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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 437-443

Low molecular weight heparin in treating patients with lung cancer received chemotherapy: A meta-analysis


1 Department of Respiratory Diseases, Huaibei Miners General Hospital, Anhui Huaibei 235000, China
2 Intensive Care Unit, Suzhou Municipal Hospital, Anhui Suzhou 234000, China
3 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Bengbu 233000, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Li-Nian Huang
287 Changhuai Road, Bengbu 233004, Anhui
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.176174

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 > Abstract 

Objective: To systematically review the efficacy and safety of low molecular weight heparin (LMWH) in treating patients with lung cancer received chemotherapy.
Materials and Methods: Databases including PubMed, The Cochrane Library, Excerpt Medica Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP, and Wanfang Data were searched for the randomized controlled trials (RCTs) about LMWH in treating patients with lung cancer received chemotherapy from the establishment to May 31, 2015. According to the inclusion and exclusion criteria, two reviewers independently screened literature, extracted data, and assessed quality of the included studies. Meta-analysis was then performed by using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) software.
Results: A total of eight RCTs involving 952 patients were finally included. Meta-analysis showed that compared with the control group, LMWH significantly improved the 1- and 2-year overall survival (OS) rates of the patients with lung cancer received chemotherapy (risk ratio [RR] =1.65, 95% confidence interval [95% CI] [1.20–2.26], P = 0.002; RR = 2.63, 95% CI [1.40–4.94], P = 0.003, respectively), and significantly reduced the incidence of venous thromboembolism (VTE) (RR = 0.40, 95% CI [0.23–0.69], P = 0.001), not significantly increased the incidence of major bleeding events and thrombocytopenia (RR = 1.29, 95% CI [0.57–2.96], P = 0.54; RR = 0.86, 95% CI [0.69–1.07], P = 0.18, respectively), and not significantly improved the overall response rate (RR = 1.24, 95% CI [0.98–1.57], P = 0.07).
Conclusion: LMWH improves the 1- and 2-year OS rates of the patients with lung cancer received chemotherapy and reduces the incidence of VTE, not increase the incidence of major bleeding events and thrombocytopenia. These show that there is a certain effect of LMWH, and the security is good.

Keywords: Chemotherapy, low molecular weight heparin, lung cancer, meta-analysis, survival


How to cite this article:
Liu ZL, Wang Q, Wang M, Wang B, Huang LN. Low molecular weight heparin in treating patients with lung cancer received chemotherapy: A meta-analysis. J Can Res Ther 2018;14, Suppl S2:437-43

How to cite this URL:
Liu ZL, Wang Q, Wang M, Wang B, Huang LN. Low molecular weight heparin in treating patients with lung cancer received chemotherapy: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Jul 21];14:437-43. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/437/176174


 > Introduction Top


Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is one of the principal causes of morbidity and mortality in cancer patients. It occurs in 4–20% of cancer patients, and it is one of the major causes of death.[1],[2] Lung cancer is the most frequently diagnosed cancer, accounting for 17% of the total cases and 23% of the total cancer deaths.[3] Studies have confirmed that lung cancer and chemotherapy were independent risk factors for VTE.[4] Several studies have implied that low molecular weight heparin (LMWH) may improve plasma D-dimer levels in patients with advanced lung cancer, prolong survival and improve the quality of life.[5],[6] However, most existing research conclusions are inconsistent, and the sample size is too small. Therefore, an extensive search of relevant studies was performed for a meta-analysis to comprehensively estimate the effect and safety of LMWH in treating patients with lung cancer received chemotherapy. We aimed to guide clinical rational drug use.


 > Materials and Methods Top


Search strategy and selection criteria

We searched the randomized controlled trials (RCTs) about LMWH in treating patients with lung cancer received chemotherapy in the databases including PubMed, The Cochrane Library, Embase, CBM, CNKI, VIP, and Wanfang Data. The search was ended on May 31, 2015, and no lower date limit was employed. The terms lung cancer or small cell lung cancer (SCLC) or non-SCLC and low molecular weight heparin or LMWH or heparin or enoxaparin or dalteparin or bemiparin or nadroparin or anticoagulant were cross searched.

