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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 948-956

Bleeding risk in cancer patients treated with sorafenib: A meta-analysis of randomized controlled trials


1 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China
2 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University; Jiangxi Provincial Engineering Technology Research Center for Hepatobiliary Disease, Nanchang 330006, China

Date of Web Publication11-Dec-2018

Correspondence Address:
Fan Zhou
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, 1 Mingde Road, Nanchang 330006
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.188430

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 > Abstract 


Objective: Sorafenib, an oral vascular endothelial growth factor receptor tyrosine-kinase inhibitor, has become a cornerstone in the treatment of various malignancies. However, concerns have arisen regarding the risk of hemorrhage with sorafenib use. Nevertheless, the contribution of sorafenib to hemorrhage and the underlying risk factors remains unclear.
Materials and Methods: We performed a meta-analysis to determine the incidence and risk of hemorrhage associated with sorafenib treatment. Multiple databases were searched to identify relevant studies. The analysis included randomized controlled trials (RCTs) that directly compared cancer patients treated with or without sorafenib. Statistical analyses were conducted to determine the overall incidence, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effect models.
Results: Ten RCTs involving 4720 patients were included in the analysis. Overall, the incidence rates of all- and high-grade hemorrhage in patients receiving sorafenib were 9.89% (95% CI: 8.73–11.18%) and 2.86% (95% CI: 2.25–3.63%), respectively. Sorafenib treatment increased the risk of all-grade hemorrhage in patients compared to control treatment (RR: 1.99; 95% CI: 1.59–2.49; P < 0.00001), but did not increase the incidence of high-grade hemorrhage (RR: 1.42; 95% CI: 0.95–2.12; P = 0.09). Subgroup analysis showed no significant increase in the risk of hemorrhage between patients with various malignancies or concurrent treatment. No evidence of publication bias was observed.
Conclusion: In patients with malignancy, sorafenib treatment combined with standard treatment significantly increases the risk of low-grade hemorrhagic events.

Keywords: Hemorrhage, meta-analysis, sorafenib


How to cite this article:
Dai C, Zhou F, Shao JH, Wu LQ, Yu X, Yin XB. Bleeding risk in cancer patients treated with sorafenib: A meta-analysis of randomized controlled trials. J Can Res Ther 2018;14, Suppl S5:948-56

How to cite this URL:
Dai C, Zhou F, Shao JH, Wu LQ, Yu X, Yin XB. Bleeding risk in cancer patients treated with sorafenib: A meta-analysis of randomized controlled trials. J Can Res Ther [serial online] 2018 [cited 2019 Sep 20];14:948-56. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/948/188430




 > Introduction Top


Vascular endothelial growth factor (VEGF) plays an important role in tumor growth, invasion, and metastasis by promoting tumor angiogenesis.[1],[2] Several malignancies are treated through the use of VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs).[3] In particular, sorafenib is an orally active multi-TKI that targets VEGFR-2 and -3, platelet-derived growth factor receptor β, and Raf kinase, all of which have been implicated in neovascularization and tumor progression.[4],[5] The Food and Drug Administration has approved the use of sorafenib for patients with renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and the list of indications for this drug is growing.[6],[7],[8],[9],[10],[11]

Although remarkably well-tolerated by patients, sorafenib exhibits a distinct pattern of adverse events (AEs) that are thought to be related to the inhibition of angiogenesis. Potentially, life-threatening AEs associated with sorafenib treatment include hypertension, hemorrhage, and arterial and venous thromboembolism.[12],[13],[14],[15],[16] Hemorrhagic events have major negative impacts on mortality, morbidity, and health-care costs, often leading to treatment delays and interruptions.[16],[17] Schutz et al. found that hemorrhagic events are the most common cause of fatal AEs in cancer patients treated with VEGFR-TKIs.[18] However, the reported overall incidence of hemorrhagic events associated with sorafenib therapy has varied substantially between clinical trials, and an accurate quantification of this risk remains to be performed.

