Should capecitabine replace 5-fluorouracil in the first-line treatment of metastatic colorectal cancer?

Table 1 Comparison of treatment efficacy as a monotherapy

Clinical trial	Type	Treatments	ORR	PFS (mo)	OS (mo)
Van Cutsem et al[12] (2001)	Phase III	Capecitabine vs 5-FU/LV	18.9% vs 15.0% (P = 0.013)	5.2 vs 4.7 (HR = 0.96, P = 0.65)	13.2 vs 12.1 (HR = 0.92, P = 0.33)
Hoff et al[11] (2001)	Phase III	Capecitabine vs 5-FU/LV	24.8% vs 15.5% (P = 0.005)	4.3 vs 4.7 (HR = 1.03, P = 0.72)	12.5 vs 13.3 (HR = 1, P = 0.97)
Van Cutsem et al[13] (2004)	Integrated Analysis (Phase III)	Capecitabine vs 5-FU/LV	26% vs 17% (P < 0.0002)	4.6 vs 4.7 (HR = 0.99, P = 0.95)	12.9 vs 12.8 (HR = 0.95, P = 0.48)

Capecitabine: 1250 mg/m² every 12 h (days 1-14), 3-wk regimen cycle; 5-FU/LV (Mayo clinic): 425 mg/m² 5-FU bolus + LV 20 mg/m² (days 1-5), 4-wk regimen cycle. ORR: Overall response rate; PFS: Progression-free Survival; OS: Overall survival; HR: Hazard ratio; LV: Leucovorin.

Table 2 Comparison of treatment safety (Grade 3/4 events) as a monotherapy

Clinical trial	Treatments	Diarrhea	Neutropenia	Stomatitis	HFS
Van Cutsem et al[12] (2001)	Capecitabine vs 5-FU/LV	10.7% vs 10.4%	2.0% vs 19.8%a	1.3% vs 13.3%a	16.2% vs 0.3%a
Hoff et al[11] (2001)	Capecitabine vs 5-FU/LV	15.4% vs 13.9%	2.6% vs 25.9%a	3.0% vs 16.0%a	18.1% vs 0.7%a
Cassidy et al[14] (2002)	Capecitabine vs 5-FU/LV	13.1% vs 12.2%	2.3% vs 22.8%a	2.0% vs 14.7%a	17.1% vs 1%a

^aP < 0.05 vs capecitabine group; HFS: Hand-foot syndrome; LV: Leucovorin.

Table 3 Comparison of treatment efficacy in combination with oxaliplatin

Clinical trial	Type	Treatment	ORR	PFS (mo)	OS (mo)
Díaz-Rubio et al[20] (2007)	Phase III	XELOX vs FUOX	37% vs 46% (P = 0.154)	8.9 vs 9.5 (HR = 1.18, P = 0.153)	18.1 vs 20.8 (HR 1.22, P = 0.145)
Cassidy et al[45] (2008)	Phase III	XELOX vs FOLFOX-4+/- Bev	47% vs 48% (OR 0.94)	8 vs 8.5 (HR = 1.04)1	19.8 vs 19.6 (HR = 0.99)
Ducreux et al[42] (2011)	Phase III	XELOX vs FOLFOX-6	42% vs 46%	8.8 vs 9.3 (HR = 1)	19.9 vs 20.5 (HR = 1.02)
Porschen et al[22] (2007)	Phase III	CAPOX vs FUFOX	48% vs 54% (P = 0.7)	7.1 vs 8.0 (HR = 1.17, P = 0.117)	16.8 vs 18.8 (HR = 1.12, P = 0.26)
Comella et al[23] (2009)	Phase III	OXXEL vs OXAFAFU	34% vs 33% (P = 0.999)	6.6 vs 6.5 (HR = 1.12, P = 0.354)	16.0 vs 17.1 (HR = 1.01, P = 0.883)
Hochster et al[25] (2008)	Phase II	XELOX vs FOLFOX-6 vs bFOL+ Bev	27% vs 41% vs 20%; 46% vs 52% vs 39%	5.9 vs 8.7 vs 6.9; 10.3 vs 9.9 vs 8.3	17.2 vs 19.2 vs 17.9; 24.6 vs 26.1 vs 20.4

