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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 881-887

Irinotecan compared with etoposide in combination with platinum in previously untreated extensive stage small cell lung cancer: An updated systemic review


Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China

Date of Web Publication25-Jul-2016

Correspondence Address:
Qibin Song
Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.138002

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 > Abstract 


Objective: To compare the therapeutic effect of irinotecan/platinum (IP) and etoposide/platinum (EP) in treatment-naïve extensive small cell lung cancer patients.
Methods: Systematic computerized searches of PubMed database and Chinese National Knowledge Infrastructure were performed. Summary odds ratio (OR) or hazard ratio (HR), and 95% confidence intervals (95% CI) were used to compare IP with EP in previously untreated small cell lung cancer patients.
Results: A total of 10 randomized trials were included in the analyses. The result showed the patients treated with irinotecan combinations experienced longer overall survival than epotoside, the pooled HR was 0.85 (95% CI = 0.78-0.92). The pooled OR revealed that IP stated better objective overall response than EP regimens (OR = 1.10, 95% CI = 0.92-1.32). Treatment-related deaths were similar between the two groups.
Conclusion: IP regimens could be used as first-line treatment for extensive stage small cell lung cancer patients.

Keywords: Irinotecan, meta-analysis, small cell lung cancer


How to cite this article:
Hu Q, Wang Q, Zhu H, Yao Y, Song Q. Irinotecan compared with etoposide in combination with platinum in previously untreated extensive stage small cell lung cancer: An updated systemic review. J Can Res Ther 2016;12:881-7

How to cite this URL:
Hu Q, Wang Q, Zhu H, Yao Y, Song Q. Irinotecan compared with etoposide in combination with platinum in previously untreated extensive stage small cell lung cancer: An updated systemic review. J Can Res Ther [serial online] 2016 [cited 2019 Dec 10];12:881-7. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/881/138002




 > Introduction Top


Lung cancer is one of the most common human malignant diseases and the leading cause of cancer-related death in Western society. It accounts for 87,697 deaths in males and 70,389 deaths in females of American in 2009.[1] Small cell lung cancer (SCLC) accounts for approximately 15% of new cases of lung cancers and is one of the most aggressive types of cancer with fast growth and early metastatic spread characteristics.[2] At the time of presentation, more than two-thirds of patients present with extensive disease (ED), which is characterized by distant lymph node or organ metastases. Although SCLC is initially considered chemotherapy-sensitive, and response rates to first-line chemotherapy are relatively high, median survival is 8–10 months and 1-year survival rates are 30–40% only.

In most countries, etoposide in combination with cisplatin (etoposide/platinum [EP]) or carboplatin is considered the standard of care in the extensive stage. Since decades, different combinations using new generation drugs, such as gemcitabine and paclitaxel, were tried out in several clinical trials. Nevertheless, the results have not shown advantages in terms of survival.[3],[4],[5] In 2002, the first evidence for a superiority of irinotecan over etoposide in combination with cisplatin had been reported in a Japanese phase III clinical trial.[6] Hermes et al.[7] also found that irinotecan plus carboplatin (irinotecan/platinum [IP]) improved survival in extensive SCLC with better quality of life. However, another large clinical trial [8] failed to confirm the same result. The inclusion criteria of patient, difference in dose and schedule of IP and EP may influence the results of different clinical trials. The Southwest Oncology Group (SWOG) designed another phase III randomized controlled study (SWOG 0124) in North American patients with ED-SCLC, in which both dose and schedule of IP and EP were the same with Japan Clinical Oncology Group (JCOG) 9511.[2] Unfortunately, SWOG 0124 also failed to repeat the positive results. Following several large phase III randomized controlled trials (RCTs) completed, the results still remain controversial.[9],[10],[11],[12],[13] Therefore, we conducted a meta-analysis to pool available data, as an attempt to comparing IP regimens versus EP regimens in first-line therapy for patients with ED-SCLC.


