Chemotherapy for Small Cell Lung Cancer

Small-cell lung cancer accounts for 20 to 25 percent of all new cases of lung cancer. At diagnosis, 40 percent of patients have limited disease, defined as disease confined to the thorax. With chemotherapy plus radiotherapy and the selective use of prophylactic cranial irradiation, the median survival of these patients is 18 to 24 months, and up to 20 percent of them may survive for more than 2 years. Without treatment, the median survival is only 6 to 12 weeks.

Patients with extensive disease (the remaining 60 percent of all new cases of small-cell lung cancer) have, at the time of diagnosis, metastases involving one or more sites such as the brain, liver, bone, or bone marrow. With combination chemotherapy, the median survival of these patients is seven to nine months, and few, if any, live more than two years. Twenty years of clinical trials involving such patients have yielded an improvement in survival of only two months. The current standard chemotherapy regimen is etoposide plus cisplatin (or carboplatin). In this issue Noda report results with a new combination of irinotecan (a topoisomerase I inhibitor) and cisplatin for the treatment of extensive small-cell lung cancer. They found a 3-month prolongation of the median survival with this combination (12.8 months, vs. 9.4 months with etoposide plus cisplatin), as well as an impressive 2-year survival rate of 19.5 percent with this regimen (as compared with 5.2 percent with etoposide plus cisplatin). These results appear to indicate an advance in the treatment of extensive small-cell lung cancer, but confirmatory trials are required before the new combination becomes the standard of therapy for this disease.

Irinotecan plus Cisplatin Compared with Etoposide plus Cisplatin for Extensive Small-Cell Lung Cancer
Kazumasa Noda,

The usual chemotherapy for extensive small-cell lung cancer is etoposide plus cisplatin or this combination in alternation with a regimen of cyclophosphamide, doxorubicin, and vincristine.1,2,3,4 In preliminary studies, irinotecan hydrochloride, a topoisomerase I inhibitor, was effective against small-cell lung cancer,5 and a phase 2 study of irinotecan plus cisplatin yielded a rate of complete response of 29 percent and an overall response rate of 86 percent (median survival, 13.2 months) in patients with extensive small-cell lung cancer.6 For these reasons, we conducted a randomized, phase 3 study to compare irinotecan plus cisplatin with etoposide plus cisplatin in patients with extensive small-cell lung cancer. We conducted a multicenter, randomized, phase 3 study in which we compared irinotecan plus cisplatin with etoposide plus cisplatin in patients with extensive (metastatic) small-cell lung cancer.

Results The planned size of the study population was 230 patients, but enrollment was terminated early because an interim analysis found a statistically significant difference in survival between the patients assigned to receive irinotecan and cisplatin and those assigned to receive etoposide and cisplatin; as a result, only 154 patients were enrolled. The median survival was 12.8 months in the irinotecan-plus-cisplatin group and 9.4 months in the etoposide-plus-cisplatin group (P=0.002 by the unadjusted log-rank test). At two years, the proportion of patients surviving was 19.5 percent in the irinotecan-plus-cisplatin group and 5.2 percent in the etoposide-plus-cisplatin group. Severe or life-threatening myelosuppression was more frequent in the etoposide-plus-cisplatin group than in the irinotecan-plus-cisplatin group, and severe or life-threatening diarrhea was more frequent in the irinotecan-plus-cisplatin group than in the etoposide-plus-cisplatin group.

Conclusions Irinotecan plus cisplatin is an effective treatment for metastatic small-cell lung cancer.

The current standard chemotherapy for extensive small-cell lung cancer — a regimen of etoposide and cisplatin or this combination alternating with a combination of cyclophosphamide, doxorubicin, and vincristine — yields a median survival of 8 to 10 months and a 2-year survival rate of 10 percent. In this phase 3 study, 77 patients with metastatic small-cell lung cancer who were treated with irinotecan plus cisplatin had a median survival of 12.8 months, whereas the group that received etoposide plus cisplatin had a median survival of 9.4 months (P=0.002). The overall rates of survival in these two groups at two years were 19.5 percent and 5.2 percent, respectively. Volume 346:85-91 January 10, 2002 Number 2