Background
Lung cancer, which represents 13% of newly diagnosed cancers worldwide, is the most common tumor type [
1]. Small cell lung cancer (SCLC) accounts for approximately 15% of new cases of annually diagnosed lung cancer, and up to 25% of lung cancer deaths each year [
2]. Approximately two-thirds of patients with SCLC are diagnosed with extensive-stage disease [
3], which is defined as disease dissemination beyond the ipsilateral hemithorax including malignant pleural or pericardial effusion or hematogenous metastases [
4]. Over the past 20 years, the standard therapy for most patients with extensive-staged small cell lung cancer (ES-SCLC) has been either carboplatin or cisplatin in combination with etoposide (EP) [
5]. In 2002, the Japan Clinical Oncology Group (JCOG-9511) first acquired evidence for superior outcomes following therapy with irinotecan in combination with cisplatin (IP). Nevertheless, a subsequent and larger study failed to validate the observed difference survival benefit in JCOG-9511 between the IP and EP treatment arms. In 2010, in a meta-analysis, Jiang et al. [
6] concluded that IP may have an advantage in overall response and OS as compared to EP in patients with ES-SCLC, but did not find superior results in progression-free survival (PFS); however, the authors did not include ethnicity in their analysis. Therefore, our meta-analysis was performed based on these prior studies to compare the efficacies and toxicities of IP and EP in patients with ES-SCLC, and these parameters were further analyzed in patient subpopulations.
Discussion
Chemotherapy is an essential component of appropriate treatment for patients with SCLC [
18]. The current standard treatment is chemotherapy with or without local radiotherapy for patients with SCLC who have a good performance status (0–2), as recommended by the National comprehensive cancer network guidelines as category 1 evidence. EP is the most commonly used chemotherapy regimen. This regimen provides response rates of 60% to 80%, with a median survival time of 8 to 10 months. Thus, chemotherapeutic agents with greater activity are urgently needed.
JCOG previously reported the results of a randomized phase III trial (JCOG9511). They found that irinotecan, an inhibitor of the nuclear enzyme topoisomerase I, could improve OS and PFS when combined with platinum. Nevertheless, a series of studies conducted in America and Europe failed to confirm these positive results [
9‐
12]. More rigorous studies were included in this meta-analysis to further compare efficacy and toxicity between IP and EP regimens; we subsequently analyzed the combined results thereof within the various subgroups.
In this meta-analysis, IP and EP regimens were compared in terms of OS, PFS, ORR, DCR, 1-year survival rate, 2-year survival rate, and common toxic adverse events. We found that an IP regimen significantly improves OS as compared to an EP regimen in ED-SCLC patients. When stratifying subgroup analysis by platinum type and ethnicity, OS results were consistent with the overall results. However, we found that the HRs were lower in patients treated with carboplatin and in Asian patients. These data indicate that irinotecan is superior to etoposide in combination with carboplatin-based chemotherapy, and that Asian patients receive a greater benefit from an IP regimen.
The OS of the patients who received follow-up treatment could be influenced and this may explain the inconspicuous superior result. PFS as a more meaningful measure of treatment effects, a superior outcome of IP treatment was found. That is to say, the IP regimen showed a increase in PFS, and the difference was statistically significant. When we performed subgroup analysis stratified by ethnicity, we found that the HR for Asian patients was 0.79, which was statistically significant (
P = 0.002, 95% CI, 0.68–0.92). The HR for non-Asian patients was 0.92 (95% CI, 0.84–1.01), indicating that the IP and EP regimens led to comparable PFS in this subgroup. This is probably because a reduction of irinotecan often occurs in non-Asian patients who more frequently carry the UGT1A1*28 allele and are thus at an increased risk for severe diarrhea [
19,
20]. Thus, the efficacy of irinotecan might be influenced by dose reduction in non-Asian patients.
Sensitivity analysis was performed excluding the Noda trial (JCOG9511), which prematurely concluded after interim analysis because they found significant differences in OS, and reduced heterogeneity (in OS: P = 0.51, I2 = 0%; in PFS: P = 0.36, I2 = 9%). The HRs, which were 0.87 for OS (95% CI, 0.80–0.94; P = 0.0008) and 0.90 for PFS (95% CI, 0.83–0.98; P = 0.01), were almost in line with the overall results. In addition, a different extent of dose reduction was present in each study. Therefore, we conclude that the trial conducted by Noda et al. (JCOG9511) and the various doses of chemotherapy regimens used in various countries might account for some of the observed heterogeneity in our meta-analysis.
That the pooled RR showed superior ORR of IP regimen implies that more patients will respond to chemotherapy when treated with an IP regimen, especially for Asian patients. Differences in DCR and 1-year survival rate were not statistically significant. Moreover, we found that irinotecan was superior to etoposide in 2-year survival rate. However, the outcome of relatively higher RR for 2-year survival rate warrants further discussion due to the low number of studies and recruited patients.
Toxicity analyses indicated that more patients treated with an IP regimen were likely to experience grade 3–4 diarrhea, and fewer experienced grade 3–4 hematologic toxic effects than those treated with an EP regimen. These results are in agreement with those of previous studies and the meta-analysis of safety of IP and EP [
21]. We also performed subgroup analysis to explore diarrhea as an adverse event. The pooled RR in Asian patients was 5.93 (95% CI, 2.67–13.16; P < 0.0001) and 8.74 in non-Asian patients (95% CI, 5.30–14.41;
P < 0.00001). This indicates that non-Asian patients are more likely to experience grade 3–4 diarrhea. However, the difference was not statistically significant (Chi
2 = 0.65; df = 1;
P = 0.42; I
2 = 0%). This difference occurred might because the aforementioned UGT1A1*28 genotype, which bears a lower allele frequency in Asians than in Caucasians [
19], confers a marked increase in irinotecan-induced grade 3–4 diarrhea [
20]. Thus, a dose reduction of irinotecan is more likely to occur in Caucasians. Meanwhile some in vitro studies indicated that gene polymorphisms in the UGT1A1*6 gene were also associated with irinotecan metabolism [
22,
23]. The frequency of the UGT1A1*6 mutant genotype was higher in Asian patients than in Caucasians [
22]. A meta-analysis by Cheng et al. demonstrated that the heterozygous variant of UGT1A1*6 showed no significant risk for severe diarrhea, while there was a significant risk associated with the homozygous variant [
24]. Therefore, we speculate that the UGT1A1*6 gene polymorphism may have an impact on the development of irinotecan-induced diarrhea in the Asian population. Confounding factors, such as differing doses of irinotecan, and the UGT1A1 gene polymorphism may be the reasons why there was no significant association between ethnicities and development of grade 3–4 diarrhea in populations.
We believe that the strength of this study lies in the fact that we conducted a quality assessment to guarantee that studies of a higher quality were included in the meta-analysis. Furthermore, we performed subgroup analyses of both ethnicity and platinum. Finally, the results were therefore more robust and reliable due to the consequence of sensitivity analysis.
A potential limitation of this meta-analysis is related to the different doses of chemotherapy regimens, and the performance status thereof in the included trials. A lack of information regarding the detailed dosage and performance status information for each of the groups meant that we could not perform the respective subgroup analyses. Another possible bias may have been introduced by the study conducted by Noda et al., which might lead to an overly optimistic result due to its premature conclusion. Additionally, more individual patient data were needed to conduct our meta-analysis, as extracting data from a survival curve inevitably introduced bias.