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A Modified Tumor-Node-Metastasis Classification for Primary Operable
Colorectal Cancer
Chundong Zhang , MD,
1,2,†
Zubing Mei, MD, PhD,
3,4,†
Junpeng Pei, MD,
1,†
Masanobu Abe, DMD, PhD,
5
Xiantao Zeng, MD, PhD,
6,7
Qiao Huang, MD,
6,7
Kazuhiro Nishiyama, MD,
8
Naohiko Akimoto , MD, PhD,
9
Koichiro Haruki , MD, PhD,
9
Hongmei Nan, MD, PhD,
10,11
Jeffrey A. Meyerhardt , MD, MPH,
12
Rui Zhang, MD, PhD,
13
Xinxiang Li, PhD,
14,15,
* Shuji Ogino , MD, PhD, MS,
9,16,17,18,‡
Tomotaka Ugai , MD, PhD
9,16,
*
,‡
1
Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China,
2
Department of Gastrointestinal Surgery,
Graduate School of Medicine, University of Tokyo, Tokyo, Japan,
3
Department of Anorectal Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional
Chinese Medicine, Shanghai, China,
4
Anorectal Disease Institute of Shuguang Hospital, Shanghai, China,
5
Division for Health Service Promotion, University of Tokyo,
Tokyo, Japan,
6
Center for Evidence-based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China,
7
Department of Evidence-based
Medicine and Clinical Epidemiology, The Second Clinical College of Wuhan University, Wuhan, China,
8
Division of Gastrointestinal Surgery, Department of Surgery,
Graduate School of Medicine, Kyoto University, Kyoto, Japan,
9
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s
Hospital and Harvard Medical School, Boston, MA, USA,
10
Department of Global Health, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis,
IN, USA,
11
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA,
12
Department of Medical Oncology,
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA,
13
Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning
Cancer Hospital and Institute, Shenyang, China,
14
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China,
15
Department of
Oncology, Shanghai Medical College, Fudan University, Shanghai, China,
16
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA,
17
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA and and
18
Cancer Immunology and Cancer Epidemiology Programs,
Dana-Farber Harvard Cancer Center, Boston, MA, USA
*Correspondence to: Tomotaka Ugai, MD, PhD, Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital,
Harvard Medical School, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 221 Longwood Ave., EBRC Room 404, Boston, MA 02115, USA (e-mail:
tugai@bwh.harvard.edu) and Xinxiang Li, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China (lxx1149@163.com)
†
These authors contributed equally as co-first authors.
‡
These authors contributed equally as co-last authors.
Abstract
Background: The American Joint Committee on Cancer (AJCC) 8th tumor-node-metastasis (TNM) classification for colorectal
cancer (CRC) has limited ability to predict prognosis. Methods: We included 45 379 eligible stage I-III CRC patients from the
Surveillance, Epidemiology, and End Results Program. Patients were randomly assigned individually to a training (n ¼31 772)
or an internal validation cohort (n ¼13 607). External validation was performed in 10 902 additional patients. Patients were
divided according to T and N stage permutations. Survival analyses were conducted by a Cox proportional hazard model and
Kaplan-Meier analysis, with T1N0 as the reference. Area under receiver operating characteristic curve and Akaike informa-
tion criteria were applied for prognostic discrimination and model fitting, respectively. Clinical benefits were further assessed
by decision curve analyses. Results: We created a modified TNM (mTNM) classification: stages I (T1-2N0-1a); IIA (T1N1b,
T2N1b, T3N0); IIB (T1-2N2a-2b, T3N1a-1b, T4aN0); IIC (T3N2a, T4aN1a-2a, T4bN0); IIIA (T3N2b, T4bN1a); IIIB (T4aN2b, T4bN1b);
and IIIC (T4bN2a-2b). In the internal validation cohort, compared with the AJCC 8th TNM classification, the mTNM classifica-
tion showed superior prognostic discrimination (area under receiver operating characteristic curve ¼0.675 vs 0.667, respec-
tively; 2-sided P<.001) and better model fitting (Akaike information criteria ¼70 937 vs 71 238, respectively). Similar findings
were obtained in the external validation cohort. Decision curve analyses revealed that the mTNM had superior net benefits
over the AJCC 8th TNM classification in the internal and external validation cohorts. Conclusions: The mTNM classification
provides better prognostic discrimination than AJCC 8th TNM classification, with good applicability in various populations
and settings, to help better stratify stage I-III CRC patients into prognostic groups.
Received: 27 April 2020; Revised: 7 August 2020; Accepted: 12 September 2020
©The Author(s) 2020. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecom-
mons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work
is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
1of10
JNCI Cancer Spectrum (2021) 5(1): pkaa093
doi: 10.1093/jncics/pkaa093
First published online 16 October 2020
Article
Downloaded from https://academic.oup.com/jncics/article/5/1/pkaa093/5926092 by guest on 04 February 2021
Colorectal cancer (CRC) is a public health concern worldwide (1-
3). Although its incidence and mortality rates have been declin-
ing in recent decades, CRC remains the fourth most frequently
diagnosed cancer and second-leading cause of cancer-related
death in the United States (2,3).
The American Joint Committee on Cancer (AJCC)–Union for
International Cancer Control tumor-node-metastasis (TNM)
classification has been the main prognostic assessment tool for
cancer for several decades. The AJCC TNM classification of CRC
has been revised several times to improve its prognostic ability,
and the latest 8th edition was released in 2016 (4). In both the
AJCC 7th and 8th TNM classifications, the N component (re-
gional lymph node involvement) is considered to be a more im-
portant prognostic factor than the T component (depth of
tumor invasion into the colorectal wall), considering that T1N1a
is staged as IIIA, whereas T4bN0 is staged as IIC (4,5). However,
multiple studies have indicated that the T and N components
have comparable importance, given that T4N0 tumors had sta-
tistically significantly poorer outcomes than T1-2N1-2a tumors,
regardless of the number of lymph nodes examined (6-11). This
suggests that the discrimination and accuracy of prognostic
assessments using the AJCC TNM classification remain contro-
versial, especially for stage II and III CRC, leading to calls for a
modified TNM (mTNM) classification.
