Abstract
Objective
To systematically evaluate the efficacy and safety of sodium cantharidinate and vitamin B6 (SC/B6) combined with conventional medical treatment (CMT) for the treatment of patients with advanced digestive system neoplasms (DSNs).
Methods
The Cochrane Library, Embase, PubMed, Web of Science, Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure, and Wanfang databases were searched for clinical trials using SC/B6 for DSNs. Outcome measures, including therapeutic efficacy, quality of life (QoL), and adverse events, were extracted and systematically evaluated.
Results
Data from 24 trials including 1,825 advanced DSN patients were included. Compared with CMT alone, its combination with SC/B6 significantly improved the patients’ overall response rate (OR =2.25, 95% CI =1.83–2.76, P<0.00001), disease control rate (OR =2.41, 95% CI =1.85–3.15, P<0.00001), and QoL improvement rate (OR =2.75, 95% CI =2.13–3.55, P<0.00001). Moreover, adverse events caused by chemotherapy, including leukopenia, nausea and vomiting, gastrointestinal side effects, hepatotoxicity, diarrhea, transaminase disorder, myelosuppression, anorexia, and anemia, were significantly alleviated (P<0.05) when SC/B6 was applied to DSN patients. Nephrotoxicity, thrombocytopenia, hand-foot syndrome, and oral mucositis were not significantly alleviated in patients receiving combination therapy (P>0.05).
Conclusion
The combination of SC/B6 and CMT is more effective in treating DSNs than CMT alone. This combination alleviates the adverse effects associated with chemotherapy and improves the QoL of DSN patients, and its application in the clinic is worth promoting.
Introduction
Digestive system neoplasms (DSNs) are the leading cause of cancer-related death worldwide, and cause 3,056,412 deaths in 2018, which accounts for 32% of all cancer deaths worldwide.Citation1–Citation3 This category comprises colorectal cancer, gastric cancer, liver cancer, esophageal cancer, and pancreatic cancer, which are the fourth, sixth, seventh, ninth, and fourteenth most common cancers, respectively.Citation1 Despite improvements in diagnostic and therapeutic methods in the past decades,Citation4 the prognosis of DSNs is still poor, because they are mostly diagnosed at advanced stages, which may be accompanied by extensive invasion and distant metastasis.Citation4–Citation6 Therefore, effective therapeutic approaches should be developed.
In recent years, traditional Chinese medicine has been more widely used as auxiliary treatment in tumor therapy and has shown promising therapeutic effects in many clinical studies.Citation7–Citation9 Sodium cantharidinate/vitamin B6 (SC/B6) is a combination of sodium cantharidinate (SC) and vitamin B6, and has the pharmacologic characteristics of both.Citation7,Citation8 SC is a derivative of cantharidin, which is extracted from the body of meloidae insects such as Mylabris phalerata pallas and Mylabris cichorii linnaeus.Citation10 SC preserves the unique anticancer activity of cantharidin and has lower toxicity and fewer adverse effects.Citation7,Citation10 Its combination with vitamin B6 can even further lower the side effects.Citation7 In recent years, SC has been used as a safe auxiliary antitumor drug for malignancies such as gastric cancer, liver cancer, and non-small-cell lung cancer.Citation7–Citation9,Citation11 Tao et alCitation12 indicated that SC induces HepG2 cells to undergo apoptosis through the LC3 autophagy pathway. Liang et alCitation13 showed that SC can inhibit tumor growth by downregulating vascular endothelial growth factor expression and blocking tumor angiogenesis. In addition, SC can also have an anticancer effect by blocking progression through the cell cycle, inhibiting invasion/metastasis, and improving the immunity of cancer patients.Citation14–Citation18
Several clinical studiesCitation8,Citation19–Citation41 have revealed the prominent therapeutic effects of SC/B6 and conventional medical treatment (CMT, including chemotherapy, symptomatic, and supporting therapy) for advanced DSNs but clinical efficacy and safety have not been systematically evaluated. In this study, we performed a meta-analysis to evaluate the efficacy and safety of SC/B6 for DSN treatment, with a comparison between SC/B6 and CMT combined therapy and CMT alone, in order to provide scientific reference for the design of future clinical trials.
Materials and methods
Search strategy and selection criteria
Publications were searched across the Cochrane Library, Embase, Pubmed, Web of Science, Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure, and Wanfang databases, using the search terms “sodium cantharidinate” or “disodium cantharidinate” and “vitamin B6” combined with “gastric cancer” or “colorectal cancer” or “gastrointestinal cancer” or “liver cancer” or “esophageal cancer” or “pancreatic cancer” or “digestive system neoplasms” without restriction on the language. The retrieval was initiated in May 2018 and updated in August 2018.
