Adjuvant chemotherapy for resected colorectal cancer metastases: Literature review and meta-analysis

doi:10.3748/wjg.v22.i2.519

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World J Gastroenterol. Jan 14, 2016; 22(2): 519-533
Published online Jan 14, 2016. doi: 10.3748/wjg.v22.i2.519

Table 1 Adjuvant systemic chemotherapy after primary resectable colorectal cancer

Trials	No. of patients	Schedules	DFS	P value	OS	P value
Oxaliplatin-based regimes
X-ACT	1987	CAPECITABINE (1004)	64.2%	0.12	81.3%	0.07
(Twelves et al[32], 2005)	1987	5FU/LV (983)	60.6%	0.12	77.6%	0.07
NSABP C-07	2407	5FU/LV (1207)	67.0%	0.0034	-	-
(Kuebler et al[30], 2007)	2407	FLOX (1200)	73.2%	0.0034	-	-
MOSAIC	2246	5FU/LV (1123)	67.4%	0.003	68.7%	0.46
(André et al[29], 2009)	2246	FOLFOX4 (1123)	73.3%	0.003	78.5%	0.46
XELOXA	1886	XELOX (944)	70.9%	0.045	77.6%	0.15
(Haller et al[31], 2011)	1886	5FU/LV (942)	66.5%	0.045	74.2%	0.15
Irinotecan-based regimes
CALGB-89803	1264	Irinotecan + 5FU/LV (635)	59.0%	0.85	64.0%	0.74
(Saltz et al[35], 2007)	1264	5FU/LV (629)	61.0%	0.85	67.0%	0.74
PETACC-3	2982	Irinotecan + 5FU/LV (1485)	56.7%	0.106	73.6%	0.094
(Van Cutsem et al[36], 2009)	2982	5FU/LV (1497)	54.3%	0.106	71.3%	0.094
Bevacizumab + chemotherapy
NSABP C-08	2710	FOLFOX6 + Bevacizumab (1354)	77.4%	0.15	-	-
(Allegra et al[37], 2011)	2710	FOLFOX6 (1356)	75.5%	0.15	-	-
AVANT	2867	FOLFOX4 + Bevacizumab (960)	73.0%	0.07	81.0%	0.02
(de Gramont et al[38], 2012)		FOLFOX4 (955)	76.0%	0.07	85.0%	0.02
		XELOX + Bevacizumab (952)	75.0%	0.44	82.0%	0.21
Cetuximab + chemotherapy
NCCTG NO147	2686	FOLFOX6 + Cetuximab (1349)	71.5%	0.08	72.5%	0.03
(Alberts et al[41], 2012)	2686	FOLFOX6 (1337)	74.6%	0.08	86.2%	0.03
PETACC-8	337	FOLFOX4 + Cetuximab (169)	60.45	0.60	46.0%	0.064
(Taieb et al[42], 2012)	337	FOLFOX4 (168)	60.7%	0.60	36.0%	0.064
Oral flupropyrimidine in monotherapy
JCOG02051	1092	5-FU/LV (550)	74.3%	0.0236	-	-
(Shimada et al[33], 2014)	1092	UFT/LV (551)	73.6%	0.0236	-	-
ACT-CC¹	1518	S-1 (758)	75.5%	< 0.01	-	-
(Yoshida et al[34], 2014)	1518	UFT/LV (760)	72.5%	< 0.01	-	-

¹These trials were randomized, controlled non-inferiority studies. 5-FU/LV: 5-fluorouracil/leucovorin; FOLFOX: 5-FU/LV plus oxaliplatin; DFS: Disease-free survival; OS: Overall survival; UFT: Tegafur-uracil.

