Background
Malignant pleural effusion (MPE) poses a significant clinical problem. In oncology patients, there are a number of common medical problems associated with the development of pleural effusion which frequently coexist with the malignancy. Tumor-induced impairment of pleural fluid drainage and pertinent findings point toward another pathway to MPE formation: a vicious loop of interactions between pleural-based tumor cells and the host vasculature and immune system that results in increased net fluid production via enhanced plasma extravasation into the pleural space [
1]. As a result, patients with MPE face a limited survival of a few months, depending on the underlying malignancy. First-line treatment of MPE may include chemotherapy aimed at tumor shrinkage and pleural fluid absorption. However, most causative tumors are or become chemoresistant, and many patients with MPE are not fit for chemotherapy. Therefore, treatment commonly relies on palliative measures aimed at improving quality of life [
1]. Therefore, novel, effective, safe, and convenient treatment modalities for patients with MPE are needed. Nowadays, novel strategy and effective therapies that were needed to improve outcome of these patients remain challenging. Nowadays, to discover and develop novel natural compounds that have therapeutic selectivity or that can preferentially kill lung cancer cells without significant toxicity to normal cells is an important tendency for therapy of MPE. Accumulating research evidence suggests that many medicinal plants may be used alone or in combination with common chemotherapeutic agents to treat MPE. Due to their wide range of biological activities and low toxicity in animal models, these products have been used as alternative treatments for MPE.
Matrine is a naturally occurring small-molecule compound from traditional Chinese medicine
Sophora flavescens Ait. In China, matrine as a clinical drug has been used to treat cancer. The results indicated that matrine induced the apoptosis of murine hepatoma cells in vitro and in vivo as well as inhibited tumor growth [
2] and also inhibited the invasiveness and metastasis of human malignant melanoma cell line A375 [
3]. Some studies reported that matrine induced gastric cancer MKN45 cell apoptosis [
4] and reduced Hela cell adhesion and migration [
5]. Matrine was approved by the China State Food and Drug Administration (SFDA) for the treatment of cancer in 1992. To date, some studies discuss the efficacy and safety of murine in treating MPE by thoracic perfusion. Whether or not matrine has the potential therapeutic and/or adjuvant therapeutic application in the treatment of human MPE is conflicting. This study presents a systematic study to quantify the toxicities and clinical benefits of matrine combined with other medications versus other medications alone in treating advanced MPE.
Methods
Search strategy and data extraction
An electronic search of scientific literature published in the databases of MEDLINE/PubMed, Embase, Cochrane Library, Science Citation Index, and CNKI was performed using free text and Medical Subject Heading terms such as “malignant pleural effusion,” “MPE,” “matrine,” “oxymatrine,” “matrine injection,” “kushenzongjian zhusheye,” “fufang kushen zhusheye,” “chemotherapy,” “sophora flavescens ait,” and “shrubby sophora extract.” The search period was from the start of each database up to May 2015 without language restrictions. Moreover, a manual revision of the bibliographical references of the selected articles was done. The extracted data are summarized as follows: (1) general information, including the title, author, publication date, and literature sources; (2) design and implementation, including the type of design, research and follow-up time, interventions, measurement indicator, the number of lost and processed samples; and (3) outcome indicators, including response rate (RR), disease control rate (DCR), mean survival time (MST), time to progression (TTP), quality of life (QOL), and adverse effects (AEs).
Criteria for inclusion and exclusion
Inclusion criteria were as follows: (1) trials must compare matrine combined with other medications to other medications alone through thoracic perfusion; (2) patients in the studies must be diagnosed and confirmed by cytology and pathology; (3) age and gender must not be restricted; (4) must report on at least one of the outcome measures mentioned in the succeeding portion of this study; and (5) the total number of cases must be greater than or equal to 80. The following studies were excluded: (1) those with no clearly reported outcomes of interest; (2) studying on animals not on human; and (3) studies lacking control groups.
Type of trial design, interventions, and indicators to determine efficacy
Trial design: randomized controlled trials of matrine combined with other medications versus other medications alone in treating MPE by thoracic perfusion. Type of interventions: matrine + other medications vs. other medications alone; efficacy indicators: ORR, DCR, MST, TTP, QOL, and AEs (according to the toxicity criteria of WHO).
Methodological quality assessment
The methodological quality for RCTs was assessed using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions (version 5.0.1). The quality of trials was categorized into low risk of bias, unclear risk of bias, or high risk of bias. This categorization was according to the risk for each important outcome within included trials, including adequacy of the generation of allocation sequence, allocation concealment, blinding, and the presence of incomplete outcome data, selective outcome, or other sources of bias. The intention-to-treat (ITT) analysis was also assessed for the randomized controlled trials included into the present meta-analysis [
6,
7].
Statistical analysis
To assess the efficacy and safety of matrine combined with other medications versus other medications alone for treating MPE, fixed effects model was performed. Dichotomous variables were analyzed using estimation of odds ratios (OR) with a 95 % confidence interval (95 % CI). The overall effect was tested using Z-scores, with significance being set at p < 0.05. Pooled effect was calculated using either the fixed effects model or random effects model. Heterogeneity was evaluated through chi-square and I
2. Meta regression was done to evaluate whether results were different between two groups. Sensitivity was analyzed by omitting each study from the estimated pool conducted at each step. Finally, publication bias was evaluated using funnel plots, the Egger’s test, and the Begg’s test. Statistical analyses were performed using SPSS (SPSS Institute, version 19.0, Chicago, USA), RevMan 5.2 (The Cochrane Collaboration), and Stata version 13.0 (Stata Corporation, TX, USA). All p values were two-sided, and p < 0.05 was considered to indicate statistical significance.