A recent meta-analysis of published clinical trials indicated that the VEGFR-TKIs sunitinib and sorafenib are associated with a significant increase in the risk of patient bleeding.[16] However, the study design may have been insufficient to detect whether sorafenib treatment influences the risk of hemorrhage, due to the limited number of randomized controlled trials (RCTs; only two) included in the analysis. Several additional RCTs evaluating hemorrhagic events due to sorafenib treatment have been performed.[19],[20],[21],[22],[23],[24],[25] To understand the overall risk of hemorrhagic events induced by sorafenib therapy and to identify the underlying risk factors, we conducted a meta-analysis of published RCTs that report the occurrence of hemorrhagic events in sorafenib-treated cancer patients.


 > Materials and Methods Top


Data sources

An independent search of PubMed for RCTs published between January 1, 1966, and June 30, 2014, was performed. Keywords used for the search were “sorafenib,” “BAY43-9006,” “Nexavar,” and “cancer.” The following terms were used to refine the search and to identify additional relevant information: “bleeding,” “hemorrhage,” “angiogenesis,” “side effects,” “AE,” and “VEGF”. Abstracts from conferences and virtual meeting presentations published by the American Society of Clinical Oncology (http://www.asco.org/ASCO) between January 1, 2000, and June 30, 2014, were searched using the terms “sorafenib,” “Nexavar,” and “BAY43-9006”. Independent searches of the EMBASE, Cochrane Library, and Web of Science databases were performed to ensure that all relevant clinical trial data were included in the study. Each potentially relevant publication was fully reviewed. If more than one publication was identified from the same clinical trial, then only the most recent or complete report was selected. The updated manufacturer's package insert for sorafenib was reviewed to identify any additional relevant information.

Study selection

RCTs were included in the study if they (1) were prospective Phase II or III trials involving patients with cancer, (2) performed random group assignment of participants to the sorafenib treatment or control (placebo or active-controlled) group, and (3) provided data for events or incidence of hemorrhage and sample size. Phase I trials and single-arm Phase II trials were excluded due to a lack of control patients. The study quality was assessed using the Jadad et al. ranking system, which evaluates the studies by assessing randomization, blinding, and the description of withdrawals and dropouts.[26]

Data extraction and clinical endpoints

Data were extracted from papers independently by two investigators (FZ and CD) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.[27] Any disagreements were resolved by discussion until consensus was reached. For each study, the following information was extracted:First author's name, year of publication, trial phase, underlying malignancy, number of patients enrolled, number of patients available for analysis, treatment arms, number of hemorrhagic events in experimental and control arms, drug dose/schedule, median age, median follow-up, median treatment duration, median progression-free survival, and reported sites of hemorrhage.

To investigate whether sorafenib treatment contributes to hemorrhagic development in cancer patients, we regarded the following AEs as hemorrhagic events: ecchymosis or petechiae, purpura, epistaxis, melaena, hematemesis, hematuria, hemoptysis, hemothorax, vaginal hemorrhage (menorrhagia or metrorrhagia), and eye, gastrointestinal, gum, rectal, retroperitoneal, central nervous system (CNS), injection-site, or nonspecific hemorrhage. Hemorrhage in the RCTs was assessed and recorded according to the National Cancer Institute Common Toxicity Criteria [NCI-CTC, versions 2 and 3, [Supplementary Table S1]].[28],[29] The number of hemorrhagic events reported in the safety profile section of each study was recorded. We separated hemorrhage into an all-grade hemorrhage, high-grade hemorrhage (Grade 3–5), and fatal hemorrhage (Grade 5).



Statistical analysis

All statistical analyses were performed using Review Manager (RevMan) Version 5.0 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008) or STATA 10SE statistical software (StataCorp, College Station, TX, USA). To calculate incidence, the number of patients with each AE and the number of patients receiving sorafenib were used to derive the proportion of patients with AEs and the corresponding 95% confidence interval (CI) for each study. To calculate relative risk (RR), sorafenib-treated patients were only compared to patients assigned to the control arm in the same clinical trial.