Table 2 Systemic adjuvant chemotherapy studies after metastasectomy

Ref.	No. of patients	Setting	Randomized study	Regimes of chemotherapy	Outcomes
Ref.	No. of patients	Setting	Randomized study	Regimes of chemotherapy	DFS	PFS	OS
Controlled studies
Langer et al[90], 2002	arm2 = 55 vs arm1 = 52	Phase III	YES	5-FU/LV vs surgery + 5-FU/LV (arm2 vs arm1)	4-yr DFS:35% vs 45%(P = 0.35) HR = 1.28 (95%CI: 0.76-2.14)	-	4-yr OS:47% vs 57% (P = 0.39)HR = 1.30 (95%CI: 0.71-2.36)
Portier et al[91], 2006	171 (86 vs 85)	Phase III	YES	5-FU/LV vs surgery alone	5-yr DFS: 33.5% vs 26.7% (P = 0.028) HR = 0.66 (95%CI: 0.46-0.96)	-	5-yr OS:51.1% vs 41.9% (P = 0.13) HR = 0.73 (95%CI: 0.48-1.10)
Mitry et al[92], 2008	278 (138 vs 140)	Pooled analysis of two phase III studies	YES	5-FU/LV vs surgery alone	Median DFS: 27.9 mo vs 18.8 mo (P = 0.058) 5-yr DFS: 36.7% vs 27.7% HR = 0.76 (95%CI: 0.57-1.01)	-	Median OS: 62.2 vs 47.3 mo (P = 0.095) 5-yr OS: 52.8% 39.6%HR = 0.76 (95%CI: 0.55-1.05)
Kanemitsu et al[94], 2009	300	Phase II/III	YES	FOLFOX6 vs surgery alone	In progress (results not yet available)
Ychou et al[99], 2009	306 (153 vs 153)	Phase III	YES	FOLFIRI vs 5-FU/LV	2-yr DFS: 50.7% vs 46.2% (P = 0.44) HR = 0.89 (95%CI: 0.66-1.19)	-	3-yr OS: 72.7% vs 71.6% (P = 0.69) HR = 1.09 (95%CI: 0.72-1.64)
Kim et al[98], 2009	156 [58 + 48 + 50]	Retrospective	NO	Oxaliplatin regimes (group I); Irinotecanregimes (group II) orFluoropyrimidine alone(group III)	Median DFS:23.4, 14.1 and 16.3 mo(respectively, P = 0.088)HR group1 vs 3: 0.63 (95%CI: 0.39-1.03) HR group2 vs 3: 0.98 (95%CI: 0.61-1.56)	-	Median OS:51.2, 47.9 and 60 mo(respectively, P = 0.219)
Liu et al[100], 2010	50 [31 (17 + 14) vs 19]	Retrospective	NO	FOLFOX/FOLFIRI vs 5-FU/LV	3-yr DFS: 50.8% vs 21.1% (P = 0.022) HR = 0.37 (95%CI: 0.15-0.94)	-	3-yr OS: 85.7% vs 51.8% (P = 0.027)5-yr OS: 54.0% vs 34.6% (P = 0.027) HR = 0.27 (95%CI: 0.083-0.86)
Snoeren et al[106], 2010				CAPOX + Bevacizumab vs CAPOX alone	In progress (results not yet available)
Kemeny et al[104], 2011	73 (35 vs 38)	Phase II	YES	HAI/systemic therapy + BEVA vs HAI/systemic therapy alone	4-yr DFS: 71% vs 83% (P = 0.4)	-	4-yr OS: 81% vs 85% (P = 0.5)
Brandi et al[101], 2013	151 (78 vs 73)	Cohort study	NO	Oxaliplatinregimes or Irinotecan regimes vs surgery alone	Median DFS: 16 vs 9.7 mo(P = 0.014) 5-yr DFS: 17.4% vs 10.5% (P = 0.82) HR = 0.64 (95%CI: 0.46-0.90)	-	Median OS: 42 vs 39 mo (P = 0.8)
Turan et al[105], 2013	204 (87 vs 117)	Cohort study	NO	Irinotecan regimes or oxaliplatin regimes + bevacizumab vs chemotherapy alone	Median DFS: 14 vs 18 mo (P = 0.37)	-	Median OS: 43 vs 54 mo (P = 0.25)
Nordlinger et al[93], 2013¹	364 (171 vs 152)	Phase III study	YES	Peri-operative FOLFOX4 vs surgery alone	-	3-yr PFS: 38.2% vs 30.3% (P = 0.0068) HR = 0.81 (95%CI: 0.64-1.02)	5-yr OS:51.2% vs 47.8% (P = 0.3) HR = 0.88 (95%CI: 0.68-1.14)
Primrose et al[107], 2014¹	236 (119 vs 117)	Phase III	YES	FOLFOX/CAPOX + cetuximab vs FOLFOX/CAPOX alone	-	Median PFS: 14.1 vs 20.5 mo(P = 0.03) HR = 1.48 (95%CI: 1.04-2.12)	Median OS: 39.1 vs 32 mo (P = 0.16) HR = 1.49 (95%CI: 0.86-2.60)
Kobayashi et al[102], 2014	177 (88 vs 89)	Phase III	YES	UFT/LV vs surgery alone	-	3-yr PFS: 38.6% vs 32.3% (P = 0.003) HR = 0.56 (95%CI: 0.38-0.83)	3-yr OS: 82.8% vs 81.6% (P = 0.41) HR = 0.80 (95%CI: 0.48-1.35)
Non controlled studies
Kim et al[97], 2011	60	Single armed	NO	FOLFOX6	Median DFS: 32.8 mo (95%CI: 5.8-59.6)5-yr DFS: 39.20%	-	Median OS: 62.8 mo (95%CI: 44.1-81.3)5-yr OS: 55.5%
Kato et al[103], 2015	60	Single armed	NO	S-1	1-yr DFS: 68.30%3-yr DFS: 47.40%	-	1-yr OS: 96.70%3-yr OS: 80%
Nakayama et al[95], 2015	88	Single armed	NO	Oxaliplatin regimes	3-yr DFS: 54%	-	-
Katayose et al[96], 2015	49	Phase II single armed	NO	mFOLFOX6	2-yr DFS: 59.20%	-	-