We therefore aimed to establish a mTNM classification for
CRC based on the updated 1973-2015 Surveillance,
Epidemiology, and End Results (SEER) program (12). We created
the mTNM classification for optimal prognostic classification
and compared the discrimination, model-fitting performance,
and net benefits of the mTNM with those of the AJCC 8th TNM
classifications in a training cohort drawn from the SEER data-
base. We validated the prognostic capacity of mTNM classifica-
tion in both the internal and external validation cohorts.
Methods
Data Source and Eligibility Criteria
We included eligible primary operable stage I-III CRC patients
from the SEER database (https://seer.cancer.gov/)(12). The eligi-
bility criteria for SEER cohort were as follows: 1) primarily single
tumor in colon or rectum; 2) availability of necessary informa-
tion for analyses, (ie, sex, age, race, location, tumor size, histo-
logical grade, pathological T (pT) stage, pathological N (pN)
stage, and number of retrieved lymph nodes); 3) no distant me-
tastasis (M0) at the time of surgery; 4) criteria met for pathologic
staging; 5) no preoperative treatments (chemotherapy and/or
radiotherapy); 6) underwent surgical treatment for tumor; 7)
follow-up of at least 5 years or until death; 8) postoperative sur-
vival of at least 1 month; 9) age 18-72 years at diagnosis
(Supplementary Figure 1, available online). The last date of
follow-up for the SEER cohort was December 2015. Patients diag-
nosed after 2010 were excluded to ensure adequate follow-up
data (60 months) for analyses of 5-year overall survival rates.
A data-use agreement for the SEER 1973-2015 research data file
was approved. Patients were randomly assigned individually to
the training or internal validation cohorts using R software, at a
randomization ratio of 7:3. The training cohort was mainly used
to develop the mTNM classification, whereas the internal and
external validation cohorts were specifically used to validate
prognostic prediction capacity of the mTNM classification.
External validation was performed using the database of
Cancer Hospital of China Medical University and Fudan
University Shanghai Cancer Center. The eligibility criteria for
the external validation cohort were as follows: the necessary in-
formation was available for analyses (ie, sex, age, race, location,
tumor size, histological grade, pT stage, pN stage, and number
of retrieved lymph nodes; no distant metastasis (M0) at the time
of surgery; and postoperative survival of at least 1 month.
Ethical reviews were approved by the Ethics Committees of the
Cancer Hospital of China Medical University and Fudan
University Shanghai Cancer Center, and written informed con-
sents were obtained from all patients in the external validation
cohort.
Regarding the cutoff age of the CRC patients, the average life
expectancy at birth in the United States was 78.8 years in 2015
(13), and patients younger than 72 years in the SEER were in-
cluded in the training and internal validation cohorts to allow
the long-term effect (eg, 5-year overall survival rates) to be
assessed. Because rectal and colon cancers usually have similar
survival outcomes (2,3,14) and share the same classification
system (4,5), both were included in the current study. The pres-
ence of tumor deposits was a statistically significant negative
prognostic factor in CRC and was included in the AJCC 7th TNM
classification as N1c stage (15). In the current study, 198 N1c
patients (0.4%) were classified into stage N1b because of the
small sample size and the similarity of their prognosis with that
of N1b patients. Furthermore, distant metastatic disease (M1)
has long been regarded as the most advanced stage with the
poorest prognosis, irrespective of T and N category, and is gen-
erally considered incurable. Only curable patients who under-
went surgical treatment were included in the current study. The
study was reported according to the STROBE checklist for cohort
studies (16,17)
The AJCC TNM Classification
The AJCC 7th TNM classification was released in 2010, and the
AJCC 8th TNM classification was released in 2016 (4,5).
Importantly, there was no substantial alteration between the
7th and 8th classifications (4,5) except in relation to stage IV
CRC (Supplementary Table 1, available online). Because the
AJCC 8th TNM classification was released in 2016, we retrospec-
tively reclassified patients according to the AJCC 8th TNM clas-
sification based on pT and pN stage. In this study, we dealt with
only pathological stages, and the terms of T1-4b and N0-2b are
used to simplify descriptions of pT1-4b and pN0-2b in TNM and
mTNM stages.
Statistical Analysis
Overall survival (OS) was calculated from the date of diagnosis
until death from any cause. Differences in overall survival rates
were analyzed by log-rank tests with Kaplan-Meier (K-M) sur-
vival curves. Hazard ratios (HRs) with 95% confidence intervals
(CIs) were estimated using a Cox proportional hazards model
(18), with stage T1N0 as the reference in the training cohort.
Hazard ratio values of 25 T and N stage combinations were or-
dered from the lowest (T1N0) to the highest (T4bN2b) (Figure 1
and Table 1). Then, log-rank tests for 5-year overall survival
were conducted between 2 sequential stages, and 24 v
2
values
were generated. Among 24 v
2
values, 6 largest v
2
values were
identified except as a v
2
value between T4bN2a and T4bN2b be-
cause these stages are nearest sequences (Supplementary
Figure 2, available online). Finally, using these 6 v
2
values, we
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created 7 categories of the modified TNM classification that par-
alleled to those of the AJCC 7th and 8th classifications.
The model discrimination and model-fitting performance of
the 2 TNM classifications were evaluated by analyzing the area
under the receiver operating characteristic curve and Akaike in-
formation criteria (AICs), respectively (19,20). A higher area un-
der the curve (AUC) indicated better discrimination, and a lower
AIC indicated superior model fitting. A statistically significant
difference in AUCs between the 2 classifications was confirmed
by applying Hanley and McNeil tests to the training cohort and
the internal and external validation cohorts (19). The clinical
benefits were further measured by decision curve analyses
(DCAs) (21-23). DCAs were used to compare clinical benefits be-
tween the modified TNM and AJCC 8th TNM classifications in 5-
year OS. Moreover, the prognostic discrimination of the mTNM
classification based on 5-year OS rates, log-rank tests of pair-
wise comparisons, and hazard ratios in the training cohort was
further tested in the internal and external validation cohorts.
Data were extracted with SEER*Stat version 8.3.5 from the
SEER. Statistical analyses and graphs were conducted with SPSS
version 22.0 and R version 3.5.3. Hanley and McNeil tests with
AUC values were conducted using MedCalc version 18.11.3. We
used stringent alevel of .005 to improve the reproducibility of
our results (24).