Discussion
MPE is a common clinical problem faced by many physicians, oncologists, and thoracic surgeons. Patients with MPE can be debilitated with dyspnea, decreased exercise tolerance, and impaired QOL. Median survival following the diagnosis of MPE ranges from 3 to 12 months, with lung cancer as the primary cancer demonstrating the shortest survival. The management options for MPE depend on several factors, including patient’s symptoms, performance status, underlying primary type, and the potential response to anti-neoplastic therapy. The overall aim is for the alleviation of symptoms and improved QOL. Matrine, a kind of alkaloid components found in the roots of
Sophora species, is demonstrated to have anti-inflammatory, anti-virus, anti-fibrotic, and cardiovascular protective effects. They are recently proved to have anti-cancer potentials, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- or radiotherapy-induced toxicity when combined with other chemotherapeutic drugs [
20].
Sophora root, which is a traditional herb medicine found in China, Japan, and some European countries, is the dried root of
Sophora flavescens Aiton (Leguminosae) and includes matrine and oxymatrine, two major tetracyclo-quinolizindine alkaloids, as its primary components [
20].
In recent years, some studies have reported on the efficacy and safety of matrine in the treatment of MPE. In this work, 12 reports of randomized trials were identified by searching from the start of each database up to January 2015. A significant benefit of matrine plus other medications in ORR was found (OR = 1.38, 95 % CI 1.17 to 1.64), translating into a 21 % absolute improvement. As follows, cisplatin + matrine versus cisplatin alone, biological agents (including IL-11, IL-2, а-IFN, and
Corynebacterium parvum) + matrine versus biological agents alone, and other chemotherapeutic agents (including MMC, BLM, and HCPT) + matrine versus chemotherapeutic agents alone showed improvements of 16.1, 11.7, 24, and 20 % in ORR, respectively, which indicates that matrine combination therapy do better benefits in treating MPE via thoracic perfusion. Three reports analyzed that the time to pleural effusion relief of matrine combined with other medications (14.33 ± 1.20 months) in treating MPE was significantly longer than that of other medications alone (8.33 ± 0.88 months). Chest pain, commonly seen in pleural metastasis of malignant tumors, is typically localized to the side of the effusion and is described as dull and aching rather than non-malignant pleuritis. In present study, four trials indicated that the chest pain was significantly decreased by treating of matrine combined with other medications than that of other medications alone (
p < 0.05). The relief of chest pain is an improvement of quality of life, and it is also an important aspect of treatment of patients. Matrine treatment has been shown to inhibit the proliferation of tumor cells in various cancers, including gastric cancer, breast cancer, hepatoma, colon cancer, melanoma, glioma, osteosarcoma, pancreatic cancer, and leukemia in a dose-dependent manner [
20]. Resistance to apoptosis is a hallmark of cancer. Studies have reported that matrine exert anti-cancer effects by inducing apoptosis in different types of cancers. In non-small cell lung carcinoma (NSCLC), MT increases the phosphorylation of p38 and generates reactive oxygen species (ROS) in a dose- and time-dependent manner, which indicated that MT could activate p38 pathway and lead to a caspase-dependent apoptosis by inducing the generation of ROS [
21].
Because QOL can be measured by various means, it is also quite easy to use it to measure and predict many variables during treatment. The benefit of chemotherapy in incurable cancers needs to be assessed directly through validated health-related QOL instruments rather than inferred from RRs, survival benefits, and other traditional endpoints. In the present study, 12 trials were enrolled in the assessment of QOL. A significant benefit of matrine plus other medications in the overall improvement rate of QOL (OR = 1.40, 95 % CI 1.18 to 1.66) was found, translating into a 24 % absolute improvement. Thus, the results showed that matrine can be used to relieve general side effects and improve patients’ QOL via pleural perfusion to cure MPE. The AEs found in the present analysis were mainly hematological reactions, diarrhea, toxicity of the liver and kidney, and nausea/vomiting, most of which were grade 1 or 2 and were well tolerated. The matrine combination arms had a lower incidence of myelotoxicity and dysfunction of the liver and kidney relative to the arms without matrine. And the incidence of nausea/vomiting of matrine combination arms was also significantly lower than that of other medications alone. The results supported that the matrine combination arms had a lower incidence of AEs compared with other medications alone, which indicates that matrine does has a impact on improving safety of chemotherapy and relieving general side effects. Overall, these results indicate that the potential benefit of matrine may be widely applicable to a patient population closely resembling clinical reality in advanced MPE.
In this review, the included studies were carefully assessed. A good clinical homogeneity was confirmed, and publication bias was not found according to the funnel plot analysis, the Egger’s test, and the Begg’s test. However, some deficiencies in the present work were found. First, the quality of subgroup analysis (age, sex, smoking, histology, and treatment status) according to the different agents (matrine plus other medications compared with other medications alone) was low because the subgroup data were only provided by a few trials. Second, some reports failed to report the method for concealment of allocation, blinding, and ITT. In addition, the partial reports comprise a small sample size, and some of the reports’ experimental control is not very balanced. Most of the included studies were published in Chinese, with heterogeneous data and analysis methods (e.g., the different scored scales were used to assess the life quality). Although such studies were reported to be of low quality, they still contain credible evidence pointing toward such new drugs. Clinical trials are expensive and difficult. Hence, these findings can help choose the most promising agents for study. However, matrine, as a new strategy, has still many issues to be resolved in further studies. Confirmation of these conclusions in rigorously controlled randomized trials is required before firm conclusions about this therapy can be drawn.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
RBX and GWL participated in the design and coordination of the study, carried out the critical appraisal of studies and statistical analysis of studies, and wrote the manuscript. MSX and YSY developed the literature search, carried out the extraction of data, assisted in the critical appraisal of included studies, and assisted in writing up. All authors read and approved the final manuscript.