Critical prognostic value of the log odds of negative lymph nodes/tumor size in rectal cancer patients

Table 1 Baseline clinicopathological features of patients in the training cohort and validation cohort

Feature	Training cohort (n = 28875)	Validation cohort (n = 12325)
	n (%)	n (%)
Median age (IQR), yr	62 (53-72)	62 (53-71)
Median tumor size (IQR) mm	40 (27-55)	40 (26-55)
Median ELN count (IQR)	14 (10-20)	15 (10-20)
Median NLN count (IQR)	13 (9-18)	13 (9-18)
Median LONS (IQR)	-0.44 (-0.66 to -0.24)	-0.44 (-0.65 to -0.22)
Sex
Male	16998 (59.1)	7262 (58.9)
Female	11757 (40.9)	5063 (41.1)
TNM stage
I	7280 (25.3)	3132(25.4)
II	10355 (36.0)	4662 (36.2)
III	11120 (38.7)	4731 (38.4)
Differentiation
Poor	3741 (13.0)	1606 (13.0)
Moderate	21590 (75.1)	9169 (74.4)
High	2032 (7.1)	893 (7.2)
Unknown	1392 (4.8)	657 (5.3)
Preoperative radiotherapy
Yes	10385 (36.1)	4419 (35.9)
No	18730 (63.9)	7906 (64.1)
Chemotherapy
Yes	17688 (61.5)	7501 (60.9)
No	11067 (38.5)	4824 (39.1)
CEA
Normal	1056 (38.4)	4712(38.5)
High	6676 (23.2)	1736 (16.0)
Unknown	11023 (38.3)	4924 45.5)
N stage
N0	17635 (61.3)	7594 (61.6)
N1	7288 (25.3)	3036 (24.9)
N2	3832 (13.3)	1668 (13.5)
Histology type
Adenocarcinoma	27233 (94.7)	11640 (94.4)
MAC and SRCC	1522 (5.3)	5.6 (13.5)
Location
Rectum	18661 (64.9)	8044 (65.3)
Rectosigmoid junction	10094 (35.1)	4281 (34.7)
Race
White	23264 (80.9)	9962 (81.1)
Black	2357 (8.2)	1028 (8.3)
Others	3062 (10.6)	1299 (10.5)

CEA: Carcinoembryonic antigen; ELNs: Examined lymph nodes; IQR: Interquartile range; LONS: Log odds of negative lymph nodes/tumor size; MAC: Mucinous adenocarcinoma; NLNs: Negative lymph nodes; SRCC: Signet-ring cell carcinoma; TNM: Tumor-node-metastasis.

Table 2 Univariate analysis of prognostic factors for cancer-specific survival

Variable	Training cohort (n = 28755)			Validation cohort (n = 12325)
	HR	95%CI	P value	HR	95%CI	P value
Age1	1.022	1.019-1.024	< 0.001	1.021	1.018-1.025	< 0.001
Tumor size1	1.004	1.003-1.004	< 0.001	1.003	1.002-1.003	< 0.001
NLNs1	0.971	0.967-0.974	< 0.001	0.970	0.964-0.975	< 0.001
LONS1	0.330	0.308-0.354	< 0.001	0.331	0.298-0.367	< 0.001
Sex (ref = male)	0.887	0.840-0.937	< 0.001	0.901	0.829-0.979	< 0.001
TNM (ref = stage III)
I	0.226	0.207-0.247	< 0.001	0.235	0.206-0.269	< 0.001
II	0.482	0.454-0.512	< 0.001	0.486	0.443-0.532	< 0.001
Differentiation (ref = G3 + G4)
G1	0.436	0.382-0.497	< 0.001	0.424	0.348-0.517	< 0.001
G2	0.573	0.536-0.613	< 0.001	0.566	0.511-0.626	< 0.001
Unknown	0.532	0.459-0.616	< 0.001	0.515	0.415-0.641	< 0.001
Histology (ref = MAC and SRCC)	0.537	0.488-0.590	< 0.001	0.531	0.462-0.612	< 0.001
Preoperative RT (ref = Yes)	0.884	0.836-0.934	< 0.001	0.938	0.861-1.020	0.135
Chemotherapy (ref = Yes)	0.746	0.705-0.790	< 0.001	0.776	0.712-0.845	< 0.001
Location (ref = rectum)	1.134	1.072-1.200	< 0.001	1.177	1.079-1.284	< 0.001
Race (ref = others)
White	1.045	0.955-1.143	0.336	1.013	0.883-1.162	0.853
Black	1.435	1.275-1.616	< 0.001	1.465	1.225-1.753	< 0.001
CEA (ref = High)
Normal	0.546	0.510-0.584	< 0.001	0.498	0.448-0.553	< 0.001
Unknown	0.684	0.641-0.729	< 0.001	0.686	0.622-0.756	< 0.001

