Prognostic Value of Post-Operative C-Reactive Protein-Based Inflammatory Biomarkers in Colorectal Cancer Patients: Systematic Review and Meta-Analysis

Figures & data

Figure 1 PRISMA flow chart.

Table 1 Characteristics of Included Studies

Study		Population			Exposure/Predictor			Outcomes: HR (95% CI)^a			Covariates Adjustment
First Author, Year, Ref	Country	N	Cancer Site/Stage	Sex (F %)	Mean Blood Sampling Time After Surgery	Biomarker (CRP/Albumin Cut-off, mg/L)	% > Cut-off	Overall Survival	Cancer Specific Survival	Recurrence Free Survival	Age and Stage
Wigmore, 2001^Citation27^,b	UK	202	CRC, Duke`s A - D	52.5	3 months	CRP (5)	11.4	NR	NR	NR	Y
McMillan, 2003^Citation20	UK	174	CRC, Duke`s A - C	51	4 months	CRP (10)	17.5	3.72 (2.04–6.79)	2.75 (1.28–5.91)	NR	Y
Crozier, 2007^Citation29	UK	180	CRC, I–III	45	2 days	CRP (163)	50	1.29 (0.77–2.16)	1.33 (0.65–2.74)	NR	N
Leitch, 2007^Citation30	UK	149	CRC, I–IV	45.6	NR	mGPS (10/35)	mGPS1 (32.2) mGPS2 (8.7)	2.08 (1.32–3.28)	2.21 (1.11–4.41)	NR	Y
Guthrie, 2013^Citation31	UK	206	CRC, I–IV	42	3.5 months^†	mGPS (10/35)	mGPS1 (9.0) mGPS2 (23.0)	NR	3.31 (2.15–5.09)	NR	N
Shibutani, 2015^Citation35	Japan	254	CRC, II–III	45.3	29 days^†	GPS (10/35)	GPS1 (19.0) GPS2 (3.4)	1.98 (0.93–4.21)^c	NR	NR	N
McSorley, 2016^Citation32	UK	377	CRC, 0 – III	45	4 days	CRP (150)	38.7	2.14 (1.34–3.41)	2.00 (1.17–3.59)	NR	Y
Watt, 2017^Citation33^,d	UK	813	CRC, 0 – III	45.5	3 days	CRP (150)	50.1	1.41 (1.12–1.78)	1.31 (0.96–1.79)	NR	N
						GPS (150/25)	GPS1 (27.5) GPS2 (22.7)	1.27 (1.10–1.47)	1.20 (0.99–1.46)
					4 days	CRP (150)	29.8	1.33 (1.02–1.74)	1.31 (0.93–1.84)	NR	N
						GPS (150/25)	GPS1 (14.2) GPS2 (15.6)	1.21 (1.03–1.42)	1.22 (0.99–1.50)
Yamamoto, 2018^Citation36	Japan	406	CRC, I–IV	39.9	1 week	CRP (170)	23.2	NR	NR	NR	N
Zhou, 2018^Citation37^,e	China	516	CRC, I–IV	35.9	1 month	GPS (10/35)	NR	1.66 (0.98–2.80)	NR	NR	Y
						mGPS (10/35)	NR	1.76 (1.05–2.95)
Matsubara, 2019^Citation38	Japan	467	CRC, I–III	46	1 week	CRP (9)	17.6	NR	NR	2.07 (1.04–3.96)	Y
Hermunen, 2020^Citation41	Finland	147	CRC, II–IV	49	48 days^†	CRP (10)	11.6	2.49 (0.95–6.51)	NR	2.53 (1.10–5.81)	Y
McSorley, 2020^Citation34	UK	544	CRC, 0 – III	45.8	3 days	GPS (150/25)	GPS1 (14.6) GPS2 (15.0)	1.39 (0.92–2.12)	NR	NR	N
Osterman, 2020^Citation42	Sweden	416	Colon, I–III	50	10 weeks	CRP (10)	19.0	2.2 (1.3–3.6)	NR	1.8 (0.9–3.9)	Y
Son, 2020^Citation21	South Korea	769	CRC, I–III	36.8	31 days	mGPS (10/35)	mGPS1 (15.8) mGPS2 (4.9)	2.32 (1.38–3.90)^f	NR	NR	N
Hua, 2021^Citation40	USA	306	CRC, II–III	51	NR	CRP (10)	19.0	1.36 (1.12–1.66)	1.75 (1.2–2.56)	NR	Y
Lehtomäki, 2021^Citation43	Finland	147	CRC, II–IV	49	48 days^†	CRP (10)	12.0	3.16 (1.20–8.27)	NR	2.12 (0.79–5.72)	Y
Li, 2021^Citation39,^g	China	208	CRC, I–III	58.7	NR	GPS (10/35)	GPS1 (23.6) GPS2 (19.2)	NR	NR	NR	N
Wesselink, 2021^Citation44	Netherlands	614	CRC, I–III	33	174 days^†	CRP (NA)	NA	1.15 (0.98–1.35)	NR	1.34 (1.16–1.55)	Y

