Recurrence-free survival as a putative surrogate for overall survival in phase III trials of curative-intent treatment of colorectal liver metastases: Systematic review

Table 1 Quality assessment of selected randomized clinical trials evaluated by Cochrane Risk-of-Bias Tool (Risk of bias per study)

Criteria	Langer	Portier	Nordlinger	Ychou	Primrose
Random sequence generation	Unclear	Low	Low	Low	Low
Allocation concealments	Low	Low	Low	Low	Low
Blinding of participants and personnel1	Low	Low	Unclear	Low	Low
Blinding of outcome assessment1,2	Low	Low	Low	Low	Low
Incomplete outcome data	Unclear	Low	Low	Unclear	Low
Selective reporting	Low	Low	Low	Low	Low
Other bias	Unclear	Low	Low	Low	Low

¹Blinding is not possible;

²Implementation of a protocol for postoperative management was considered the best alternative.

Table 2 Comparative distribution of accessible baseline characteristics of patients among studies included in the systematic review

Characteristics	Langer n = 107 (%)		Portier n = 171 (%)		Nordlinger n = 364 (%)		Ychou n = 306 (%)		Primrose1n = 257 (%)
	Surg n = 55	S + C n = 52	Surg n = 85	S + C n = 86	Surg n = 182	S + C n = 182	S + 5-FU n = 153	S + FOLFIRI n = 153	S + C n = 128	S + C + Cetuximab n = 129
Median age	60	63.5	63	63	62	64	61	63	64	63
Gender (male)	65.4	65.4	62.4	53.5	63	70	65.4	58.8	63	71
Primary site (rectum)	30.9	26.9	40	40.7	37	46	26.1	28.8	-	-
DFI ≤ 12 mo	38.2	34.6	74.1	74.4	24	27	62.3	61.4	-	-
Node-positive primary	45.4	50	50.6	44.3	57	55	-	-	-	-
No. of lesions > 1	32.7	36.5	30.1	31.4	52	51	35.9	36	-	-
Largest met ≥ 5 cm	-	-	-	-	-	-	-	-	-	-
Chemotherapy	5-FU		5-FU		FOLFOX		5 –FU	FOLFIRI	5-FU + OX or 5-FU + Cap or FOLFIRI	5-FU + OX or 5-FU + Cap or FOLFIRI or + Cetuximab

¹n of eligible patients = 257, although only 234 patients had response rates analyzed; –: Represents data not assessable by authors; Surg: Surgery only; S + C: Surgery with additional chemotherapy; 5-FU: 5-fluorouracil based; FOLFOX: Fluorouracil, leucovorin, and oxaliplatin; FOLFIRI: Fluorouracil, leucovorin, and irinotecan.

Table 3 Comparison of original planned and analyzed design of randomized clinical trials with patients who underwent surgery and additional chemotherapy for initially resectable colorectal liver metastases

Studies	Initial design			No. of patients				Chemotherapy			%	Median FU		RFS		OS
by author	Primary endpoint	Planned HR	Type of analyses	Plan-ned	Acc-rued	ITT enrolled	PP (weight)	Regimen	Std Arm	Exp Arm	Resected	Std Arm	Exp Arm	Std Arm	Exp Arm	Std Arm	Exp Arm
Langer	OS	NR	PP	NR	129	129	107 (9)	Adj	0	5-FU × 6	100%	NR	NR	20	39	43 median	53 median
Portier	RFS	20% abs dif 2 yr1	ITT	200	173	171	171 (15)	Adj	0	5-FU × 6	100%	87.4	87.4	17.6	24.4	46.4 median	62.1 median
Nord-linger	RFS	0.714	Both	NR	364	364	342 (29)	Periop	0	FOLFOX × 12	93%	8.7 yr	8.7 yr	20	12.5	54.3	61.3
Ychou	RFS	NR	PP	420	321	321	306 (26)	Adj	1 5FU	FOLFIRI × 6	100%	42.4	41.7	21.6	24.7	72% at 3-yr	73% at 3-yr
Pri-mrose	RFS	0.68	ITT	268	272	257	236 (20)	Periop	FOL-FOX	Cetux + FOLFOX (70%)	85% (Chemo)	21.1	19.8	14.1	20.5	39.1	NR
											82% (Cetux)

¹Absence of difference at 2-year. HR: Hazard ratio; OS: Overall survival; RFS: Recurrence free survival; ITT: Intention to treat; PP: Per protocol; Std: Standard; Exp: Exposed; Adj: Adjuvant; Periop: Perioperative; 5-FU: 5-Fluorouracil; FOLFOX: 5-FU + Leucovorin + Oxaliplatin; FOLFIRI: 5-FU + Leucovorin + irirnotecan; Cetux: Cetuximab; Chemo: Chemotherapy; NR: Non-reported.

Table 4 Comparison of original hazard ratio and those from linear regression formula

Studies (by author)	n total (weight %)	RFS			OS			Assumption OS HR
		HR	95%CI		HR	95%CI
Langer	107 (9)	0.78	0.46	1.31	0.77	0.42	1.4	0.87
Portier	171 (15)	0.66	0.45	0.96	0.73	0.48	1.1	0.75
Nordlinger1	342 (29)	0.78	0.61	0.99	0.87	0.66	1.14	0.87
Ychou	306 (26)	0.89	0.66	1.19	1.09	0.72	1.64	0.97
Primrose	236 (20)	1.48	1.04	2.12	1.49	0.86	2.6	1.52

¹Intention-to-treat analysis. HR: Hazard ratio; OS: Overall survival; RFS: Recurrence free survival.