¹The primary end-point was PFS because these studies evaluated the role of peri-operative chemotherapy, but some patients became ineligible for surgical treatment during the study. 5-FU/LV: 5-fluorouracil/leucovorin; FOLFOX: 5-FU/LV plus oxaliplatin; DFS: Disease-free survival; PFS: Progression-free survival; OS: Overall survival; UFT: Tegafur-uracil.

Table 3 Hepatic arterial infusion plus systemic chemotherapy in the adjuvant setting

Ref.	Numbers of patients	Setting	Randomized study	Regimes of therapy	Outcomes
Ref.	Numbers of patients	Setting	Randomized study	Regimes of therapy	DFS	PFS	OS/DSS
Controlled studies
Ota et al[115], 1999	84 (37 vs 47)	Cohort study	NO	HAI/5-FU vs control group	5-yr DFS: 72.6% vs 29.8% (P = 0.0005)	-	5-yr OS:61.4% vs 28% (P = 0.0069)
Kemeny et al[112], 2005	156 (74 vs 82)	Phase III	YES	HAI/FUDR plus systemic 5-FU ± LV vs systemic 5-FU ± LV alone	-	Median PFS: 31.3 vs 17.2 mo (P = 0.02)	Median OS:68.4 vs 58.8 mo (P = 0.10)
House et al[113], 2011	250 (125 vs 125)	Cohort study	NO	HAI/FUDR plus systemic chemotherapy (5FU/LV + irinotecan or oxaliplatin) vs systemic chemotherapy alone	5-yr DFS: 48% vs 25% (P < 0.01)HR = 0.71 (95%CI: 0.48-0.96)	-	5-yr DSS:75% vs 55% (P < 0.01) HR = 0.39 (95%CI: 0.23-0.68)
Goéré et al[116], 2013	98 (44 vs 54)	Cohort study	NO	HAI/oxaliplatin plus systemic 5-FU/LV vs systemic irinotecan regimes or oxaliplatin regimes alone	3-yr DFS: 33% vs 5%(P < 0.0001) HR = 0.37 (95%CI: 0.23-0.60)	-	3-yr OS:75% vs 62% (P = 0.17) 5-yr OS:54% vs 52% (P = 0.34)
Non controlled studies
Alberts et al[114], 2010	55	Phase II single armed	NO	HAI/FUDR plus systemic capecitabine + oxaliplatin	2-yr DFS:59.7% Median DFS: 32.7 mo	-	2-yr OS:89.10%

DFS: Disease-free survival; PFS: Progression-free survival; OS: Overall survival; DSS: Disease-specific survival.

Citation: Brandi G, De Lorenzo S, Nannini M, Curti S, Ottone M, Dall’Olio FG, Barbera MA, Pantaleo MA, Biasco G. Adjuvant chemotherapy for resected colorectal cancer metastases: Literature review and meta-analysis. World J Gastroenterol 2016; 22(2): 519-533
URL: https://www.wjgnet.com/1007-9327/full/v22/i2/519.htm
DOI: https://dx.doi.org/10.3748/wjg.v22.i2.519