Demographic and clinical characteristics
A total of 34933 patients with distant metastases and 31288 patients with liver metastases, 10598 patients with lung metastases, 2553 patients with bone metastases, and 587 patients with brain metastases were included in this study. The detailed workflow for patient selection is shown in Fig. 1. The mean age of all 34933 CRC patients with distant metastases was 64.19 ± 14.13 years (range 14 to 108), 55.2% of patients (N = 19273) were male, and 44.8% of patients (N = 15660) were female. Most of the patients were white (75.1%, N = 26234), followed by black (15.5%, N = 5400). Forty-eight percent (N = 16944) of patients were married, and 77.7% (N = 27152) were insured. Regarding the primary tumour sites, most were localized in the left colon (35.70%, N = 12470) and right colon (35.17%, N = 12285), followed by the rectum (20.31%, N = 7098). A total of 30.38% (N = 10612) of patients were initially diagnosed with a stage T3 tumour, and 47.23% (N = 16498) were diagnosed with a grade II tumour. Detailed demographic and clinical characteristics are shown in Table 1.
Table 1
Patient characteristics and 1-, 3-, and 5-year overall survival rates for colorectal cancer with distant metastases
Subject characteristics
|
CRC patients with distant metastases (N = 34933)
|
N
|
%
|
1-year (%)
|
3-year (%)
|
5-year (%)
|
Age(years)
|
|
|
|
|
|
≤ 50
|
5936
|
17.0
|
69.4
|
28.9
|
15.1
|
51–60
|
8382
|
24.0
|
60.4
|
24.9
|
12.2
|
61–70
|
9035
|
25.9
|
52.1
|
25.8
|
10.2
|
71–80
|
6460
|
18.5
|
38.1
|
12.3
|
6.1
|
81–90
|
4269
|
12.2
|
20.8
|
4.2
|
2.1
|
≥ 91
|
851
|
2.4
|
8.7
|
1.6
|
0
|
Sex
|
|
|
|
|
|
Female
|
15660
|
44.8
|
47.1
|
18.5
|
9.7
|
Male
|
19273
|
55.2
|
51.4
|
19.2
|
9.3
|
Race
|
|
|
|
|
|
White
|
26234
|
75.1
|
49.6
|
19.5
|
9.9
|
Black
|
5400
|
15.5
|
46.7
|
14.7
|
6.8
|
Othersa
|
3205
|
9.2
|
52.9
|
20.7
|
10.4
|
Unknown
|
94
|
0.3
|
66.7
|
40.0
|
26.7
|
Marital status
|
|
|
|
|
|
Married
|
16944
|
48.5
|
56.2
|
23.0
|
11.8
|
Unmarriedb
|
16189
|
46.3
|
42.5
|
14.7
|
7.0
|
Unknown
|
1800
|
5.2
|
48.7
|
18.7
|
10.2
|
Insurance status
|
|
|
|
|
|
Insured
|
27152
|
77.7
|
50.4
|
20.0
|
10.2
|
Any medic aid
|
6045
|
17.3
|
45.4
|
14.3
|
6.4
|
Uninsured
|
1736
|
5.0
|
48.7
|
17.9
|
8.5
|
Site
|
|
|
|
|
|
Right coon
|
12285
|
35.2
|
43.3
|
14.3
|
7.4
|
Left colon
|
12470
|
35.7
|
57.4
|
24.6
|
12.4
|
Rectum
|
7098
|
20.3
|
58.4
|
22.9
|
11.1
|
Unknown
|
3080
|
8.8
|
21.5
|
5.1
|
2.7
|
Histological grade
|
|
|
|
|
|
Grade I
|
1420
|
4.1
|
60.8
|
27.5
|
14.6
|
Grade II
|
16498
|
47.2
|
63.4
|
26.2
|
13.5
|
Grade III
|
5496
|
15.7
|
41.6
|
13.7
|
6.5
|
Grade IV
|
1037
|
3.0
|
38.3
|
13.6
|
5.9
|
Unknown
|
10482
|
30.0
|
31.2
|
9.3
|
4.3
|
Lymphatic metastasis
|
|
|
|
|
|
N0
|
11445
|
32.8
|
45.8
|
18.2
|
10.1
|
N1
|
11055
|
31.6
|
57.0
|
24.0
|
12.1
|
N2
|
7034
|
20.1
|
58.5
|
21.3
|
9.6
|
Unknown
|
5399
|
15.5
|
29.8
|
7.0
|
2.9
|
T stage
|
|
|
|
|
|
T1
|
3267
|
9.4
|
42.8
|
12.4
|
5.1
|
T2
|
735
|
2.1
|
66.9
|
37.0
|
25.1
|
T3
|
10612
|
30.4
|
67.2
|
31.3
|
16.9
|
T4
|
7962
|
22.8
|
51.3
|
18.0
|
8.2
|
Unknown
|
12357
|
35.4
|
32.9
|
8.5
|
3.5
|
