chemotherapy (CT) could still be tolerated by elderly patients after careful selection.[6] Hence, a comprehensive meta-analysis was performed to provide more convincing evidence on the benefits of bevacizumab for geriatric ACRC patients.

 Subjects and Methods



Data sources

The workflow of this meta-analysis is shown in [Figure 1]. A prospective protocol of objectives, literature-search strategies, inclusion and exclusion criteria, outcome measurements, and methods of statistical analysis were prepared a priori, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement and Meta-analysis of Observational Studies in Epidemiology recommendations for study reporting.[7],[8],[9] All the citations in English were independently reviewed from PubMed, Web of Science, EMBASE, and Ovid without restriction of publication dates, regions, and types.{Figure 1}

The following words were searched in the abstract/title as keywords or terms: bevacizumab/avastin, elderly/old, adults/geriatric, colorectal/colon/rectal, and cancer/carcinoma/tumor. To avoid missing publications, a related function in the databases was applied to broaden the search field, and the computer retrieval was supplemented with manual searches in the reference list of all retrieved studies and review articles. Conference abstracts of major meetings, including the American Society of Clinical Oncology, European Society for Medical Oncology, and European Cancer Organization annual meetings, were also searched. If multiple reports described the same population, the most recent or complete report was involved. The types of CT combined with bevacizumab or line of the studied regimens were not restricted. The data from the included studies were carefully extracted and independently summarized by two authors, and any instance of ambiguity was resolved by the senior adjudicating author.

Selection criteria and quality evaluation

Studies meeting the following criteria were included: (1) focusing on the efficacy and safety of bevacizumab combined with CT compared with single CT in advanced CRC (ACRC) patients; (2) cases of patients older than 65 years; (3) confirmed cases of metastasis CRC or relapse; (4) randomized controlled trials (RCTs) or retrospective comparative analyses; and (5) sufficient data regarding the efficacy and/or toxicity. Studies that did not meet above inclusion criteria, such as editorials, letters to the editor, review articles, case reports, and animal experimental studies, were excluded.

The included studies were ranked based on the level of evidence, which was determined per the criteria provided by the Centre for Evidence-Based Medicine in Oxford, UK.[10] The methodological quality of RCTs was assessed with the Cochrane risk of bias tool. The methodological quality of the retrospective studies was assessed by a modified Newcastle-Ottawa scale (with a scale ranged 0–9), which comprised of three factors: selection of patients, comparability of study groups, and assessment of outcome.[10],[11],[12],[13] Studies with a score of six or more were considered as high-quality studies.

Study endpoint

One primary endpoint was progression-free survival (PFS), defined as randomization to disease progress or death. Another primary endpoint was incidence of grade 3–5 toxicities, including arterial thromboembolism, venous thromboembolism, fistulae, proteinuria, congestive heart failure, hypertension, hemorrhage, and bowel perforation. The incidence of all-grade adverse events (AEs) was also evaluated. The second endpoints were overall survival (OS), defined as randomization to the time of death from any cause, and objective response rate (ORR), defined as the sum of partial response rate plus complete response rate.

Statistical analysis

The meta-analysis was performed with Review Manager 5.3.5 (Cochrane Collaboration, Oxford, UK). Hazard ratios (HRs) and corresponding 95% confidence interval (CI) were summarized as generic inverse variance outcomes. The outcomes of AEs presented as odds ratios (ORs); furthermore, the proportions of patients with grades 3–5 or total toxicities were reported as dichotomous data. Statistical heterogeneity among studies was estimated with I2 statistic, and the obtained value was applied to determine whether fixed-effects or random-effects model should be applied. If there was a significant heterogeneity (I2 ≥ 50%), the randomized-effects model was applied; if there was low-level heterogeneity (I2 < 50%), the fixed-effects model was applied.[10] Funnel plots were applied to monitoring the potential publication bias.

