Evidence of elemene injection combined radiotherapy in lung cancer treatment among patients with brain metastases: A systematic review and meta-analysis.

BACKGROUND: This review evaluates the effectiveness and safety of elemene injection combined radiotherapy in the treatment of lung cancer with brain metastases.
METHODS: A systematic literature research was conducted from EMBASE, Cochrane Library, PubMed, Chinese biomedical database, Chinese scientific journal database, China knowledge resource integrated database, and WanFang Database from established to July 2016 without language restriction. The Cochrane Collaboration tool was used to evaluate the risk of bias. All statistical analyses were conducted with STATA (version 14.0) and RevMan (version 5.3).
RESULTS: Eleven randomized controlled trials (765 patients) were included for determining the effectiveness and safety of elemene combined with radiotherapy in the treatment of lung cancer with brain metastases. Objective response rate (ORR) [odds ratio (OR) = 2.89, 95% confidence interval (95% CI) 2.04-4.08, P < .00001] and symptoms (OR = 4.06, 95% CI 2.00-8.25, P = .0001) improved more in the elemene-based combination treatment group than in the radiotherapy-alone control group. The Karnofsky Performance Status (KPS) score was used to measure patients' improvement rate. The patients who were treated with elemene-based combination with radiotherapy were higher than those patients who were treated with radiotherapy alone (OR = 3.51, 95% CI 2.20-5.61, P < .00001]. The incidence of bone marrow suppression (OR = 0.27, 95% CI 0.11-0.68, P = .006) and leukopenia (OR = 0.23, 95% CI 0.12-0.46, P < .00001) decreased in the elemene-based combination treatment group by radiotherapy significantly.
CONCLUSIONS: The elemene injection combined radiotherapy in the treatment of lung cancer with brain metastases appears to improve the treatment response rate and alleviated symptoms. The combined treatment has showed positive impact to reduce adverse reactions and improve quality of life.

Introduction

Lung cancer, one of the most common cancers with a nature of malignancy, imposes a serious damage to human health in the world. In 2012, it was estimated that there were 1.8 million (13% of total) new cases of lung cancer globally.[ It was the leading cause of death among malignant tumor in China, which accounts for more than 569,000 deaths in both rural and urban areas of the country. The incidence of lung cancer continued to increase worldwide.[ Risk factors may include high rates of smoking, aging, and environmental changes that caused by industrialization and urbanization.[

Brain metastasis, a lethal complication of lung cancer, is the main reason for the failure of treatment and poor prognosis. Surgical treatment, radiotherapy, chemotherapy, and molecular targets agents comprise the treatment protocol for lung cancer patients with brain metastases. The whole-brain radiation therapy (WBRT) is the most widely used therapeutic modality among these treatments; however, it induces severe adverse reactions, including neuroendocrine dysfunction and progressive dementia, which limit the efficacy and clinical application.[

Western medicine proved to be beneficial in tumor diagnosis and treatment, but it induces serious adverse reactions. Traditional Chinese medicine may also improve patients’ quality of life. However, the lack of an effective evaluation system restricts the development of traditional Chinese medicine.[ The integration of Western and traditional Chinese medicine may work synergistically to become the new mainstream treatment for cancer patients.[

Elemene, a natural lipid-soluble plant drug extracted from Curcuma Wenyujin, has been widely used as an effective anticancer drug.[ The active ingredients of an elemene injection are β-elemene, γ-elemene, α-elemene, and the excipients include granulesten, cholesterol, alcohol, disodium hydrogen phosphate and sodium dihydrogen phosphate.[ The β-elemene has been proven to be the main active ingredient. Thus far, it is known that elemene has a broad-spectrum anticancer effect with bioapplications in bone cancer, lung cancer, ovarian cancer, and so on.[ It is considered to be safe when compared with other traditional chemotherapy drugs due to its low toxicity level to the normal cells.[