All of the clinical trials brought into this analysis were randomized controlled trials with reference to advanced DSNs, in which patients in the experimental groups were treated by SC/B6 and CMT combined therapy, and patients in the control groups were treated by CMT alone.
Data extraction and quality assessment
Literature screening and data extraction were carried out by two independent investigators (Meirong Liu and Chunhong Xu) and verified by a third reviewer (Yingying Sun). All included studies were summarized as follows: first author name, year of publication, study location, Karnofsky Performance Score (KPS), number of cases, patient ages, study parameter type, treatment regimen and enrollment period, and administration route and dosage of SC/B6. The quality of the included trials was evaluated as described in the Cochrane Handbook.Citation42
Outcome definition
Clinical responses, including therapeutic effects, quality of life (QoL), and adverse events, were analyzed. Therapeutic effects were evaluated by overall survival (OS) rate, complete response (CR) rate, partial response (PR) rate, stable disease (SD) rate, progressive disease (PD) rate, overall response rate (ORR, ORR = CR + PR), and disease control rate (DCR = CR + PR + SD). OS was defined as the length of time from the start of treatment to death from any cause; QoL was assessed using KPS scales and the European Organization for Research and Treatment of Cancer core quality-of-life questionnaire. The QoL improvement rate (QIR) was defined as the improvement in QoL after treatment. Adverse events, including leukopenia, nausea and vomiting, gastrointestinal side effects, hepatotoxicity, nephrotoxicity, diarrhea, thrombocytopenia, transaminase disorder, myelosuppression, hand-foot syndrome, oral mucositis, anorexia, and anemia, were also assessed.
Statistical analysis
Review Manager 5.3 (Nordic Cochran Centre, Copenhagen, Denmark) and Stata 13.0 (Stata Corp., College Station, TX, USA) were the main statistical analysis tools in this study. P<0.05 indicated statistically significant differences. Cochran’s Q test was used to determine heterogeneity among studies,Citation43 and publication bias was analyzed by Begg’s and Egger’s regression asymmetry tests and presented by funnel plots.Citation44 I2<50% or P>0.1 indicated study homogeneity. Therapeutic effects were mainly represented by HRs and ORs presented with 95% CIs. HRs were collected for survival data. If HRs can neither be collected directly nor calculated, survival curve plots were extracted by Engauge Digitizer software and then transformed by specialized form.Citation45–Citation47
Pooled analysis with publication bias determined that the trim-and-fill method would be applied to coordinate the estimates of unpublished studies, and the adjusted results were compared with the original pooled OR.Citation48 Sensitivity analysis (subgroup analyses) was conducted to evaluate the impact of different cancer types, SC/B6 dosages, therapeutic regimens, sample sizes, and study types on clinical efficacy.
A total of 974 articles were identified with the initial search, and 602 papers were excluded due to duplication. After title and abstract review, 269 articles were further excluded because they did not include clinical trials (n=209), were reviews or meta-analyses (n=6), were unrelated studies (n=43), or were case reports (n=11), leaving 103 studies as potentially relevant. After detailed assessment of full texts, articles without a control group (n=11), studies with inappropriate criteria in the experimental or control group (n=16), studies with insufficient data (n=5), and studies including patients with non-digestive system tumors (n=47) were excluded. Finally, data from 24 trialsCitation8,Citation19–Citation41 (gastric cancer, n=7; colorectal cancer, n=5; gastrointestinal cancer, n=3; liver cancer, n=7; esophageal cancer, n=1; and pancreatic cancer, n=1) including 1,825 advanced DSN patients were included in the present analysis ().
Figure 1 Flow diagram of the selection process.
Patient characteristics
All studies involved in this analysis were carried out in different hospitals in China. These trials include 1,825 patients with advanced DSNs; of these, 933 were treated by combined SC/B6 and CMT, and 892 were treated by CMT alone. Detailed information on the included trials and patients is presented in and .
Table 1 Clinical information from the eligible trials in the meta-analysis
Table 2 Information of SC/B6 combined with conventional medical treatment
Quality assessment
The evaluation of bias risk is presented in . Twenty-two studies had low risk, and the other two articles did not have a clear description of the randomization process. None of the included trials provided a clear description of the performance and detection risks. Two studies were regarded as high-risk due to the absence of follow-up and seven trials were considered as unclear risk owing to selective reporting.
Figure 2 Risk of bias summary: review of authors’ judgments about each risk of bias item for included studies.
