Metastatic colorectal cancer-past, progress and future

Table 1 Common chemotherapy regimens for metastatic colorectal cancer

Regimen	Description Cycle length
5FU Mayo[93,94]	5-FU 425 mg/m2/d D1-5	4 wk
	LV 20 mg/m2/d D 1-5
5FU Roswell Park[45]	5-FU 500 mg/m2/d weekly × 6	8 wk
	LV 500 mg/m2/d weekly × 6
LVFU2[95]	5FU 400 mg/m2 bolus D1 and D2	2 wk
(de Gramont)	LV 200 mg/m2 D1 and D2
	5FU 600 mg/m2 CIVI 22 h D1 and D2
LV5FU2 (AIO)[96]	LV 500 mg/m2 D1 weekly × 6	8 wk
	5FU 2300-2600 mg/m2 CIVI 24 h D1 weekly × 6
Capecitabine[48]	1250 mg/m2 BD, D1-14	3 wk
FOLFOX4[53]	Oxaliplatin 85 mg/m2 D1	2 wk
	LV 200 mg/m2 D1 and D2
	5FU 400 mg/m2 D1 and D2
	5FU 600 mg/m2 CIVI 22 h D1 and D2
FOLFOX6[97]	Oxaliplatin 100 mg/m2 D1	2 wk
	LV 400 mg/m2 D1
	5FU 400 mg/m2 D1
	5FU 2400-3000 mg/m2 CIVI 46 h (D1, D2)
bFOL[98]	Oxaliplatin 85 mg/m2 D1, D15	4 wk
	LV 20 mg/m2 D1, D8, D15
	5FU 500 mg/m2 D1, D8, D15
FUFOX[99]	Oxaliplatin 85 mg/m2 D1, 15, 29;	8 wk
	LV 20 mg/m2 D1, 8, 15, 22, 29;
	5FU 500 mg/m2 D 1, 8, 15, 22, 29
FLOX[100]	Oxaliplatin 85 mg/m2 D1 wk 1, 3, 5	8 wk
	5FU 500 mg/m2 bolus weekly wk 1-6
	LV 500 mg/m2 bolus weekly wk 1-6
FOLFIRI[63]	Irinotecan 180 mg/m2 D1,	2 wk
	LV 200 mg/m2 D1 and D2,
	5FU 400 mg/m2 bolus D1 and D2,
	5FU 600 mg/m2 CIVI 22h D1 and D2
IFL[62]	Irinotecan 100-125 mg/m2 weekly × 4 wk	6 wk
	LV 20 mg/m2 weekly × 4 wk,
	5FU 400-500 mg/m2 bolus weekly × 4 wk
XELOX[54]	Oxaliplatin 130 mg/m2 D1	3 wk
	Capecitabine 1 g/m2 BD D1-14
CAPOX[55]	Capecitabine 1 g/m2 BD D1-14	3 wk
	Oxaliplatin 70 mg/m2 D1, D8
XELIRI[64]	Irinotecan 200-250 mg/m2 D1	3 wk
	Capecitabine 1 g/m2 BD D1-14
CAPIRI[65]	Capecitabine 1 g/m2 BD D1-14	3 wk
	Irinotecan 100 mg/m2 D1, D8
FOLFOXIRI [91,101]	Irinotecan 125-175 mg/m2 D1	2 wk
	Oxaliplatin 85-100 mg/m2 D1
	LV 200 mg/m2 D1
	5FU 400 mg/m2 bolus D1
	5FU 3200 mg/m2 CIVI 48 h

D1: day 1; LV: leucovorin; CIVI: continuous intravenous infusion; BD: twice daily; d: daily.

