Irinotecan, a key chemotherapeutic drug for metastatic colorectal cancer

Table 1 Representative phase III clinical trials evaluating first-line chemotherapies in patients with metastatic colorectal cancer

Trials (primary endpoint)	Regimens	Overall survival (OS) (mo)	P value	Progression-free survival (PFS) (mo)	P value	Response rate (RR)	P value	Ref.
0038 (PFS)	5-FU/LV	12.6	0.040	4.3	0.004	21%	< 0.001	[33]
	IFL	14.8		7.0		39%
V303 (RR)	5-FU/LV	14.1	0.031	4.4	< 0.001	22%	< 0.005	[34]
	FOLFIRI	17.4		6.7		35%
(PFS)	5-FU/LV	14.7	0.120	6.2	< 0.001	22.3%	< 0.001	[35]
	FOLFOX	16.2		9.0		50.7%
V308 (2nd PFS)1	FOLFIRI→FOLFOX6	21.5	0.990	8.5	0.260	56%	> 0.05	[39]
	FOLFOX6→FOLFIRI	20.6		8.0		54%
GONO (RR)	FOLFIRI	16.7	0.032	6.9	0.001	41%	< 0.001	[40]
	FOLFOXIRI	22.6		9.8		66%
NO16966 (PFS)	FOLFOX/CapeOX	19.9	0.077	8.0	0.002	49%	0.310	[45]
	FOLFOX/CapeOX + Bev	21.3		9.4		47%
CRYSTAL (PFS)	FOLFIRI	18.6	0.310	8.0	0.048	38.7%	0.004	[42]
	FOLFIRI + Cet	19.9		8.9		46.9%
PRIME (PFS)	FOLFOX	19.7	0.072	8.0	0.020	48%	0.068	[46]
	FOLFOX + Pan	23.9		9.6		55%
FIRE-3 (PFS)	FOLFIRI + Bev	25.0	0.017	10.3	0.550	58%	0.180	[44]
	FOLFIRI + Cet	28.7		10.0		62%
TRIBE (PFS)	FOLFIRI + Bev	25.8	0.054	9.7	0.003	53.1%	0.006	[3]
	FOLFOXIRI + Bev	31.0		12.1		65.1%

¹Second PFS for FOLFIRI followed by FOLFOX6 and FOLFOX6 followed by FOLFIRI was 14.2 and 10.9 mo, respectively. Anticancer drugs; Bev: Bevacizumab; Cet: Cetuximab; 5-FU: 5-fluorouracil; LV: Leucovorin; Pan: Panitumumab: Regimens; CapeOX: Capecitabin and oxaliplatin; IFL: Irinotecan and bolus 5-FU/LV; FOLFIRI: Irinotecan, bolus 5-FU/LV and infusional 5-FU; FOLFOX: Oxaliplatin, bolus 5-FU/LV and infusional 5-FU; FOLFOXIRI: Irinotecan, oxaliplatin, bolus 5-FU/LV and infusional 5-FU.

Table 2 Factors affecting SN-38 exposure and dosage recommendation of irinotecan summarized in this review

Factors	Exposure to SN-38	Irinotecan-induced toxicity	Dosage recommendation	Ref.
Pharmacogenetic factors
UGT1A1*6 and *28	AUC ↑	Severe neutropenia (diarrhea)↑	Need to be reduced (prescription information in the US and Japan etc.)	[10-13,53,54,59,60]
SLCO1B1*15	AUC ↑	Severe neutropenia↑	No recommendation exists (need to be reduced?)	[62-64,67]
Physiological factors
Age (elderly patients)	Comparable to younger	Comparable to younger	No need to be modified	[82,87-89]
Body size (obesity)	Similar in BSA-based and flat-fixed dosing	Similar in BSA-based and flat-fixed dosing	No need to be modified (flat-fixed dosing)	[48,54,68]
Organ dysfunctions
Liver	AUC ↑	Severe neutropenia (diarrhea)↑	Need to be reduced	[95-97]
Kidney	AUC ↑	Mild to moderate, but prolonged neutropenia	Probably need to be reduced	[101,103]
Gender	Lower in female?	Severe hematologic toxicity in female?	No recommendation exists	[8,65,88,112,113]
Environmental factors
Medication (drug-drug interactions)	No data available	Polypharmacy-related toxicity	No recommendation exists	[114]
Life style
Smoking	AUC ↓	Lower toxicity	No recommendation exists	[115]

AUC: Area under the plasma concentration-time curve.