 Results



A total of 371 papers on bevacizumab in geriatric ACRC patients were identified in initial and raw literature searches. After screening in titles/abstracts and the full text, 50 duplicated studies were removed and 313 studies without valid information provision were subsequently excluded. Eight studies satisfying the predefined criteria were involved in the final analysis, including a single RCT, five subgroups analyses of RCTs, and two retrospective comparative analyses. The references of these studies were double-checked without enrolling further studies. The quality of the survival outcomes in all RCT studies was with the analysis of intent-to-treat method [Figure 2]. Half of the RCTs were double-blind studies,[14],[15],[16] while the other half showed an open level of masking.[17],[18],[19] Two retrospective analyses were also of high quality, with a score of eight. For the publication bias of ORR, PFS, OS, and toxicity, all the included studies fell within the 95% CIs, with an even distribution around the vertical, indicating no publication bias.{Figure 2}

Baseline characteristics of searches involved in the present meta-analysis

The baseline characteristics of studies included herein are presented in [Table 1]. One RCT and five subgroup analyses of RCTs, comprising one phase 2 clinical trial and five phase 3 studies, focused on the efficacy and toxicity in elderly patients treated with bevacizumab plus CT versus CT alone. For the remaining two studies, there was one pooled analysis on the efficacy and toxicity of the combined treatment regimen, while another cohort study primarily focused on the toxicity. There were 2813 cases in the present study, including 1391 cases treated with bevacizumab plus CT and 1422 cases treated with single CT. The follow-up time in the present study was 24.8–30.8 months, and the median cycles of therapy were 9–10 for the combination therapy and 6–8 cycles for CT. The confounding factors were matched in all studies, except one. The CT regimens employed in these studies were classic regimens for treating CRC in clinical practice.{Table 1}

Efficacy of bevacizumab plus chemotherapy versus chemotherapy alone

In all six RCTs, PFS was consistently longer for patients treated with bevacizumab plus CT (8.8–10.4 months) than those treated with CT alone (5.1–6.9 months),[14],[15],[16],[17],[18],[19] and the median absolute increasing time was 2.4–4.0 months. The heterogeneity among all the RCTs was low (P = 0.76, I2 = 0.00%), and the fixed-effects model revealed a statistically significant improvement regarding PFS after the addition of bevacizumab to CT (HR 0.55, 95% CI, 0.48–0.63, P < 0.001) [Figure 3]. The data for the six RCTs showed a significantly longer OS in the combination group (15.7–20.7 months) than in the CT group (13.4–16.8 months), and the median absolute increasing time was 2.9–3.9 months. The treatment with AVF2107 g alone (Hurwitz et al.) resulted in a statistically longer OS. There was low statistical heterogeneity between individual trials (heterogeneity P = 0.14, I2 = 39.00%) [Figure 3]. The data for all six RCTs were pooled with a fixed model, demonstrating a significant extension of OS in elderly patients who received combination therapy compared to those treated with CT alone (HR 0.83, 95% CI, 0.74–0.94, P = 0.003). The results indicated that ORR was available in two studies and a significantly higher ORR was observed in the bevacizumab plus CT group than in CT group (25.2% vs. 13.6%, OR 1.94, 95% CI, 1.13–3.36, P = 0.02).{Figure 3}

Toxicities of bevacizumab plus chemotherapy versus chemotherapy

Valuable toxicities during the treatment were reported in each study, and there was a statistically significant increase in some adverse effects for the bevacizumab group [Table 2]. For total-grade toxicities [Figure 4], the OR was 1.85 (95% CI, 1.12–3.04) in the random effects model, indicating the distinct heterogeneity among studies (P < 0.001, I2 = 71.00%). Proteinuria (OR 10.89, 95% CI 1.37–86.28), hypertension (OR 4.44, 95% CI 1.85–10.62), and fistulae/abscess (OR 12.07, 95% CI 1.54–94.88) were significantly higher in patients treated with bevacizumab plus CT compared with patients receiving CT alone. However, the conclusion for above-mentioned toxicity of the total grade was supported by only one study. For grade 3–5 toxicities, the OR was 2.09 (95% CI, 1.69–2.58) according to the fixed-effects model, reflecting the low heterogeneity among the studies (P = 0.19, I2 = 22%) [Figure 5]. The statistically significant increase in risk of hypertension (OR 3.91, 95% CI 2.48–6.16), arterial thromboembolism (OR 3.25, 95% CI 1.70–6.19), and venous thromboembolism (OR 2.17, 95% CI 1.11–4.25) was observed in bevacizumab-treated patients. AEs caused death was observed in 3.1% patients with the bevacizumab-containing regimen and in 1.5% patients with CT alone.{Table 2}{Figure 4}{Figure 5}

