CHICAGO – Cisplatin, etoposide, and irinotecan provide a significant survival advantage over topotecan as second-line chemotherapy in sensitive relapsed small cell lung cancer, but the toxicity of the combination dampened the overall results of the phase III JCOG0605 trial.
The primary end point of median overall survival was 12.5 months with topotecan (Hycamtin) and 18.2 months with cisplatin (Platinol), etoposide, and irinotecan (PEI) chemotherapy (hazard ratio, 0.67; P = .0079).
"This is the first time that combination chemotherapy has demonstrated a survival benefit, compared with single-agent topotecan," Dr. Koichi Goto reported at the annual meeting of the American Society of Clinical Oncology.
PEI chemotherapy also substantially improved median progression-free survival from 3.6 months with topotecan to 5.7 months (HR, 0.50; P less than .0001) and the overall response rate from 26.7% to 84.3% (P less than .01).
Phase II data from the same investigators showed an overall response rate of 78% and a median survival time of 11.8 months with PEI chemotherapy in 40 patients with sensitive relapsed small cell lung cancer (SCLC) (Br. J. Cancer 2004;91:659-65).
"Combination chemotherapy with cisplatin, etoposide, and irinotecan should be considered the standard second-line treatment for sensitive relapsed small cell lung cancer," said Dr. Goto of the division of thoracic oncology, National Cancer Center Hospital East, Kashiwa, Japan.
At first glance, the results seem impressive, but the higher than expected survival rates in both arms suggest the patients were selected, said Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, who was invited to discuss the results.
Patients in the trial also mostly had progression 6 months after initial treatment, and current National Comprehensive Cancer Network guidelines recommend rechallenging such patients with their original chemotherapy regimen.
"Furthermore, the treatment with the three-drug regimen was given at the cost of severe toxicities," he said.
There were higher rates of grades 3/4 leukopenia (80% vs. 51%), febrile neutropenia (31% vs. 6.7%), and diarrhea (7.8% vs. 0%), and 50% of patients treated with PEI required a dose reduction. Dr. Lee noted that these findings support those in other trials where the addition of a third drug in small cell lung cancer creates greater toxicity without providing any further benefit in outcomes.
"This begs the question of whether the outcomes in this trial would have been the same if patients had been merely rechallenged with the same first-line treatment they’d received," he said. "I think the bigger issue though is that we’ve reached a therapeutic plateau with our current chemotherapy options, and we’re going to need to explore some new, innovative strategies in order to make any real, significant differences in this disease."
Topotecan is the only drug approved by the Food and Drug Administration as second-line chemotherapy for relapsed SCLC.
SCLC accounts for about 15% of lung cancers, and without treatment has a median survival from diagnosis of only 2-4 months.
The Japan Clinical Oncology Group 0605 trial enrolled 180 patients, who responded to first-line platinum-based chemotherapy or chemoradiotherapy, but relapsed 90 days or more after the completion of treatment. Patients were evenly randomized to topotecan or PEI chemotherapy. Patients also received granulocyte colony-stimulating factor support.
The median time from completion of first-line chemotherapy to relapse/progression was 148 days in the topotecan arm and 181 days in the PEI arm. A performance status of 0 was present in 44% and 58%, respectively. The median age was 64 years.
There were nine complete responses and 61 partial responses to PEI chemotherapy among 83 patients with measurable lesions, compared with no complete responses and 23 partial responses in 86 such patients treated with topotecan.
The study was supported by grants from the Ministry of Health, Labour, and Welfare of Japan. Dr. Goto reported no financial disclosures.