Criteria of literature inclusion were as follows: (1) the trials must be RCTs that compared the addition of LMWH to chemotherapy in lung cancer patients, (2) lung cancer patients were clearly diagnosed by pathology, (3) the study was fully published in English or Chinese language. When the results reported in identified studies have the possible overlap (e.g., same authors, institutions), only the most recent or the most complete study was included in the analysis. The following studies were excluded: (1) nonlung cancer patients; (2) surgery was performed due to lung cancer in the past; (3) gave only symptomatic treatment, performed without chemotherapy; (4) patients diagnosed with DVT; (5) review, nonhuman research, and lacking information.

Data extraction and quality assessment

The process of data extraction was completed independently by two authors according to the prespecified criteria. The database recorded the most relevant data comprising name of the first author, publication year, numbers of patients, age, LMWH schedule, duration of treatment, cancer type, and concomitant therapy. The data relevant to the outcomes (survival, VTE, and safety data) of the study and quality variables were extracted, if necessary, we would contact the authors of included studies.

The same two authors independently assessed the risk of bias in the included trials. We used the Cochrane Collaboration's tool for assessing the risk of bias. We individually assessed the following contents: random method, allocation concealment, blinded, selective outcome reporting, incomplete information bias, and other sources of bias. We separately evaluated each item according to the quality evaluation criteria recommended in the Cochrane Handbook version 5.1.0 (Reviews of Interventions, The Cochrane Collaboration; 2011).[7] If there was disagreement, the two authors would discuss or consult a third party to resolve.

Outcome measures

The primary efficacy outcomes were 1- and 2-year overall survival (OS) rates. Secondary outcomes were the overall response rate to chemotherapy, incidence of VTE, PE, and DVT. The safety outcomes were the incidence of the major bleeding events and thrombocytopenia. Overall response to chemotherapy was defined as complete response plus partial response. Major bleeding was defined as bleeding associated with a decrease in hemoglobin of at least 2 g per deciliter, involved a critical site (e.g., intracranial or retroperitoneal bleeding), contributed to death, or any clinically relevant bleeding that required to stop treatment.

Statistical analysis

Risk ratios (RRs) and 95% confidence intervals (95% CIs) for dichotomous data were estimated using the Mantel–Haenszel method. A RR <1.0 was in favor of LMWH therapy. We assessed heterogeneity among studies by calculating a χ2 test of heterogeneity and the I2 measure of inconsistency. P ≥ 0.10 for the χ2 test and I2 ≤50%, was not considered statistically significant for heterogeneity, then the fixed effects model (Mantel–Haenszel method) was used.[8] Otherwise, the random-effects model (DerSimonian–Laird method) was used.[9] All statistical analyses were performed with Review Manager 5.3 (Cochrane Collaboration, Oxford, UK).


 > Results Top


Studies characteristics

As shown in [Figure 1], according to the search strategies as described, 89 primary studies were identified. We carefully reviewed the abstracts or full texts of these papers. Totally, eight papers (English: Three, Chinese: Five)[10],[11],[12],[13],[14],[15],[16],[17] including 475 LMWH cases and 477 controls met the inclusion criteria and were subjected to final analysis. The basic characteristics of included studies are summarized in [Table 1].
Figure 1: Flow chart of study selection

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Table 1: Basic characteristics of included studies in the meta-analysis

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Quality of trials

Random method was depicted in two studies [11],[12] and was not depicted in the other six studies. Allocation concealment was reported as adequate in four studies [11],[12],[14],[16] and was not reported in the other four studies. The quality assessment of the included studies is described in detail in [Table 2].
Table 2: The quality assessment of the included studies in the meta-analysis

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1- and 2-year overall survival rates