Fixed- and random-effect models were considered in the meta-analyses. For each meta-analysis, the Cochran Q statistic and I2 score were calculated to assess heterogeneity among the proportions of included trials. If the P < 0.1, then the assumption of homogeneity was deemed invalid, and a random-effect model using the DerSimonian and Laird method was reported after exploring the causes of heterogeneity.[30],[31] Otherwise, results from the fixed-effect model were reported using the inverse variance method.[32] Statistical heterogeneity was evaluated by I2 statistics, with values <25%, 25–50%, and >50% indicating low, moderate, and high levels of heterogeneity, respectively. A Chi-squared test for heterogeneity was performed, and P < 0.1 was considered statistically significant.

Hemorrhagic incidence rates observed with sorafenib treatment may be influenced by confounding factors, such as the underlying malignancy or concurrent treatment. Subgroup risk-stratified analysis was performed according to the above-mentioned potential confounding factors. Q statistic analysis was performed to determine statistical relevance between the subgroup results. Publication bias was evaluated using funnel plots and quantified by Begg's and Egger's tests.[33],[34] A two-tailed P < 0.05 was considered statistically significant.


 > Results Top


Search results and study quality

Our search yielded 223 potentially relevant studies for sorafenib-treated cancer patients, of which 152 studies were initially excluded for not meeting the inclusion criteria. After evaluating each remaining study, ten RCTs were selected for meta-analysis, encompassing two Phase II,[24],[35] and eight Phase III studies.[19],[20],[21],[22],[23],[25],[36],[37] The selection process is summarized in [Figure 1]. Randomized treatment allocation sequences were generated for all trials. Seven trials were double-blind and placebo-controlled. Two additional trials were placebo-controlled. The remaining trials were active-controlled. Follow-up time was adequate for each trial.
Figure 1: Selection process for randomized controlled trials included in the meta-analysis

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Jadad scores for each trial are listed in [Table 1]. The mean score was 4.40 ± 1.07. There was only one trial in the low-quality group (Jadad score 1–2), and the overall quality of the remaining trials was high (Jadad score 3–5). Therefore, the quality was acceptable for all trials. RRs for hemorrhage among the high- and low-quality studies were 1.95 (95% CI: 1.52–2.50) and 2.15 (95% CI: 1.33–3.48), respectively, with no significant difference between these subgroups (P = 0.72).
Table 1: Characteristics of randomized controlled clinical trials included in the meta-analysis

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Patient characteristics

A total of 4720 patients from 10 clinical trials were included in the analysis. Underlying malignancies included HCC (four trials),[19],[22],[23],[37] RCC (two trials),[24],[36] nonsmall cell lung cancer (NSCLC; two trials),[20],[25] and melanoma (two trials).[21],[35] The trial characteristics are presented in [Table 1]. Sorafenib dosing was 400 mg twice daily for all trials.

In general, the baseline Eastern Cooperative Oncology Group status of patients was between 0 and 1. According to the inclusion criteria of each trial, patients were required to have adequate hepatic, renal, and hematologic functions. Exclusion criteria reported by the studies included: significant cardiovascular disease, peripheral vascular disease, uncontrolled hypertension, serious nonhealing wounds, major surgery within the previous 28 days, preexisting bleeding diathesis, brain metastasis, regular use of aspirin (>325 mg/d) or nonsteroidal anti-inflammatory drugs, pregnancy or lactation, and the current use of oral or parenteral anticoagulants (patients using prophylactic anticoagulants to maintain patency of vascular device access were an exception).