Notes: ^†Median value was reported. ^aGPS/mGPS hazard ratios are per unit increase unless otherwise stated. ^bStudy was not included in meta-analyses because authors did not report HRs. ^cHazard Ratio was for GPS1&2 vs GPS0. ^dCRP and GPS used the meta-analyses were assessed on day 3 and day 4 after surgery, respectively. ^eStudy also reported HRs (95% CIs) for associations of progression free survival per unit increase of mGPS and GPS [1.16 (0.79–1.71) and 1.21 (0.83–1.77), respectively]. ^fHazard Ratio is for mGPS2 vs mGPS0. Authors also reported HR for mGPS1 vs mGPS0 [1.35 (0.92–1.96)]. ^gStudy was not included in meta-analyses; authors log2 transformed CRP values for their Cox regression model. Hazard Ratio for this study refer to doubling of CRP values.

Abbreviations: Ref, reference; %, percentage (proportion of patients categorized as having elevated inflammatory response); CRC, colorectal cancer; N, sample size; F, female; CRP, c-reactive protein; GPS, Glasgow Prognostic Score; mGPS, modified Glasgow Prognostic Score; NR, not reported; NA, not applicable; Y/N, yes/no; HR, hazard ratio; CI, confidence interval; UK, United Kingdom; USA, United States of America.

Figure 2 Graphical presentation of quality assessment of 19 studies included in the systematic review (QUIPS risk of bias assessment).

Figure 3 Meta-analysis of studies on the association between post-operative C-reactive protein with overall survival (A), CRC-specific survival (B) and recurrence-free survival (C) among patients with colorectal cancer. (A): Hazard ratio of CRP on overall survival; N/events = 3174/1033. (B): Hazard ratio of CRP on CRC-specific survival; N/events = 1850/352. (C): Hazard ratio of CRP on recurrence-free survival; N/events = 1177/228.

Figure 4 Sensitivity meta-analysis of studies on the association between post-operative C-reactive protein with overall survival (A–C) and CRC-specific survival (D and E) among patients with colorectal cancer. (A): Hazard ratio of overall survival predicted by CRP (cut-off = 10mg/L) assessed ≥4 weeks post-operatively; N/events = 1190/428. (B): Hazard ratio of overall survival predicted by CRP (cut-off = 10mg/L) assessed ≥4 weeks post-operatively for studies that controlled for age and cancer stage; N/events = 710/275. (C): Hazard ratio of overall survival predicted by CRP (cut-off range = 150–170mg/L) assessed ≤1 week post-operatively; N/events = 1270/478. (D): Hazard ratio of CRC-specific survival predicted by CRP (cut-off = 10mg/L) assessed ≥4 weeks post-operatively for studies that controlled for age and cancer stage; N/events = 480/94. (E): Hazard ratio of CRC-specific survival predicted by CRP (cut-off range = 150–170mg/L) assessed ≤1 week post-operatively; N/events = 1776/340.

Figure 5 Meta-analysis of studies on the association of the Glasgow Prognostic Score with overall survival (A), and the modified Glasgow Prognostic Score with overall survival (B) and cancer-specific survival (C) among patients with colorectal cancer. (A): Hazard ratio of overall survival per unit increase in GPS assessed ≤1 week post-operatively; N/events = 1357/408. (B): Hazard ratio of overall survival per unit increase in mGPS assessed ≥4 weeks post-operatively; N/events = 665/126. (C): Hazard ratio of cancer specific survival per unit increase in mGPS assessed ≥4 weeks post-operatively; N/events = 355/49.

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