INTRODUCTION: Irinotecan has an important place in the treatment of metastatic 
colorectal cancer. It was initially administered as monotherapy, but is now 
generally used in combination with 5-fluorouracil or targeted therapies 
(cetuximab or bevacizumab), with various doses.
METHODS: We here review the main studies assessing irinotecan doses escalation, 
and discuss the potent advantages of this escalation.
RESULTS: Several studies have demonstrated a dose-intensity relationship for 
irinotecan, and high doses (up to 600 mg/m2 as monotherapy, 260 mg/m2 in 
combination therapy) have been used with satisfactory safety and higher 
objective response rates. It is possible that, in practice, some patients 
receive insufficient doses of irinotecan. Dose escalation could be considered in 
carefully selected patients: young patients with a good performance status and 
normal liver function. This approach could be useful in patients with liver 
metastases, which may become resectable in the case of a major tumour response. 
It is wise to perform UGT1A1 genotyping prior to dose escalation to detect 
patients at high risk of toxicity (genotype 7/7). The role of another laboratory 
parameter, which needs to be evaluated is the KRAS status of the tumour. A KRAS 
mutation confers resistance to cetuximab, which reduces treatment options, 
especially in first-line. However, in the CRYSTAL trial comparing FOLFIRI to 
FOLFIRI-cetuximab as first-line therapy, the presence of a KRAS mutation did not 
appear to influence the efficacy of FOLFIRI. The value of irinotecan dose 
escalation needs to be determined in this setting.
CONCLUSION: Irinotecan dose escalation is potentially of interest in highly 
selected patients, but this concept is only based on phase I or II trials and 
must be validated by a randomized trial. Its value regarding other regimens such 
as FOLFIRINOX or combinations with targeted therapies also needs to be 
determined.