The evidence supporting this regimen comes from 2 randomised phase III trials by Thuss-Patience et alr and Kang et al.r
Thuss-Patience et alr
Between October 2002 and December 2006, 21 patients were randomised to receive irinotecan (irinotecan 250 mg/m2 cycle 1 and increased to 350 mg/m2 in subsequent cycles as tolerated; repeated every 3 weeks) and 19 patients were randomised to best supportive care.
The primary end point was overall survival and secondary end points were response rate, time to tumour progression and toxicity. The study was closed prematurely due to poor accrual.
In the second line setting, three weekly irinotecan significant prolonged overall survival compared to best supportive care in the studied patients. The median overall survival (OS) improved to 4 months for irinotecan arm compared to 2.4 months in the best supportive care (BSC) arm (p-value=0.012; HR:0.48, 95% CI: 0.25-0.92).
Kang et alr
Between September 2008 and September 2010, 126 patients were randomised to receive salvage chemotherapy (irinotecan 150 mg/m2 repeated every 2 weeks or docetaxel 60 mg/m2 every 3 weeks) plus best supportive care and 62 patients were randomised to best supportive care.
The primary end point was overall survival.
Compared to best supportive care in the second or third line setting, for ECOG 0 and 1 patients, irinotecan delivered at 150 mg/m2 every two weeks improved overall survival from 3.8 months in best supportive care arm to 5.3 months in salvage chemotherapy arm (p=0.007). An exploratory analysis demonstrated no significant overall survival difference between salvage chemotherapy options of docetaxel (n=66) compared to irinotecan (n=60), 5.2 months vs 6.5 months respectively (p=0.116).
Efficacy
Thuss-Patience et alr
Efficacyr |
Irinotecan (n=21) |
BSC (n=19) |
p-value |
Overall survival |
4 months |
2.4 months |
0.012 |
Kaplan-meier curves of overall survival (intention to treat population)r
© European Journal of Cancer 2011
Optional dose escalation of irinotecan to 350 mg/m2 was dependent on toxicity. 37% of patients underwent this dose escalation according to protocol. Assessment of quality of life using the EORTC QLQ C30 questionnaire was planned but return of the forms was too poor to undertake meaningful analyses.
Kang et alr
Efficacyr |
Arm A (n=126) |
Arm B (n=62) |
p-value |
Overall survival |
5.3 months |
3.8 months |
0.007 |
Arm A: salvage chemotherapy (docetaxel or irinotecan), Arm B: best supportive care
Exploratory analysis - Docetaxel vs irinotecan
Efficacyr |
Docetaxel (n=66) |
Irinotecan (n=60) |
p-value |
Overall survival |
5.2 months |
6.5 months |
0.116 |
Kaplan-meier curves of overall survivalr
© Journal of Clinical Oncology 2012
No data on quality of life was collected.
Toxicity
Thuss-Patience et alr
Grade 3/4 diarrhoea and neutropenia occurred in 26% and 21% of patients treated with three weekly irinotecan respectively.
Grade 3/4 Toxicity |
Arm A: Irinotecan (n=19)
% |
Nausea |
5 |
Vomiting |
5 |
Diarrhoea |
26 |
Neutropenic fever |
16 |
Leucocytopenia |
21 |
Thrombocytopenia |
- |
Haemoglobin |
11 |
Kang et alr
Grade 3/4 diarrhoea and neutropenia occurred in 8% and 18% of patients treated with two weekly irinotecan respectively.
Grade 3/4 Toxicity |
Docetaxel (n=66)
% |
Irinotecan (n=60)
% |
BSC (n=62)
% |
Neutropenia |
15 |
18 |
2 |
Anaemia |
30 |
32 |
23 |
Thrombocytopenia |
2 |
3 |
0 |
Fatigue |
26 |
10 |
27 |
Anorexia |
20 |
5 |
10 |
Nausea |
19 |
3 |
6 |
Diarrhoea |
9 |
8 |
5 |
Stomatitis |
11 |
5 |
2 |
BSC: best supportive care