The evidence supporting the use of cisplatin/irinotecan in the first line setting for extensive disease small cell lung cancer initially came from the JCOG study, a phase III multicentre, randomised trial undertaken in Japan comparing cisplatin/irinotecan vs cisplatin/etoposide. Between November 1995 and November 1998, 77 patients were randomised to receive cisplatin 60 mg/m2 intravenously (IV) on day 1 and irinotecan 60 mg/m2 IV on days 1, 8 and 15 every 28 days and 77 patients were randomised to receive cisplatin 80 mg/m2 IV on day 1 and etoposide 100 mg/m2 IV on days 1 to 3 every 21 days for four cycles. The primary end point was overall survival and secondary end points were objective tumour response rate, progression free survival, sites of relapse and toxicity profile.
The evidence supporting this protocol is provided by the Hanna study, a phase III open label multicentre international randomised trial, involving 331 patients comparing cisplatin/irinotecan with cisplatin/etoposide in patients with previously untreated extensive disease small cell lung cancer. Between December 2000 and June 2013, 221 patients were randomised to receive cisplatin 30 mg/m2 IV and irinotecan 65 mg/m2 IV on days 1 and 8 every 21 days and 110 patients were randomised to receive cisplatin 60 mg/m2 IV on day 1 and etoposide 120 mg/m2 IV on days 1 to 3 every 21 days for at least four cycles, until disease progression or unacceptable toxicity resulted. This 3 weekly cisplatin/irinotecan regimen was chosen in response to the lower rates of drug compliance for irinotecan in the JCOG trial. The primary end point was overall survival and secondary end points were objective tumour response rate, time to disease progression and toxicity profile.
Evidence is also provided by the Kim study, a phase III multicentre randomised trial undertaken in Korea, involving 362 patients comparing irinotecan/cisplatin with etoposide/cisplatin in patients with extensive stage small cell lung cancer. Between June 2006 and November 2011, 173 patients were randomised to receive irinotecan 65 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 IV on day 1 every 21 days. 189 patients were randomised to receive cisplatin 70 mg/m2 IV on day 1 and etoposide 100 mg/m2 IV on days 1 to 3 every 21 days. Treatment in each arm was repeated for a maximum of six cycles. The primary end point was overall survival.
A meta-analysis of seven randomised trials comparing first line irinotecan-platinum doublets versus etoposide-platinum doublets in extensive-disease small cell lung cancer was reported in 2012. Doses and treatment regimens differed between trials.
The overall response rate (84.4% vs 67.5%; p=0.02), median progression free survival (6.9 months vs 4.8 months; p=0.003) and median overall survival (9.4 months vs 12.8 month; p=0.002) were significantly higher in the cisplatin/irinotecan group compared to the cisplatin/etoposide group.
Overall and progression-free survivalr
© N Engl J Med 2002
There was no significant difference in response rates (48% vs 43.6%), median time to progression (4.1 months vs 4.6 months; p=0.37) or median overall survival (9.3 months vs 10.2 months; p=0.74) between the cisplatin/irinotecan and cisplatin/etoposide groups.
Time to progression and overall survivalr
© J Clin Oncol 2006
There was no significant difference in overall survival (median OS 10.9 v 10.3 months, p=0.12) and progression free survival (6.5 years v 5.8 months, p=0.115) between the irinotecan/cisplatin and etoposide/cisplatin groups. There was a significant difference in objective response rate 62.4% and 48.2% (p=0.006) in the irinotecan/cisplatin and etoposide/cisplatin groups respectively.
In the meta-analysis, the pooled hazard ratio for overall survival was found to favour irinotecan-platinum doublet (HR=0.81, 95% CI =0.71-0.93; p=0.003) with no significant heterogeneity (p=0.081). Progression free survival was similar between the two regimens (HR=0.90; 95%CI: 0.76-1.07, p=0.227) but with significant heterogeneity (p=0.012). There was no difference in overall response rate (RR=1.04, 95% CI=0.95-1.13, p=0.378) and test for heterogeneity was not significant (p=0.190).
© J Thorac Oncol 2012
Fewer patients receiving cisplatin/irinotecan had grade 3/4 anaemia, thrombocytopenia and neutropenia compared with patients receiving cisplatin/etoposide, but had more grade 3/4 diarrhoea and vomiting.r,r
© J Clin Oncol 2006r
In the Kim study, more patients receiving irinotecan/cisplatin had grade 3/4 anaemia, nausea and diarrhoea compared with patients receiving etoposide/cisplatin.r
© Cancer Research and Treatment 2018r