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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 735-743

Injectable Chinese herbal formula Kang'ai for nonsmall cell lung cancer: Trial sequential analysis of 2,259 participants from 31 randomized controlled trials


Department of Integration of Traditional Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China

Date of Web Publication25-Jul-2016

Correspondence Address:
Ping-Ping Li
Department of Integration of Traditional Chinese and Western Medicine, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Peking University Cancer Hospital and Institute, Beijing 100142
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.150411

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 > Abstract 


Objective: The aim was to evaluate the efficacy and safety of Kang' ai (KA) injection for patients with nonsmall cell lung cancer (NSCLC). Furthermore, to identify if more trials are needed before reliable conclusions could be drawn with regard to these outcomes.
Materials and Methods: We searched the Cochrane library, PubMed, EMBASE, VIP, CBMdisc, and CNKI in September 2012, and then an additional updated search was conducted in January 2013. Only relevant randomized controlled trials (RCTs) on KA injection plus first-line cisplatin-based chemotherapy in the treatment of NSCLC were identified. Trials' data was reviewed and extracted by two reviewers independently. The quality of included studies was assessed according to a statement from Cochrane Handbook. RevMan 5 Software and Trial sequential analysis (TSA) software were applied for data analyses.
Results: A total of 31 RCTs involving 2259 patients were included. The results of meta-analysis showed that compared with chemotherapy alone, the combination of KA injection plus chemotherapy had a statistically significant benefit in improving clinical response rate (relative risk [RR] =1.29, 95% confidence interval [CI]: 1.17-1.41, P < 0.00001), clinical benefit rate (RR = 1.19, 95% CI: 1.14-1.25, P < 0.00001) and quality of life (RR = 1.79, 95% CI: 1.63-1.98, P < 0.00001); hematological toxicity (white blood cell) (RR = 0.71, 95% CI: 0.66-0.76, P < 0.00001) and nonhematological toxicity (nausea and vomiting) (RR = 0.73, 95% CI: 0.65-0.83, P < 0.00001) were improved as well. TSA showed that all cumulative Z-score crossed their monitoring boundaries, demonstrating that no more trials are needed before reliable conclusions could be drawn.
Conclusion: Current evidence presented that KA injection might improve the therapeutic effect when combined with chemotherapy. Moreover, no more trials are needed in future according to TSA. Nevertheless, additional randomized studies investigating KA injection are needed to be further evaluated.

Keywords: First-line chemotherapy, Kang' ai injection, meta-analysis, nonsmall cell lung cancer, traditional Chinese medicine, trial sequential analysis


How to cite this article:
He XR, Han SY, Li PP. Injectable Chinese herbal formula Kang'ai for nonsmall cell lung cancer: Trial sequential analysis of 2,259 participants from 31 randomized controlled trials. J Can Res Ther 2016;12:735-43

How to cite this URL:
He XR, Han SY, Li PP. Injectable Chinese herbal formula Kang'ai for nonsmall cell lung cancer: Trial sequential analysis of 2,259 participants from 31 randomized controlled trials. J Can Res Ther [serial online] 2016 [cited 2019 Dec 15];12:735-43. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/735/150411




 > Introduction Top


Lung cancer is one of the most common malignancies, which is regarded as the leading cancer-related death around the world.[1] According to WHO, the morbidity and mortality of lung cancer rank the first place. In 2013, lung cancer is expected to account for 26-28% of all cancer death.[2] Furthermore, >20% of death resulted from lung cancer occurs in China.[3] The number of newly diagnosed patients will be > 100 million in the year of 2025, and nonsmall cell lung cancer (NSCLC) will account for 80-85%.[4] One-third of these patients have been locally advanced with no chance of the operation when they are first diagnosed, and 5-year survival is < 10%.[5],[6] Thus, promoting therapeutic effects for lung cancer and reducing adverse drug reactions (ADRs) resulted from conventional treatments still remain a major health issue around the world.

