Background: Much research has confirmed the favorable effect of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) on extensive-stage small cell lung cancer (E-SCLC). This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC.
Methods: Ninety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS), ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP. 
Results: Median overall survival was 15.4 months in group A (IP followed by EP) versus 15.7 months in group B (EP followed by IP; P=0.483). The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361). As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256). Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as second-line treatment developed grade 3/4 neutropenia than those who received the IP regimen as first-line therapy.
Conclusion: There were no statistically significant differences in between the two sequences of IP and EP in the treatment of E-SCLC. Except EP regimen, IP may be another reserved regimen in the first-line treatment of E-SCLC.
Keywords: small cell lung cancer, sequential chemotherapy, irinotecan, etoposide


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INTRODUCTION

Small cell lung cancer (SCLC) accounts for nearly 15% of new lung cancer cases and for about 25% of lung cancer deaths annually.1 Although the efficacy of chemotherapy for SCLC may be as high as 80%, the 1-year and 2-year survival rates are only 35%–45% and 10%–20%, respectively.2 The long-term prognosis is very poor. Chemotherapy plays a key role in the treatment of extensive-stage SCLC (E-SCLC), in that it not only alleviates symptoms but also prolongs survival in most patients.3,4Etoposide and cisplatin (EP) is a classic chemotherapy regimen and is very widely used.5,6 The traditional standard treatment for E-SCLC is etoposide and cisplatin, and this combination alternating with a regimen of cyclophosphamide, doxorubicin, and vincristine yields a median survival of 8–10 months and a 2-year survival rate of 10%. Some newer agents, including the taxanes, vinorelbine, gemcitabine, topotecan, and irinotecan have shown significant activity in single use. However, in the last decade, a large number of platinum-based combination therapies tested in Phase III trials failed to demonstrate efficacy superior to that of EP, until the advent of irinotecan.7 In 2000, the Japan Clinical Oncology Group reported a randomized clinical trial (JCOG-9511) of 154 patients with E-SCLC treated with irinotecan in combination with cisplatin (IP) or EP as first-line treatment. Median overall survival (OS) was significantly longer in the IP group than in the EP group (12.8 months and 9.4 months, respectively, P<0.002).8 This was the first trial in over 20 years to demonstrate a significant improvement in survival using a regimen other than EP. Hermes et al subsequently reported that IP not only improved quality of life scores but also prolonged survival in patients with E-SCLC,9 and a further clinical trial demonstrated that IP could improve PFS compared with less toxicities in E-SCLC.10,11 Therefore, the National Comprehensive Cancer Network guidelines added the IP protocol as a first-line therapy for patients with E-SCLC. However, two subsequent randomized studies conducted in the USA, Canada, and Australia failed to demonstrate a difference in OS between their IP and EP treatment arms, so the role of the IP regimen remains controversial in patients with E-SCLC.12