Results
Patient Characteristics
After excluding ineligible patients in the SEER, a total of 45 379
stage I to III CRC patients were finally included (Supplementary
Figure 1, available online). Among them, 31 772 patients were
assigned to the training cohort, and 13 607 patients were
assigned to the internal validation cohort. Additional 10 902
stage I to III CRC patients in the database of Cancer Hospital of
China Medical University and Fudan University Shanghai
Cancer Hospital were used as the external validation cohort.
The baseline characteristics of the training, internal, and exter-
nal cohorts are shown in Supplementary Table 2 (available
online).
In the training cohort, patients were staged according to the
AJCC 8th classification as follows: stage I (n ¼7428, 23.4%); IIA
(n ¼9422, 29.7%); IIB (n ¼709, 2.2%); IIC (n ¼606, 1.9%); IIIA
(n ¼1673, 5.3%); IIIB (n ¼8838, 27.8%); and IIIC (n ¼3096, 9.7%).
The AJCC 8th TNM Classification
Stage distributions and the 5-year overall survival rates based
on the AJCC 8th TNM classification in the training cohort are
shown in Supplementary Table 3 (available online; log-rank
test, pairwise comparisons, IIB vs IIC: P¼.002, others P<.001).
These results indicated that the AJCC 8th classification did not
show optimal prognostic discrimination, given that stage IIIA
was associated with a statistically significantly better 5-year
overall survival rate than stages IIB and IIC, and patients with
stage IIIB had a statistically significantly better 5-year overall
survival rate than those with stage IIC.
We further assessed the prognostic discrimination perfor-
mance of the AJCC 8th TNM classification by presenting 5-year
overall survival rates, log-rank tests, and hazard ratios for dif-
ferent population sets of the training cohort (Supplementary
Table 3, available online). The AJCC 8th TNM classification
showed poor prognostic discrimination in analyses stratified by
sex, age (younger than 60 years, 60 years or older), race, location
(colon, rectum), tumor size (<4 cm, 4 cm) (25), and number of
retrieved lymph nodes (<12, 12, 20, 30) (4,5)
(Supplementary Figure 3 and Supplementary Table 3, available
online).
The mTNM Classification
The mTNM classification was generated using 6 identified v
2
values. Using these values, we classified patients as follows:
stages I (T1N0, T1N1a, T2N0, T2N1a); IIA (T1N1b, T2N1b, T3N0);
IIB (T1N2a, T1N2b, T2N2a, T2N2b, T3N1a, T3N1b, T4aN0); IIC
(T3N2a, T4aN1a, T4aN1b, T4aN2a, T4bN0); IIIA (T3N2b, T4bN1a);
IIIB (T4aN2b, T4bN1b); and IIIC (T4bN2a, T4bN2b) (Figure 1 and
Table 1). The details of the mTNM and AJCC 8th TNM classifica-
tions are shown in Figure 2.
The 5-year overall survival rates of the mTNM classification
in the training cohort steadily decreased as stage number in-
creased, and hazard ratios increased as stage number increased
(Supplementary Table 4, available online).
The mTNM vs the AJCC 8th TNM Classification
Stage distributions based on the mTNM classification in the in-
ternal validation cohort are shown in Figure 3 and Table 2.
In the training cohort, we compared the model discrimina-
tion and model-fitting performance of the mTNM and AJCC 8th
TNM classifications. Compared with the AJCC 8th TNM classifi-
cation, the mTNM showed superior prognostic discrimination
(AUC, 0.670 vs 0.658; Hanley and McNeil test, P<.001) and better
model fitting (AIC, 175 506 vs 176 436). Similar findings were ob-
served in additional stratified analyses (Supplementary Table 5,
available online).
T1N0
T1N1a
T2N0
T2N1a
T1N1b
T2N1b
T3N0
T2N2a
T1N2b
T3N1a
T2N2b
T1N2a
T3N1b
T4aN0
T4aN1a
T3N2a
T4bN0
T4aN1b
T4aN2a
T3N2b
T4bN1a
T4bN1b
T4aN2b
T4bN2a
T4bN2b
0246810 1412
Years after diagnosis
)%( etar lavivrus llarevO
0
20
40
60
80
100
Log-rank P<0.001
The training cohort mTNM
Stage I
Stage IIA
Stage IIB
Stage IIC
Stage IIIA
Stage IIIB
Stage IIIC
Number at risk
8337 8008 7620 5957 3449 1526 062
10143 9480 8767 6793 3997 1731 064
6903 6251 5483 4064 2373 1034 032
3610 3071 2486 1780 984 456 010
1917 1462 1100 782 427 177 02
484 332 223 136 72 34 01
378 221 130 82 44 20 01
mTNM
Stage I
Stage IIA
Stage IIB
Stage IIC
Stage IIIA
Stage IIIB
Stage IIIC
Figure 1. Kaplan-Meier estimates of the proposal modified tumor-node-metas-
tasis (mTNM) classification in the training cohort.
C. Zhang et al. |3of10
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In the internal validation cohort, the 5-year overall survival
rates of the mTNM classifications also steadily decreased as
stage number increased according to the mTNM classification,
and hazard ratios increased as stage number increased
(Table 2). Compared with the AJCC 8th TNM classification, the
mTNM showed superior prognostic discrimination (AUC, 0.675
vs 0.667; Hanley and McNeil test, P<.001) and better model fit-
ting (AIC, 70 937 vs 71 238) (Supplementary Figure 4, A, available
online; Table 3). Stratified analyses suggested that the mTNM
had better prognostic discrimination and superior model-fitting
performances compared with the AJCC 8th TNM classification
in various populations in the internal validation cohort
(Supplementary Figure 4, C and E, available online; Table 3).
We further performed DCA to assess the clinical utility of
the modified TNM and AJCC 8th TNM classification in the inter-
nal validation cohort. The DCA revealed that the mTNM had su-
perior net benefits over the AJCC 8th TNM classification
between threshold probabilities of 18%-32% in CRC patients of
the internal validation cohort. Similar results were found both
in colon cancer and rectal cancer (Supplementary Figure 5, A, C,
and E, available online).
