|Year : 2016 | Volume
| Issue : 4 | Page : 1298-1306
Efficacy of compound Kushen injection plus radiotherapy on nonsmall-cell lungcancer: A systematic review and meta-analysis
Shanshan Wang1, Xiaobo Lian1, Miaomiao Sun1, Lei Luo1, Lizhong Guo2
1 Department of Internal Medicine of Traditional Chinese Medicine, First Clinical Medical College, Nanjing University of Traditional Chinese Medicine, Nanjing 210000, China
2 Famous Doctor's Studio of Zhongying Zhou, First Clinical Medical College, Nanjing University of Traditional Chinese Medicine, Nanjing 210000, China
|Date of Web Publication||7-Feb-2017|
Famous Doctor's Studio of Zhongying Zhou, Nanjing University of Chinese Medicine, Nanjing 210000
Source of Support: None, Conflict of Interest: None
Objective: To evaluate the benefits of compound Kushen injection (CKI) combined with radiotherapy for nonsmall cell lung cancer.
Materials and Methods: We searched nine electronic databases and six gray literature databases comprehensively until June 2015. Two reviewers independently selected and assessed the included trials according to the inclusion and exclusion criteria. The risk of bias tool from the Cochrane Handbook version 5.1.0, the Review Manager 5.3 software was employed for data analysis. Funnel plot and Egger's test were applied to evaluate the publication bias.
Results: Thirteen studies including 1558 participants met the inclusion criteria, most of which were low quality. Compared with radiotherapy alone, CKI plus the same radiotherapy significantly improved the effective rate (odds ratio [OR] =1.92, 95% confidence interval [95% CI]: [1.42, 2.60] P < 0.0001) and quality of life (OR = 4.61, 95% CI: [3.28, 6.48], P < 0.00001). There was a significant decrement in the incidences of acute radiation pneumonia (OR = 0.48, 95% CI: [0.37, 0.61], P < 0.00001), radiation pneumonia 3 months after radiotherapy (OR = 0.29, 95% CI: [0.20, 0.41], P < 0.00001), radiation pneumonia 6 months after radiotherapy (OR = 0.24, 95% CI: [0.08, 0.69], P < 0.009), radiation esophagitis (OR = 0.29, 95% CI: [0.19, 0.45], P < 0.00001), and bone marrow suppression (OR = 0.35, 95% CI: [0.24, 0.51], P < 0.00001).
Conclusion: CKI combined with radiotherapy significantly improved the clinical effect and reduced the incidence of adverse events. Use of the CONSORT statement for randomized controlled trials is recommended for rigorous reporting.
Keywords: Compound Kushen injection, meta-analysis, nonsmall cell lung cancer, radiotherapy
|How to cite this article:|
Wang S, Lian X, Sun M, Luo L, Guo L. Efficacy of compound Kushen injection plus radiotherapy on nonsmall-cell lungcancer: A systematic review and meta-analysis. J Can Res Ther 2016;12:1298-306
|How to cite this URL:|
Wang S, Lian X, Sun M, Luo L, Guo L. Efficacy of compound Kushen injection plus radiotherapy on nonsmall-cell lungcancer: A systematic review and meta-analysis. J Can Res Ther [serial online] 2016 [cited 2020 Oct 29];12:1298-306. Available from: https://www.cancerjournal.net/text.asp?2016/12/4/1298/199538
| > Introduction|| |
Lung cancer is one of the most common carcinomas worldwide as well as the first leading cause of cancer-related death globally. It was estimated that 86,380 men and 71,660 women were killed in the USA in 2015, corresponding to 27.7% and 25.8% of all cancer deaths in males and females, respectively. In China, the registered lung cancer mortality increased by 464.84% during the past three decades, and the crude mortality rates in 2008 were 47.51 per 100,000 men and 22.69 per 100,000 women. Nonsmall cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers and of these, adenocarcinoma and squamous cell carcinoma account for 50% and 30%, respectively., Most of the patients have been found to be present with locally advanced inoperable or metastatic disease, making it difficult to cure the disease. Despite great progress in the staging, diagnosis, and therapeutic methods, the prospect has not greatly changed for 5-year survival rate and has only slightly increased from 15.7% to 17.4% over the last decade.
Radiation is a main therapeutic tool for the treatment of advanced or metastasis malignant tumors. It has been widely used for NSCLC., About 70–80% of NSCLC had an advanced stage when diagnosis. For these advance or metastasis stages of NSCLC, radiotherapy is an important and major treatment method. However, radiotherapy for NSCLC still has shortages of low efficacy and high toxicity. The most common side effects are radiation pneumonia, radiation esophagitis, and marrow suppression. Some patients even cannot finish the whole treatment procedure due to serious adverse reactions.