 > Materials and Methods Top


Publication search

Systematic computerized searches of PubMed, EMBASE, ISI Web of Science databases, and Chinese National Knowledge Infrastructure without language restriction (up to September 14, 2014) were performed. The search was further augmented by checking the clinical trial registry (www.clinicaltrials.gov) for additional studies. Following search terms were utilized “SCLC” or “small cell lung carcinoma,” “chemotherapy,” “etoposide,” and “irinotecan.” The search was limited to human studies. All eligible studies were retrieved, and their bibliographies were checked for further relevant publications. The results of an RCT are often published in a series of articles, thus when the same data were used in several publications, the most recent, largest, or complete study of these publications was included in this meta-analysis.

The included studies met the following criteria: (1) RCTs published as articles that compared EP versus IP in patients with previously untreated ED-SCLC; (2) patients had pathologically confirmed SCLC and diagnosed ED-SCLC; (3) studies with full-text articles. Exclusion criteria included: (1) Reviews, tutorials, and letters; (2) not case–control studies; (3) animal studies; (4) duplicate data.

Data extraction

The following information was carefully extracted from all eligible studies:First author's name, year of publication, the number of patients screened, amount of patients eligible for response evaluation, performance status, first- and second-line treatment protocols, evaluation criteria, and median follow-up time. The primary endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Other points of interest included incidence of Common Toxicity Criteria scale, Grade 3/4 toxicities. Data extraction was performed independently by two of the authors, and disagreements were resolved by discussion. If the two authors could not reach a consensus, another author was consulted, and a final decision was made by voting.

Statistical methods

The comparison of EP to IP according to PFS or OS was expressed as a hazard ratio (HR). For those trials that did not provide this information, data were extracted from published survival curves were available to estimate the values of the log HR and variance according to previously described methods.[14] Heterogeneity was assessed by the Q-test.[15],[16] If significant heterogeneity was found (P < 0.10, I2 > 40%), the random-effects model instead of the fixed-effects model was used for further analysis. The further stratified analysis was conducted as required. Begg's test [17] and Egger's test [18] was used to assess publication bias, which was adjusted using the trim-and-fill method. All the statistical tests used in this meta-analysis were performed with RevMan 5.3 (Cochrane Collaboration, Oxford, United Kingdom) and STATA version 10.0 (Stata Corporation, College Station, TX, USA).


 > Results Top


Characteristics of the included studies

907 reports were retrieved originally after electronic searching. After exclusion of duplicate and irrelevant studies [Figure 1], ten studies were identified according to the inclusion criteria of the meta-analysis. Among these nine studies, five studies in western society and five in Asia. Considering the ten selected studies, cisplatin was the platinum compound evaluated in most trials, two studies used carboplatin, and one used nedaplatin. Seven studies provided sufficient data of survival time, only three studies illustrated amount of patients received 2nd line treatment and the detailed treatment regimens. In total, the ten RCTs were comprised of a total of 2319 patients, with sample sizes ranging from 61 to 671. Response Evaluation Criteria in Solid Tumor criteria or World Health Organization criteria were used to classify tumor response in all studies. Detailed information of these articles was listed in [Table 1].
Figure 1: Flow chart of literature search and study selection procedure

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Table 1: Characteristics of included literatures

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Objective response rate

Information concerning ORR was available in 9 studies. Hermas et al.[7] only reported number of complete response patients and did not supplied number of patients who were non-responders, so the analysis excluded it. A total of 2048 ED-SCLC patients included in the analysis, after rondomization, 1077 patients received IP regimens and 971 patients received EP regimens. IP regimens versus EP regimens analysis was feasible with acceptable heterogeneity (χ2 = 8.86, I2= 10%, P = 0.35). The pooled OR for ORR of IP regimens over EP regimens was 1.10 (95% CI = 0.92–1.32). There was no significant difference in ORR between IP and EP regimens. We further conducted stratified analysis according to ethnicity and platinum compound. Asians were enrolled in five studies, Caucasians were enrolled in four studies. The subgroup analysis based on ethnicity suggested ethnicity was attributed to heterogeneity (Asians: χ2 = 2.45, P = 0.65; Caucasians: χ2 = 3.06, P = 0.38). In the studies enrolled Asians, IP could acquire more overall response than EP regimens (OR = 1.55, 95% CI = 1.03-2.31; shown in [Figure 2]). However, the analysis conducted among Caucasians failed to show same conclusion. No publication bias was found by Begg's test (P = 0.108) and Egger's test (P = 0.193).
Figure 2: Overall response rate meta-analysis of irinotecan versus etoposide-based chemotherapy in extensive-stage small cell lung cancer