In recent years, several systematic investigations have been carried out on antitumor mechanisms of elemene. Clinical studies have shown a significant role in inhibiting tumor growth. Combined treatment of elemene injection, radiotherapy, and chemotherapy may enhance the effectivity of the treatment, and mitigate several serious adverse reactions.[ Elemene injection combined with radiotherapy in the treatment of lung cancer with brain metastases has already been adopted in clinical settings. Its effectiveness and safety have already been reported from clinical trials; however, a systematic review, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), which can provide guidance for this combination therapy regimen is lacking. Hence, this meta-analysis aims to provide an evidence of effectiveness and safety for the clinical use of elemene injection combined with radiotherapy in the treatment of lung cancer with brain metastases.

Methods

Searching strategies

Published studies were retrieved from 7 databases, including EMBASE, PubMed, Cochrane Library, China Knowledge Resource Integrated Database (CNKI), Chinese Scientific Journal Database (VIP), Chinese Biomedical Database (CBM), and Wanfang Database (from established to July 2016). The initial search was designed to find all trials using the following search phrases either separately or in combination, “lung cancer,” “brain metastases,” “elemene injection,” “radiotherapy.” All randomized controlled trials (RCTs) were reviewed as the systematic literature review in Chinese and English. Ethical approval was not required, as this study is a meta-analysis of published studies.

Inclusion criteria

Types of study

Randomized controlled clinical trials focused on the treatment of lung cancer with brain metastases using elemene injection and radiotherapy were selected, regardless of blinding or publication date. Only RCTs with complete and precise data were included.

Exclusion criteria

We excluded RCTs of those had flawed data presentation, those had adopted different intervention measures, those had not provided precise data counting on response rate, and those had participants with any comorbidity. Non-RCTs were excluded from this meta-analysis.

Types of participant

All patients were 18 years old and above, and histologically or cytologically confirmed non-small cell lung cancer and brain metastases documented by magnetic resonance imaging or computed tomography scan.

Types of intervention

This meta-analysis included all randomized trials involving lung cancer with brain metastases undergoing chemotherapy and radiotherapy. The intervention treatment group combined elemene injection with radiotherapy, and the control group was treated with only radiotherapy.

Outcome measurement

Two of the reviewers independently extracted data on objective tumor response, reductions in radiotherapy toxicity, and improved or stable performance status. The outcomes were evaluated using Objective Response Rate (ORR), Karnofsky Performance Status (KPS) score improvement rate, and the symptoms improvement rate. The ORR was calculated as the number of patients presenting any response (partial response along with complete response) divided by the total number of patients in each treatment group. The KPS score improvement rate was calculated as the number of patients whose KPS scores increased by more than 10 points divided by the total number of patients in each treatment group. The common symptoms improvement rate was considered to assess the efficacy of therapeutic regimen. The incidence of adverse reactions was also systematically evaluated.

Data extraction

Data and information, including the name of first author, year of publication, the number of cases, demographic characteristics (age and sex), details of intervention, and outcomes were carefully extracted by 2 authors according to the predefined criteria.

Quality assessment

The methodological quality of each RCT was evaluated in terms of selective reporting, allocation concealment, random sequence generation, blinding of outcome, blinding of participants and personnel, incomplete outcome data, and other sources of bias based on the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0). The judgment was categorized as “Low risk,” “High risk,” or “Unclear risk” of bias. Two reviewers evaluated the studies that were matched with the pre-specified criteria for determining the effectiveness and safety of elemene injection combined with radiotherapy for the treatment of lung cancer with brain metastases independently to ensure validity. If there were disagreements between the 2 reviewers, a third researcher would resolve differences over the results of the studies. The Risk of bias graph and the Risk of bias summary were generated by using Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Statistical analysis

The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each of the 4 outcomes: ORR; performance status; improvement of symptom; and the adverse reactions (bone marrow suppression and leukopenia). For the pooling analysis, Chi-square test was used to assess the existence of statistical heterogeneity. Fixed effect model was used when individual study results showed homogeneity (P > .1 and I2 < 50%), otherwise, we used the random effect model (P < .1 and I2 > 50%) to estimate the summary OR. Egger test and Begg funnel plot were evaluated to assess publication bias. The level of significance was considered at P < .05. All statistical analyses were conducted with STATA (version 14.0; StataCorp LLC, Lakeway Drive, College Station, TX) and RevMan (version 5.3).