Four trials [10],[12],[15],[17] evaluated the effect of LMWH for the 1-year OS rate of lung cancer, and three trials [10],[12],[15] evaluated the effect of LMWH for the 2-year OS rate of lung cancer. LMWH significantly improved the 1- and 2-year OS rates of the patients with lung cancer received chemotherapy (RR = 1.65, 95% CI [1.20–2.26], P = 0.002; RR = 2.63, 95% CI [1.40–4.94], P = 0.003, respectively) [Figure 2].
Figure 2: Forest plot of risk ratios for (a) the 1-year overall survival rate and (b) the 2-year overall survival rate of two groups

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The overall response rate

Six trials [10],[12],[13],[15],[16],[17] reported on the overall response rate. LMWH had no significant effect on the overall response rate (RR = 1.24, 95% CI [0.98–1.57], P = 0.07) [Figure 3].
Figure 3: Forest plot of risk ratios for the overall response rate of two groups

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Incidence of venous thromboembolism

Five trials [10],[11],[12],[14],[16] reported on the incidence of VTE. LMWH significantly reduced the incidence of VTE (RR = 0.40, 95% CI [0.23–0.69], P = 0.001) [Figure 4]. Furthermore, we further analyzed the incidence of DVT and PE. LMWH significantly reduced the incidence of DVT (RR = 0.45, 95% CI [0.22–0.91], P = 0.03); however, there was no significant difference in the incidence of PE between LMWH group and control group (RR = 0.29, 95% CI [0.08–1.02], P = 0.05).
Figure 4: Forest plot of risk ratios for the incidence of venous thromboembolism of two groups

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Adverse events

Four trials [10],[11],[12],[14] assessed the incidence of major bleeding events of LMWH. There was no significant difference in the major bleeding events between LMWH group and control group (RR = 1.29, 95% CI [0.57–2.96], P = 0.54) [Figure 5]. Moreover, five trials [11],[12],[13],[14],[17] assessed the incidence of thrombocytopenia of LMWH. There was no statistical difference in the incidence of thrombocytopenia between the two groups (RR = 0.86, 95% CI [0.69–1.07], P = 0.18) [Figure 6].
Figure 5: Forest plot of risk ratios for the incidence of major bleeding events of two groups

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Figure 6: Forest plot of risk ratios for the incidence of thrombocytopenia of two groups

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 > Discussion Top


Several types of cancers including lung cancer serious harm to human health in recent years. The study had shown that anticoagulant treatment could improve survival in cancer patients.[18] Kakkar et al.[19] performed a FAMOUS study to evaluate survival in advanced cancer. This study included 385 advanced solid malignancies. This study demonstrated that dalteparin not significantly improve the 1- and 2-year survival rate in patients with advanced malignancy. But dalteparin could improve survival in a subgroup of patients with a better prognosis. The result intimated that dalteparin had a potential modifying effect on tumor biology. A randomized clinical trial was designed to determine whether the addition of LMWH to combination chemotherapy would improve SCLC outcome compared with chemotherapy alone.[10] The experimental group demonstrated a significant survival advantage on the 1- and 2-year progression-free survival (PFS), OS and 1- and 2-year PFS rate, OS rate. Our meta-analysis showed that LMWH could significantly improve the 1- and 2-year OS rates of the patients with lung cancer received chemotherapy.

The existing study suggested that LMWH improved survival of lung cancer patients by anti-tumor effect or preventing VTE-related death.[20] The mechanism of heparin as anticancer treatment is complex, including inhibition of tumor cell proliferation, apoptosis induction, inhibition of angiogenesis and extracellular matrix remodeling or prevention of metastatic spread by interfering with the adhesion of cancer cells to endothelium or proteins in the extracellular matrix, inhibition of heparanase and thrombin.[18],[21],[22],[23] A study was carried out to verify whether LMWH would affect the biological properties of cancer side population (SP) cells.[24] The result showed LMWH combined with cisplatin could overcome cisplatin resistance and induced lung SP cells apoptosis both in vitro and in vivo. This study provides an experimental basis for using a combination of LMWH, which targets lung SP cells, with chemotherapy to improve lung cancer survival.