During last decades, chemotherapy has been accepted worldwide, which is regarded as one of the most sufficient treatments for patients with advanced lung cancer. Furthermore, first-line chemotherapy (cisplatin based) has been fully developed, as well as the application of numerous new drugs including vinorelbine, gemcitabine, and paclitaxel.[7] However, for many patients who underwent several cycles of chemotherapy, the accompanying cytotoxicity could lead to poor health conditions such as nausea and vomiting and severely damaged immune function. To reduce these associated ADRs and to promote corresponding therapeutic efficacy, complementary and alternative medicine are often attempted.[8],[9],[10] It is reported that the majority of chemotherapy-related ADRs might be observably ameliorated when traditional Chinese medicine (TCM) applied as adjuvant drugs, and curative effects are also markedly improved.[11],[12],[13],[14]

Kang' ai (KA) injection, a typical anti-tumor injection of TCM formula, mainly consists of ginseng, astragali radix and matrine. The studies of modern pharmacology also have confirmed that saponins and polysaccharides (contained in ginseng) have benefits in improving immune function [15],[16] and raising white blood cell (WBC) count.[17],[18],[19]Astragali radix has obvious inhibitory effect on tumor cell cloning.[20]Matrine and oxymatfine, two kinds of alkaloid from Radix Sophorae Flavescentis, have various pharmacological activities, and more attention has been paid to their anti-tumor potential in recent years. Their effects of inhibiting the proliferation of cancer cells,[21] inducing cell cycle arrest,[22],[23] eliciting apoptosis [24],[25] and inhibiting invasion and metastasis [26],[27] have been studied. Furthermore, they could reverse the multidrug resistance and enhance the anti-cancer potential when combined with other chemotherapeutic drugs.[28] In the clinic, Guo et al. expounded that Astragalus polysaccharide (isolated from the radix of Astragalus) could markedly improve the overall quality of life (QOL), physical function, fatigue, nausea and vomiting, pain, and loss of appetite.[29] Huang et al. also elaborated that compared with cisplatin chemotherapy, compound matrine injection combined with cisplatin chemotherapy could significantly improve the efficiency, QOL and myelosuppression, and reduce adverse events.[30]

Although there are some reviews and clinical trials focusing on KA injection for NSCLC, they lack required information size calculation (sample size included in pooling outcomes). To evaluate therapeutic effects of KA injection for NSCLC, highly compelling and persuasive evidences are required to draw a firm conclusion. Hence, it is necessary to carry out a new meta-analysis and cumulative meta-analysis (trial sequential analysis [TSA]) on the basis of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) items,[31] and grade the quality of overall evidence on outcomes by the GRADE system.[32]


 > Materials and Methods Top


Protocol and registration

No protocol has been registered in the public database, but considerable amount of drafts already exist.

Literature search

We searched PubMed, EMBASE, the Cochrane library, ISI Web of Knowledge, Chinese Biomedical Literature Database, Chinese Journal Full-text Database, Chinese Science and Technology Periodicals Database and WanFang database, with the addition of Google Scholar, and manual searches, which were completed in September 2012 and then updated in January 2013. The search strategies were “nonsmall cell lung cancer OR nonsmall cell lung carcinoma OR nonsmall cell lung carcinomas OR nonsmall cell lung OR NSCLC” AND “Kang ai OR Kangai OR Kang-ai OR Kang' ai OR KA”. Search strategies of randomized controlled trials (RCTs) followed strictly Cochrane Handbook and used Medical Subject Headings terms combined with free text terms. All search strategies were determined eventually after numerous presearches. Two reviewers conducted the search independently, and the disagreements were resolved by discussion.

Included trials

Types of studies

We included all randomized trials of KA injection plus chemotherapy versus chemotherapy alone for NSCLC.

Types of participants

(1) Identified patients were all adults (age >18 years), who were diagnosed with NSCLC by pathological and cytological examinations. None of gender, ethnicity, nationality or language was limited; (2) Karnofsky Performance Status (KPS) Scale was >60 points or survival time was >3 months; (3) patients did not receive any chemotherapy before, no contraindications-related to chemotherapy, no serious dysfunctions of either liver or kidney; (4) patients had formal hematological and electrocardiographic examinations. Patients diagnosed with other type of cancer, suffered from serious organ damages, or with infectious diseases, but no subgroup analysis was excluded.

