Capecitabine for locally advanced and metastatic colorectal cancer: A review

Table 1 Randomized controlled trials comparing capecitabine with standard 5-fluorouracil/leucovorin in patients with metastatic colorectal cancer

Author	Treatment arms	OS (mo)	RR (%)	PFS (mo)	FFS (mo)	Major toxicity
Hoff et al[12]	ARM1: LV 20 mg/m2 iv + 5-FU 425 mg/m2/per day iv, days 1-5 every 4 wk	13.3	11.6	4.7	3.1	More stomatitis with 5-FU/LV (16% vs 3%)
	ARM2: Capecitabine 2500 mg/m2 per day, for 14 d every 21 d per os	12.5	25.8 (P = 0.005)	4.3	4.1	More hand-foot syndrome with capecitabine (18% vs 1%)
Van Cutsem et al[13]	ARM1: LV 20 mg/m2 iv + 5-FU 425 mg/m2 per day iv, days 1-5 every 4 wk	12.1	15	4.7	4.0	More stomatitis with 5-FU/LV (13.3% vs 1.3%)
	ARM2: Capecitabine 2500 mg/m2per day, for 14 d every 21 d per os	13.2	18.9	5.2	4.2	More hand-foot syndrome with capecitabine (16.2% vs 0.3%)

OS: Overall survival; RR: Response rate; PFS: Progression-free survival; FFS: Failure-free survival; LV: Leucovorin; 5-FU: 5-fluorouracil.

Table 2 Non-comparative phase II trials on Capecitabine with either Oxaliplatin or Irinotecan combination in patients with metastatic colorectal cancer

Author	Patients	Drugs used	Regimen	RR (%)	mTTP (mo)	MS (mo)
Cassidy et al[16]	96	Capecitabine	2000 mg/m2 per day (days 1-14)	55	7.7	19.5
		Oxaliplatin	130 mg/m2 day 1
Zeuli et al[17]	43	Capecitabine	2500 mg/m2 per day (days 1-14)	44	-	20
		Oxaliplatin	120 mg/m2 day 1
Borner et al[18]	43	Capecitabine	2500 mg/m2 per day (days 1-14)	49	5.9	17.1
		Oxaliplatin	130 mg/m2 day 1
Shields et al[19]	35	Capecitabine	1500 mg/m2 per day (days 1-14)	37.1	-	NR
		Oxaliplatin	30 mg/m2 day 1
Bajetta et al[20]	68	Capecitabine	2500 mg/m2 per day (days 2-15)	47	8.3	-
		Irinotecan	300 mg/m2 day 1
Bajetta et al[20]	66	Capecitabine	2500 mg/m2per day (days 2-15)	44	7.6	-
		Irinotecan	150 mg/m2 days 1and 8
Patt et al[21]	52	Capecitabine	2000 mg/m2 per day (days 2-15)	46	7.1	15.6
		Irinotecan	250 mg/m2 day 1
Cartwright et al[22]	49	Capecitabine	2000 mg/m2 per day (days 2-15)	45	5.7	13.4
		Irinotecan	240 mg/m2 day 1
Kim et al[23	43	Capecitabine	2000 mg/m2 per day (days 2-15)
		Irinotecan	100 mg/m2 days 1and 8	46.6	NR	NR
Rosati et al[24]	46	Capecitabine	1000 mg/m2 per day twice daily on days 1-14 every 3 wk	38	8	19.3
		Oxaliplatin	oxaliplatin 65 mg/m2 iv days 1 and 8
Garcia-Alfonso et al[25]	53	Capecitabine	1000 mg/m2/d twice daily on days 2-8 every 2 wk	32	9	19.2
		Irinotecan	irinotecan 175 mg/m2 on day 1

RR: Response rate; mTTP: Median time to progression; MS: Median survival; NR: Not recorded. All capecitabine doses were divided equally and dosed twice daily. Regimens were administered every 3 wk.

Table 3 Randomized trials that compare oxaliplatin plus capecitabine with oxaliplatin plus 5-fluorouracil ± folinic acid in metastatic colorectal cancer