We conducted additional analyses by adding a total of 10 152
CRC patients who were older than 72 years or received preoper-
ative treatment into the internal validation cohort (total
n¼23 759). The results showed that the mTNM classification
showed better prognostic discrimination and net benefits (eg,
K-M curves, receiver operating characteristic curves, and DCA
curves) than the AJCC 8th TNM classification in CRC, colon can-
cer, and rectal cancer (Figure 3, B, D, and E;Supplementary
Figures 4, B and D, and 5, B, D, and E, available online).
External Validation
In the external validation cohort, we observed similar findings
regarding the 5-year overall survival rates and hazard ratios
Table 1. The proposed modified TNM classification in the training cohort
Stage
a
No. 3-year OS, % (95% CI) 5-year OS, % (95% CI) HR (95% CI)
b
Log-rank (Mantel-Cox)
c
v
2
P
Stage I 8337 94.6 (94.1 to 95.1) 91.0 (90.4 to 91.6)
T1N0 3034 95.7 (94.9 to 96.3) 92.8 (91.8 to 93.6) 1 (Referent) — —
T1N1a 283 94.0 (90.5 to 96.2) 90.4 (86.3 to 93.3) 1.19 (0.86 to 1.65) 1.08 .30
T2N0 4394 94.2 (93.5 to 94.9) 90.2 (89.3 to 91.0) 1.37 (1.21 to 1.56) 0.74 .39
T2N1a 626 93.0 (90.6 to 94.7) 88.9 (86.1 to 91.1) 1.48 (1.20 to 1.84) 0.57 .45
Stage IIA 10 143 91.0 (90.4 to 91.5) 85.1 (84.4 to 85.8)
T1N1b 187 91.9 (87.0 to 95.1) 86.4 (80.6 to 90.6) 1.85 (1.33 to 2.57) 1.40
d
.24
T2N1b 534 91.5 (88.8 to 93.6) 85.2 (81.9 to 88.0) 1.91 (1.56 to 2.36) 0.049 .83
T3N0 9422 90.9 (90.3 to 91.5) 85.1 (84.3 to 85.8) 1.94 (1.70 to 2.17) 0.008 .93
Stage IIB 6903 85.1 (84.2 to 85.9) 76.3 (75.2 to 77.3)
T2N2a 219 89.0 (84.1 to 92.5) 81.2 (75.3 to 85.8) 2.53 (1.94 to 3.31) 4.49
d
.03
T1N2b 20 80.0 (55.1 to 92.0) 75.0 (50.0 to 88.7) 2.53 (1.05 to 6.12) <0.001 .99
T3N1a 2724 87.4 (86.1 to 88.6) 79.8 (78.2 to 81.2) 2.54 (2.24 to 2.88) <0.001 .99
T1N2a 43 90.5 (76.6 to 96.3) 73.8 (86.3 to 93.3) 3.15 (1.85 to 5.37) 0.62 .43
T2N2b 96 84.4 (75.4 to 90.3) 79.1 (69.5 to 86.0) 3.17 (2.21 to 4.55) <0.001 .99
T3N1b 3092 83.8 (82.5 to 85.1) 73.8 (72.2 to 75.3) 3.22 (2.86 to 3.63) 0.015 .90
T4aN0 709 80.9 (77.8 to 83.7) 72.4 (68.9 to 75.5) 3.45 (2.93 to 4.05) 0.91 .34
Stage IIC 3610 77.0 (75.6 to 78.3) 65.4 (63.8 to 66.9)
T4aN1a 254 77.1 (71.4 to 81.8) 68.3 (62.2 to 73.6) 3.94 (3.15 to 4.92) 1.32
d
.25
T3N2a 2081 79.0 (77.2 to 80.7) 66.9 (64.8 to 68.9) 4.24 (3.75 to 4.79) 0.43 .51
T4bN0 606 74.2 (70.5 to 77.5) 65.2 (61.2 to 68.8) 4.52 (3.85 to 5.30) 0.77 .38
T4aN1b 352 74.7 (69.8 to 79.0) 62.7 (57.4 to 67.6) 4.98 (4.14 to 6.00) 0.86 .35
T4aN2a 317 72.1 (66.8 to 76.7) 57.4 (51.7 to 62.6) 5.70 (4.74 to 6.86) 1.53 .22
Stage IIIA 1917 65.3 (63.2 to 67.4) 52.7 (50.5 to 55.0)
T3N2b 1726 65.5 (63.2 to 67.7) 53.2 (50.8 to 55.6) 6.48 (5.75 to 7.32) 2.24
d
.13
T4bN1a 191 64.1 (56.8 to 70.5) 48.2 (40.9 to 55.1) 7.16 (5.79 to 8.85) 0.83 .36
Stage IIIB 484 53.5 (48.9 to 57.9) 41.9 (37.4 to 46.3)
T4bN1b 181 55.0 (47.4 to 61.9) 43.9 (36.5 to 51.1) 8.51 (6.87 to 10.5) 1.25
d
.26
T4aN2b 303 52.6 (46.8 to 58.1) 40.8 (35.2 to 46.3) 9.45 (7.95 to 11.2) 0.93 .33
Stage IIIC 378 42.3 (37.3 to 47.3) 30.7 (26.1 to 35.5)
T4bN2a 175 46.3 (38.7 to 53.5) 34.9 (27.8 to 42.0) 11.5 (9.43 to 14.1) 2.45
d
.12
T4bN2b 203 38.9 (32.1 to 45.6) 27.2 (21.2 to 33.5) 13.7 (11.4 to 16.5) 2.02 .16
a
Log-rank tests were conducted between 2 sequential stages, and 24 v
2
values were generated. CI ¼confidence interval; HR ¼hazard ratio; OS ¼overall survival; TNM
¼tumor-node-metastasis; — ¼not estimated.
b
All stages were compared with T1N0 as reference by values of hazard ratios of Cox proportional hazards.
c
Log-rank tests were conducted between 2 sequential stages.
d
Hazard ratios with 95% confidence intervals were estimated using a Cox proportional hazards model, with stage T1N0 as the reference in the training cohort. Hazard
ratios values of 25 T and N stage combinations were ordered from the lowest (T1N0) to the highest (T4bN2b). Then, log-rank tests for 5-year overall survival were con-
ducted between 2 sequential stages, and 24 v
2
values were generated. Among 24 v
2
values, 6 largest v
2
values were identified except as a v
2
value between T4bN2a and
T4bN2b because these stages are nearest sequences. Finally, using these 6 v
2
cutoff values (1.40, 4.49, 1.32, 2.24, 1.25, 2.45), we created 7 categories of the modified TNM
classification that paralleled to those of the AJCC 7th and 8th classifications.