CEA
|
|
|
|
|
|
Negative
|
3499
|
10.0
|
64.1
|
33.6
|
21.3
|
Positive
|
20199
|
57.8
|
51.7
|
17.4
|
7.9
|
Unknown
|
11235
|
32.2
|
42.8
|
16.9
|
8.7
|
Surg(pri)
|
|
|
|
|
|
Yes
|
15634
|
44.8
|
66.4
|
31.0
|
16.8
|
None
|
19190
|
54.9
|
35.5
|
8.5
|
3.1
|
Unknown
|
109
|
0.3
|
36.8
|
14.7
|
10.5
|
Abbreviations: CEA = carcinoembryonic antigen; Surg(pri) = surgical treatments of primary site. |
a Includes American Indian/Alaska Native and Asian or Pacific Islander |
b Includes single, separated, widowed, and divorced |
c Sites were unclear |
Survival Outcomes In Patients With Distant Metastases
The 1-, 3-, and 5-year OS rates were 49.5%, 18.9%, and 9.5% for all patients, respectively. The mean survival time was 20.94 months. The 1-, 3-, and 5-year OS rates rapidly decreased with increasing age. However, the 1-, 3-, and 5-year OS rates in patients who underwent surgery at the primary site were much higher than those in patients who did not (p < 0.001). The detailed data of the patients’ 1-, 3-, and 5-year OS rates are listed in Table 1, and the median survival times are listed in Table 2.
Table 2
Multivariable Cox regression for analyzing the prognosis factors for colorectal cancer with distant metastases.
Subject characteristics
|
No. of CRC patients with distant metastases
|
Survival median, months
|
Univariate
|
Multivariate
|
HR (95% CI)
|
P-value
|
HR (95% CI)
|
P-value
|
Age (years)
|
|
|
|
|
|
|
≤ 50
|
5936
|
22.00(21.25–22.75)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
51–60
|
8382
|
18.00(17.39–18.61)
|
1.20(1.15–1.25)
|
<0.001
|
1.15(1.10–1.20)
|
<0.001
|
61–70
|
9035
|
14.00(13.42–14.58)
|
1.44(1.38–1.5)
|
<0.001
|
1.38(1.32–1.44)
|
<0.001
|
71–80
|
6460
|
7.00(6.55–7.45)
|
2.02(1.93–2.1)
|
<0.001
|
1.93(1.85–2.01)
|
<0.001
|
81–90
|
4269
|
3.00(2.78–3.22)
|
3.25(3.1–3.4)
|
<0.001
|
2.79(2.66–2.93)
|
<0.001
|
≥ 91
|
851
|
1.00(0.74–1.26)
|
5.00(4.63–5.4)
|
<0.001
|
3.62(3.34–3.92)
|
<0.001
|
Sex
|
|
|
|
|
|
|
Female
|
15660
|
11.00(10.59–11.41)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Male
|
19273
|
13.00(12.62–13.38)
|
0.93(0.91–0.96)
|
<0.001
|
1.07(1.04–1.1)
|
<0.001
|
Race
|
|
|
|
|
|
|
White
|
26234
|
12.00(11.67–12.33)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Black
|
5400
|
11.00(10.38–11.62)
|
1.12(1.08–1.16)
|
<0.001
|
1.10(1.07–1.14)
|
<0.001
|
Othersa
|
3205
|
14.00(12.91–15.09)
|
0.91(0.88–0.96)
|
<0.001
|
0.97(0.92–1.01)
|
0.133
|
Unknown
|
94
|
25.00(13.41–36.59)
|
0.58(0.42–0.79)
|
0.001
|
0.57(0.41–0.78)
|
0.001
|
Marital status
|
|
|
|
|
|
|
Married
|
16189
|
16.00(15.55–16.45)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Unmarriedb
|
16944
|
9.00(8.64–9.36)
|
1.37(1.34–1.41)
|
<0.001
|
1.20(1.17–1.23)
|
<0.001
|
Unknown
|
1800
|
12.00(10.6–13.4)
|
1.18(1.11–1.25)
|
<0.001
|
1.09(1.03–1.15)
|
0.005
|
Insurance status
|
|
|
|
|
|
|
Insured
|
27152
|
13.00(12.67–13.33)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Any medic aid
|
1736
|
11.00(10.44–11.56)
|
1.15(1.11–1.19)
|
<0.001
|
1.24(1.19–1.28)
|
<0.001
|
Uninsured
|
6045
|
12.00(10.68–13.32)
|
1.05(0.99–1.11)
|
0.082
|
1.30(1.23–1.38)
|
<0.001
|
Site