Incidence of hemorrhagic events

There were 225 all-grade hemorrhagic events reported for 2276 patients who received sorafenib treatment [Table 2]. The highest incidence of 14.23% (95% CI: 11.55–17.42%) was observed in the trials with RCC patients. The lowest incidence of 3.24% (95% CI: 1.46–7.03%) was seen in trials with melanoma patients. Using a random-effect model, the summary incidence of all-grade hemorrhagic events in patients receiving sorafenib was 9.89% (95% CI: 8.73–11.18%), whereas the incidence was 4.73% (95% CI: 3.92–5.69%) in control patients.
Table 2: Incidence and relative risk of all-grade and high-grade hemorrhagic events with sorafenib, according to tumor type, and concurrent treatment

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For the incidence of high-grade hemorrhage, all sorafenib treatment arms were included, representing 65 events reported for 2276 patients. Incidence ranged between 0.97% and 4.57%, with the lowest incidence observed in patients with NSCLC, and the highest incidence in patients with HCC [Table 2]. Using a random-effect model, the summary incidence of high-grade hemorrhage in patients receiving sorafenib was 2.86% (95% CI: 2.25–3.63%), whereas in the controls, the incidence was 1.62% [95% CI: 1.17–2.24%, [Table 2]. The risk of fatality may also be influenced by the anatomic site of hemorrhage. In the ten RCTs, the highest incidence of fatality was observed for pulmonary hemorrhage (62.50%), followed by CNS hemorrhage (37.50%), and abdominal hemorrhage (12.50%).

Relative risk of hemorrhagic events

To assess the contribution of sorafenib treatment to hemorrhage development, we calculated the overall RR of hemorrhagic events from 10 RCTs encompassing 4497 patients. Numbers of events for the sorafenib and control arms were 225/2276 and 105/2221, respectively, giving an overall RR of 1.99 (95% CI: 1.59–2.49; P < 0.00001) for the fixed- and random-effect models [Figure 2]a. These data suggest a significantly increased risk of all-grade hemorrhage in sorafenib-treated patients compared to control patients. No significant heterogeneity was found among the included trials (Q = 5.97; P = 0.74; I2 = 0.0%). However, the RR of high-grade hemorrhage was not significantly increased in sorafenib-treated patients compared to control patients [RR: 1.42; 95% CI: 0.95–2.12; P = 0.09, [Figure 2]b, and no significant heterogeneity was detected in these studies (Q = 5.08; P = 0.83; I2 = 0.0%).
Figure 2: Relative risk of all-grade (a) and high-grade (Grade 3–5) (b) hemorrhage associated with sorafenib-treated versus control patients. The relative risk for each study is displayed numerically and graphically. Total events and sample sizes are also displayed for each study

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In addition, we determined whether sorafenib treatment increased the risk of fatal hemorrhage. Eight fatal hemorrhagic events occurred in sorafenib-treated patients, whereas four fatal events occurred in control patients from three RCTs comprising 955 patients. The summary RR of fatal hemorrhage was 1.90 (95% CI: 0.58–6.29; P = 0.29). These data suggest that sorafenib treatment did not significantly increase the risk of fatal hemorrhage compared to control treatment.

Subgroup analysis

The observed incidence rates of all- and high-grade hemorrhage with sorafenib treatment may be influenced by other confounding factors, such as the type of underlying malignancy or concurrent treatment. Subgroup risk-stratified analysis was performed according to the above-mentioned factors. Patients with different types of malignancies had variable risks of hemorrhage. The incidence ranged between 3.24% and 14.23% for all-grade hemorrhage in patients with various tumor types. The lowest incidence was observed in patients with melanoma and the highest in patients with RCC. However, the RRs of all- and high-grade hemorrhage did not vary by tumor type [P = 0.45, [Figure 3]a and P = 0.66, [Figure 3]b, respectively]. These data suggest that the risk of hemorrhage is not influenced by tumor type in sorafenib-treated patients.
Figure 3: Subgroup risk stratification analysis for tumor type in all-grade (a) and high-grade (Grade 3–5) (b) hemorrhagic events. Relative risks of all- and high-grade hemorrhage did not vary significantly by tumor type. No significant heterogeneity was found among the included trials (P = 0.74, I2 = 0.0% and P = 0.83, I2 = 0.0%, respectively)