Types of outcome measures

Efficacy evaluation of outcomes included clinical response rate, clinical benefits rate, and QOL. Safety evaluation of outcomes included hematologic toxicity (WBC count) and nonhematologic toxicity (nausea/vomiting). The criteria on outcomes of included studies are shown in [Table 1].
Table 1: The characteristics of including studies

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Document screening and data extraction

To identify all relevant eligible studies, the search was performed by two reviewers independently. Using EndNote X5 (provided by Thomson Reuters, visiting http://endnote.com/downloads/available-updates to download), unqualified articles (including reviews, comments, letters, and case reports) were excluded after titles and abstracts were screened initially. Finally, the eligible trials (RCTs) were identified after reading the full texts. Disagreements were resolved by discussions. Data extraction was carried out by the same reviewer independently, using standard data extraction form, which was developed to record details (including study design, participants and corresponding characteristics, setting and period, intervention and outcomes).

Quality evaluation

Two reviewers assessed the quality of studies using items recommended by Cochrane Handbook,[33] which included sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. We recorded problems corresponding to these issues in full texts respectively. For each individual study, each criterion was assigned a label of “yes”, “unclear” or “no” to estimate the risk of bias.

By using GRADEpro (provided by The Cochrane Collaboration, visiting ims.cochrane.org/revman/other-resources/gradepro/download. to download), we also assessed the quality of all outcomes. As we know, RCTs are regarded as high-quality evidence unless they are weakened by serious defects that resulted from the low quality of studies such as inconsistency, indirectness, imprecise or sparse data, or high probability of reporting bias.[34] If any of these items mentioned above existed, the rating quality of evidence grade could be downgraded to moderate, low, or very low.[35]

Statistical analysis

Statistical analysis was performed, and forest plots were generated by Review Manager 5(version 5.2, provided by The Cochrane Collaboration, visiting ims.cochrane.org/revman/download. to download).[36] The relative risk (RR) was calculated along with its 95% conifdence intervals (CIs) for dichotomous outcomes and mean difference for continuous outcomes. Statistical heterogeneity between studies was assessed by Chi-square, and the extent of the inconsistency was assessed by I2 statistics. When I2 < 40%, heterogeneity was considered as questionably important; 30-60% was thought to possibly represent moderate heterogeneity; 50-90% was regarded as possible substantial heterogeneity; and higher than 75% was deemed a considerable level. If there were no heterogeneity in therapeutic effects among studies, the fixed-effects model was conducted, otherwise, the random-effect model was used. Descriptive techniques were used when clinical heterogeneity existed, and no data could be used in statistical analysis. The stability of outcome was tested by sensitivity analysis when needed.

Trial sequential analysis (TSA, provided by Copenhagen Trial Unit, visiting http://www.ctu.dk/tsa/downloads.aspx to download) was performed to reduce the risk of random errors. TSA is a tool for quantifying the statistical reliability of the data in a cumulative meta-analysis,[37],[38] controlling alpha and beta values for sparse data and repetitive testing on accumulating data.[39],[40] It is also a methodology combining a required information size calculation (cumulated sample sizes of included trials) with the threshold of statistical significance. In order to control the risks of random errors due to sparse data and multiplicity, TSA was performed for both the dichotomous outcomes and the continuous outcomes.[41] We adapted a relative risk reduction of 20%, an alpha (type I error) of 5%, a beta (type II error) of 20%, and the diversity of the meta-analysis.[39]


 > Results Top


Literature search

A total of 394 studies were identified based on the search strategies. Using EndNote X5 software, 180 duplicates were removed. Of the initial 214 records, 139 studies were excluded through skimming titles, keywords, and abstracts. After reading full-texts, 31 RCTs [42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72] with 2259 patients were identified. [Figure 1] shows the screening process by PRISMA 2009 flow diagram.
Figure 1: Preferred reporting items for systematic reviews and meta-analysis 2009 flow diagram

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Description of studies included

A total of 31 RCTs with 2259 patients met the included criteria.[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72] There were differences among the criteria on outcomes in these included studies. WHO Response Criteria and Assessment of Response on UICC [73] and RECIST criteria [74] (response evaluation criteria in solid tumors) were used for clinical response rate and clinical benefits rate. Only one study [56] used Chinese criteria (Guidelines on Diagnosis and Treatment of Common Malignancy in China [75]). The outcome on QOL was performed by KPS (Karnofsky score [76]), and two studies [46],[66] conducted it without criteria or statement. Hematologic toxicity (WBC) and nonhematologic toxicity (nausea/vomiting) were followed by WHO Toxicity Criteria.[73] The comprehensive characteristics of included studies are shown in [Table 1].