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based on the mTNM classifications (Supplementary Figure 6
and Supplementary Table 6, available online). The mTNM clas-
sifications also showed better prognostic discrimination (AUC,
0.659 vs 0.636; Hanley and McNeil test, P¼.02) and net benefits
compared with the AJCC 8th TNM classification in the external
validation cohort (Supplementary Figures 7 and 8 and
Supplementary Table 7, available online).
Discussion
In the current study, we established a modified and reasonable
TNM classification and validated it in both the internal and ex-
ternal validation cohorts. This mTNM classification showed su-
perior prognostic discrimination and model-fitting
performances and applicability in various populations and set-
tings compared with the AJCC 8th TNM classification.
The AJCC TNM classification of CRC, which has been revised
several times to improve its prognostic ability and accuracy, has
been considered the most important prognostic tool in this
field. However, it has demonstrated inadequate prognostic dis-
criminatory performance, especially for stage II and III CRC, and
its prognostic accuracy therefore remains controversial. Rottoli
et al. showed that stage IIC (T4N0) cancers had poorer outcomes
than IIIA (T1-2N1) cancers and were comparable to IIIB (T3N1)
cancers, regardless of the number of retrieved lymph nodes (6).
In addition, Kim et al. reported that stage IIC (T4N0) colon can-
cers had poorer oncologic outcomes than IIIA and B (T1-2N1)
cancers (8), and Chan et al. demonstrated that stage IIC (T4N0)
and IIIB (T3N1) colon cancer had similar outcomes (11). Similar
results were obtained in our study. Patients with T4bN0 CRC
(74% of 3-year OS rate, 65% of 5-year OS rate) showed statisti-
cally significantly poorer survival than patients with T1N1a CRC
(3-year OS rate: 94%; 5-year OS rate: 90%). This result suggests
that the prognostic weight of the T component should be in-
creased in further AJCC TNM classifications.
We further assessed the prognostic discriminatory ability of
the AJCC 8th TNM classification in populations stratified by sex,
age, race, location, tumor size, and the number of retrieved
lymph nodes. The AJCC 8th TNM classification showed poor
prognostic discrimination in all of these populations, although
the reasons for this poor performance are unclear (26). Some
experts believe that an inadequate number of retrieved lymph
nodes would cause stage migration, associated with poor sur-
vival rates in patients with CRC (27-29). Chen et al. also showed
that more extensive lymph node retrieval improved survival
outcomes in patients with stages I-III colon cancer (30). We
therefore hypothesized that an inadequate number of retrieved
lymph nodes could explain the inferior prognostic discrimina-
tion performance and accuracy of the current AJCC 8th TNM
classification. However, this classification also demonstrated
poor prognostic discrimination even in patients with adequate
retrieved lymph nodes (12, 20, 30), suggesting that too few
retrieved lymph nodes was not the main reason for its poor per-
formance, consistent with several previous studies (31-33).
Further investigations are therefore needed to explain its poor
performance in other datasets with more detailed clinical
information.
The mTNM classification has several advantages over the
AJCC 8th TNM classification. First, hazard ratios, 5-year OS
rates, and log-rank tests differed statistically significantly be-
tween each pair of stage groups using the mTNM, suggesting
enhanced stratification. Second, AUCs were statistically signifi-
cantly increased in the mTNM classification, indicating better
prognostic discrimination. Third, the mTNM classification
showed better model fitting, indicated by a smaller AIC value.
Fourth, the mTNM classification was shown to have superior
net benefits by DCA. Furthermore, stratified analyses confirmed
that the mTNM classification had good model applicability in
various populations and settings. The results of the current
study should be considered reliable, given that they were based
on the large-sample SEER database with internal and external
validations. The current evidence thus suggests that the mTNM
is a more reasonable classification than the AJCC 8th TNM
classification.
Colon and rectal cancers were included in the current study
based on the colorectal continuum model (34,35). However,
there is a possibility that the mTNM classification is devoid of
patients with advanced rectal cancer because we excluded
patients receiving preoperative therapy in the training cohort.
Therefore, we validated the mTNM classification in the internal
and external validation cohorts including patients receiving
preoperative therapy. Furthermore, we also validated the
mTNM classification in both colon and rectal cancer. These
results suggest that the mTNM classification can be useful for
both colon cancer and rectal cancer, including locally advanced
rectal cancer.
The AUCs (model discrimination) and AICs (model fitting)
between the mTNM and AJCC 8th TNM classifications showed a
statistically significant difference in the training cohort,
whereas it appeared a statistically significant but relatively
small difference in the internal validation cohort. Therefore, we
further performed DCAs in the internal validation cohort to as-
sess the clinical utility of the modified TNM classification. In
the internal validation cohort, mTNM had superior net benefits
over the AJCC 8th TNM classification between threshold proba-
bilities for additional treatment of 18%-32%, but both depicted
little difference across other ranges of threshold probabilities.
Similar findings were observed in the external validation co-
hort. Further prospective studies with more detailed clinical in-
formation (especially on treatment) are needed to clarify the
clinical utility of the modified TNM classification.
We acknowledge some limitations of our study. First, the
current mTNM classification was established based on survival
outcomes; thus, those unavailable factors, including surgical
The modified TNM (mTNM) classification
The AJCC 8th TNM (8th TNM) classification
A
B
Figure 2. Details of 2 tumor-node-metastasis (TNM) classifications. (A) AJCC 8th
TNM classification; B) mTNM classification.
C. Zhang et al. |5of10
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strategy and use of postoperative adjuvant chemotherapy regi-
men, could also affect the prognosis (36,37). Second, although
the SEER used in the current study is well-established data in
the United States, it has inherent limitations in terms of under-
representation of young patients. The incidence of colorectal
cancer in the young population group (ie, younger than 50 years)
is increasing in the United States (38). Also, younger CRC
patients may have different prognosis than older CRC patients
included in SEER data. Similarly, those patients older than
72 years of age who were excluded in the training cohort and in-
ternal validation cohort may also have different prognosis.