¹These variables were treated as continuous data.

CI: Confidence interval; CEA: Carcinoembryonic antigen; HR: Hazard ratio; LONS: Log odds of negative lymph nodes/tumor size; MAC: Mucinous adenocarcinoma; NLNs: Negative lymph nodes; RT: Radiotherapy; SRCC: Signet-ring cell carcinoma; TNM: Tumor-node-metastasis.

Table 3 Multivariate analysis of prognostic factors for cancer-specific survival

Variable	Training cohort (n = 28755)			Validation cohort (n = 12325)
	HR	95%CI	P2 value	HR	95%CI	P2 value
Age (ref: ≤ 60 years old)	1.54	1.46-1.63	< 0.001	1.50	1.37-1.62	< 0.001
Tumor size1	1.00	1.00-1.00	0.637	1.00	1.00-1.00	0.987
LONS1	0.47	0.44-0.51	< 0.001	0.46	0.41-0.52	< 0.001
Sex (ref = male)	0.90	0.85-0.95	< 0.001	0.91	0.83-0.99	0.021
TNM1 (ref = stage III)
I	0.28	0.22-0.26	< 0.001	0.264	0.23-0.31	< 0.001
II	0.47	0.45-0.51	< 0.001	0.50	0.46-0.55	< 0.001
Differentiation (ref = G3 + G4)
G1	0.63	0.56-0.72	< 0.001	0.60	0.49-0.73	< 0.001
G2	0.72	0.67-0.77	< 0.001	0.71	0.62-0.82	< 0.001
Unknown	0.63	0.54-0.73	< 0.001	0.63	0.51-0.79	< 0.001
Histology (ref = MAC and SRCC)	0.78	0.71-0.86	< 0.001	0.71	0.62-0.82	< 0.001
Preoperative RT (ref = Yes)	0.90	0.85-0.96	< 0.001	0.92	0.83-1.03	0.147
Chemotherapy (ref = Yes)	1.42	1.32-1.52	< 0.001	1.36	1.22-1.51	< 0.001
Location (ref = rectum)	0.82	0.77-0.87	< 0.001	0.77	0.70-0.85	< 0.001
Race (ref = others)
White	1.10	1.00-1.20	0.043	1.04	0.91-1.20	0.555
Black	1.45	1.29-1.63	< 0.001	1.49	1.25-1.79	< 0.001
CEA (ref = High)
Normal	0.66	0.62-0.71	< 0.001	0.60	0.54-0.67	< 0.001
Unknown	0.80	0.75-0.85	< 0.001	0.77	0.7-0.86	< 0.001

¹These variables were treated as continuous data.

²P values were adjusted for sex, age, race, tumor-node-metastasis stage, location, preoperative radiotherapy, carcinoembryonic antigen, differentiation and chemotherapy as covariates.

CI: Confidence interval; CEA: Carcinoembryonic antigen; HR: Hazard ratio; LONS: Log odds of negative lymph nodes/tumor size; MAC: Mucinous adenocarcinoma; SRCC: Signet-ring cell carcinoma; RT: Radiotherapy; TNM: Tumor-node-metastasis.