Methodological quality of studies

Most of the trials did not describe how the random allocation sequence was generated, only marked “randomized” without exact methods (except six trials [48],[49],[52],[56],[59],[63]), which implied that the selection bias might have been produced. Moreover, none of the trials reported whether the blinding was adopted, which suggested that performance bias and measurement bias might exist. Finally, none of the trials had addressed incomplete outcome data. Other items were all “unclear.” The methodological quality of these included trials was shown in [Figure 2].
Figure 2: The summary of methodological quality of these included trials

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The results of meta-analysis and trial sequential analysis

[Table 2] shows the summaries of meta-analysis and [Table 3] illustrates the specific results of GRADE.
Table 2: The summary of results of meta-analyses

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Table 3: KA injection plus chemotherapy compared to chemotherapy alone for no-small cell lung cancer

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Clinical response rate

All included studies except one [71] reported clinical response rate (moderate-quality evidence according to GRADE), and the fixed model was used (Phet = 1.00, I2 = 0%). The results of a meta-analysis showed that there was a significant difference in clinical response rate (RR = 1.29, 95% CI: 1.17-1.41, P < 0.00001), which demonstrated that the combination had advantages in promoting clinical response. TSA found that in 2008, after one trial [62] with 51 patients were published, the evidence had already clearly displayed a benefits effect of the combination on clinical response rate [Figure 3]a. Subsequently, additional 21 RCTs involving 1623 patients reported similar clinical response rate.
Figure 3: Trial sequential analysis (TSA) of 31 randomized controlled trials (RCTs) on Kang' ai injection plus chemotherapy versus chemotherapy alone. The red line is the TSA monitor boundary according to a relative risk reduction of 20%, type I error of 5% and type II error of 20%. The red horizontal line is the Z-score of ± 1.96, equal to two-side P= 0.05. X-axis: the number of patients randomized, Y-axis: the Z-score. (a) TSA on clinical response rate, of 30 RCTs (marked with black dots) illustrated that the cumulative Z-curve crossed the monitoring boundary after 10 trials. The required information size was calculated to 1162 (the vertical line). (b) TSA on clinical benefit rate, involving 28 RCTs illustrated that the cumulative Z-curve crossed the monitoring boundary after five trials. The required information size was calculated to 503. (c) TSA on quality-of-life, involving 26 RCTs illustrated that the cumulative Z-curve crossed the monitoring boundary after six trials. The required information size was calculated to 1433. (d) TSA on hemotologic toxicity (white blood cell), involving 26 RCTs illustrated that the cumulative Z-curve crossed the monitoring boundary after six trials. The required information size was calculated to 661. (e) TSA on unhemotologic toxicity (nausea and vomiting), involving 23 RCTs illustrated that the cumulative Z-curve crossed the monitoring boundary after 12 trials. The required information size was calculated to 1150

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Clinical benefit rate

Except three studies,[51],[55],[71] 28 studies reported clinical benefit rate (moderate-quality evidence according to GRADE), and the fixed model was used (Phet = 0.11, I2 = 26%). The meta-analysis showed that the combination would improve the clinical benefit rate when compared with chemotherapy alone (RR = 1.19, 95% CI: 1.14-1.25, P < 0.00001). The cumulative Z-curve had crossed the monitoring boundary after five trials published according to TSA and the evidence had clearly showed a benefit of KA injection plus chemotherapy on clinical benefit rate [Figure 3]b.

Quality of life

Except five studies,[45],[57],[59],[63],[67] the remaining 26 studies reported the KPS related QOL (moderate-quality evidence according to GRADE), and a fixed model was also performed (Phet = 0.45, I2 = 1%). Compared with chemotherapy alone, the combination could improve QOL (RR = 1.79, 95% CI: 1.63-1.98, P < 0.00001). Based upon the results of TSA, the cumulative Z-curve had crossed the monitoring boundary after six trials published. The evidence had clearly proved that there was a benefit of KA injection plus chemotherapy on QOL [Figure 3]c.

Hematologic toxicity (white blood cell count)

Except five studies,[51],[54],[59],[62],[68] 26 studies reported the hematologic toxicity (moderate-quality evidence according to GRADE), and the fixed model was also performed (Phet = 0.02, I2 = 40%). The results proved that there were benefits in increasing WBC count (RR = 0.71, 95% CI: 0.66-0.76, P < 0.00001). As shown in [Figure 3]d, the cumulative Z-curve had also crossed the monitoring boundary after six trials published. Compared with chemotherapy alone, benefits related to the combination had been proven on WBC count.