Using the external validation cohort including both the younger
and the older patients, we confirmed that compared with AJCC
8th TNM classification, the mTNM classification shows better
prognostic discrimination and net benefits. Third, we were not
able to include important molecular markers, including micro-
satellite instability, KRAS,orBRAF, in the mTNM classification.
Integrating these factors could further improve classification.
Lastly, approximatively 26% of patients in the training cohort
had less than 12 retrieved lymph nodes, which could also affect
the accuracy of the mTNM classification. However, it remains
controversial how many retrieved lymph nodes are optimal for
0
20
40
60
80
100
)%( etar lavivruS
CRC (+additional patients)
1.00
1.37
2.34
3.62
5.26
6.44
9.59
1.00
1.28
1.78
2.44
3.20
3.93
5.41
HR
0
20
40
60
80
100
)%( etar lavivruS
1.00
1.30
2.29
3.48
5.15
6.03
9.27
HR
1.00
1.25
1.73
2.42
3.12
3.80
5.36
HR
CRC
Colon cancer (+additional patients)Colon cancer
Rectal cancer (+additional patients)Rectal cancer
)%( etar lavivruS
1.00
1.68
2.47
4.10
5.58
8.71
10.5
HR
1.00
1.36
1.92
2.42
3.45
4.31
5.22
HR
0
20
40
60
80
100
Log-rank P<0.001 Log-rank P<0.001
Log-rank P<0.001 Log-rank P<0.001
Log-rank P<0.001 Log-rank P<0.001
AB
CD
EF
0246810 1412 0 2 4 6 8 10 1412
0
20
40
60
80
100
0
20
40
60
80
100
0
20
40
60
80
100
0246810 1412 0 2 4 6 8 10 1412
0246810 1412 0 2 4 6 8 10 1412
Years after diagnosis Years after diagnosis
HR
I
IIA
IIB
IIC
IIIA
IIIB
IIIC
mTNM
Figure 3. Kaplan-Meier estimates of the modified tumor-node-metastasis (mTNM) classification in the internal validation cohort. (A) Colorectal cancer (CRC); B) CRC
(þ10 152 additional patients); C) Colon cancer; D) Colon cancer (þ7956 additional patients); E) Rectal cancer; F) Rectal cancer (þ2156 additional patients). Additional
patients were those who were older than 72 years or received preoperative treatments. All statistical testswere 2-sided. HR ¼hazard ratio.
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Table 2. Validation of the modified TNM classification in the internal validation cohort
Characteristics I IIA IIB IIC IIIA IIIB IIIC Overall
Overall (n ¼13 607)
5-y OS, % (95% CI) 90.0 (89.0 to 91.0) 85.8 (84.7 to 86.8) 75.0 (73.4 to 76.6) 63.1 (60.7 to 65.5) 50.5 (47.0 to 54.0) 43.4 (37.0 to 49.6) 28.1 (21.1 to 35.5) 78.5 (77.8 to 79.2)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.37 (1.24 to 1.53) 2.34 (2.11 to 2.60) 3.62 (3.24 to 4.05) 5.26 (4.65 to 5.95) 6.44 (5.39 to 7.70) 9.59 (7.83 to 11.74) —
Sex
Female (n ¼6278)
5-y OS, % 91.3 (89.8 to 92.6) 87.2 (85.6 to 88.5) 76.6 (74.3 to 78.8) 62.8 (59.2 to 66.3) 53.7 (48.4 to 58.7) 48.2 (38.8 to 57.0) 23.5 (14.3 to 34.1) 79.8 (78.7 to 80.7)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.41 (1.19 to 1.66) 2.45 (2.07 to 2.89) 4.24 (3.57 to 5.04) 5.51 (4.54 to 6.70) 7.01 (5.35 to 9.18) 12.31 (9.14 to 16.57) —
Male (n ¼7329)
5-y OS, % 89.0 (87.5 to 90.3) 84.6 (83.1 to 86.0) 73.6 (71.3 to 75.8) 63.4 (60.0 to 66.6) 48.0 (43.2 to 52.6) 39.0 (30.4 to 47.5) 32.1 (22.2 to 42.5) 77.4 (76.5 to 78.4)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.36 (1.19 to 1.56) 2.30 (2.01 to 2.63) 3.23 (2.80 to 3.74) 5.14 (4.38 to 6.03) 6.16 (4.85 to 7.83) 7.84 (5.93 to 10.36) —
Age
<60 y (n ¼6690)
5-y OS, % 93.9 (92.6 to 95.0) 89.5 (88.1 to 90.8) 79.1 (76.9 to 81.0) 68.0 (64.6 to 71.1) 56.5 (51.8 to 61.0) 45.5 (36.6 to 53.9) 28.2 (19.1 to 37.9) 81.7 (80.8 to 82.7)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.52 (1.26 to 1.84) 3.11 (2.59 to 3.73) 4.90 (4.05 to 5.91) 7.06 (5.77 to 8.64) 10.3 (7.89 to 13.44) 15.31 (11.45 to 20.47) —
60 y (n ¼6917)
5-y OS, % 86.8 (85.2 to 88.2) 82.4 (80.8 to 83.9) 70.8 (68.4 to 73.1) 57.9 (54.3 to 61.4) 43.0 (37.8 to 48.1) 41.0 (31.9 to 50.0) 27.9 (17.3 to 39.4) 75.4 (74.4 to 76.4)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.34 (1.18 to 1.52) 2.11 (1.86 to 2.41) 3.25 (2.83 to 3.74) 4.95 (4.21 to 5.82) 4.97 (3.86 to 6.39) 7.44 (5.53 to 10.02) —
Race
White (n ¼10 419)
5-y OS, % 90.3 (89.1 to 91.3) 86.5 (85.3 to 87.6) 76.2 (74.3 to 77.9) 65.1 (62.3 to 67.7) 52.7 (48.6 to 56.6) 43.5 (36.3 to 50.5) 30.9 (22.6 to 39.6) 79.5 (78.7 to 80.3)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.34 (1.19 to 1.51) 2.28 (2.02 to 2.57) 3.46 (3.04 to 3.92) 4.99 (4.33 to 5.76) 6.52 (5.33 to 7.96) 9.24 (7.29 to 11.72) —