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Additional subgroup analyses were performed by stratifying samples according to malignancy (HCC vs. non-HCC; RCC vs. non-RCC; NSCLC vs. non-NSCLC; and melanoma vs. nonmelanoma). The RRs for all-grade hemorrhagic events in sorafenib-treated patients were 1.62 (95% CI: 1.00–2.63; P = 0.05) for HCC and 2.10 (95% CI: 1.64–2.70; P < 0.00001) for non-HCC compared to control patients. However, the increased RR observed in non-HCC patients was not significant compared to HCC patients (P = 0.35). The RRs for high-grade hemorrhagic events were 1.60 (95% CI: 0.87–2.96; P = 0.13) and 1.29 (95% CI: 0.75–2.21; P = 0.36) for sorafenib-treated HCC and non-HCC patients, respectively. The difference in RRs between HCC and non-HCC patients was not statistically significant (P = 0.60).

The RRs for all-grade hemorrhagic events were 1.79 (95% CI: 1.26–2.55; P = 0.001) for RCC patients and 2.13 (95% CI: 1.60–2.84; P < 0.00001) for non-RCC patients. The RRs for all-grade hemorrhagic events were not significantly different between RCC and non-RCC patients treated with sorafenib (P = 0.35). The RRs for high-grade hemorrhagic events were 1.16 (95% CI: 0.59–2.29; P = 0.66) and 1.58 (95% CI: 0.96–2.62; P = 0.07) for RCC and non-RCC patients treated with sorafenib, respectively (P = 0.47 for difference). The RRs for all- and high-grade hemorrhagic events were not significantly different between NSCLC and non-NSCLC patients (P = 0.17 and 0.70, respectively) or between melanoma and non-melanoma patients (P = 0.52 and 0.30, respectively).

To determine whether the concurrent treatment had an influence on the RR of hemorrhage, trials were stratified by nonconcurrent versus concurrent treatment groups. The RRs for all-grade hemorrhagic events for patients without or with concurrent treatment were 1.72 (95% CI: 1.28–2.31; P = 0.0003) and 2.40 (95% CI: 1.72–3.36; P < 0.00001), respectively [P = 0.15 between subgroups, [Supplementary Figure S1]a]. The RRs for high-grade hemorrhagic events were 1.35 (95% CI: 0.85–2.13; P = 0.20) and 1.69 (95% CI: 0.72–3.96; P = 0.22) for patients without or with concurrent treatment, respectively [P = 0.64 between subgroups; [Supplementary Figure S1]b]. In summary, no significant difference in RR for hemorrhagic events was observed between all of the stratified groups investigated.



Publication bias

No evidence of publication bias was detected for the primary endpoint of this study (RR of hemorrhage with sorafenib treatment) by Begg's test (P = 0.283) or Egger's test (P = 0.733). Funnel plots are shown in [Supplementary Figure S2].




 > Discussion Top


Hemorrhage is an indicated complication of VEGFR-TKIs, such as sunitinib and sorafenib, because these drugs disrupt tumor vasculature through inhibition of VEGF signaling.[38],[39] Hence, concerns have arisen regarding the risk of hemorrhage, especially high-grade and fatal hemorrhages, with the use of these VEGFR-TKIs.[40] In one meta-analysis of VEGFR-TKI-related toxicity, hemorrhagic events accounted for 47.5% of the fatal AEs observed.[18] As sorafenib is used widely in routine cancer treatment and clinical trials, usually in combination with many other agents, it is especially important to establish the potential risks to intervene promptly to reduce morbidity and mortality.