Therapeutic efficacy assessments
As shown in and , , and , patients who underwent combined therapy had a significantly improved CR rate (OR =2.06, 95% CI =1.41–3.00, P=0.0002), PR rate (OR =1.85, 95% CI =1.50–2.29, P<0.00001), ORR (OR =2.25, 95% CI =1.83–2.76, P<0.00001), and DCR (OR =2.41, 95% CI =1.85–3.15, P<0.00001), and significantly decreased SD and PD rates (SD, OR =0.77, 95% CI =0.63–0.93, P=0.009; PD, OR =0.45, 95% CI =0.35–0.59, P<0.00001) compared to patients receiving CMT alone. The OS rates of patients who received combination treatment (HR =0.74, 95% CI =0.47–1.17, P=0.20) did not differ significantly from those in patients who received CMT alone.
Table 3 Comparison of CR, PR, SD, PD, ORR, and DCR between the SC/B6 + CMT and SC/B6 group
Figure 3 Forest plot of the comparison of overall survival between the experimental and control groups.
Abbreviations: CMT, conventional medical treatment; IV, intravenous.
Figure 4 Forest plot of the comparison of overall response rate (A) and disease control rate (B) between the experimental and control groups.
Abbreviations: CMT, conventional medical treatment; M–H, Mantel–Haenszel.
QoL assessment
QoL evaluation demonstrated that SC/B6 and CMT combined therapy-treated DSN patients had improved QoL compared to those treated by CMT alone (, OR =2.75, 95% CI =2.13–3.55, P<0.00001).
Figure 5 Forest plot of the comparison of quality-of-life improved rate between the experimental and control groups.
Abbreviations: CMT, conventional medical treatment; M–H, Mantel–Haenszel; SC/B6, sodium cantharidinate and vitamin B6 injection.
Adverse events assessment
As shown in and , patients treated by SC/B6 and CMT combined therapy had lower incidences of leukopenia, nausea and vomiting, gastrointestinal side effects, hepatotoxicity, diarrhea, transaminase disorder, myelosuppression, anorexia, and anemia than those treated with CMT alone (leukopenia: OR =0.29, 95% CI =0.21–0.39, P<0.00001; nausea and vomiting: OR =0.30, 95% CI =0.22–0.40, P<0.00001; gastrointestinal side effects: OR =0.42, 95% CI =0.29–0.62, P<0.00001; hepatotoxicity: OR =0.49, 95% CI =0.30–0.78, P=0.003; diarrhea: OR =0.37, 95% CI =0.23–0.60, P<0.0001; transaminase disorder: OR =0.23, 95% CI =0.09–0.62, P=0.003; myelosuppression: OR =0.33, 95% CI =0.18–0.60, P=0.0003; anorexia: OR =0.37, 95% CI =0.20–0.68, P=0.001; anemia: OR =0.54, 95% CI =0.32–0.91, P=0.02). No significant difference was found in the occurrence of nephrotoxicity, thrombocytopenia, hand-foot syndrome, and oral mucositis (nephrotoxicity: OR =0.70, 95% CI =0.38–1.30, P=0.26; thrombocytopenia: OR =0.77, 95% CI =0.31–1.92, P=0.57; hand-foot syndrome: OR =0.75, 95% CI =0.40–1.40, P=0.36; oral mucositis: OR =0.45, 95% CI =0.13–1.62, P=0.22) between patients receiving combination treatment and those receiving CMT alone.
Table 4 Comparison of adverse events between the SC/B6 + CMT and SC/B6 group
Publication bias
Publication bias of primary outcomes (CR, PR, SD, PD, ORR, DCR, QIR, and adverse events) was evaluated and presented by funnel plots. All plots were approximately symmetrical, indicating generally controlled publication bias ( and ).
Figure 6 Funnel plot of percentage of overall response rate (A), disease control rate (B), quality-of-life improved rate (C), leukopenia (D), nausea and vomiting (E), gastrointestinal side effects (F), and hepatotoxicity (G).
We also assessed the publication bias by Begg’s and Egger’s regression asymmetry tests, and SD and leukopenia were found to have bias (SD, Egger: 0.024, Begg: 0.039; leukopenia, Egger: 0.041, Begg: 0.080; ). To determine whether the bias affected the pooled risk, we conducted trim-and-fill analysis. The adjusted OR indicated the same trend as the primary analysis (SD, before: P=0.010, after: P<0.0001; leukopenia, before: P<0.0001, after: P<0.0001), reflecting the reliability of our primary conclusions, except those based on a small number of trials.