Black (n ¼1906)
5-y OS, % 85.4 (81.7 to 88.4) 79.9 (76.6 to 82.9) 65.3 (60.7 to 69.5) 49.8 (43.0 to 56.1) 38.1 (29.3 to 46.9) 37.9 (20.9 to 54.9) 23.1 (9.4 to 40.3) 70.1 (68.0 to 72.1)
P
a
—<.001 <.001 .002 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.35 (1.05 to 1.74) 2.40 (1.88 to 3.08) 3.66 (2.80 to 4.80) 5.37 (3.98 to 7.25) 4.99 (3.04 to 8.19) 7.83 (4.95 to 12.39) —
Other (n ¼12 82)
5-y OS, % 94.3 (91.0 to 96.3) 88.4 (84.9 to 91.1) 81.7 (76.6 to 85.8) 67.9 (59.5 to 75.0) 52.0 (40.2 to 62.6) 50.0 (27.1 to 69.2) 10.0 (0.6 to 35.8) 82.7 (80.4 to 84.6)
P
a
— .007 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.78 (1.17 to 2.69) 2.69 (1.77 to 4.09) 5.55 (3.63 to 8.50) 8.25 (5.22 to 13.05) 9.60 (4.94 to 18.65) 19.24 (9.13 to 40.55) —
Location
Colon (n ¼10 768)
5-y OS, % 89.8 (88.5 to 90.9) 86.0 (84.8 to 87.1) 75.0 (73.2 to 76.7) 62.9 (60.2 to 65.5) 49.3 (45.3 to 53.2) 45.2 (38.3 to 51.9) 28.7 (21.2 to 36.6) 78.1 (77.3 to 78.9)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.30 (1.15 to 1.46) 2.29 (2.03 to 2.58) 3.48 (3.07 to 3.95) 5.15 (4.47 to 5.93) 6.03 (4.96 to 7.34) 9.27 (7.44 to 11.54) —
Rectum (n ¼2839)
5-y OS 90.8 (88.7 to 92.5) 84.8 (82.2 to 87.1) 75.3 (71.5 to 78.7) 64.2 (58.0 to 69.8) 54.5 (47.1 to 61.3) 32.4 (17.6 to 48.0) 23.5 (7.3 to 44.9) 80.0 (78.5 to 81.4)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.68 (1.35 to 2.08) 2.47 (1.98 to 3.08) 4.10 (3.22 to 5.22) 5.58 (4.34 to 7.17) 8.71 (5.59 to 13.55) 10.47 (6.04 to 18.17) —
(continued)
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Table 2. (continued)
Characteristics I IIA IIB IIC IIIA IIIB IIIC Overall
Tumor size
<4cm(n¼5840)
5-y OS, % 90.0 (88.8 to 91.1) 85.9 (84.0 to 87.6) 74.2 (71.5 to 76.8) 65.1 (60.4 to 69.4) 55.3 (48.4 to 61.6) 43.6 (29.3 to 56.9) 29.2 (13.0 to 47.6) 82.4 (81.4 to 83.3)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.47 (1.28 to 1.70) 2.53 (2.20 to 2.91) 3.58 (3.02 to 4.24) 4.78 (3.89 to 5.88) 6.59 (4.55 to 9.55) 8.54 (5.33 to 13.70) —
4cm(n¼7767)
5-y OS, % 90.0 (87.8 to 91.8) 85.7 (84.4 to 86.9) 75.5 (73.5 to 77.4) 62.4 (59.5 to 65.1) 48.8 (44.7 to 52.8) 43.3 (36.2 to 50.3) 27.9 (20.3 to 36.0) 75.6 (74.6 to 76.5)
P
a
— .001 .009 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.27 (1.06 to 1.52) 2.15 (1.79 to 2.57) 3.46 (2.89 to 4.15) 5.17 (4.27 to 6.26) 6.05 (4.77 to 7.68) 9.20 (7.11 to 11.91) —
Retrieved lymph notes
<12 (n ¼3509)
5-y OS, % 87.6 (85.7 to 89.4) 79.6 (77.0 to 81.9) 66.3 (62.7 to 69.6) 51.3 (45.8 to 56.6) 37.6 (27.0 to 48.2) 42.9 (26.4 to 58.3) 25.9 (11.5 to 43.1) 75.2 (73.7 to 76.6)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.61 (1.36 to 1.89) 2.63 (2.24 to 3.10) 4.15 (3.44 to 4.99) 5.57 (4.16 to 7.46) 5.59 (3.67 to 8.49) 7.91 (5.06 to 12.35) —
12 (n ¼10 098)
5-y OS, % 91.3 (90.1 to 92.4) 87.7 (86.6 to 88.8) 78.0 (76.2 to 79.7) 66.3 (63.6 to 68.9) 51.9 (48.2 to 55.5) 43.5 (36.6 to 50.2) 28.6 (20.8 to 36.8) 79.6 (78.8 to 80.4)
P
a
—<.001 <.001 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.37 (1.19 to 1.57) 2.36 (2.06 to 2.71) 3.77 (3.28 to 4.35) 5.91 (5.09 to 6.86) 7.39 (6.01 to 9.07) 11.09 (8.78 to 14.00) —
20 (n ¼4758)
5-y OS, % 92.8 (90.9 to 94.4) 89.8 (88.3 to 91.2) 80.4 (77.8 to 82.7) 69.3 (65.5 to 72.8) 54.2 (49.3 to 58.8) 45.2 (35.6 to 54.4) 23.2 (13.2 to 34.8) 80.6 (79.4 to 81.7)
P
a
—<.001 .008 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.37 (1.09 to 1.72) 2.55 (2.03 to 3.20) 4.21 (3.34 to 5.32) 6.63 (5.24 to 8.39) 8.52 (6.23 to 11.65) 14.45 (10.15 to 20.56) —
30 (n ¼1562)
5-y OS, % 94.3 (90.8 to 96.4) 91.4 (88.7 to 93.5) 78.5 (73.7 to 82.5) 68.9 (61.6 to 75.1) 56.6 (48.2 to 64.2) 46.4 (31.1 to 60.4) 22.3 (7.1 to 42.8) 81.1 (79.0 to 83.0)
P
a
—<.001 .24 <.001 <.001 <.001 <.001 <.001
HR (95% CI) 1 (Referent) 1.31 (0.84 to 2.04) 3.34 (2.18 to 5.11) 4.85 (3.11 to 7.56) 7.13 (4.59 to 11.09) 9.71 (5.63 to 16.74) 18.53 (9.83 to 34.92) —
a
Pvalue was obtained by a log-rank test to compare overall survivals for sequential stages. 5-y OS ¼5-year overall survival; CI ¼confidence interval; HR ¼hazard ratio; mTNM ¼modified tumor-node-metastasis.