Results

The flow chart of the detailed searching steps for this meta-analysis is illustrated in Fig. 1. Twenty-one of all 170 screened clinical trials were matched with the inclusion criteria for determining the effectiveness and safety of elemene injection combined with radiotherapy in the treatment of lung cancer with brain metastases. Furthermore, after a thorough assessment, we excluded 10 RCTs: 5 trials were non-RCTs, 2 trials had data errors, and 3 trials adopted different intervention measures. Finally, we identified 11 studies that involved a total of 765 lung cancer patients with brain metastases. We assigned 383 patients who were treated with elemene injection and radiotherapy in the experimental group, and 382 patients who were treated with radiotherapy only in the control group. The main characteristics of all 11 included studies are given in Table 1.[

Figure 1

Results of trial searching and reasons for excluding. nRCTs = nonrandomized controlled trials.

Table 1

Study characteristics of clinical trials comparing and safety the effectiveness between elemene-based combinations and radiotherapy alone.

Risk of bias

Figure 2 evaluates the risk of bias based on the quality of the included RCTs. Only 4 of 11 studies mentioned randomized grouping despite there was a lack of sufficient reporting of the randomization methods. In summary, 2 studies grouped the patients on the basis of the hospital admission sequence and 4 studies used a random number table. None of the identified trials provided the details of the allocation concealment and blinding of outcome. All the included trials had a low risk of bias of incomplete outcome data. Other bias was evaluated as an unclear risk. However, we were unable to judge selective reporting bias because of the insufficient evidence provided by all of the identified trials. The summary of the authors’ judgments of the risk of bias is indicated in Fig. 3.

Figure 3

Authors’ judgment on the risk of bias.

Objective response rate

All the identified studies for this meta-analysis reported ORR. The ORR (OR = 2.89, 95% CI 2.04–4.08, P < .00001) was higher in the elemene-based combination treatment group than those treated with radiotherapy alone, with no significant heterogeneity (χ2 = 3.89, P = .95, I2 = 0%) (Fig. 4).

Figure 4

The forest plot of objective response rate.

Symptoms improvement rate

We identified 3 trials representing a total of 188 patients of lung cancer with brain metastases. Patients who were treated with elemene-based combinations (OR = 4.06, 95% CI 2.00–8.25, P = .0001) reported higher symptoms improvement rate than those patients who were treated with radiotherapy alone, with no significant heterogeneity (χ2 = 3.88, P = .99, I2 = 0%) (Fig. 5).

Figure 5

The forest plot of symptoms improvement rate.

KPS score improvement rate

We identified 6 studies (350 patients) that reported the performance status of lung cancer patients with brain tumor metastases and treated with elemine-based combinations with radiotherapy or radiotherapy alone. The KPS score improvement rate of patients treated with elemene-based combinations with radiotherapy was higher than that of patients treated with radiotherapy alone (OR = 3.51, 95% CI 2.20–5.61, P < .00001), with no significant heterogeneity (χ2 = 2.59, P = .76, I2 = 0%) (Fig. 6).

Figure 6

The forest plot of KPS score improvement rate.

Adverse reactions

Bone marrow suppression

Patients who received the combined treatment regimen (elemene injection along with radiotherapy) had a lower incidence of bone marrow suppression (OR = 0.27, 95% CI 0.11–0.68, P = .006) than that of patients treated with radiotherapy alone, with no statistical heterogeneity (χ2 = 1.64, P = .20, I2 = 39%). The forest plot of the incidence of bone marrow suppression is given in Fig. 7.

Figure 7

The forest plot of the incidence of bone marrow suppression.

