Incidence
There were 166,388 patients diagnosed as having CRC in our analyses. This included 41.5% with RCC, 26.8% with LCC, and 31.7% with RSC, respectively. There were 30,203 patients with metastasis disease at any site and of these, there were 12,396 (41.0%), 8,758 (29.0%), and 9,049 (30.0%) patients with RCC, LCC, and RSC, respectively. The distribution of patients with CRC and identified bone metastases at diagnosis are provided in Table 1, as stratified by tumor location. Among the entire cohort, 1,659 patients presented with bone metastases at diagnosis, representing 1% of the entire study and 5.5% of the subset with metastatic disease at any site. Bone metastasis numbers were 563 (0.8%), 407 (0.9%) and 689 (1.3%) for RCC, LCC, and RSC, respectively. RSC had the highest incident percentage of bone metastasis (1.3% of the entire cohort; 7.6% of the metastatic subset).
Table 1
Incidence and median survival of patients diagnosed with CRC and bone metastases
Subtype | Patient numbers | Percentage Incidence of bone Metastases (%) | Survival Among Patients With Bone Metastases, Median (IQR), Mo | Survival Among Patients Without Bone Metastases, Median (IQR), Mo |
With CRC | Among Subset With Metastatic Disease | Bone Metastases | Among Entire cohort | Among Subset With Metastatic Disease |
Whole cohort | 166,388 | 30,203 | 1,659 | 1% | 5.5% | 11.37 (10.54–12.19) | 19.91 (19.65–20.17) |
RCC | 69,065 | 12,396 | 563 | 0.8% | 4.5% | 8.34 (7.38–9.40) | 16.54(16.16–19.9) |
LCC | 44,548 | 8,758 | 407 | 0.9% | 4.6% | 12.43 (10.62–14.24) | 22.29 (21.79–22.29) |
RSC | 52,739 | 9,049 | 689 | 1.3% | 7.6% | 12.98 (11.61–14.34) | 22.23 (21.74–22.72) |
Abbreviations: CRC, colorectal cancer; RCC, right-sided colon cancer; LCC, left-sided colon cancer; RSC, rectosigmoid cancer. |
When multivariable logistic regression (Table 2) was performed on patients with metastatic cancer, being male (Female vs. male, OR = 0.854, 95%CI, 0.762–0.958, P < 0.001), advanced stage (N1 vs. N0, OR = 1.278, 95%CI, 1.102–1.483, P = 0.001; N2 vs. N0, OR = 1.548, 95%CI, 1.548–1.949, P < 0.001), mucinous carcinoma (mucinous vs. adenocarcinoma, OR = 1.447, 95%CI, 1.142–1.832, P = 0.002), poorly or undifferentiated (poorly vs. well, OR = 1.024, 95%CI, 1.186–2.309, P = 0.003; poorly differentiated vs. well-differentiated, OR = 1.913, 95%CI, 1.244–2.941, P = 0.003), and non-receipt of surgery (Yes, No, OR = 0.363, 95%CI, 0.309–0.426, P < 0.001) were all associated with significantly greater odds of having bone metastases at diagnosis. Notably, patients with brain metastasis were at highest risk of bone metastasis compared with other organ metastasis (brain metastasis (Yes vs. No, OR = 6.035, 95%CI, 2..848-12.787, P < 0.001), lung metastasis (Yes vs. No, OR = 3.881, 95%CI, 1.873–8.040, P < 0.001), and liver metastasis (Yes vs. No, OR = 2.168, 95%CI, 1.055–4.452, P = 0.035)). RAS cancer patients had higher risk of bone metastasis compared with RCC (HR = 1.600, 95%CI, 1.427–1.795, P < 0.001). Patients who had more organ metastatic lesions were at increased risk of bone metastasis (more extra-bone metastatic lesions (1 vs. 0, OR = 3.826, 95%CI, 1.662–8.808, P = 0.002; 2 vs. 0, OR = 6.557, 95%CI, 5.641–7.623, P < 0.001; 3 vs. 0, OR = 8.191, 95%CI, 6.381–10.514, P < 0.001)).
