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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 4  |  Page : 745-751

The effect of kanglaite injection in combination with gefitinib versus gefitinib alone in patients with nonsmall cell lung cancer: A meta-analysis


Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

Date of Submission28-Oct-2016
Date of Acceptance23-May-2017
Date of Web Publication07-Jul-2017

Correspondence Address:
Zhou Xianmei
Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing 210029
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1213_16

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 > Abstract 


Objective: The objective of the study was to evaluate the clinical efficacy of kanglaite (KLT) injection combined with gefitinib versus gefitinib alone in the treatment of nonsmall cell lung cancer (NSCLC).
Methods: The randomized controlled trials involving NSCLC treatment with KLT injection combined with gefitinib versus gefitinib alone were searched on seven medical databases up to October 2016. Two reviewers independently assessed the methodological quality of the included studies. The RevMan 5.3 software was employed for data analysis.
Results: Seven randomized trials involving 554 patients met our criteria. Compared with gefitinib alone, KLT injection combined with gefitinib showed significant effects in increasing objective response rate (relative risk [RR] =1.38; 95% confidence interval [CI], 1.09–1.75), improving the performance status (RR = 1.80; 95% CI: 1.34–2.42), raising the percentages of CD4+ cells (weighted mean difference [WMD] = 4.45; 95% CI: 2.61–6.28), natural killer cells (WMD = 4.43; 95% CI: 3.85–5.01), and ratio of CD4+/CD8+ (WMD = 0.08; 95% CI: 0.02–0.14), whereas the difference was not significant in gefitinib toxicity including rash (RR 0.90; 95% CI: 0.58–1.40, P = 0.65), diarrhea (RR 1.04; 95% CI: 0.66–1.64, P = 0.88), and liver injury (RR 1.00; 95% CI: 0.58–1.73, P = 1.00), CD3+ cells (WMD = 1.16; 95% CI: -2.64–4.97) and CD8+ cells (WMD = 6.78; 95% CI: -1.68–15.23).
Conclusion: Co-use of KLT injection and gefitinib may benefit the patients with NSCLC through enhancing the therapeutic effectiveness compared with gefitinib alone. To confirm these results, further rigorously designed trials are warranted.

Keywords: Gefitinib, kanglaite injection, meta-analysis, nonsmall cell lung cancer, systematic review


How to cite this article:
Hailang H, Jiping Z, Ailing C, Xianmei Z. The effect of kanglaite injection in combination with gefitinib versus gefitinib alone in patients with nonsmall cell lung cancer: A meta-analysis. J Can Res Ther 2020;16:745-51

How to cite this URL:
Hailang H, Jiping Z, Ailing C, Xianmei Z. The effect of kanglaite injection in combination with gefitinib versus gefitinib alone in patients with nonsmall cell lung cancer: A meta-analysis. J Can Res Ther [serial online] 2020 [cited 2020 Sep 30];16:745-51. Available from: http://www.cancerjournal.net/text.asp?2020/16/4/745/209959

Dr. Hailang He and Dr. Jiping Zhu contributed equally to this work.





 > Introduction Top


Lung cancer is the leading cause of cancer-related death, and there will be approximately 224,000 new cases and 158,000 deaths from lung cancer in the United States in 2016.[1] In China, lung cancer has the highest incidence and mortality rates of all cancer types.[2] Nonsmall cell lung cancer (NSCLC) accounts for 83% of all lung cancer, and the current 5-year survival rate is about only 21%.[3]

Gefitinib, a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved by the US Food and Drug Administration as the first-line treatment for NSCLC patients harboring activating EGFR mutations. Compared with the traditional platinum-based chemotherapy, the NSCLC patients with EGFR mutation-positive NSCLC are highly responsive to gefitinib.[4] However, patients harboring activating EGFR mutations who are initially responsive to gefitinib eventually develop acquired resistance after 10–16 months of consistent clinical benefit followed by disease progression.[5] Moreover, despite technological advances, gefitinib is still associated with some side effects such as diarrhea, skin rash, paronychia, and liver toxicity.[6],[7] In the recently reported LUX Lung-7 study, 3.1% and 1.9% of patients discontinued gefitinib because of alanine transaminase and aspartate transaminase elevation, respectively.[8] In addition, gefitinib is also associated with a significantly increased risk of critical interstitial lung disease, which is a potentially fatal adverse effect.[9] Due to the toxicity, some patients cannot continue the gefitinib treatment, some even finally die of the serious pulmonary adverse reactions. These poor outcomes in acquired resistance and toxicity for advanced NSCLC patients with the gefitinib treatment emphasize the need for additional improvements in approaches to treatment.