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adequate staging. Several factors may be associated with the
number of retrieved lymph nodes, such as surgical skills, actual
numbers of lymph nodes surrounding tumors, and immune
responses. In the current study, to avoid the selection bias, we
did not exclude patients with an inadequate number of re-
trieved lymph nodes in the training cohort. Overall, to success-
fully apply the mTNM classification to clinical practice, future
studies are needed to validate the mTNM classification in other
validation cohorts that is inclusive of younger and older
patients, locally advanced rectal cancer patients, and patients
with adequate retrieved lymph nodes.
In conclusion, the mTNM provides better prognostic discrim-
ination for stage I-III CRC than the AJCC 8th TNM and can help
better stratify primary operable CRC patients into prognostic
stages. It is a prognosis-based classification, with good applica-
bility in various populations and settings to help better stratify
primary operable CRC patients into prognostic groups.
Moreover, evidence indicates that the current AJCC 8th TNM
classification for CRC can be improved by further modification.
Funding
This work was supported by the US National Institutes of
Health (NIH) grant (R35 CA197735 to SO), the National
Natural Science Foundation of China (81774112 to ZM), and
the China Scholarship Council (201908050148 to CZ). TU was
supported by a grant from Overseas Research Fellowship
(201960541) from Japan Society for the Promotion of Science.
TU was supported by fellowship grants from Yasuda
Memorial Foundation and the Uehara Memorial
Foundation. KH was supported by the Mitsukoshi Health
and Welfare Foundation and the Uehara Memorial
Foundation. JAM is supported by the Douglas Gray Woodruff
Chair Fund, the Guo Shu Shi Fund, Anonymous Family Fund
for Innovations in Colorectal Cancer, Project P Fund, and the
George Stone Family Foundation.
Notes
Role of the funders: The funders had no role in study design,
data collection and analysis, decision to publish, or preparation
of the manuscript.
Disclosures: Dr Meyerhardt has received institutional research
funding from Boston Biomedical, served as an advisor/consul-
tant to Ignyta and COTA Healthcare, and served on a grant re-
view panel for the National Comprehensive Cancer Network
funded by Taiho Pharmaceutical. This study was not funded by
any of these commercial entities. The other authors declare
that they have no conflicts of interest.
Disclaimers: The content is solely the responsibility of the authors
and does not necessarily represent the official views of NIH.
Author contributions: All authors contributed to review and re-
vision. CZ, ZM, JP, XL, SO, and TU developed the main concept
and designed the study. CZ, JP, RZ, and XL were responsible for
collection of all clinical and pathological data. CZ and JP per-
formed data analysis and interpretation. CZ, SO, and TU drafted
the manuscript. CZ, ZM, JP, MA, XZ, QH, KN, NA, KH, HN, JAM,
RZ, XL, SO, and TU contributed to editing and critical revision
for important intellectual contents.
Table 3. Comparison of the modified TNM and AJCC 8th TNM classifications in the internal validation cohort
Characteristics
AJCC 8th TNM classification mTNM classification
P
a
AIC AUC (95% CI) AIC AUC (95% CI)
Overall (n ¼13 607) 71 238 0.667 (0.659 to 0.675) 70 937 0.675 (0.667 to 0.683) <.001
Sex
Female (n ¼6278) 27 357 0.676 (0.665 to 0.688) 27 199 0.687 (0.675 to 0.698) .002
Male (n ¼7329) 38 504 0.662 (0.651 to 0.672) 38 361 0.668 (0.657 to 0.678) .045
Age
<60 y (n ¼6690) 26 668 0.705 (0.694 to 0.716) 26 514 0.712 (0.701 to 0.723) .06
60 y (n ¼6917) 39 009 0.650 (0.638 to 0.661) 38 870 0.657 (0.646 to 0.668) .007
Race
White (n ¼10 419) 51 266 0.662 (0.653 to 0.671) 51 030 0.671 (0.662 to 0.680) <.001
Black (n ¼1906) 10 103 0.680 (0.658 to 0.701) 10 083 0.680 (0.658 to 0.701) .97
Other (n ¼1282) 4057 0.691 (0.665 to 0.716) 4011 0.705 (0.680 to 0.730) .06
Location
Colon (n ¼10 768) 55 393 0.666 (0.657 to 0.675) 55 175 0.673 (0.664 to 0.682) .004
Rectum (n ¼2839) 11 902 0.672 (0.655 to 0.689) 11 819 0.682 (0.665 to 0.700) .04
Tumor size
<4cm(n¼5840) 24 185 0.651 (0.639 to 0.664) 24 090 0.658 (0.645 to 0.670) .08
4cm(n¼7767) 41 860 0.669 (0.659 to 0.680) 41 672 0.678 (0.668 to 0.688) .002
Retrieved lymph nodes
<12 (n ¼3509) 18 839 0.662 (0.646 to 0.677) 18 757 0.671 (0.655 to 0.686) .04
12 (n ¼10 098) 47 445 0.681 (0.672 to 0.690) 47 191 0.690 (0.680 to 0.699) <.001
20 (n ¼4758) 19 380 0.695 (0.682 to 0.708) 19 240 0.706 (0.693 to 0.719) .003
30 (n ¼1562) 5177 0.720 (0.697 to 0.742) 5158 0.724 (0.701 to 0.746) .55
a
The Hanley and McNeil tests were applied to analyze whether statistically significant difference exist in AUCs between 2 TNM classifications in external validation co-
hort. AIC ¼Akaike information criterion; AJCC ¼American Joint Committee on Cancer; AUC ¼area under the curve; CI ¼confidence interval; mTNM ¼modified tu-
mor-node-metastasis.
C. Zhang et al. |9of10
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Data Availability
The data underlying this article will be shared on reasonable re-
quest to the corresponding author.
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