 Discussion



This synthetic meta-analysis, involving six RCTs and two retrospective analyses, suggested that, when bevacizumab was added to CT for the treatment of elderly patients with ACRC, there was a significant improvement of PFS and OS with some increased toxicities. With bevacizumab treatment, PFS was statistically significantly improved, consistent with the results of all included RCT, while only one single RCT showed an obviously extended OS. When the data in these six RCTs were integrated and performing a pooled analysis, we considered that geriatric patients were significantly benefited with the addition of bevacizumab, not only in PFS (P < 0.001) but also in OS (P = 0.003). Prolonged PFS and OS with bevacizumab exhibited not only statistical significance but also clinical significance because the absolute increased time was obvious, 2.4–4.0 months and 2.9–3.9 months for PFS and OS, respectively. The results of this meta-analysis were consistent with those of many well-known clinical trials conducted in common populations without age restriction,[15],[17],[20] which showed significantly prolonged OS and PFS. Until recently, many studies have only suggested that prolonged PFS could be obtained from bevacizumab in elderly advanced colorectal patients but not OS, except for the AVF2107 g study. It would be exciting that both PFS and OS were improved for this special group in this pooled analysis.

As for the toxicities caused by bevacizumab, the same types of AEs were observed in elderly patients with ACRC as general patients.[21],[22],[23] Hypertension was the most common complication of bevacizumab.[24] In the present study, subset analysis revealed that the risk of hypertension would be increased with the addition of bevacizumab to CT by 4.44 and 3.91 times, respectively, in both the total grade (19.4% vs. 5.15%) and high grade (11.66% vs. 3.34%). One large case observation showed that the bevacizumab-induced hypertension of the total grade and grades 3–5 in elderly ACRC was 11.4% and 4.8%, consistent with our study.[25] Most antihypertensive agents were effective at reducing blood pressure, except diuretics and miscellaneous antihypertensive.[26] According to our clinical experiences, it was easy to treat hypertension and the patient would soon return to normal blood pressure after the cessation of bevacizumab. Therefore, both the doctor and patient need not worry about this complication as long as blood pressure was monitored and controlled during the administration of bevacizumab. Another study suggested that the risk of hypertension would not be increased with shorter bevacizumab infusions (0.5 mg/kg/min).[27] Interestingly, several studies have observed prolonged PFS and OS in patients with bevacizumab-related hypertension.[28],[29],[30] One meta-analysis confirmed this opinion in PFS (HR = 0.57, P < 0.001), OS (HR = 0.50, P < 0.001), and ORR (relative risk ratio [RR] = 1.57, P < 0.05).[31] Hence, bevacizumab-related hypertension indicated that more benefits were obtained from bevacizumab. By contrast, high basal proteinuria before treatment might be a bad prognostic factor of bevacizumab.[32] However, some studies have revealed bevacizumab-related proteinuria as a predictive factor although there was a lack of evidence.[33] Two meta-analyses, one with 14,548 patients, of proteinuria for all-grade toxicities was improved by bevacizumab. The result was 7.46% versus 0.74% and 8.2% versus 4.6%, respectively, in the bevacizumab and control groups, and some patients developed severe proteinuria and renal dysfunction.[34] In clinical practice, urine protein would be examined biweekly and bevacizumab would be discontinued when obvious proteinuria persisted and nephritic syndrome occurred.