The pooled incidence rates of all- and high-grade hemorrhage were 9.89% and 2.86%, respectively. The results of our meta-analysis of ten RCTs indicate that the risk of all-grade hemorrhage was significantly increased in sorafenib-treated patients compared to control patients. However, the risk of high-grade hemorrhage did not significantly increase with treatment. Fatal bleeding events reported in these trials primarily involved pulmonary and CNS hemorrhage, consistent with other analyses of trials enrolling patients treated with sunitinib and bevacizumab.[16],[41] However, in contrast to our observations, the anti-VEGF monoclonal antibody bevacizumab was shown to increase the risks of all- and high-grade bleeding.[42]

Currently, the risk factors for hemorrhagic events associated with sorafenib treatment are poorly understood. Based on the published data, we evaluated the association between sorafenib treatment and hemorrhagic events according to tumor type and concurrent treatment (primarily chemotherapeutic agents). Subgroup analyses showed that the incidence of hemorrhagic events with sorafenib treatment did not vary significantly among patients with different tumor types. However, the highest incidence of all-or high-grade hemorrhage was observed in RCC or HCC, respectively. These findings might be explained by the underlying organ dysfunctions in RCC or HCC patients. Many RCC patients have decreased renal function,[43] which may diminish the clearance of TKIs, leading to the impaired integrity of the capillary wall.[16] Fujihara et al. reported a case series with advanced RCC in which endoscopic hemostasis effectively resolved high-grade, life-threatening gastrointestinal bleeding that occurred during targeted therapy.[44] As most patients with HCC also have liver cirrhosis,[45] they are at an elevated risk for hemorrhage at baseline. Kang et al. reported a unique case of hemobilia occurring in a patient with hepatitis B virus-related HCC on Barcelona Clinic Liver Cancer advanced stage after 7 days of treatment with sorafenib. After the patient stopped sorafenib administration and received a regular irrigation of saline via nasobiliary tube, the bleeding was stopped.[46] Hence, patients with RCC or HCC warrant more careful and continued surveillance when treated with sorafenib therapy.

To improve the survival of patients with numerous types of advanced cancer, concurrent treatment with chemotherapeutic regimens (doxorubicin, gemcitabine, cisplatin, paclitaxel, and carboplatin) and VEGFR-TKIs is performed.[47],[48],[49],[50],[51],[52] Hematologic toxicities, including thrombocytopenia, are generally characterized as side effects of chemotherapy.[53] We investigated whether concurrent chemotherapeutic and VEGFR-TKI treatment might promote the risk of hemorrhage. The risk of hemorrhagic events did not vary significantly among sorafenib-treated patients receiving different classes of chemotherapeutic agents, suggesting that the concurrent use of chemotherapy and VEGFR-TKIs may be safe.

Our study has several limitations that should be considered when interpreting the results. First, because this study was designed as a meta-analysis of published data, we were unable to obtain individual patient data. This limitation prevented us from adjusting the treatment effect according to disease and patient characteristics. Second, the study may have a potential observation time bias as patients in the sorafenib treatment group often had prolonged progression-free survival, resulting in a longer follow-up time compared to controls. Furthermore, hemorrhagic events were not the primary end point in any of the included studies, and hemorrhagic events with sorafenib treatment may not occur uniformly over time. Third, the studies included in this meta-analysis were conducted at various institutions by different investigators with patients of different nationalities/ethnicities, and these differences may have biased the reported incidences. Finally, these studies were conducted at academic centers and large institutions, using patients with adequate major organ function, which might not reflect the patient population in other communities or patients with organ dysfunction.


 > Conclusion Top


Our study shows that sorafenib treatment is associated with an increased risk of hemorrhage, primarily for low-grade events. The RR of high-grade hemorrhagic events was not significantly increased, likely due to the limited sample size. Risk of hemorrhage is not influenced by tumor type or concomitant use of chemotherapeutic agents. These results provide important information for clinicians and patients to recognize the risks associated with sorafenib treatment so that hemorrhagic events may be detected early and resolved.

Financial support and sponsorship

This work was supported by grants from the Jiangxi provincial science and technology plan project (No. 20141BBG70042), the Youth Science Foundation of Jiangxi Provincial Science and Technology Department (No. 20151BAB205105).

Conflicts of interest

There are no conflicts of interest.



 
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