Nonhematologic toxicity (nausea and vomiting)

Except for eight studies,[42],[45],[46],[54],[59],[62],[68],[71] 23 studies reported nonhematologic toxicity, such as nausea/vomiting (low-quality evidence according to GRADE), and the random model was performed (Phet = 0.001, I2 = 53%). The meta-analysis showed that there was significant difference in nausea and vomiting (RR = 0.73, 95% CI: 0.65-0.83, P < 0.00001). The results of TSA [Figure 3]e showed that the cumulative Z-curve had crossed the monitoring boundary after 12 trials published. The evidence has clearly proved the benefit of the combination on nausea and vomiting.

Publication bias

Funnel plot analysis was performed, and the results showed an unsymmetrical funnel plot. The risk of publication bias probably occurred. The funnel plot on outcome of clinical response rate was shown in [Figure 4].
Figure 4: The funnel plot on outcome of clinical response rate

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 > Discussion Top


As one of the preferentially recommended anti-cancer injections of TCM, KA injection (containing ginseng, astragali radix, and matrine) has demonstrated satisfactory effects on clinical applications.[52],[56],[57],[58],[64],[67],[72] Studies of modern pharmacology have confirmed that it could improve immune function and raise WBC count. It also has obvious inhibitory effects towards tumor cell cloning. Hence, KA injection is regarded as an excellent adjuvant therapy to alleviate side effects of chemotherapy.[44],[60],[62],[63]

According to our initial search strategies, 394 records were identified. In addition, we performed a manual search based on references of those included studies to identify more articles. After screening the titles and abstracts, observational studies and clinical series were removed. Finally, 31 studies involving 2259 patients were identified. All of these identified studies were comparable [Table 1]. The quality of eligible studies was a moderate risk of bias due to the unclarity of randomization methods and applications of blinding [Figure 2], which implied that the risk of performance bias and measurement bias might exist.

The present study showed that KA injection might be regarded as an adjuvant treatment for NSCLC. Furthermore, according to the results of TSA, all outcomes had crossed the monitoring boundary and the firm conclusion could be drawn. Due to the moderate risk of bias in included studies, the present results still might be reliable. Moreover, the quality of all outcomes based on GRADE system were moderate except for the outcomes on nausea and vomiting, which was caused by the low methodology of included studies and the unclarity of randomized methods in 80% of the identified studies. Furthermore, the unexplained heterogeneity existed among the included studies. All of these results demonstrated moderate strength of evidence, indicating that further research likely have an important impact on our confidence in the estimation of effects and might change the estimation.

The limitations of the present study were as followings:First, the methods of estimating sample size were unclear, and the sample sizes were small in most identified studies, which would result in low test power. Second, the dosage and duration of KA injection, the criteria of all outcomes among those studies were different, which might lead to the internal heterogeneity. Third, none of the included trials described allocated concealment, and it has been reported that exaggerated therapeutic effects may occur if allocated concealment or adequate allocated concealment was not conducted. Since the subjective indexes were used, it was important for authors to use the method of blinding in the original studies of the treatment of KA injection in NSCLC. Finally, some included studies did not describe clearly the statistical methods they adopted, which limited us to assess the internal validity. Although the quality of this analysis was relatively low, the evidence we have drawn could be worth discussing in future clinical practice.


 > Conclusion Top


In summary, the weak evidence showed that KA injection might be regarded as an adjuvant treatment for patients with NSCLC, and the results of TSA indicated that no more trials were needed. However, on account of the low methodological quality of included studies and weak recommendations according to GRADE system, these conclusions we drew should be applied cautiously in future clinical practice. Furthermore, TSA is a wonderful tool and worth the attempt to be introduced into meta-analysis of TCM.


 > Acknowledgement Top


We thank Quan Wang (The First Clinical Medical College of Lanzhou University) for the methods of trial sequential analysis in the section of data analyses; We are also grateful for the kindly guides and good suggestions on literature collection from Dr. Jin-Hui Tian (The Evidence-Based Medicine Center of Lanzhou University). This review was not supported by a grant from any resource.

 
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