Leukopenia

Figure 8 illustrates that the patients who were treated with elemene injection combined with radiotherapy had a lower incidence of leukopenia (OR = 0.23, 95% CI 0.12–0.46, P < .00001) than the patients treated with radiotherapy alone, with no substantial heterogeneity (χ2 = 0.74, P = .86, I2 = 0%).

Figure 8

The forest plot of the incidence of leukopenia.

Publication bias

There was lower publication bias according to the Begg funnel plot and the Egger test (P = .476) in our study. Figure 9 indicates the funnel plot of the publication bias.

Figure 9

(A, B) The funnel plot of the publication bias.

Discussion

The meta-analysis results from this study suggest that combining elemene injection with radiotherapy may improve tumor response, performance status, and symptoms of the disease, and reduce adverse effects (particularly bone marrow suppression and leukopenia) more than treatment with radiotherapy alone. We were unable to draw definitive conclusions, as most of the studies reviewed were of poor quality. Previous meta-analysis has proven poor methodological quality among the RCTs published in the Chinese and English journals[ and these scenario persisted in this meta-analysis. Although the findings of this meta-analysis may be restricted by the low quality of the trials identified in our systematic search, our findings proved that patients who were treated with elemene injection combined with radiotherapy had significant health benefits than those who were treated with radiotherapy alone.

The antitumor mechanisms of elemene contain the following elements: inhibiting the proliferation of tumor cells[; inducing apoptosis of tumor cells[; inhibition of tumor angiogenesis[; reversing multidrug resistance of tumor cells[; and radiosensitization.[ It should be noted that some previous published studies reported several adverse reactions caused by elemene injection, such as phlebitis, fever, pain, chest distress, and bleeding tendency.[ The lung cancer patients with brain metastases and being treated with elemene-based combinations reported higher symptoms and performance status improvement rate than those patients who were treated with the radiotherapy alone. For this reason, the elemene injection combined with radiotherapy appears to have a positive effect in improving the treatment of radiotherapy and the quality of life.

In this meta-analysis, the incidence of bone marrow suppression and leukopenia was found to be significantly decreased. However, the adverse effect of elemene injection was not reported in these included RCTs. Therefore, the safety of elemene injection could not be evaluated, and the potential adverse reactions need further investigation. In this regard, this study requires further clinical trials to report sufficient evidence on the safety of elemene injection in the treatment of lung cancer with brain metastases.

This is the first meta-analysis, which evaluates the efficacy of elemene injection along with radiotherapy against radiotherapy alone in the treatment of lung cancer with brain metastases. Indeed, the elemene-based combination therapy had a better outcome than radiotherapy alone. However, it is noteworthy that the findings of this meta-analysis might be affected due to several limitations, such as insufficient reporting of the randomization methods used in the included trials, or the poor methodological quality of the RCTs. Moreover, most of the identified trials included small sample sizes. Therefore, it is difficult to evaluate the long-term efficacy and safety of elemene-based combination treatment for lung cancer with brain metastases comprehensively and objectively. In addition, none of the identified trials provided the details of the allocation concealment and blinding of outcome, and we were also unable to judge selective reporting bias due to limited information provided by all the identified trials. Although the findings of this meta-analysis were limited by the low quality of the published studies, we identified insufficient reporting of the randomization methods. Therefore, we strongly recommend researchers to strictly follow the Cochrane handbook or Consolidated Standards of Reporting Trials (CONSORT). Complementary and alternative medicines require evidence-based standards for the demonstration of clinical effectiveness.[ Also, further study designs should consider standard treatment protocols in order to minimize the likelihood of generating unbiased results on the efficacy and safety of elemene combined with radiotherapy due to diversity of study designs.

Conclusion

Compared with radiotherapy alone, elemene injection combined with radiotherapy in the treatment of lung cancer with brain metastases may improve the treatment efficacy, alleviate the symptoms of patients, and reduce the adverse reactions induced by radiotherapy. However, additional randomized clinical trials with high methodological quality are required to generate conclusive results.