Trial	Arms	Patients No.	PFS (mo)	OS (mo)	RR (%)	Severe toxicity≥grade 3
FOCA trial[31]	XELOX: (oxaliplatin 130 mg/m2 on day 1 and capecitabine 2000 mg/m2 per day for 14 d, repeating every 21 d) pviFOX: (protracted fluorouracil intravenous infusion plus oxaliplatin)	62 56	7 9	NR NR	43 48	Less diarrhea (8 vs 18%) and stomatitis (19 vs 29 %) in XELOX arm
US TREE-1[32]	XELOX: as above bFOL: (oxaliplatin 85 mg/m2 on day 1 and fluorouracil 500 mg/m2 plus folinic acid 20 mg/m2 intravenously on days 1 and 8, every 2 wk) mFOLFOX: (oxaliplatin 85 mg/m2, folinic acid 350 mg/m2, fluorouracil 400 mg/m2 bolus and 2400 mg/m2 46-h infusion on day 1)	49 50 49	5.9 6.9 8.7	17.2 17.9 17.6	27 20 41	Less neutropenia (15%) but more dehydration (27%) with XELOX
German trial[33]	CAPOX: (oxaliplatin 70 mg/m2 on days 1 and 8, and capecitabine 2000 mg/m2 per day for 2 wk, recycling every 3 wk) FUFOX: (fluorouracil 2000 mg/m2 infused over 24 h, folinic acid 500 mg/m2 and oxaliplatin 50 mg/m2 infused over 2 h)	241 233	7.1 8.0	16.8 18.8	48 54	More skin toxicity (10% vs 4%) with CAPOX
Spanish trial[34]	XELOX: as above FUOX: (fluorouracil 2250 mg/m2 infused over 48 h once a week plus oxaliplatin 85 mg/m2 twice a week)	171 171	8.9 9.5	18.1 20.8	37 46	Less diarrhea (14% vs 24%) with XELOX
French trial[35]	XELOX: as above FOLFOX6: (oxaliplatin 100 mg/m2, folinic acid 200 mg/m2 infused over 2, fluorouracil 400 mg/m2 bolus and 2400 mg/m2 infused over 48 h)	156 150	8.8 9.3	19.9 20.5	39 46	Less neutropenia (5% vs 47%), febrile neutropenia (0% vs 6%) and neuropathy (11% vs 25%) with XELOX
NO16966 trial[36]	XELOX: as above FOLFOX4: (oxaliplatin 85 mg/m2 on day 1, folinic acid 100 mg/m2, fluorouracil 400 mg/m2 bolus and 600 mg/m2 infused over 22 h)	317 317	7.3 7.7	NR NR	37 39	Less neutropenia (7% vs 43%) but more diarrhea (20% vs 11%) and Hand Foot Syndrome (6% vs 1%) with XELOX
COFFEE trial[38]	OXXEL: (oxaliplatin 100 mg/m2 on day 1 and capecitabine 2000 mg/m2 per day from day 1 to day 11 every 2 wk) OXAFAFU: (oxaliplatin 85 mg/m2 infused over 2 h on day 1, folinic acid 250 mg/m2 infused over 2 h on day 1, fluorouracil 850 mg/m2 bolus on day 2)	158 164	6.2 6.3	16.0 17.1	34 33	Less neutropenia (10% vs 27%) and febrile neutropenia (6% vs 13%), more gastric symptoms (8% vs 3%) and diarrhea (13% vs 8%) with OXXEL

PFS: Progression free survival; OS: Overall survival; RR: Response rate; NR: Not recorded.

Table 4 Phase II trials for locally advanced rectal cancer treated with preoperative chemo-radiation therapy using orally capecitabine

Study	Patients enrolled	Treatment used	Complete response (%)	Down staging (%)	Severe toxicity
Dupuis et al[42]	51	RT: 45 Gy/1.8 Gy fraction/25 fractions Capecitabine: 825 mg/m2 bid throughout RT	20	48	No grade 4 toxicity
Desai et al[43]	30	RT: 50.4 Gy/1.8 Gy day Capecitabine: 1330 mg/m2 per day in 2 divided doses throughout RT	11	37	No grade 4 toxicity
Korkolis et al[44]	30	RT: 50.4 Gy/1.8Gy day Capecitabine: 825 mg/m2 bid throughout RT	23	84	No grade 4 toxicity
Willeke et al[45]	36	RT: 50.4 Gy/1.8Gy day Capecitabine: 500 mg/m2 bid ( days 1-38) Irinotecan: 50 mg/m2 weekly	15	41	Grade 4 leucopenia in 2 patients
Velenik et al[46]	57	RT: 45Gy/25 fractions/1.8 Gy Capecitabine: 1650 mg/m2 per day in 2 divided doses throughout RT	9.1	49.1	No grade 4 toxicity
Krishnan et al[47]	54	RT: 52.5 Gy/30 fractions Capecitabine: 825 mg/m2 bid throughout RT	18	52	No grade 4 toxicity
De Paoli et al[48]	53	RT: 50.4 Gy/1.8 Gy day Capecitabine: 825 mg/m2 bid throughout RT	24	57	No grade 4 toxicity
Machiels et al[49]	40	RT: 45 Gy/25 fractions/1.8 Gy Capecitabine: 825 mg/m2 bid throughout RT Oxaliplatin: 40 mg/m2 weekly for 5 wk	14	32	Grade 3/4 toxicity 30%
Kim et al[50]	95	RT: 50 Gy/25 fractions Capecitabine: 1650 mg/m2 per day in 2 divided doses throughout RT	12	71	No grade 4 toxicity
Carlomagno et al[51]	43	RT: 45 Gy/25 fractions Capecitabine: 825 mg/m2 per day twice daily on days 1-14 every 3 wk/2 Cycles Oxaliplatin 50 mg/m2 days 1 and 8 every 3 wk	20.9	NR	No grade 4 toxicity
Fakih et al[52]	25	RT: 50.4 Gy/1.8 Gy day Capecitabine: 725 mg/m2/d twice daily Monday to Friday concomitant with RT Oxaliplatin 50 mg/m2 weekly for 5 wk	24	52	Grade 3 diarrhea, in 20% of patients
Craven et al[53]	70	RT: 45 Gy/1.8 Gy day Capecitabine: 900 mg/m2 per day Monday to Friday concomitant with RT	9.2	66	No grade 4 toxicity

RT: Radiation therapy; bid: Twice daily; NR: Not recorded.