Hence, the most important thing was improving the radiation efficacy and decreasing the radiation-related toxicities for the radiotherapy of NSCLC. In complementary and alternative medicines, Chinese herbal medicine has become increasingly popular for cancers patients undergoing radiotherapy or chemotherapy. Compound Kushen injection (CKI) has been approved to treat patients with cancer by the Chinese State Food and Drug Administration in 1992. It was also known as Yanshu injection. CKI is a mixture of natural compounds extracted from two medical herbs: Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae). Kushen has a long history of use for the treatment of solid tumors, inflammation, and other diseases. The primary compounds found in CKI are matrine, oxymatrine, and sophoridine., The anti-tumor mechanisms of CKI may include (1) Increased protein expression of p16; (2) reduced unmethylated state of the p16 gene; (3) inhibited vascular endothelial growth factor and microvessel density (MVD) expression in neoplastic tissues; and (4) decreased MVD.,, Shao reported that CKI combined with radiotherapy could significantly reduce adverse effects and improve the quality of life, the symptoms, and the efficacy in elderly esophageal cancer patients.
Several clinical studies reporting CKI plus radiotherapy for treating NSCLC patients ranged from case reports, case series, and controlled trials to randomized controlled trials (RCTs). However, there was no systematic review, especially assessing its effectiveness and safety in the treatment of NSCLC. In this paper, a comprehensive systematic review is conducted on the efficacy and toxicities of CKI for current or future research and clinical application.
| > Materials and Methods|| |
Data sources and search strategies
Two investigators (Shanshan Wang and Lin Zhu) searched the articles independently from the following electronic databases of PubMed, Embase, the Cochrane Central Register of Controlled Trials in the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Database (Wanfang), and Chinese Biomedical Literature Database. All articles were searched from their individual inceptions to June 2015 and no language restrictions were applied.
The following terms were retrieved in databases as keywords or free-text terms: (Lung cancer or NSCLC) and (Kushen or Kushen injection or Yanshu or Yanshu injection) and (radiation or radiotherapy). Manual searching for bibliographies of all retrieved trials, relevant peer-reviewed journals, conference proceedings, and unpublished studies was conducted.
Studies must meet all the following criteria: (1) Participants: NSCLC patients had to be diagnosed by pathological sections and were treated by radiotherapy. (2) Type of studies: only clinical RCTs were eligible. (3) Type of intervention: studies provided the treatment group with CKI in combination with radiotherapy and the control group with radiotherapy alone was included for analysis. (4) Type of outcome measurements: tumor response and performance status, reduction in the toxicity of radiotherapy, such as acute radiation pneumonitis, radiation pneumonitis 3 months and 6 months after radiotherapy, radiation esophagitis, and bone marrow suppression.
Duplicate studies resulting from various databases were removed by two reviewers (Shanshan Wang and Lin Zhu). Furthermore, they screened the titles and abstracts of all remaining citations independently to exclude articles that obviously did not satisfy the inclusion criteria and then scrutinized the full text of any article that was deemed to be potentially eligible. Finally, the selection results were discussed together by a third reviewer (Miaomiao Sun). Any disagreement about study eligibilities after the discussion was resolved by consulting the fourth reviewer (Lizhong Guo).
Data concerning authors, title of study, year of publication, study size, age and sex of the participants, details of methodological information, treatment process, details of the interventions, outcomes, and adverse effects for each study were extracted by two reviewers (independently Shanshan Wang and Lin Zhu) and checked by a third reviewer (Miaomiao Sun).
Two reviewers (Shanshan Wang and Lin Zhu) assessed the methodological quality of RCTs separately using the criteria in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Cochrane Collaboration-Cochrane Tool of Risk of Bias). Information on methodological quality was sought for the following seven domains: randomization sequence generation; allocation concealment; blinding of participants, experimenters, and personnel; blinding of outcome assessment; a statement on how dropouts and patients lost to follow-up were handled and use of an intention-to-treat analysis; selective reporting bias; and other source of potential bias resulting from the interest-related issues. The risk of bias for each domain was summarized into three categories: a “yes” for low consideration of bias, a “no” for high risk of bias, and an “unclear” for insufficiently required information. Disagreements between review authors were resolved by discussion or with the third author (Lizhong Guo).
Tumor response was calculated as the number of patients with complete response (CR) plus partial response (PR) based on the WHO scale  divided by the total number of patients in each treatment group. The performance status of patients was investigated based on the Karnofsky performance score (KPS), and the improved performance status was calculated as the number of patients with improved performance status (>10-point increase) divided by the total. Radiotherapy toxicity was investigated based on the WHO scale; the reduction of radiotherapy toxicity was calculated as the number of patients with any toxicity (WHO grades 1, 2, 3, and 4) divided by the total number of patients in each treatment group (WHO grades 0, 1, 2, 3, and 4).
