For more than two decades, etoposide in combination with cisplatin has been the standard chemotherapy regimen for small cell lung cancer (SCLC). The standard treatment regimen currently in use is etoposide in combination with cisplatin for limited-stage small cell lung cancer, followed by early concurrent thoracic radiotherapy and then prophylactic cranial radiotherapy. This regimen was established by the INT0096 trial1 in 1999. In recent years, however, progress in standard regimens of chemotherapy for small cell lung cancer has been lacking, not because of insufficient effort, but because of the lack of reproducible evidence in clinical trials for many novel treatment regimens. The most widely studied alternative regimen is irinotecan in combination with cisplatin. This option attracted much attention with the report of a randomized clinical trial2 from the Japanese Clinical Oncology Group (JCOG), which showed a significant improvement in survival with irinotecan combined with cisplatin over etoposide combined with cisplatin for extensive stage SCLC. However, the results of the clinical trial threw cold water on this, as it failed to demonstrate the superiority of irinotecan combined with cisplatin over etoposide combined with cisplatin in patients with non-Japanese extensive SCLC. Since then, two Meta-analyses have shown that irinotecan improves overall survival, and the debate over the superiority of irinotecan versus etoposide will continue. In a randomized trial including 281 Japanese patients with limited-stage SCLC, patients were initially treated with etoposide in combination with cisplatin followed by accelerated hyperfractionated thoracic radiation therapy (AHTRT) and then consolidated with irinotecan in combination with cisplatin and etoposide in combination with cisplatin. Compared to previous JCOG studies comparing several treatment regimens for extensive SCLC, this trial did not demonstrate a significant difference in overall survival between irinotecan in combination with cisplatin versus etoposide in combination with cisplatin. The effectiveness of irinotecan in combination with cisplatin in locally advanced lung cancer was explored in a phase 1 and phase 2 trial, respectively. Considering the radiosensitizing properties of irinotecan, the use of irinotecan in combination with cisplatin was attempted in the preliminary study, along with concurrent thoracic radiotherapy. (For safety reasons, this regimen was changed to irinotecan combined with cisplatin as induction or consolidation therapy, evaluated before or after etoposide combined with cisplatin and thoracic radiotherapy.) In addition, the results of two phase 2 studies show that the current JCOG trials present reasonable treatment outcomes using the same regimen, with etoposide in combination with cisplatin for one cycle of simultaneous accelerated hyper-segmented thoracic radiation therapy (AHTRT) and sequential irinotecan in combination with cisplatin for three cycles. Importantly, overall survival in these trials was not significantly different from INT0096 after four cycles of treatment with etoposide plus cisplatin in combination with AHTRT, with median overall survival of 20 months and 23 months vs. 23 months, respectively; at two years, patient survival in the study was 41% and 49% vs. 47%, respectively. In a retrospective analysis, the investigators concluded that these findings predicted a negative outcome in the JCOG trial and suggested that clinical investigators should raise the bar for positive Phase 2 trial results. In a comprehensive analysis of the results of previous phase 2 trials, it was concluded that the best outcome for the current trial was an improvement in overall survival at the borderline of clinical statistical significance. Why did this study fail to demonstrate any improvement with irinotecan in combination with cisplatin? The most likely explanation is that, despite the previous JCOG study and the recent Meta-analysis, irinotecan in combination with cisplatin was not substantially superior to etoposide in combination with cisplatin. The drug regimen applied in this study is identical to that used by the JCOG for the treatment of extensive stage SCLC, except for the staging, and the inclusion criteria for the subject population are essentially the same, with patients under 70 years of age being included. The current trial showed clinical results that irinotecan in combination with cisplatin was more toxic than etoposide in combination with cisplatin. The data suggest that because of the greater toxicity of irinotecan in combination with cisplatin therapy, the acceptable dose intensity is lower and a large proportion of patients discontinue treatment. Importantly, previous interim analyses of the JCOG trial in extensive-stage SCLC showed positive results, so the trial was terminated early, and favorable results in a small sample size of patients may have led to misleading conclusions. The JCOG trial began 11 years ago in 2002. Is a trial designed to compare the efficacy of two cytotoxic chemotherapeutic agents still relevant in today’s era of genomics-based individualized medicine? Could topoisomerases I and II still be targets for future drugs? Unfortunately, today cytotoxic chemotherapeutic agents remain an essential part of the standard of care for small cell lung cancer, and the choice of treatment regimen remains a major clinical challenge. Many molecular targets for small cell lung cancer have long been identified, yet therapeutic strategies for these targets have not yielded promising results in clinical trials to date. Now that SCLC is entering the era of broad genetic analysis, more trials will explore new therapeutic options using genetic analysis. This is the hope for the future. However, the current reality is that even with the best treatment options, only 1/3 of patients with limited-stage SCLC survive beyond 5 years. Nevertheless, etoposide in combination with four cycles of cisplatin plus early concurrent thoracic radiotherapy remains the standard chemotherapy regimen for the treatment of patients with limited-stage SCLC.