Prognostic role of a new inflammatory index with neutrophil-to-lymphocyte ratio and lactate dehydrogenase (CII: Colon Inflammatory Index) in patients with metastatic colorectal cancer: results from the randomized Italian Trial in Advanced Colorectal Cancer (ITACa) study

Figures & data

Figure 1 Flowchart of the study.

Abbreviation: CII, Colon Inflammatory Index.

Table 1 Baseline characteristics according to CII. Good (0 factor: NLR<3 e LDH≤UNL); intermediate (1 factor: NLR≥3 o LDH>UNL); poor (2 factors: NLR≥3 e LDH>UNL)

	Good (0 factor)	Intermediate (1 factor)	Poor (2 factors)	Overall	p
	N=114, 41.3%	N=98, 35.5%	N=64, 23.2%	N=276, 100%
n (%)	n (%)	n (%)	n (%)
Median age (range)	66 (33–83)	65 (34–82)	65 (37–81)	66 (33–83)	0.877
Gender
Male	73 (64.0)	55 (56.1)	36 (56.2)	164 (59.4)
Female	41 (36.0)	43 (43.9)	28 (43.8)	112 (40.6)	0.254
ECOG PS
0	98 (86.0)	85 (86.7)	37 (57.8)	220 (79.7)
1–2	16 (14.0)	13 (13.3)	27 (42.2)	56 (20.3)	<0.0001
Tumor localization
Rectum	30 (26.3)	27 (27.5)	15 (23.4)	72 (26.1)
Colon	84 (73.7)	71 (72.5)	49 (76.6)	204 (73.9)	0.732
Right-sided	65 (58.0)	68 (70.1)	44 (68.7)	177 (64.8)
Left-sided	47 (42.0)	29 (29.9)	20 (31.3)	96 (35.2)	0.102
Stage at diagnosis
I–III	36 (34.0)	24 (25.3)	6 (9.7)	66 (25.1)
IV	70 (66.0)	71 (74.7)	56 (90.3)	197 (74.9)	0.0006
Grade
1	5 (5.1)	3 (4.1)	4 (8.5)	12 (5.5)
2	68 (69.4)	45 (61.6)	25 (53.2)	138 (63.3)
3	25 (25.5)	25 (34.3)	18 (38.3)	68 (31.2)	0.263
CT regimen
FOLFOX4	71 (62.3)	59 (60.2)	41 (64.1)	171 (62.0)
FOLFIRI	43 (37.7)	39 (39.8)	23 (35.9)	105 (38.0)	0.877
KRAS status^a
Wild type	70 (61.4)	63 (64.3)	41 (64.1)	174 (63.0)
Mutated	44 (38.6)	35 (35.7)	23 (35.9)	102 (37.0)	0.688
ITACa treatment
CT+B	62 (54.4)	42 (42.9)	29 (45.3)	133 (48.2)
CT	52 (45.6)	56 (57.1)	35 (54.7)	143 (51.8)	0.171

Notes: ^aMandatory as consequence of amendment n. 1 of May 3, 2009.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; ITACa, Italian Trial in Advanced Colorectal Cancer; CT, chemotherapy; B, bevacizumab; CII, Colon Inflammatory Index; NLR, neutrophil-lymphocyte ratio; PS, performance status.

Figure 2 Kaplan–Meier curves of progression free survival (PFS) (A) and overall survival (OS) (B) of patients for the Colon Inflammatory Index.

Table 2 Association between Colon Inflammatory Index and toxicity

	Grade	Good	Intermediate	Poor	p
n	n	n
Nausea	0	58	52	39
	1–2	50	46	24
	3–4	6	0	1	0.100
Vomiting	0	86	76	51
	1–2	24	20	13
	3–4	4	2	0	0.299
Diarrhea	0	57	43	43
	1–2	47	50	19
	3–4	10	5	2	0.034
Stomatitis	0	93	70	52
	1–2	20	25	9
	3–4	1	3	3	0.401
Fatigue	0	61	55	38
	1–2	47	36	20
	3–4	6	7	6	0.857
Anemia	0	96	78	47
	1–2	18	17	15
	3–4	0	3	2	0.045
Neutropenia	0	34	37	28
	1–2	26	22	8
	3–4	53	39	28	0.187
Thrombocytopenia	0	89	72	54
	1–2	22	24	9
	3–4	3	2	1	0.433
Febrile neutropenia	0	111	95	64
	1–2	1	1	0
	3–4	2	2	0	0.333
Hemorrhage	0	101	84	56
	1–2	13	14	8
	3–4	0	0	0	0.757
Hypertension	0	79	84	54
	1–2	32	11	9
	3–4	3	3	1	0.017
Thrombosis	0	92	85	48
	1–2	6	5	8
	3–4	16	5	8	0.905
Proteinuria	0	92	76	45
	1–2	22	21	19
	3–4	0	1	0	0.125
Neurologic system	0	69	65	45
	1–2	35	28	16
	3–4	10	5	3	0.126