Review Manager 5.3 (http://www.cochrane.org; The Cochrane Collaboration, London, England) software developed by the Cochrane Collaboration Group was employed for statistical analyses. A fixed-effects model was used if no statistical heterogeneity (P < 0.05) was detected. Data from individual studies were pooled using a random effects model in cases of statistical heterogeneity. Subgroup analysis was conducted, if necessary. Dichotomous data were presented as relative risks, and continuous data as weighted mean differences or standardized mean differences with corresponding 95% confidence intervals (95% CIs). Heterogeneity was assessed graphically using forest plots and statistically using the Chi-square test.
| > Results|| |
Literature search results
After the initial search, 108 potentially relevant publications were identified. All records were imported into EndNote X7 (http://thomsonreuters.com; Thomson Corporation, Stamford, USA) and 66 trials were excluded because of duplication. Among the remaining 42 trials, 29 were excluded because they were animal studies (n = 4), non-RCTs (n = 3), 12 articles in which the drug used in the experimental or control group did not meet the inclusion criteria, eight articles in which the study purpose and object did not meet inclusion criteria, and two duplicates. Finally, 13 studies were evaluated in our analysis [Figure 1].
|Figure 1: Flow diagram showing the trial selection process for the systematic review and meta-analysis. CBM = Chinese Biomedical Literature Database, CNKI = Chinese National Knowledge Infrastructure, RCT = Randomized controlled trials|
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Characteristics of the eligible studies
The characteristics of the eligible studies were shown in [Table 1]. About 783 and 775 subjects in the experiment and control groups, respectively, were involved in the 13 studies. The stages of NSCLC TNM of the patients recruited in the current studies were as follows: one study  was at I to IV, one study  was at I to IIIB, two studies , were at II to III, one study  was at II to IV, two studies , were at III, and three studies ,, were at III to IV. The other three studies ,, did not mention the stage condition. Seven studies ,,,,,, employed the conventional radiotherapy; three studies ,, adopted three-dimensional conformal radiotherapy; two studies , used conventional radiotherapy combined with three-dimensional conformal radiotherapy; and stereotactic radiation therapy was applied in one study. The dose of radiation therapy varied from 40 to 70 Gy in the included studies. All the patients received CKI 5–30 ml, qd. The durations of the treatments varied from 4 to 8 weeks in the included studies [Table 1].
Risk of bias in the included studies
The risk of bias of each study was assessed by the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. Of all the involved studies, three studies ,, used random number table and two studies , used drawing lots randomization. The remaining eight trials just mentioned randomization, but did not describe the method; no trials mentioned the blinding procedures and details on how allocation being concealed. One of the 13 studies  was judged to meet the criterion of incomplete outcome data. No preceding protocols for the eligible trials were included. Therefore, it was difficult to determine whether there was selective result reporting. We were unable to determine whether the 13 RCTs had other potential sources of bias [Table 2].
Ten studies ,,,,,,,,, including 988 patients reported the tumor response [Figure 2]. The fixed-effects model was used to analyze the data because there was no heterogeneity across the trials (P = 0.89, I2 = 0%). The analytical results demonstrated that the combination treatment of CKI combined with radiation therapy was associated with a significant increase in the number of patients reported CR and PR when compared with the radiotherapy alone group (odds ratio [OR] =1.92, 95% CI: [1.42, 2.60], P < 0.0001).
|Figure 2: Tumor response with compound Kushen injection and radiotherapy versus radiotherapy alone|
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Quality of life
KPS was used to evaluate the quality of life in six studies.,,,,,, There was no heterogeneity across the trials (P = 0.87, I2 = 0%), so the fixed-effects model was used to pool the data. The injection combined with radiation therapy significantly improved the quality of life for patients when compared with the radiotherapy alone group (OR = 4.61, 95% CI: [3.28, 6.48], P < 0.00001) [Figure 3].