Treatments: XELOX: Capecitabine 1000 mg/m² every 12 h (days 1-14) + 130 mg/m² oxaliplatin (day 1), 3-wk regimen cycle; FUOX: 2250 mg/m² 5-FU continuous infusion for 48 h (days 1, 8, 15, 22, 29 and 36) + 85 mg/m² oxaliplatin (days 1, 15 and 29) 6-wk regimen cycle; FOLFOX-4: 400 mg/m² 5-FU bolus + 200 mg/m² LV + 600 mg/m² continuous infusion 5-FU for 22 h (days 1 and 2) + oxaliplatin 85 mg/m² (day 1) 2-wk regimen cycle, FOLFOX-6: 400 mg/m² 5-FU bolus + 400 mg/m² LV + 2400 mg/m² 46 h 5-FU continuous infusion + 100 mg/m² oxaliplatin (day 1), 2-wk regimen cycle); CAPOX: 1000 mg/m² capecitabine every 12 h (days 1-14) + 70 mg/m² oxaliplatin (days 1 and 8, 3-wk regimen cycle; FUFOX: 500 mg/m² LV + 50 mg/m² oxaliplatin + 2000 mg/m² 5-FU continuous infusion for 22 h (days 1, 8, 15 and 22), 5-wk regimen cycle; OXXEL: 1000 mg/m² capecitabine every 12 h (days 1-11) + 100 mg/m² oxaliplatin (day 1), 2-wk regimen cycle; OXAFAFU: 250 mg/m² LV + 85 mg/m² oxaliplatin (day 1) + 850 mg/m² 5-FU bolus (day 2), 2-wk regimen cycle; bFOL: 20 mg/m² LV + 85 mg/m² oxaliplatin (days 1 and 15) + 500 mg/m² 5-FU bolus (days 1 and 8-15), 4-wk regimen cycle. ORR: Overall response rate; PFS: Progression-free survival; OS: Overall survival; HR: Hazard ratio; Bev: Bevacizumab.

¹Significant PFS difference between XELOX + bevacizumab (HR = 0.77, P = 0.0026).

Table 4 Comparison of treatment safety (Grade 3/4 events) in combination with oxaliplatin

Clinical trial	Treatments	Diarrhea	Mucositis/stomatitis	Neutropenia	HFS	Vomiting (%)
Díaz-Rubio et al[20] (2007)	XELOX vs FUOX	14% vs 24%a	2% vs 4%	7% vs 11%	2% vs 1%	5% vs 8%
Cassidy et al[21] (2008)	XELOX vs FOLFOX-4 +/- Bev	19% vs 11%	1% vs 2%	7% vs 44%	6% vs 1%	5% vs 4%
Ducreux et al[9] (2011)	XELOX vs FOLFOX-6	14% vs 7%a	0% vs 1%	5% vs 47%a	3% vs 1%	2% vs 5%
Porschen et al[22] (2007)	CAPOX vs FUFOX	15% vs 14%	1% vs 3%	-	10% vs 4%c	6% vs 6%
Comella et al[23] (2009)	OXXEL vs OXAFAFU	13% vs 8%	2% vs 2%	10% vs 27%e	4% vs 1%	3% vs 8%e
Hochster et al[25] (2008)	XELOX vs FOLFOX-6 vs bFOL	31% vs 31% vs 26%	-	15% vs 53% vs 18%	19% vs 8% vs 2%	38% vs 31% vs 24%
	+ Bev1	19% vs 11% vs 26%	-	10% vs 49% vs 19%	10% vs 0% vs 0%	21% vs 7% vs 24%