Table 3 Prognostic/predictive value of the Colon Inflammatory Index in the total population (overall) and in CT plus B and CT-only treatment arms

	n patients	n events	Median PFS (months) (95% CI)	p	HR (95%CI)^a	p	n events	Median OS (months) (95% CI)	p	HR (95% CI)^a	p
Overall
Good	114	104	10.3 (9.3–13.1)		1.00		88	29.9 (24.3–37.3)		1.00
Intermediate	98	93	8.7 (6.9–10.3)		1.21 (0.90–1.63)		82	20.9 (16.8–25.4)		1.51 (1.09–2.08)
Poor	64	63	7.3 (5.5–8.9)	<0.0001	2.27 (1.59–3.23)	<0.0001	60	14.4 (11.4–17.1)	<0.0001	2.38 (1.64–3.44)	<0.0001
CT+B
Good	62	56	12.1 (9.8–14.7)		1.00		49	31.6 (22.3–41.7)		1.00
Intermediate	42	40	10.0 (6.9–12.9)		1.31 (0.86–2.00)		36	20.6 (13.6–27.0)		1.63 (1.02–2.60)
Poor	29	29	8.6 (3.7–9.4)	0.0004	1.97 (1.20–3.24)	0.027	28	12.7 (5.4–14.6)	0.0009	2.34 (1.37–3.99)	0.006
CT
Good	52	48	9.6 (8.6–13.0)		1.00		39	27.1 (20.8–38.7)		1.00
Intermediate	56	53	8.4 (6.2–9.1)		1.29 (0.83–1.99)		46	21.3 (16.8–28.0)		1.58 (0.98–2.52)
Poor	35	34	7.3 (4.5–9.0)	0.002	2.40 (1.43–4.01)	0.004	32	17.1 (11.5–23.2)	0.0001	2.25 (1.31–3.87)	0.010

Notes: ^aAdjusted by ITACa treatment, center, CT regimen, KRAS status and baseline characteristics.

Abbreviations: PFS, progression-free survival; OS, overall survival; CT, chemotherapy; B, bevacizumab; ITACa, Italian Trial in Advanced Colorectal Cancer.

Table 4 Association between the Colon Inflammatory Index and response

	Good	Intermediate	Poor	p^a
n (%)	n (%)	n (%)
Overall
CR+PR	69 (46.9)	46 (31.3)	32 (21.8)
SD+PD	45 (35.2)	51 (39.8)	32 (25.0)	0.136
CT+B
CR+PR	37 (51.4)	21 (29.2)	14 (19.4)
SD+PD	25 (41.7)	20 (33.3)	15 (25.0)	0.530
CT
CR+PR	32 (42.7)	25 (33.3)	18 (24.0)
SD+PD	20 (29.4)	31 (45.6)	17 (25.0)	0.214

Notes: ^aAdjusted by ITACa treatment, center, CT regimen, KRAS status and baseline characteristics.

Abbreviations: LIPI, lung immune prognostic index; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ITACa, Italian Trial in Advanced Colorectal Cancer; CT, chemotherapy; B, bevacizumab.

Figure 3 Kaplan–Meier curves of PFS (A) and OS (B) for the Colon Inflammatory Index patients treated with CT +B. Abbreviations: CT, chemotherapy; B, bevacizumab.

Figure 4 Kaplan–Meier curves of progression free survival (PFS) (A) and overall survival (OS) (B) for Colon Inflammatory Index in patients treated with chemotherapy alone.

Table 5 Colon Inflammatory Index in relation to tumor localization in the overall/total population

		PFS			HR (95%CI)^a	p	OS			HR (95% CI)^a	p
n patients	n events	Median PFS (months) (95% CI)	p	n events	Median OS (months) (95% CI)	p
Right-sided
Good	47	44	10.4 (8.3–13.7)		1.00		38	26.4 (19.2–35.7)		1.00
Intermediate	29	28	7.7 (5.1–10.2)		2.10 (1.20–3.65)		24	15.0 (11.5–20.9)		2.17 (1.20–3.93)
Poor	20	20	8.9 (1.0–10.3)	0.002	2.44 (1.32–4.50)	0.005	19	15.0 (2.4–24.5)	0.004	2.69 (1.43–5.08)	0.003
Left-sided
Good	65	58	10.3 (9.1–13.7)		1.00		48	36.6 (24.8–44.4)		1.00
Intermediate	68	65	9.1 (6.5–11.3)		1.07 (0.73–1.56)		58	24.8 (19.3–28.0)		1.34 (0.89–2.03)
Poor	44	43	6.5 (3.7–8.8)	<0.0001	2.33 (1.47–3.70)	0.0005	41	13.7 (8.2–16.8)	<0.0001	2.29 (1.41–3.72)	0.003

Notes: ^aAdjusted by ITACa treatment, center, CT regimen, KRAS status and baseline characteristics.