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Progression-free survival

Information on PFS comparing IP and EP protocols in ED-SCLC patients was available in 6 articles. The heterogeneity test yield a significant result (χ2 =14.41, I2= 65%, P = 0.01) and the pooled HR for PFS was calculated using random-effects model. Compared to EP regimens, ED-SCLC patients did not seem to benefit from IP as first-line treatment (HR = 0.94, 95% CI = 0.84–1.05; shown in [Figure 3]). Stratified analyses based on ethnicity and platinum compound showed similar survival benefit in EP and IP regimens. However, The subgroup analysis based on ethnicity reduced between-study heterogeneity(Western: χ2=5.6, I2=46%, P = 0.13; Asian: χ2 = 8.58, I2=88%, P = 0.003) and suggested ethnicity might be the major resources of heterogeneity. The Begg's test (P = 0.133) and Egger's test (P = 0.277) showed no evidence of publication bias in meta-analysis.
Figure 3: Progression-free survival meta-analysis of irinotecan versus etoposide-based chemotherapy in extensive-stage small cell lung cancer

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Overall survival

5 studies provided adequate information on OS comparing IP and EP regimens in previously untreated ED-SCLC patients. There was no statistically significant heterogeneity and the pooled HR was calculated using fixed-effects model (χ2 = 10.58, I2=43%,

P = 0.10). Overall, among ED-SCLC patients, the analysis showed survival benefit of IP regimens (HR = 0.85, 95% CI = 0.78–0.92). The subgroup analysis based on ethnicity revealed that Caucasians had survival benefit from IP regimens compared to EP regimens (HR = 0.92; 95%CI = 0.68-0.98; shown in [Figure 4]). The subgroup analysis of Asians showed no significant difference between two regimens. We excluded Noda's study and conducted meta-analysis again. The pooled HR is 0.87 (95% CI = 0.80–0.95) without significant heterogeneity (χ2 = 5.39, I2 = 7%, P = 0.37). Begg's test (P = 0.072) and Egger's tests (P = 0.034) revealed that there might be some unpublished positive articles, especially some small sample size studies, were not included in the meta-analysis.
Figure 4: The pooled analysis for overall survival of irinotecan versus etoposide-based regimen in extensive-stage small cell lung cancer

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Adverse reaction

The toxic effects were classified as hematologic and non-hematologic toxicity. The hematologic toxicity included anemia, leukopenia, neutropenia, thrombocytopenia and febrile neutropenia. We conducted a meta-analysis of grade 3/4 hematologic toxicities that decreased quality of life. There was no patient experienced anemia in Wang Xiaojie's study, so we excluded it in analysis of anemia. The IP regimens led to less grade 3 to 4 hematologic toxicities than EP regiments (leukopenia: OR = 0.41, 95% CI = 0.25-0.66; neutropenia:

OR = 0.25, 95% CI = 0.16–0.42; thrombocytopenia: OR = 0.38, 95% CI = 0.23–0.62; febrile neutropenia: OR = 0.35, 95% CI = 0.21–0.59; anemia: OR = 0.64, 95% CI = 0.46–0.89).

The non-hematologic toxicities included diarrhea, nausea, vomiting, infections and treatment-related death. We excluded Wang Huijuan's study in diarrhea analysis due to no patient underwent diarrhea in her study. There was statistically significant heterogeneity in analysis, so we conducted meta-analyses in random-effects model in order to the conservation of conclusions. The analyses showed that IP resulted in more grade 3/4 non-hematologic toxicities than EP regimens (diarrhea: OR = 8.87, 95% CI = 4.27–18.19; nausea: OR = 1.63, 95% CI = 1.15–2.30; vomiting: OR = 2.00, 95% CI = 0.96–4.18). Although EP regimens led to more hematologic toxicities than IP regimens, the incidence of infections was similar between two regimens. Treatment-related deaths were also comparable between the two groups (OR = 1.11, 95% CI = 0.49–2.50). No publication bias was Begg's test and Egger's test, indicating the results were statistically robust.