¹Reduced XELOX dose (850 mg/m² capecitabine). Treatments: XELOX: Capecitabine 1000 mg/m² every 12 h (days 1-14) + 130 mg/m² oxaliplatin (day 1), 3-wk regimen cycle; FUOX: 2250 mg/m² 5-FU continuous infusion for 48 h (days 1, 8, 15, 22, 29 and 36) + 85 mg/m² oxaliplatin (days 1, 15 and 29) 6-wk regimen cycle; FOLFOX-4: 400 mg/m² 5-FU bolus + 200 mg/m² LV + 600 mg/m² continuous infusion 5-FU for 22 h (days 1 and 2) + oxaliplatin 85 mg/m² (day 1) 2-wk regimen cycle, FOLFOX-6: 400 mg/m² 5-FU bolus + 400 mg/m² LV + 2400 mg/m² 46 h 5-FU continuous infusion + 100 mg/m² oxaliplatin (day 1), 2-wk regimen cycle); CAPOX: 1000 mg/m² capecitabine every 12 h (days 1-14) + 70 mg/m² oxaliplatin (days 1 and 8, 3-wk regimen cycle; FUFOX: 500 mg/m² LV + 50 mg/m² oxaliplatin + 2000 mg/m² 5-FU continuous infusion for 22 h (days 1, 8, 15 and 22), 5-wk regimen cycle; OXXEL: 1000 mg/m² capecitabine every 12 h (days 1-11) + 100 mg/m² oxaliplatin (day 1), 2-wk regimen cycle; OXAFAFU: 250 mg/m² LV + 85 mg/m² oxaliplatin (day 1) + 850 mg/m² 5-FU bolus (day 2), 2-wk regimen cycle; bFOL: 20 mg/m² LV + 85 mg/m² oxaliplatin (days 1 and 15) + 500 mg/m² 5-FU bolus (days 1 and 8-15), 4-wk regimen cycle. Bev: Bevacizumab; HFS: Hand-foot syndrome.

^aP < 0.05 vs XELOX;

^cP < 0.05 vs CAPOX;

^eP < 0.05 vs OXXEL.

Table 5 Comparison of treatment efficacy in combination with irinotecan

Clinical trial	Type	Treatment	ORR	PFS (mo)	OS (mo)
Fuchs et al[39] (2007)	Phase III	CapeIRI1vs FOLFIRI vs mIFL	38.6% vs 47.2% vs 43.3%	5.8 vs 7.6 (1) vs 5.9 (2)	18.9 vs 23.1 (3) vs 17.6
Köhne et al[34] (2008)2	Phase III	CAPIRI vs FOLFIRI-2		5.9 vs 9.6	14.75 vs 19.9
		+ Celecoxib	22% vs 32%
		- Celecoxib	48% vs 45%
Souglakos et al[40] (2012)	Phase II	CAPIRI + Bev vs FOLFIRI-2 + Bev	39.8% vs 45.5% (P = 0.32)	8.9 vs 10.0 (P = 0.64)	27.5 vs 25.7 (P = 0.55)
Pectasides et al[41] (2012)	Phase III	XELIRI + Bev vs FOLFIRI + Bev	38.5% vs 40.1% (P = 0.81)	10.2 vs 10.8 (P = 0.74)	20.0 vs 25.3 (P = 0.099)
Ducreux et al[42] (2013)	Phase II	XELIRI-2+ Bev vs FOLFIRI + Bev	62% vs 63%	9 vs 9	23 vs 23

¹Arm excluded after protocol amendment for toxicity;