Table 2 Key phase III trials in metastatic colorectal cancer

Author/trial	n	Arms	RR (%)	TTP (mo)	OS (mo)
Van Cutsem[48]	602	Capecitabine	18.90	5.2	13.2
		5FU/LV Mayo	15.00	4.7	12.1
			(P NA)	(P = 0.65 NS)	(P = 0.33 NS)
De Gramont[53]	420	FOLFOX4	50.70	9	16.2
		LV5FU2	22.30	6.2	14.7
			(P = 0.0001)	(P = 0.0003)	(P = 0.12 NS)
Hochster	147	FOLFOX	41	8.7	19.2
TREE-1[56]		bFOL	20	6.9	17.9
		CapeOx	27	5.9	17.2
			(P NA)	(P NA)	(P NA)
Hochster	213	FOLFOX + bevacizumab	52	9.9	26
TREE-2[56]		bFOL + bevacizumab	39	8.3	20.7
		CapeOx + bevacizumab	46	10.3	27
			(P NA)	(P NA)	(P NA)
Fuchs	430	FOLFIRI	46.60	7.6	23.1
BICC-Ca[66]		mIFL	41.90	5.8	17.6
					(P = 0.10)
		CAPIRI	38	5.5	18.9
			(P NA)	(P NA)	(P = 0.19 NS)
Fuchs	117	FOLFIRI + bevacizumab	54.40	9.9	NR
BICC-C 2[66]		mIFL + bevacizumab	53.30	8.3	18.7
			(P NA)	(P NA)
Saltz[62]	683	IFL	39	7	14.8
		5FU/LV (Mayo)	21	4.3	12.6
			(P < 0.001)	(P = 0.004)	(P = 0.04)
		Irinotecan
Douillard[63]	387	FOLFIRI	35	6.7	17.4
		LV5FU2 (AIO)	22	4.4	14.1
			(P =0.005)	(P < 0.001)	(P = 0.031)
Tournigand[88]	220	FOLFIRI ≥ FOLFOX6	56	8.5	21.5
GERCOR		FOLFOX6 ≥ FOLFIRI	54	8	20.6
			(P = NS)	(P = 0.26 NS)	(P = 0.99 NS)
Goldberg[89]	795	FOLFOX4	45	8.7	19.5
N9741		IFL	31	6.9	15
			(P = 0.002)	(P = 0.0014)	(P = 0.0001)
		IROX	35	6.5	17.4
			(P = 0.03)	(P = 0.001)	(P = 0.09 NS)
Colucci[90]	360	FOLFIRI	31	7	14
		FOLFOX4	34	7	15
			(P = 0.60 NS)	(P = NS)	(P = 0.28 NS)
Ross[71]	200	Mitomycin C + infusional 5FU	54	7.9	14
		Infusional 5FU	38	5.4	15
			(P = 0.024)	(P = 0.033)	(P = NS)
Souglakos et al[91]	283	FOLFOXIRI	43	8.4	21.5
		FOLFIRI	33.6	6.9	19.5
			(P = 0.168 NS)	(P = 0.17 NS)	(P = 0.337 NS)
Falcone [92]	244	FOLFOXIRI	66	9.8	22.6
		FOLFIRI	41	6.9	16.7
			(P = 0.0002)	(P = 0.0006)	(P = 0.032)
Hurwitz[24]	813	IFL + bevacizumab	44.8	10.6	20.3
		IFL	34.8	6.2	15.6
			(P = 0.004)	(P < 0.001)	(P < 0.001)
Giantonio[78]	822	FOLFOX4 + bevacizumab	22	7.2	12.9
ECOGE 3200		FOLFOX4	9	4.8	10.8
				(P < 0.0001)	(P = 0.0018)
		Bevacizumab	Discontinued
Cunningham[81]	329	Cetuximab + irinotecan	22.9	4.1	8.6
BOND-1		Irinotecan	10.8	1.5	6.9
			(P = 0.007)	(P < 0.001)	(P = 0.48 NS)
BOND-2[102]	74	Cetuximab + irinotecan + bevacizumab	38	8.5	n/a
		cetuximab + bevacizumab
			23	6.9	n/a
Peeters[87]	463	Panitumumab		Improved PFS	Approx 6.5 m both arms
		BSC		(HR 0.54 P < 0.0001)	(P = NS)

NS: Not significant; BSC: Best supportive care; NA: Not available. aIn the BICC-C trial all arms were also randomized to +/- celecoxib, which neither improved efficacy nor toxicity of chemotherapy.