|Figure 3: Improved Karnofsky performance status with compound Kushen injection and radiotherapy versus radiotherapy alone|
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The radiation pneumonia, radiation esophagitis, and bone marrow suppression are the common side effects that radiation therapy resulted in. There were 10 studies ,,,,,,,,, including 1360 patients reporting the acute radiation pneumonia [Figure 4]. The statistical analysis with fixed-effects model revealed that CKI plus radiation therapy had a significant decrease in radiation pneumonia when compared with the radiotherapy alone group (OR = 0.48, 95% CI: [0.37, 0.61], P < 0.00001). We used subgroup meta-analysis to evaluate the improvement for radiation pneumonia 3 months and 6 months after radiotherapy [Figure 5]. The statistical analysis with fixed-effects model revealed that CKI plus radiation therapy had a significant decrement in radiation pneumonia 3 months after radiotherapy (OR = 0.29, 95% CI: [0.20, 0.41], P < 0.00001) and 6 months after radiotherapy (OR = 0.24, 95% CI: [0.08, 0.69], P < 0.009) when compared with the radiotherapy alone group; we identified five studies ,,,, including 467 patients with radiation esophagitis [Figure 4]. The statistical analysis with fixed-effects model revealed that CKI plus radiation therapy had a significant decrement in radiation esophagitis when compared with the radiotherapy alone group (OR = 0.29, 95% CI: [0.19, 0.45], P < 0.00001. Nine studies ,,,,,,,, including 937 patients reported the bone marrow suppression. The results demonstrated that CKI plus radiation therapy had a significant reduction in bone marrow suppression when compared with the radiotherapy alone group (OR = 0.35, 95% CI: [0.24, 0.51], P < 0.00001). The funnel plot revealed an asymmetrical distribution of studies around the line of identity, indicating the possibility of publication bias [Figure 6].
|Figure 4: Radiation pneumonia radiation esophagitis and marrow suppression with compound Kushen injection and radiotherapy versus radiotherapy alone|
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|Figure 5: Radiation pneumonia 3 months and 6 months after radiotherapy with compound Kushen injection and radiotherapy versus radiotherapy alone|
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| > Discussion|| |
In our meta-analysis, there were 13 studies with 1558 characters. The main findings of the present study demonstrate that CKI plus radiation therapy in the treatment of NSCLC may increase tumor response and quality of life and reduce radiation-related toxicities when compared with the radiotherapy alone. However, due to the poor methodological quality of the included studies, we are unable to make definite conclusions.
CKI could reduce the adverse events caused by radiotherapy. As we all know, radiation pneumonia, radiation esophagitis, and bone marrow suppression are the most common side effects in the treatment of radiation therapy. CKI plus radiotherapy achieved a statistically significant reduction in the incidences of acute radiation pneumonia and radiation pneumonia 3 months and 6 months after radiotherapy. Furthermore, CKI plus radiation therapy had a significant decrement in the incidences of radiation esophagitis and bone marrow suppression. That was in conformity with the superiority of traditional Chinese medicine (TCM) in toxicity reduction and efficacy enhancement.
All included RCTs were randomized, but 8/13 studies (61.5%) failed to describe the randomization methods. Three studies ,, used a table of random numbers and two studies , used drew lots to generate randomized sequences, which are both considered to have a low risk of bias. Other studies used a statement such as “we randomly allocated” or “use a randomized design” which is considered to have a high risk of bias. Blinded assessors were not mentioned in any study. None of the studies reported a central randomization procedure to ensure the concealment of treatment allocation. This result could lead to implementation and measurement bias. Moreover, the outcome measures of this study may be subjective, such as quality of life. Lack of long-term follow-up outcome such as survival rates makes it difficult to determine the long-term efficacy of CKI plus radiotherapy. One of the 13 studies  was judged to meet the criterion of incomplete outcome data. There were no patients lost to follow-up or dropping out in other studies in current meta-analysis. Furthermore, all studies included in this meta-analysis used an “A + B versus B” design to compare CKI plus radiotherapy group with radiotherapy alone group, without a rigorous control for the placebo group. This kind of design may lead to false-positive results. Besides, although the radiation technology was the same between the groups of CKI plus radiotherapy and the radiotherapy alone in every included study, some employed the conventional radiotherapy, some used three-dimensional conformal radiotherapy, and one adopted stereotactic radiation therapy. The dose of CKI ranged from 5 to 30 ml. The duration was 4–8 weeks. Hence, performance bias might arise. In addition, the funnel graph indicated a high risk of publication bias, which means that negative results are less likely to be published.
Although we did not restrict the publishing language, all studies in our meta-analysis were published in Chinese and conducted in China. This limitation would lead to a location bias. In addition, no multicenter trials were included. More large-scale randomized double-blind control and multicenter trials are needed to overcome methodological and reporting flaws.
CKI may have beneficial effects in the improvement of tumor response and quality of life and reduction of side effects. However, current evidence is insufficient to support the efficacy of CKI because the included studies were of generally poor quality and had small sample sizes. Future research should focus on methodologically strong RCTs to determine the potential efficacy of CKI. The CONSORT statement  should be employed as a criterion when conducting and reporting RCTs for TCM in the future.
| > Conclusion|| |
We found evidence that CKI may improve the tumor response and quality of life and reduce the toxicity of radiotherapy when combined with radiotherapy. However, we need further rigorously controlled trials to confirm the exact advantages.
The current work was partially supported by the National Science and Technology Pillar Program during the 12th 5-year plan period (2013BAI02B08).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]