In China, herbal medicine has been widely used as an adjunctive therapy for lung cancer and showed the potential therapeutic beneficial effects in increasing the therapeutic effectiveness and reducing the toxicity of chemotherapy, radiotherapy, and EGFR-TKI.[10],[11],[12],[13] Kanglaite (KLT) injection, one of Chinese herb preparations, is prepared as a microemulsion for intravenous use. The main ingredient of KLT is Coix seed oil, which has been widely used for cancer treatment in China.[14] A meta-analysis demonstrated that KLT injection combined with chemotherapy could improve the short-term efficacy, performance status, and decrease the risk of gastrointestinal reaction compared with systematic chemotherapy alone in patients with NSCLC.[15]

In recent years, there are an increasing number of published clinical trials of KLT injection combined with gefitinib for the treatment of NSCLC. However, these trials have a modest sample size and convey inconclusive results, and the evidence for the effects of KLT injection has not been systematically assessed. Therefore, we conducted this meta-analysis to systematically study the efficacy and toxicity of combination of gefitinib and KLT for patients with NSCLC.


 > Methods Top


Data sources and search strategies

The following databases were retrieved: PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database (CBM), and Wanfang Database (Wanfang). All of those searches ended on October 2016.

The following terms were retrieved in databases as medical subject headings or free-text terms: “nonsmall cell lung cancer,” “gefitinib,” “Coix seed oil,” “Kanglaite injection,” and “randomized controlled trials” (and multiple synonyms for each term). The bibliographies of the included studies were also searched to identify additional trials. No restrictions were placed on the publication language. Two reviewers independently identified studies.

Inclusion criteria

Randomized controlled trials (RCTs) of KLT injection combined with gefitinib for the treatment of NSCLC compared with gefitinib alone were included in the study. Studies included in the meta-analysis had to meet the following items as essential inclusion criteria.[1] Participants: NSCLC patients were diagnosed by pathological sections and treated by gefitinib.[2] Type of studies: clinical RCTs with or without blinding were eligible.[3] Type of intervention: studies provided the treatment group with KLT injection in combination with gefitinib and the control group with gefitinib alone were included for analysis.[4] Type of outcome measurements: overall response rate (ORR) and performance status were the main outcome measurements; other outcome measurements included immune function and reduction in the toxicity of gefitinib were also considered.

Data extraction and quality assessment

Two reviewers extracted data independently. We assessed the methodological quality of all included trials with the criteria in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0.[16] Random sequence generation, allocation concealment, blinding (or masking), incomplete data assessment, selective outcome reporting, and other sources of bias were assessed with three potential responses: Yes, no, and unclear. Disagreements were resolved by discussion with a third author.

Outcome measures

The ORR was calculated as the sum of complete response and partial response (PR) rates based on the World Health Organization (WHO) scale.[17] The performance status of patients was evaluated based on the Karnofsky Performance Score (KPS),[18] and the improved performance status was defined as the number of patients with improved performance status (>10 -point increase) divided by the total. Gefitinib toxicity was evaluated based on the WHO scale,[17] and we calculated the probability of occurrence of gefitinib toxicity as the number of patients experiencing any toxicity (WHO Grades 1, 2, 3, and 4) divided by the total.

Data analysis

The Review Manager 5.3 software (http://www.cochrane.org/) was employed for data analysis. Dichotomous data were expressed as relative risk (RR) with 95% confidence interval (CI). For continuous data, the weighted mean differences (WMDs) were calculated with the 95% CI. If the heterogeneity exists in pooled studies (I2 > 50%), a random model was applied; otherwise, the fixed model was applied. Statistical significant difference was considered as P < 0.05. Funnel plot was applied to evaluate the potential publication bias if at least ten trials were available for a meta-analysis.


 > Results Top


Description of studies

After primary search from the six databases, 355 trials were identified as shown in [Figure 1], of which the majority were excluded because of obvious ineligibility from reading title. Fourteen studies were identified as requiring relevant abstracts retrieval. Close reviewing of the 14 abstracts excluded seven due to inappropriate interventions (n = 1) and not being RCTs (n = 6). Seven full-text articles were further retrieved for eligibility. Finally, the total of seven eligible studies[19],[20],[21],[22],[23],[24],[25] were included in the current meta-analysis. A total of 554 participants were involved in the seven studies, at which 279 patients participated in KLT injection combined with gefitinib group and 275 in gefitinib alone group. All of these studies were conducted in China. The baseline data including age, histopathology, or tumor node metastasis (TNM) stage of all studies were comparable [Figure 1].
Figure 1: The trial selection process for the systematic review

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Characteristics of the eligible studies