Table 4 Multivariate analyses for evaluating log odds of negative lymph nodes/tumor size effect on cancer-specific survival based on different clinicopathological factors¹

Variable	Training cohort (n = 28755)			Validation cohort (n = 12325)
	HR	95%CI	P2 value	HR	95%CI	P2 value
All	1.673	1.57-1.78	< 0.001	1.715	1.56-1.86	< 0.001
N stage
N0	1.53	1.37-1.71	< 0.001	1.422	1.20-1.68	< 0.001
N1a	1.49	1.24-1.78	< 0.001	1.73	1.26-2.36	0.001
N1b	1.42	1.21-1.65	< 0.001	1.61	1.28-2.04	< 0.001
N1c	1.68	0.96-2.92	0.069	2.12	0.98-4.60	0.057
N2a	1.64	1.40-1.93	< 0.001	1.7	1.33-2.18	< 0.001
N2b	1.55	1.34-1.79	< 0.001	1.37	1.10-1.71	0.005
T stage
T1	1.69	1.47-1.95	< 0.001	1.96	1.19-3.22	0.008
T2	1.42	1.16-1.73	0.001	1.6	1.18-2.16	0.003
T3	1.63	1.56-1.80	< 0.001	1.653	1.48-1.85	< 0.001
T4a	1.51	1.18-1.94	0.001	1.64	1.12-2.40	0.011
T4b	1.22	0.97-1.53	0.084	1.52	1.04-2.21	0.03
TNM stage
I	1.68	1.54-1.87	< 0.001	1.59	1.13-2.23	0.007
II	1.55	1.37-1.75	< 0.001	1.36	1.12-1.65	0.002
III	1.73	1.60-1.87	< 0.001	1.79	1.60-2.02	< 0.001
Sex
Male	1.722	1.59-1.86	< 0.001	1.715	1.52-1.94	< 0.001
Female	1.588	1.44-1.76	< 0.001	1.715	1.47-1.99	< 0.001
Age, yr
≤ 60	1.884	1.71-2.08	< 0.001	1.936	1.67-2.25	< 0.001
> 60	1.554	1.44-1.68	< 0.001	1.598	1.42-1.80	< 0.001
Differentiation
G1	1.268	0.94-1.72	0.125	1.549	1.03-2.33	0.035
G2	1.62	1.50-1.75	< 0.001	1.678	1.49-1.89	< 0.001
G3	1.967	1.73-2.23	< 0.001	1.859	1.53-2.26	< 0.001
Location
Rectum	1.647	1.53-1.77	< 0.001	1.613	1.44-1.81	< 0.001
Rectosigmoid junction	1.73	1.55-1.93	< 0.001	2.018	1.70-2.39	< 0.001
CEA
High	1.735	1.56-1.93	< 0.001	1.761	1.50-2.07	< 0.001
Normal	1.701	1.52-1.91	0	1.7	1.42-2.02	0
Preoperative RT
Yes	1.522	1.38-1.68	< 0.001	1.42	1.22-1.66	< 0.001
No	1.782	1.65-1.93	< 0.001	1.92	1.70-2.16	< 0.001
Chemotherapy
Yes	1.68	1.56-1.81	< 0.001	1.662	1.49-1.86	< 0.001
No	1.62	1.44-1.82	< 0.001	1.774	1.49-2.11	< 0.001
ELNs
0-10	1.415	1.29-1.56	< 0.001	1.439	1.24-1.67	< 0.001
11-20	1.79	1.61-2.00	< 0.001	2.10	1.78-2.48	< 0.001
> 20	3.30	2.64-4.14	< 0.001	2.61	1.83-3.70	< 0.001

¹Log odds of negative lymph nodes/tumor size was treated as categorical variable, and the high group as reference.

²P values were adjusted for sex, age, race, tumor-node-metastasis stage, location, preoperative radiotherapy, carcinoembryonic antigen, differentiation and chemotherapy as covariates.

CI: Confidence interval; CEA: Carcinoembryonic antigen; HR: Hazard ratio; RT: Radiotherapy; TNM: Tumor-node-metastasis; ELNs: Examined lymph nodes.