Table 2
Multivariable Logistic Regression for the Presence of Bone Metastases at Diagnosis of CRC.
Patient characteristic | Patients | Among Entire cohort | Among cohort with metastasis |
Patients | Bone metastasis | OR (95%CI) | P value | OR (95%CI) | P value |
Sex | | | | | | |
Male | 87,092 | 830 | | | | |
Female | 79,296 | 559 | 0.801 (0.723–0.888) | 0.001 | 0.854 (0.762–0.958) | < 0.001 |
Age group | | | | < 0.001 | | 0.002 |
<40 | 4,565 | 60 | Reference | | Reference | |
40–49 | 13,330 | 155 | 0.922 (0.681–1.247) | 0.596 | 0.995 (0.701–1.412) | 0.978 |
50–59 | 33,968 | 362 | 0.953 (0.722–1.256) | 0.731 | 1.126 (0.817–1.553) | 0.469 |
60–69 | 41,326 | 385 | 0.913 (0.694–1.201) | 0.516 | 1.039 (0.755–1.430) | 0.814 |
>69 | 73,199 | 427 | 0.720 (0.549–0.945) | 0.018 | 0.839 (0.611–1.152) | 0.278 |
Surgery | | | | < 0.001 | | < 0.001 |
No | 25,682 | 988 | Reference | | Reference | |
Yes | 140,425 | 398 | 0.378 (0.294–0.486) | < 0.001 | 0.363 (0.309–0.426) | P < 0.001 |
Unknown | 281 | 3 | 0.580 (0.210–1.601) | 0.293 | 0.618 (0.190–2.004) | 0.422 |
T stage | | | | < 0.001 | | |
Tis,T0,T1,T2 (0,1, 2༌3) | 54,934 | 226 | Reference | | | |
T3-T4 (4,5) | 94,713 | 627 | 1.230 (1.050–1.442) | 0.001 | | |
Unknown | 16,741 | 536 | 1.337 (1.145–1.562) | 0.01 | | |
N stage | | | | < 0.001 | | < 0.001 |
N0 | 96,044 | 464 | Reference | | Reference | |
N1 | 38,670 | 420 | 1.305 (1.135-1.500) | < 0.001 | 1.278 (1.102–1.483) | 0.001 |
N2 | 21,119 | 250 | 1.756 (1.421–2.169) | < 0.001 | 1.548 (1.229–1.949) | < 0.001 |
Unknown | 10.555 | 255 | 1.202 (1.031–1.401) | < 0.001 | 1.289 (1.095–1.517) | 0.002 |
Pathology type | | | | < 0.001 | | 0.004 |
Adenomas | 148,848 | 1,146 | Reference | | Reference | |
Mucinous | 12,430 | 110 | 1.602 (1.322–1.942) | < 0.001 | 1.447 (1.142–1.832) | 0.002 |
Other type | 3,897 | 93 | 1.322 (1.083–1.615) | 0.006 | 1.260 (1.003–1.582) | 0.047 |
Unspecified | 1,213 | 40 | 1.124 (0.833–1.518) | 0.445 | 0.907 (0.643–1.280) | 0.580 |
Pathology grade | | | | < 0.001 | | < 0.001 |
Well differentiated | 15,215 | 48 | Reference | | Reference | |
Moderately differentiated | 101,357 | 526 | 1.196 (0.907–1.575) | 0.204 | 1.024 (0.744–1.410) | 0.884 |
Poorly differentiated | 23.044 | 310 | 2.216 (1.663–2.953) | < 0.001 | 1.655 (1.186–2.309) | 0.003 |
Undifferentiated | 4,488 | 48 | 2.305 (1.580–3.362) | < 0.001 | 1.913 (1.244–2.941) | 0.003 |
Unknown | 22,284 | 457 | 1.483 (1.119–1.964) | < 0.001 | 1.326 (0.958–1.835) | 0.089 |
Number of Lymph node | | | | < 0.001 | | 0.012 |
0 | 74,454 | 74 | Reference | | Reference | |
<12 | 44,662 | 202 | 1.559 (1.172–2.072) | 0.002 | 0.899 (0.638–1.267) | 0.543 |
>=12 | 3,621 | 76 | 3.129 (2.163–4.525) | < 0.001 | 1.391 (0.897–2.158) | 0.140 |
Unknown | 43,651 | 1,037 | 1.786 (1.173–2.721) | 0.007 | 1.459 (0.922–2.309) | 0.107 |