[Table 1] shows characteristics of the included studies. As shown, all of the studies were conducted in China and published between 2004 and 2016 on Chinese journals. The stages of NSCLC TNM of the patients recruited in the current studies were III to IV. Regarding the line of treatment, one study was designed with first-line treatment, three studies failed second-line therapy, and the other three studies did not report the line of treatment. Only two studies reported EGFR mutation positive, whereas the other studies did not mention the EGFR mutation status. The dose of gefitinib was 250 mg daily in the included studies. The durations of the treatments varied from 1 to 3 months in the eligible studies [Table 1].
Table 1: Characteristics of the eligible studies

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Risk of bias in included studies

The risk of bias of each study was assessed by the Cochrane Handbook for Systematic Reviews of Interventions 5.3. All the eligible trials claimed randomization, but only two studies provided the detailed information on the randomization method. No trials mentioned the concealment of treatment allocation and blinding procedures. Dropout, withdrawals, and intention-to-treat (ITT) analysis were not reported in any trial. In general, all of the included RCTs were assessed to be of an unclear risk of bias. The detailed information of quality assessment is listed in [Table 2].
Table 2: Methodological quality evaluation of included studies

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Outcome measures

Overall response rate

Four studies including 258 patients that reported the tumor response were identified [Figure 2]. The analytical results with fixed effects model (homogeneity, I2 = 0%, P = 0.65) demonstrated that the ORR of the KLT injection plus gefitinib group was significantly higher than the gefitinib alone group (RR 1.38; 95% CI: 1.09–1.75, P = 0.007).
Figure 2: Meta-analysis of kanglaite injection on overall response rate when combined with gefitinib in patients with nonsmall cell lung cancer

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Performance status

Four studies including 279 patients were evaluated for the performance status about the improvement of KPS (ten-point cutoff). The four trials showed no significant heterogeneity (I2 = 0%, P = 0.56). Thus, fixed-effects model was employed for the analysis. The meta-analysis demonstrated that the combination treatment with KLT injection plus gefitinib significantly improved the performance status compared with the gefitinib alone group (RR 1.80; 95% CI: 1.34–2.42, P < 0.0001) as shown in [Figure 3].
Figure 3: Meta-analysis of kanglaite injection on quality of life when combined with gefitinib in patients with nonsmall cell lung cancer

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Immune function

Three trials including 296 patients reported percentages of CD3+ cells. There was statistical heterogeneity (I2 = 99%, P < 0.01); therefore, the random effect model was employed for the analysis. As shown in [Figure 4], the results illustrated that the percentage of CD3+ cells was similar between KLT injection combination group and control group (WMD = 6.78; 95% CI: −1.68–15.23; P = 0.12).
Figure 4: Meta-analysis of kanglaite injection on the levels of CD3+, CD4+, and CD8+ cells when combined with gefitinib in patients with nonsmall cell lung cancer

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Three studies including 296 patients evaluated the effect of KLT injection on the levels of helper T lymphocytes (CD4+ cells) after treatment. As statistical heterogeneity was detected among data from the included trials (I2 = 78%, P = 0.01), the random effect model was used in this meta-analysis. As illustrated by [Figure 4], the results demonstrated that KLT injection combination group had an advantage of increasing the percentage of helper T lymphocytes compared with control group (WMD = 4.45; 95% CI: 2.61–6.28; P < 0.00001).

Two trials including 250 patients provided the data on percentages of CD8+ cells [Figure 4]. These data were not found to be homogeneous (I2 = 96%, P < 0.01), employing the random effect model in this meta-analysis. The results showed that the percentage of CD8+ cells was similar between KLT injection combination group and control group (WMD = 1.16; 95% CI: −2.64–4.97, P = 0.55).

Three trials including 296 patients reported the data on CD4+/CD8+ and natural killer (NK) cells [Figure 5]. The analytical results with fixed effects model showed that there was significant difference in increased extent of CD4+/CD8+ and NK cells between the combination group and the gefitinib group. The WMD for CD4+/CD8+ and NK cells was 0.08 (95% CI: 0.02–0.14, P = 0.005) and 4.43 (95% CI: 3.85–5.01, P < 0.01), respectively.
Figure 5: Meta-analysis of kanglaite injection on the levels of CD4+/CD8+ and natural killer cells when combined with gefitinib in patients with nonsmall cell lung cancer

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Gefitinib toxicity

The rash is one of the main side effects that gefitinib resulted in. We identified three studies including 234 patients with rash. As shown in [Figure 6], the statistical analysis with fixed-effects model revealed that KLT injection plus gefitinib showed no significant difference in rash compared with the gefitinib alone group (RR 0.90; 95% CI: 0.58–1.40, P = 0.65). The three trials showed no significant heterogeneity (I2 = 0%, P = 0.89).
Figure 6: Meta-analysis of kanglaite injection on toxicity when combined with gefitinib in patients with nonsmall cell lung cancer

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The diarrhea is another main adverse event that gefitinib resulted in. Three studies including 234 patients reported diarrhea. The three trials showed no significant heterogeneity (I2 = 0%, P = 0.46); therefore, fixed-effects model was used for the analysis. The results demonstrated that KLT injection plus gefitinib showed no significant difference in diarrhea compared with the group receiving gefitinib alone (RR 1.04; 95% CI: 0.66–1.64, P = 0.88) [Figure 6].