Abbreviations: PFS, progression-free survival; OS, overall survival; CT, chemotherapy; B, bevacizumab; ITACa, Italian Trial in Advanced Colorectal Cancer.

Table 6 Colon Inflammatory Index  in relation to tumor localization in the overall/total population

		PFS			HR (95%CI)^a	p^a	OS			HR (95% CI)^a	p^a
n patients	n events	Median PFS (months) (95% CI)	p	n events	Median OS (months) (95% CI)	p
Right-sided
CT+B
Good	26	25	12.6 (8.0–22.3)		1.00		23	28.2 (15.9–36.7)		1.00
Intermediate	14	13	7.5 (4.7–12.9)		1.28 (0.50–3.25)		11	16.3 (6.8–21.8)		1.44 (0.57–3.65)
Poor	7	7	8.6 (1.0–8.9)	0.027	2.87 (0.99–8.34)	0.140	7	9.0 (1.0–14.6)	0.003	4.46 (1.43–13.95)	0.031
CT
Good	21	19	9.5 (5.6–13.1)		1.00		15	21.6 (17.9–68.6)		1.00
Intermediate	15	15	8.4 (2.3–9.1)		2.01 (0.96–4.22)		13	15.0 (10.1–20.8)		3.07 (1.23–7.66)
Poor	13	13	9.0 (1.0–11.4)	0.113	1.56 (0.70–3.48)	0.178	12	23.3 (2.4–26.6)	0.157	2.28 (0.97–5.40)	0.043
Left-sided
CT+B
Good	36	31	11.3 (7.7–14.0)		1.00		26	34.5 (21.3–48.0)		1.00
Intermediate	28	27	11.1 (6.9–14.3)		1.08 (0.62–1.86)		25	21.2 (13.7–27.7)		1.85 (1.02–3.35)
Poor	22	22	7.7 (3.3–9.7)	0.009	2.01 (1.08–3.71)	0.070	21	12.9 (4.7–15.3)	0.013	2.40 (1.25–4.64)	0.019
CT
Good	29	27	9.7 (8.6–17.3)		1.00		22	36.6 (20.8–45.7)		1.00
Intermediate	40	38	8.1 (5.9–10.7)		1.07 (0.61–1.86)		33	26.2 (18.5–36.7)		1.16 (0.65–2.07)
Poor	22	21	6.3 (2.0–8.0)	0.001	1.84 (0.93–3.62)	0.185	20	16.6 (10.5–19.9)	<0.0001	2.55 (1.24–5.27)	0.031

Notes: ^aAdjusted by center, CT regimen, KRAS status and baseline characteristics.

Abbreviations: PFS, Progression-dree survival; OS, overall survival; CT, chemotherapy; B, bevacizumab.

Table S1 Patient characteristics (N=276)

	CT+B arm (N=133)	CT arm (N=143)
	n (%)	n (%)	p
Median age, years (IQR)	66 (58–72)	66 (57–74)	1.000
Gender
Female	52 (39.1)	60 (42.0)
Male	81 (60.9)	83 (58.0)	0.629
Performance status (ECOG)
0	109 (82.0)	111 (77.6)
1–2	24 (18.0)	32 (22.4)	0.372
Tumor localization
Rectum	31 (23.3)	41 (28.7)
Colon	102 (76.7)	102 (71.3)	0.311
Stage at diagnosis
I–III	31 (24.0)	35 (26.1)
IV	98 (76.0)	99 (73.9)	0.697
Grade
1	3 (3.0)	9 (7.6)
2	65 (65.0)	73 (61.9)
3	32 (32.0)	36 (30.5)	0.413
CT regimen
FOLFOX4	82 (61.6)	89 (62.2)
FOLFIRI	51 (38.4)	54 (37.8)	0.921
KRAS status
Wild-type	70 (58.8)	74 (58.3)
Mutated	49 (41.2)	53 (41.7)	0.930
Prior cancer therapy
Surgery	100 (75.2)	104 (72.7)	0.642
Radiotherapy	13 (9.8)	13 (9.1)	0.846
Adjuvant chemotherapy	27 (20.3)	25 (17.5)	0.550

Abbreviations: CT, chemotherapy; B, bevacizumab; ECOG, Eastern Cooperative Oncology Group.