Tumor site | | | | 0.001 | | < 0.001 |
RCC | | | Reference | | Reference | |
LCC | | | 1.126 (0.991–1.279) | 0.068 | 0.979 (0.859–1.116) | 0.753 |
RSC | | | 1.633 (1.461–1.825 | < 0.001 | 1.600 (1.427–1.795) | < 0.001 |
Brain metastasis | | | | | | |
No | 166,004 | 1,322 | | | | |
Yes | 384 | 67 | 2.860 (2.012–4.067) | < 0.001 | 6.035 (2.848–12.787) | < 0.001 |
Lung metastasis | | | | < 0.001 | | 0.001 |
No | 158,660 | 782 | Reference | | Reference | |
Yes | 7,206 | 580 | 1.838 (1.519–2.225) | < 0.001 | 3.881 (1.873–8.040) | < 0.001 |
Unknown | 522 | 27 | 2.343 (0.952–5.764) | 0.064 | 3.734 (0.941–14.821) | 0.061 |
Liver metastasis | | | | | | 0.107 |
No | 143,768 | 378 | | | Reference | |
Yes | 22,336 | 1006 | | | 2.168 (1.055–4.452) | 0.035 |
Unknown | 284 | 5 | | | 2.032 (0.585–7.058) | 0.264 |
Extrabone metastasis sites to brain, lung and liver | | | | < 0.001 | | < 0.001 |
0 | 141,400 | 243 | Reference | | Reference | |
1 | 19,016 | 631 | 3.811 (1.655–8.773) | 0.002 | 3.826 (1.662–8.808) | 0.002 |
2 | 5,116 | 458 | 6.600 (5.676–7.674) | < 0.001 | 6.557 (5.641–7.623) | < 0.001 |
3 | 112 | 28 | 8.278 (6.448–10.628) | < 0.001 | 8.191 (6.381–10.514) | < 0.001 |
Other organ metastasis | 744 | 29 | 9.061 (4.860-16.895) | < 0.001 | 8.959 (4.805–16.703) | < 0.001 |
Abbreviations: CRC, colorectal cancer; RCC, right-sided colon cancer; LCC, left-sided colon cancer; RSC, Rectosigmoid cancer; ORs: odds ratios; CI: confidence interval. |
Survival
The median survival time (MST) for patients with bone metastasis was 11.3 months (Fig. 1A). For RCC, LCC, and RSC, the MST was 19.9 months, 22.3 months and 22.2 months when bone metastasis was absent, respectively. However, when bone metastasis was present, the MST decreased significantly and was 11.4 months, 12.4 months and 13.0 months for RCC, LCC, and RSC, respectively (Fig. 1B and Table 1). Additionally, patients with bone metastasis were able to benefit from surgery as shown in Fig. 1C.
Multivariable Cox regression (Table 3) for OS among patients with bone metastases at diagnosis revealed that older age (60–69 vs. <40, HR = 1.739, 95%CI, 1.226–2.468, P = 0.002; >69 vs. <40, HR = 2.171, 95%CI = 1.53–3.072, P < 0.001), poorly and undifferentiated (poorly vs. well, HR = 1.451, 95%CI, 1.058–1.990, P = 0.021; undifferentiated vs. well, HR = 1.845, 95%CI, 1.231–2.766, P = 0.003), RCC (LCC vs. RCC, HR = 0.844, 95%CI, 0.728–0.978, P = 0.024; RSC vs. RCC, HR = 0.709, 95% CI, 0.622–0.809, P < 0.001), and more extra-bone metastasis lesions (2 vs. 0, HR = 1.236, 95%CI, 1.050–2.429, P = 0.011; 3 vs. 0, HR = 1.612, 95%CI, 1.070–2.429, P = 0.023) were all significantly associated with poorer OS. CRC–cause mortality among patients with bone metastases at diagnosis is also presented in Table 3.