As can be seen in [Figure 6], two studies including 188 patients reported the liver injury. The meta-analysis with fixed-effects model showed that the combination treatment of KLT injection plus gefitinib did not significantly reduce liver injury risk compared with the gefitinib alone group (RR 1.00; 95% CI: 0.58–1.73, P = 1.00). There was no significant heterogeneity in the included trials (I2 = 0%, P = 0.99).


 > Discussion Top


As an orally first-generation EGFR-TKI, gefitinib is playing an increasingly important role in the treatment for advanced NSCLC, particularly in patients harboring EGFR activating mutations.[26] However, some poor outcomes including acquired resistance and toxicity have restricted the application prospect of gefitinib for the treatment for advanced NSCLC. In recent years, an increasing number of clinical trials have demonstrated that KLT injection combined with gefitinib can increase the tumor response, performance status, and decrease the risk of toxicity compared with gefitinib alone in patients with NSCLC. However, most of the trials are small sample sizes, and the effectiveness of KLT injection in combination with gefitinib has not been systematically estimated. Therefore, we systematically reviewed the published studies and conducted this meta-analysis. In the present meta-analysis, seven studies with 554 individuals suffering from advanced NSCLC were selected out. The main findings revealed that combining KLT injection with gefitinib in the treatment of NSCLC may increase the ORR, improve performance status, and increase CD4+ cells, NK cells, and ratio of CD4+/CD8+ when compared with gefitinib alone. However, the current meta-analysis showed that there was no statistically significant difference between the two groups in gefitinib toxicity, CD3+ cells, and CD8+ cells. Due to the poor methodological quality of the included trials, we are unable to make firm conclusions, and confirmation must await investigation in future trials.

The included studies had several limitations in methodological quality. The methodological quality and report of the majority of trials were variable and often inadequate. All the RCTs mentioned “patients were randomized into the two groups,” but only two studies provided the detailed information on the randomization method and none of them reported concealment of treatment allocation. Information about blinding was not reported in any study. In addition, of the seven trials, no trials mentioned dropout or withdraw, and none of the eligible studies reported whether they had used ITT analysis. Therefore, there was a high risk of selection bias, performance bias, and detection bias in the current systematic review. Moreover, the EGFR-mutation status was only assessed in two eligible trials, and the other studies did not report the EGFR-mutation status, which would increase the clinical heterogeneity among the included trials. What is more, all studies included in this meta-analysis used an “A+ B versus B” design where patients were randomized to receive KLT injection plus gefitinib versus gefitinib alone, without a rigorous control for placebo effect. This kind of design is likely to generate false-positive results.[27] Due to the small number of studies in the present meta-analysis, funnel plots were not applied to assess the risk of publication bias.

The active substance of KLT injection is extracted from the herb Semen coicis. It has been indicated that pemetrexed followed by KLT injection had a synergistic effect and an advantage over other sequences in NSCLC cell lines and the synergistic mechanism was due to KLT injection subsequently inhibiting the pemetrexed-activated mitogen-activated protein kinase signaling pathway.[28] Huang et al. have found that KLT injection is the main active ingredient of Coix seed exhibiting anticancer and immunomodulatory properties and induction of NF-κB-mediated gene transcription in CD4+ T cells is involved in the immunomodulatory activity of KLT injection.[29] These findings may provide molecular-level evidence to support the clinical treatment with KLT injection for patients with NSCLC. Those effects of KLT injection might directly associate with the benefits to the patients with NSCLC when coursed with gefitinib. However, to clarify the KLT injection function as an adjunct to gefitinib, future researches focused on the specific mechanisms are needed. What is more, it is critical to improve the methodological quality of RCTs for future researches and more methodologically rigorous studies are required to confirm or refute the results reported here. Besides, future trials need to ensure that the reporting follows the consolidated standards of reporting trials guidelines.[30]


 > Conclusion Top


We found evidence that KLT injection combined with gefitinib may increase the ORR, improve performance status, and raise CD4+ cells, NK cells, and ratio of CD4+/CD8+ but not reduce the toxicity of gifitinib and increase CD3+ cells and CD8+ cells when combined with gefitinib in patients with NSCLC. To confirm the exact merit, further large sample size and well-designed control trials are needed.

Acknowledgment

This work was supported by the Project of Key Discipline for TCM Construction of Jiangsu Province, China (No. JS1302).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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