²Premature termination due to toxicity (inconclusive results). Treatments: CapeIRI (CAPIRI): 250 mg/m² Irinotecan (day 1) + 1000 mg/m² capecitabine (days 1-14), 3-wk regimen cycle; FOLFIRI: 180 mg/m² irinotecan + 400 mg/m² LV + 400 mg/m² 5-FU bolus + 2400 mg/m² 5-FU 46-h continuous infusion, 2-wk regimen cycle; mIFL: 125 mg/m² irinotecan + 20 mg/m² LV + 500 mg/m² 5-FU bolus (days 1 and 8), 3-wk regimen cycle; FOLFIRI-2: 180 mg/m² irinotecan (days 1, 15, 22) + 200 mg/m² LV (days 1, 2, 15, 16, 29, and 30)+ 400 mg/m² bolus 5-FU, 600 mg/m² 22-h continuous infusion 5-FU (1, 2, 15, 16, 29 and 30); XELIRI: 240 mg/m² irinotecan + 1000 mg/m² capecitabine (days 1-14), 3-wk treatment regimen; XELIRI-2: 200 mg/m² irinotecan + 1,000 mg/m² capecitabine (days 1-14), 3-wk treatment regimen. ORR: Overall response rate; PFS: Progression-free survival; OS: Overall survival; HR: Hazard ratio; Bev: Bevacizumab. (1) CapeIRI vs FOLFIRI (P = 0.015); (2) CapeIRI vs mIFL (P = 0.46); and (3) CapeIRI vs FOLFIRI (P = 0.27).

Table 6 Comparison of treatment safety (Grade 3/4 events) in combination with irinotecan

Clinical trial	Treatments	Diarrhea	Vomiting	Neutropenia	HFS
Fuchs et al[39] (2007)	1CapeIRI vs FOLFIRI vs mIFL	47.5% vs 13.9% vs 19.0%	18.4% vs 8.8% vs 7.3%	31.9% vs 43.1% vs 40.9%	9.9% vs 0% vs 0%
Köhne et al[34] (2008)2	CAPIRI vs FOLFIRI-2
	+ Celecoxib	39% vs 17%	9% vs 6%	13% vs 11%	< 1% vs 0%
	- Celecoxib	35% vs 10%	5% vs 5%	15% vs 19%	< 1% vs 0%
Souglakos et al[40] (2012)	CAPIRI + Bev vs FOLFIRI-2 + Bev	15.8% vs 9.2%a	-	17.9% vs 24.5%	4.2% vs 1.2%a
Pectasides et al[41] (2012)	XELIRI + Bev vs FOLFIRI + Bev	19% vs 11%	5% vs 0%c	13% vs 22%	-
Ducreux et al[42] (2013)	XELIRI-2+ Bev vs FOLFIRI + Bev	12% vs 5%	7% vs 7%	18% vs 26%	6% vs 1%

¹Arm excluded after protocol amendment for toxicity;

²Premature termination due to toxicity (inconclusive results). Treatments: CapeIRI (CAPIRI): 250 mg/m² Irinotecan (day 1) + 1000 mg/m² capecitabine (days 1-14), 3-wk regimen cycle; FOLFIRI: 180 mg/m² irinotecan + 400 mg/m² LV + 400 mg/m² 5-FU bolus + 2400 mg/m² 5-FU 46-h continuous infusion, 2-wk regimen cycle; mIFL: 125 mg/m² irinotecan + 20 mg/m² LV + 500 mg/m² 5-FU bolus (days 1 and 8), 3-wk regimen cycle; FOLFIRI-2: 180 mg/m² irinotecan (days 1, 15, 22) + 200 mg/m² LV (days 1, 2, 15, 16, 29, and 30)+ 400 mg/m² bolus 5-FU, 600 mg/m² 22-h continuous infusion 5-FU (1, 2, 15, 16, 29 and 30); XELIRI: 240 mg/m² irinotecan + 1000 mg/m² capecitabine (days 1-14), 3-wk treatment regimen; XELIRI-2: 200 mg/m² irinotecan + 1000 mg/m² capecitabine (days 1-14), 3-wk treatment regimen. Bev: Bevacizumab; HFS: Hand-foot syndrome;

^aP < 0.05 vs CAPIRI + Bev;

^cP < 0.05 vs XELIRI + Bev.