Small-Cell Lung Cancer Treatment: Where is the Target?

Abstract

Chemotherapy is very effective for the treatment of small-cell lung cancer (SCLC). Despite the initial high response rates (RR), chemotherapy is rarely curative for extended stage (ED)-SCLC patients. In contrast to the high efficacy of first-line chemo therapy, the RR and progression-free survival of second-line treatment are very modest. Patients refractory to first-line treatments (progression during treatment) and chemotherapy (disease progression within 3 months of last chemotherapy) often gain insignificant ben efit from second-line treatments. Sensitive relapsed SCLC patients (progression 3 months after last chemotherapy) can be retreated with the first-line regimen or switched to secondline chemotherapy. However, they only represent a small proportion of patients and they generally become refractory to the treatment. 1 Multiple chemotherapeutic regimens have been tested in ED SCLC as first-line treatment with similar good RR, progression-free sur vival, and overall survival (OS) outcome. A systemic review of 5530 SCLC patients treated with platinum- versus nonplatinum-based regimens showed that there were no differences in RR and 12- or 24-month survival. 2 Currently, cisplatin and etoposide (PE) remain the most popular standard treatment for SCLC. Several new chemotherapeutic agents, including amrubicin, irinotecan, and topotecan, show good therapeutic activity as second-line treatments of SCLC. Noda et al. 3 compared the combination of irinotecan plus cisplatin (IP) with PE in 154 Japanese SCLCs. The median OS was improved from 9.4 months for patients receiving PE to 12.8 months with IP combination (hazard ratio: 0.60, p = 0.002) in the prematurely closed phase III study. However, the superiority of IP in ED SCLC was not confirmed by subsequent phase III studies. One possible explanation for the different results between this Japanese trial and the other trials is the ethnic pharmacogenomic factor between East Asian and Caucasian populations. The presence of ABCB1 and UGT1A1 gene polymorphism variants that alter irinotecan metabolism in the cellular level were correlated to the increased toxicity of diarrhea or neutropenia in Japanese populations. However, neither genotype seemed to predict efficacy outcome. The therapeutic effect of IP in SCLC has been confirmed in the meta-analysis; the results showed that irinotecan platinum regimen is borderline superior in RR (p = 0.043) and OS (p = 0.044) over the etoposide platinum combination. Moreover, when only cisplatin regimens were included in the meta-analysis, the difference between IP and PE became insignificant. 4 Amrubicin plus cisplatin combination was compared with IP in ED SCLC as first-line treatment in a Japanese randomized phase III study. The primary endpoint of noninferiority for patients treated with amrubicin plus cisplatin to IP in OS was not met. The toxicity with amrubicin and cisplatin was higher than that with IP and thus cannot be recommended as first-line treatment. 5