 > Discussion Top


The current standard chemotherapy for extensive SCLC – a treatment protocol of etoposide and cisplatin or alternating with doxorubicin- and vincristine-based platinum regimens – yields a median survival time of 8–10 months and 2-year survival rate of 10%. In JCOG 9511,[6] the Japanese study showed superior efficacy with irinotecan compared with etoposide in combination with the platinum compound in ED-SCLC patients and gave rise to a sequence of trials interested in irinotecan in SCLC. Hermes et al.[7] conducted a phase III RCTs using carboplatin instead of cisplatin. His study found IP regimens had better short-term efficacy and longer survival time than EP regimens. Following clinical trials could not identify significant differences in efficacy between irinotecan and etoposide in combination with a platinum compound.[9],[10],[11],[12],[13]

The main result of this meta-analysis is significant OS improvement in IP regimens compared with EP regimens. In the index of short-term efficacy – ORR and PFS, there was no statistically significant difference between two regimens. Further stratified analysis revealed ethnicity was the main resources of heterogeneity. Possible explanations could be attributed to differences in pharmacogenomics between different populations as demonstrated for differences in polymorphisms of genes involved in the metabolism or transport of drugs. The active metabolite of irinotecan, SN-38, is a substrate for UGT1A1, an enzyme catalyzing glucuronidation of SN-38, making it into an inactive metabolite. TSn-38 was also a target of ABCB1, which transported SN-38 out of the cell. The polymorphisms of UGT1A1 and ABCB1 could affect the gene product's function and might affect the function of SN-38 transport and metabolism, leading to clinically evident effects. SWOG 0124[2] found that UGT-1A1 G3156A, ABCB1 C3435T were associated with specific toxicities, such as diarrhea and neutropenia, but no clear correlation with chemotherapy efficacy was detected, possibly because of the limited amount of patients. Meta-analysis of OS showed IP regimens acquired longer OS than EP regimens in previously untreated ED-SCLC. Subgroup analysis based on ethnicity found that Caucasians had a survival benefit from IP regimens compared to EP regimens, but not applied to Asians. The definitive conclusion needs to be further explored and verified in more large RCTs. We excluded JCOG 9511[6] and conducted meta-analysis again. The OS improvement was still statistically significant in IP regimens than EP regimens with decreased heterogeneity. JCOG 9511 might be the main resource of heterogeneity in OS meta-analysis. The great treatment effect of IP regimens in the interim analyses led to the early stopping of JCOG 9511, which diminished when a sufficient number of events occurred. In the next place, JCOG 9511 had imbalances in the distribution of patients. There were fewer patients with borderline performance status, more woman and fewer brain metastases in the experimental group. Therefore, the heterogeneity between studies was decreased after excluding the JCOG 9511. At last, our results showed that IP produced less Grade 3/4 hematologic toxicities and more Grade 3/4 nonhematologic toxicities, such as diarrhea and nausea.

Several limitations of our meta-analysis need to be considered when interpreting these findings. First, several studies not directly provided HR, the HR acquired from Kaplan–Meier survival curve was not accuracy. Furthermore, the inclusion criteria and treatment protocols were not consistent. SWOG 0124[2] and JCOG 9511[6] used the same treatment protocols. However, SWOG 0124 excluded patients with performance status <2. Zatloukal et al.[10] and Hanna et al.[8] employed similar chemotherapeutic regimens, but Zaloukal used higher cisplatin dose than Hanna. Thus, it can be seen that chemotherapeutic regimens among different studies were not strictly consistent. General conditions, comorbidity and other clinical factors were taken consideration into inclusion criteria but were also different depending on hospital circumstances. Finally, it is apparent that SCLC is a heterogeneous disease. Moreover, OS were not only influenced by patient's condition and treatment protocols but also affected by environment and genetic background. These factors influenced results inevitably.

This systematic review indicated that IP provided longer OS compared to EP. Among Asians, IP regimens could acquire more objective overall response than EP regimens. The toxicity profile of irinotecan was acceptable, and treatment-related deaths were comparable between IP and EP regimens. In conclusion, the meta-analysis suggested that IP regimens might be strongly considered as a standard first-line treatment for patients with extensive stage SCLC.[19]

Acknowledgments

This work was supported by the National Natural Science Foundation of China 81372407 to Qibin Song. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China 81372407 to Qibin Song.

Conflicts of interest

There are no conflicts of interest.

 
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