Table 5 Publication bias on therapeutic efficacy and adverse events
Sensitivity analysis
Subgroup analysis was performed for ORR and DCR heterogeneity assessment concerning cancer types, SC/B6 dosages, therapeutic regimens, sample sizes, and study types of involved trials. No significant difference was observed in the sample sizes, study types, or SC/B6 dosages (). SC/B6 combined with CMT was more effective in treating gastric cancer, colorectal cancer, and liver cancer. Moreover, SC/B6 combined with oxaliplatin and capecitabine (XELOX) or capecitabine regimens was more effective for DSN treatment.
Table 6 Subgroup analyses of ORR and DCR between the SC/B6 + CMT and SC/B6 groups
Discussion
The chemotherapeutic regimens commonly used to treat DSNs cause serious side effects, such as myelosuppression, hepatotoxicity, and gastrointestinal side effects, which severely affect the QoL of DSN patients.Citation7,Citation9 Therefore, seeking a therapy that can improve treatment outcomes and decrease the adverse effects of chemotherapy is a major direction in the development of tumor treatment. Traditional Chinese medicine plays a unique role in improving host immunity and lowering the toxic effects of chemotherapy.Citation7,Citation9,Citation49–Citation52 In recent decades, SC/B6 has been clinically applied as an adjuvant therapy for malignancies and has been beneficial for advanced DSN patients in several trials.Citation7–Citation9,Citation11 Despite the published reports on clinical trials using SC/B6, its therapeutic effects have not been systematically demonstrated. In the present study, we performed an extensive literature search followed by rigorous contrasting and combining data analysis for categorization to provide clear and systematic conclusions.
Our meta-analysis revealed that SC/B6 and CMT combined therapy for DSN patients achieved more beneficial effects than CMT alone. Combined therapy-treated patients exhibited markedly improved ORR and DCR (P<0.05 for all) and also significantly improved QoL. These results indicated that intravenous infusion of SC/B6 improved the curative effects of CMT for advanced DSNs.
Our analysis indicates that most of the adverse events caused by chemotherapy, including leukopenia, nausea and vomiting, gastrointestinal side effects, and hepatotoxicity, were alleviated with SC/B6 combination therapy (P<0.05). Therefore, SC/B6 is a safe auxiliary antitumor medicine for DSN and can effectively alleviate the adverse events associated with chemotherapy.
The analysis of therapeutic effects may be influenced by several factors. In our study, no difference was found between sample sizes, study types, and SC/B6 dosages. SC/B6 combined with CMT was more effective in treating gastric cancer, colorectal cancer, and liver cancer than it was in treating esophageal cancer and pancreatic cancer. Moreover, our subgroup analysis showed that SC/B6 combined with XELOX/capecitabine was more effective for DSN treatment. However, recent studies on the impact of these factors on the curative effect of SC/B6 adjuvant therapy remain insufficient, and further investigations should be performed.
There are some limitations in our analysis. First, the follow-up durations of the included studies were not long enough. Second, as a traditional medicine, SC/B6 was mainly applied in China, which may bring an unavoidable regional bias and subsequently influence the clinical application of SC/B6 worldwide. Furthermore, treatment/medical history is very important for evaluating the efficacy of SC/B6-mediated therapy. However, our data were extracted from published papers rather than from the original patient records; therefore, analytical bias may possibly exist. More original data would be valuable to achieve a higher reliability of statistical analysis on SC/B6 for DSN treatment.
In summary, this meta-analysis indicated that SC/B6 and CMT combined therapy was effective in treating advanced DSNs. Intravenous infusion of SC/B6 not only greatly improved the therapeutic effects of CMT but also effectively alleviated the toxicity and most of the side effects associated with chemotherapy. Therefore, SC/B6 has potential for development as a new adjuvant therapy for the treatment of DSN.
Supplementary materials
Figure S1 Forest plot of the comparison of complete response rates (A), partial response rates (B), stable disease rates (C), and progressive disease rates (D) between the experimental and control groups. Control group, CMT alone group; Experimental group, sodium cantharidinate and vitamin B6 injection (SC/B6) + CMT. The fixed-effects meta-analysis model (M–H method) was used.
Figure S2 Forest plot of the comparison of adverse effects including leukopenia (A), nausea and vomiting (B), gastrointestinal side effects (C), hepatotoxicity (D), nephrotoxicity (E), diarrhea (F), thrombocytopenia (G), transaminase disorder (H), myelosuppression (I), hand foot syndrome (J), oral mucositis (K), anorexia (L), and anemia (M) between the experimental and control groups. Control group, CMT-alone group; Experimental group, sodium cantharidinate and vitamin B6 injection (SC/B6) + CMT.
Figure S3 Funnel plot of percentage of complete response rates (A), partial response rates (B), stable disease rates (C), and progressive disease rates (D).
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Author contributions
All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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