|
|
|
|
|
|
|
Right colon
|
12285
|
10.00(9.61–10.39)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Left colon
|
12470
|
17.00(16.45–17.55)
|
0.71(0.69–0.73)
|
<0.001
|
0.78(0.76–0.80)
|
<0.001
|
Rectum
|
7098
|
17.00(16.3–17.7)
|
0.71(0.68–0.73)
|
<0.001
|
0.66(0.63–0.68)
|
<0.001
|
Unknown
|
3080
|
2.00(1.74–2.26)
|
1.79(1.71–1.86)
|
<0.001
|
1.13(1.08–1.19)
|
<0.001
|
Histological grade
|
|
|
|
|
|
|
Grade I
|
1420
|
19.00(17.03–20.97)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Grade II
|
16498
|
20.00(19.54–20.46)
|
0.99(0.93–1.06)
|
0.821
|
1.10(1.03–1.18)
|
0.005
|
Grade III
|
5496
|
9.00(8.52–9.48)
|
1.62(1.51–1.74)
|
<0.001
|
1.72(1.6–1.85)
|
<0.001
|
Grade IV
|
1037
|
8.00(6.99–9.01)
|
1.68(1.53–1.85)
|
<0.001
|
1.92(1.74–2.11)
|
<0.001
|
Unknown
|
10482
|
5.00(4.73–5.27)
|
2.15(2.01–2.3)
|
<0.001
|
1.40(1.3–1.5)
|
<0.001
|
Lymphatic metastasis
|
|
|
|
|
|
|
N0
|
11445
|
10.00(9.51–10.49)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
N1
|
11055
|
16.00(15.41–16.59)
|
0.78(0.76–0.81)
|
<0.001
|
1.06(1.03–1.10)
|
<0.001
|
N2
|
7034
|
17.00(16.38–17.62)
|
0.80(0.77–0.83)
|
<0.001
|
1.36(1.30–1.42)
|
<0.001
|
Unknown
|
5399
|
5.00(4.66–5.34)
|
1.56(1.5–1.62)
|
<0.001
|
1.13(1.09–1.18)
|
<0.001
|
T stage
|
|
|
|
|
|
|
T1
|
3267
|
9.00(8.27–9.73)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
T2
|
735
|
24.00(20.78–27.22)
|
0.47(0.43–0.52)
|
<0.001
|
0.74(0.67–0.83)
|
<0.001
|
T3
|
10612
|
22.00(21.35–22.65)
|
0.53(0.51–0.56)
|
<0.001
|
0.81(0.77–0.85)
|
<0.001
|
T4
|
7962
|
13.00(12.47–13.53)
|
0.80(0.77–0.84)
|
<0.001
|
1.08(1.03–1.14)
|
0.002
|
Unknown
|
12357
|
5.00(4.72–5.28)
|
1.28(1.22–1.33)
|
<0.001
|
1.03(0.98–1.07)
|
0.246
|
CEA
|
|
|
|
|
|
|
Negative
|
3499
|
22.00(20.68–23.32)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
Positive
|
20199
|
13.00(12.65–13.35)
|
1.56(1.49–1.63)
|
<0.001
|
1.38(1.32–1.45)
|
<0.001
|
Unknown
|
11235
|
9.00(8.55–9.45)
|
1.78(1.7–1.87)
|
<0.001
|
1.45(1.38–1.52)
|
<0.001
|
Surg(pri)
|
|
|
|
|
|
|
Yes
|
15634
|
22.00(21.47–22.53)
|
1(Reference)
|
1.00
|
1(Reference)
|
1.00
|
None
|
19190
|
7.00(6.76–7.24)
|
2.27(2.21–2.33)
|
<0.001
|
2.17(2.09–2.26)
|
<0.001
|
Unknown
|
109
|
7.00(2.87–11.13)
|
1.81(1.45–2.25)
|
<0.001
|
1.53(1.23–1.91)
|
<0.001
|
Abbreviations: CEA = carcinoembryonic antigen, NA = not available, Surg(pri) = surgical treatments of primary site. |
a Includes American Indian/Alaska Native and Asian or Pacific Islander. |
b Includes single, separated, widowed, and divorced. |
The median survival times of patients with liver metastases, lung metastases, bone metastases, and brain metastases were 12.00 months (95% CI: 11.71–12.29 months), 10.00 months (95% CI: 9.57–10.43 months), 5.00 months (95% CI: 4.47–5.53 months), and 3.00 months (95% CI: 2.31–3.70 months), respectively, with a significant difference (p < 0.001) (Fig. 2). The 1-year survival rate was highest for patients with liver metastases (49.1%), followed by those with lung metastases (44.2%), bone metastases (29.3%), and brain metastases (26.0%). The 3-year survival rates for patients with liver metastasis and lung metastases