Some dangerous complications of bevacizumab treatment should be paid more attention, despite their low incidence. Senility and Trousseau's syndrome both resulted in a higher risk of developing venous and arterial thromboembolism; thus, we must be aware of thromboembolism with the administration of this drug in elderly cancer patients.[35],[36] We observed that elderly patients using bevacizumab plus CT had a greater risk of high-grade arterial thromboembolism and venous thromboembolism than those using CT, 5.11% versus 1.60%, P < 0.001 and 3.85% versus 1.83%, P < 0.05, respectively, and these results were similar to those of subsequent meta-analyses including many varieties of cancer. Scappaticci et al. reported that arterial thromboembolism was significantly high (HR 3.65, 95% CI 1.92–6.92), but venous thromboembolism was not high in patients aged >65 years with bevacizumab.[37] However, Nalluri et al. suggested that venous thromboembolism was both significantly high in all grade (11.9%) and high grade (6.3%) in whole populations.[38] One study showed D-dimer could be used as prognostic factor in ACRC elderly patients receiving bevacizumab.[39] Thus, bevacizumab was likely to increase arterial thromboembolism in geriatric patients, and this drug may be closely associated with venous thromboembolism. A meta-analysis published in Lancet Oncology showed that the addition of bevacizumab was associated with a statistically higher risk of developing gastrointestinal perforation (RR 3.1, 95% CI 1.62–7.63) in CRC compared with other types of cancer within unselected populations,[40] while the data in the present study showed a negative result in the geriatric population. Gastrointestinal perforation is a rare complication of bevacizumab, but it could directly threaten the life of the patients if diagnosis and emergent surgery are not performed in an adequate amount of time.[41],[42] In addition, the high risk of gastrointestinal perforation was related to intact primary tumor, recent history of sigmoidoscopy or colonoscopy, or previous adjuvant radiotherapy,[43] and cases with extensive peritoneal stripping in the prior abdomen surgery easily suffered perforation when treated with bevacizumab. Different from other studies,[44],[45] these data showed that bleeding was not significantly high in geriatric population for both total-grade and high-grade incidence. Nevertheless, we must be careful to accept this conclusion since brain metastasis patients with a potential hemorrhage were excluded in half of the studies of our analysis. Fistulae/fasciitis with an incidence of 2% in ACRC was recently approved by the FDA as a label warning of the risk of bevacizumab, which severely affects the quality of life. Fistulae/abscess (8.21% vs. 0.74%) for all-grade toxicities in the present study were significantly increased by bevacizumab. In a previous meta-analysis, Ranpura et al. suggested that fatal AEs were associated with different CT types but not with the bevacizumab dose or tumor types. We did not conduct this subgroup analysis in the present study as there were insufficient raw data available.[46]

For the bevacizumab treatment toward geriatric patients with ACRC, there were a few RCT studies with inconsistent results. These studies adopted different CT regimens, matching criteria, samples, bevacizumab dose, and measurement of outcomes, all of which would contribute to the heterogeneity. In this meta-analysis, we observed that the heterogeneity between included studies was so low that it hardly had any effect on the subgroup analysis of high-grade AEs, PFS, and OS. In addition, the heterogeneity influence on total-grade AEs of bleeding and bowel perforation was partially solved by pooling data with the random-effects model. Hence, this meta-analysis undoubtedly provided more convincing evidence than any individual report.

Nevertheless, there were also several limitations in this meta-analysis. First, there were only one RCT, five subgroup analyses of RCTs, and two retrospective analyses, with small cases in some trials (99–1292 cases). Second, the subgroup analysis reduced the power of these analyses, particularly for side effects with low incidence rates. Moreover, there may be performance and detection bias in half of the RCTs because of a lack of masking.[17],[18],[19] Fortunately, both attrition and reporting biases were relatively low.

 Conclusions



We synthesized the information on the efficacy and side effects of bevacizumab combined CT in ACRC for a geriatric population. Furthermore, the present meta-analysis indicated that both PFS and OS would be prolonged with bevacizumab, while also inducing a higher risk of some specific AEs of grade 3–5, including hypertension, arterial thromboembolism, and venous thromboembolism. Still, the existing data for studying the pros and cons of combining bevacizumab with CT to treat geriatric ACRC patients have not been sufficient. Hence, large-scale RCTs are warranted to further explore the conclusions of the present study.

Financial support and sponsorship

Our study was supported by the National Natural Science Foundation of China (No. 81302141) and the fundamental research funds for the Sun Yat-sen University young teacher training project (No. 12ykpy56).

Conflicts of interest

There are no conflicts of interest.

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