Abu Arab et al.[25] found enoxaparin displayed a direct dose and exposure duration dependent suppressor effect on A549 cell proliferation and the expression of both c-Myc and CD44 in vitro, suggesting reduced proliferative and metastatic potentials of these cells. Carmazzi et al.[26] reported that nadroparin inhibited cell proliferation by 30% in A549 and CALU1 cell lines; it affected the cell cycle in A549, but not in CALU-1 cells, inducing G (2)/M phase cell-cycle arrest that was dependent on the Cdc25C pathway. This result provided the theoretical basis for heparin treatment improving survival of lung cancer patients.

Sørensen et al.[27] found VTE was associated with an advanced stage of cancer and a poor prognosis. Agnelli et al.[28] performed a randomized, placebo-controlled, double-blind trial to assess the clinical benefit of the nadroparin for the prophylaxis of thromboembolic events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid cancer. One thousand and one hundred and fifty patients with lung, gastrointestinal, breast, and other cancers were included in the analyses of the study. The incidence of thromboembolic events of the nadroparin group and the placebo group were 2.0% (15/769) and 3.9% (15/381), respectively (single-sided P = 0.02). The incidence of a major bleeding event of the nadroparin group and the placebo group were 0.7% and 0%, respectively (P = 0.18). This study showed that nadroparin reduced the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy, and not significantly increased the incidence of the major bleeding event. Ben-Aharon et al.[29] performed a meta-analysis to assess the effect and safety of LMWH as primary prophylaxis in ambulatory patients with solid malignancies. Eleven trials were included in the study, involving 6942 patients. LMWH significantly reduced symptomatic VTE (RR = 0.46, 95% CI 0.32–0.67), any VTE (RR = 0.56, 95% CI 0.38–0.81), symptomatic DVT (RR = 0.35, 95% CI 0.21–0.61), and PE (RR = 0.49, 95% CI 0.29–0.84). A subgroup analysis of VTE showed that LMWH further reduced VTE in patients with lung cancer and pancreatic cancer (RR = 0.42 [95% CI 0.25–0.71]; RR = 0.31 [95% CI 0.18–0.55], respectively). Moreover, LMWH not significantly increased the incidence of clinically relevant bleeding and major bleeding events ([RR = 1.29, 95% CI 0.95–1.77]; [RR = 1.28, 95% CI 0.84–1.95], respectively). Our meta-analysis showed that LMWH significantly reduced the incidence of VTE (including DVT), not significantly increased the incidence of major bleeding events and thrombocytopenia. This result was consistent with most studies. The fatal bleeding events caused by LMWH were rare. This showed that LMWH had a good security. There was not statistically significant difference in the incidence of PE in LMWH group and control group in our meta-analysis. This result differed from Ben-Aharon et al. We analyzed it might be due to too few number of cases included in the study or a low incidence of PE in lung cancer. Our meta-analysis showed that LMWH not significantly improved the overall response rate. This result was consistent with most studies. This result suggested that the main anti-tumor effect of LMWH in vivo might be the prevention of development of distant metastasis rather than direct cytoreduction.

Several limitations should be considered in the meta-analysis. First, most studies included not described the random method, allocation concealment blinded, and selective outcome reporting. Second, PFS and OS that reflected survival in the lung cancer patients failed to incorporate outcomes because of insufficient data of the included studies. Third, most studies included had small sample size, quality varied, it might not have a sufficient statistical power in estimating the effect and safety of LMWH in treating patients with lung cancer received chemotherapy, especially on the survival advantage. In addition, we were not able to perform some important subgroup analyses such as the type and stage of lung cancer because of insufficient data.


 > Conclusion Top


Our meta-analysis shows that LMWH can significantly improve the 1- and 2-year OS rates of the patients with lung cancer received chemotherapy and significantly reduce the incidence of VTE, not significantly increase the incidence of major bleeding events and thrombocytopenia, and not significantly improve the overall response rate. LMWH demonstrates some efficacy and safety in treating patients with lung cancer received chemotherapy. Given the limited literature included in this meta-analysis, it is necessary to perform more large-scale and high-quality RCTs to guide clinical practice.

Acknowledgments

The authors thank Wen-Jia Peng, teacher of the Department of Epidemiology and Biostatistics of Bengbu Medical College to give us help in the topic and data processing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

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