were 18.4% and 13.5%, respectively, which were higher than those for patients with bone metastases (7.0%) and brain metastases (5.1%). The 5-year survival rates for patients with liver metastases (9.2%), lung metastases (5.2%), bone metastases (3.0%), and brain metastases (3.6%) were all poor and lower than 10%. Details on the 1-, 3-, and 5-year OS rates of CRC patients with liver metastases, lung metastases, bone metastases and brain metastases are listed in Tables S1-S4.
Prognostic Factors In Crc Patients With Distant Metastases
Age, sex, race, marital status, insurance status, primary tumour site, histological grade, lymphatic metastasis, T stage, carcinoembryonic antigen (CEA) level and surgical treatment at the primary site were correlated with the prognosis of patients with distant metastases in the univariate analysis. The results of the multivariable model indicated that older age, male sex, black race, unmarried status, uninsured status, poor histological grade, stage T4/T1, high CEA level and no surgical treatment all showed positive associations with the prognosis of patients with metastases (see Table 2). The associated prognostic factors and their HRs with 95% CIs according to the different sites of metastases are presented in Tables S5-S8.
The prognostic factors associated with CRC with metastases at different organs were homogeneous and heterogeneous. Both older age and no surgery at the primary site showed positive associations with the prognosis of CRC patients with distant metastases. Male sex, black race, unmarried status, uninsured status, poor histological grade, lymphatic metastasis, stage T4/T1, high CEA level, and metastatic organ showed positive associations with the prognosis of CRC patients with liver metastases. Unmarried status, uninsured status, poor histological grade, lymphatic metastasis, high CEA level, and metastatic organ showed positive associations with the prognosis of CRC patients with lung metastases. Unmarried status, poor histological grade, lymphatic metastasis, and metastatic organ showed positive associations with the prognosis of CRC patients with bone metastases, and high CEA level showed a positive association with the OS of CRC patients with brain metastases (see Fig. 3).
Performance Of The Prognostic And Predictive Nomogram
All significant variables associated with the prognosis of CRC patients with distant metastases were incorporated into the nomogram for predicting the 1-, 3-, and 5-year OS rates of CRC patients with liver metastases, lung metastases, bone metastases, and brain metastases (Fig. 4(A-D)). The C-indexes for the prediction of the OS of patients with liver metastases, lung metastases, bone metastases, and brain metastases were 74.4% (95% CI, 74.2–74.8%), 77.6% (95% CI, 77.1–78.1%), 83.6% (95% CI, 82.8–84.4%), and 85.3% (95% CI, 83.6–87.1%), respectively. The calibration curves revealed good agreement between the predicted and observed survival probabilities of CRC patients with liver metastases (Fig. 5A1–A3), lung metastases (Fig. 5B1–B3), bone metastases (Fig. 5C1–C3), and brain metastases (Fig. 5D1–D3).