Table 3
Multivariable Cox Regression for All-Cause Mortality and CRC Cancer–Specific Mortality
Patient characteristic | All-cause Mortality | CRC-Specific Mortality |
HR (95%CI) | P value | HR (95%CI) | P value |
Age group | | < 0.001 | | < 0.001 |
<40 | Reference | | Reference | |
40–49 | 1.157 (0.791–1.695) | 0.452 | 1.211 (0.805–1.823) | 0.358 |
50–59 | 1.354 (0.951–1.927) | 0.093 | 1.340 (0.913–1.966) | 0.135 |
60–69 | 1.739 (1.226–2.468) | 0.002 | 1.799 (1.229–2.634) | 0.003 |
>69 | 2.171 (1.534–3.072) | < 0.001 | 2.183 (1.493–3.194) | < 0.001 |
Surgery | | < 0.001 | | < 0.001 |
No | Reference | | Reference | |
Yes | 0.598 (0.512–0.698) | < 0.001 | 0.551 (0.461–0.660) | < 0.001 |
Unknown | 1.393 (0.517–3.757) | 0.214 | 1.712 (0.541–5.417) | 0.360 |
N stage | | < 0.001 | | < 0.001 |
N0 | Reference | | Reference | |
N1 | 0.923 (0.802–1.063) | 0.267 | 0.856 (0.728–1.008) | 0.062 |
N2 | 1.180 (0.984–1.414) | 0.074 | 1.255 (1.023–1.539) | 0.030 |
Unknown | 1.076 (0.920–1.259) | 0.362 | 1.075 (0.897–1.288) | 0.431 |
Diagnosed methods | | | | |
Other method vs. Biopsy | | < 0.001 | | < 0.001 |
Pathology type | | < 0.001 | | < 0.001 |
Adenomas | Reference | | Reference | |
Mucinous | 1.165 (0.954–1.423) | 0.135 | 1.301 (1.039–1.630) | 0.022 |
Other type | 1.435 (1.168–1.763) | 0.001 | 1.536 (1.204–1.958) | 0.001 |
Unspecified | 2.465 (1.822–3.334) | < 0.001 | 2.033 (1.399–2.955) | < 0.001 |
Pathology grade | | < 0.001 | | < 0.001 |
Well differentiated | Reference | | Reference | |
Moderately differentiated | 0.960 (0.705–1.308) | 0.797 | 0.951 (0.672–1.345) | 0.777 |
Poorly differentiated | 1.451 (1.058–1.990) | 0.021 | 1.477 (1.036–2.106) | 0.031 |
Undifferentiated | 1.845 (1.231–2.766) | 0.003 | 2.199 (1.385–3.493) | 0.001 |
Unknown | 1.107 (0.809–1.515) | 0.524 | 1.136 (0.800-1.614) | 0.475 |
Tumor site | | < 0.001 | | < 0.001 |
RCC | Reference | | Reference | |
LCC | 0.844 (0.728–0.978) | 0.024 | 0.857 (0.724–1.016) | 0.075 |
RSC | 0.709 (0.622–0.809) | < 0.001 | 0.733 (0.631–0.850) | < 0.001 |
Liver metastasis | | | | 0.001 |
Yes | | | Reference | |
No | | | 1.227 (1.060–1.421) | 0.006 |
Unknown | | | 4.792 (1.748–13.134) | 0.002 |
| | | | |
Extrabone metastasis sites to brain, lung and liver | | 0.008 | | 0.012 |
0 | Reference | | Reference | |
1 | 1.029 (0.882–1.201) | 0.713 | 1.167 (0.887–1.535) | 0.271 |
2 | 1.236 (1.050–1.457) | 0.011 | 1.309 (1.129–1.517) | < 0.001 |
3 | 1.612 (1.070–2.429) | 0.023 | 1.855 (1.509–2.281) | < 0.001 |
Other organ metastasis 4 | 1.141 (0.780–1.670) | 0.495 | 1.044 (0.776–1.405) | 0.775 |
Abbreviations: CRC, colorectal cancer; RCC, right-sided colon cancer; LCC, left-sided colon cancer; RSC, Rectosigmoid cancer; HRs: hazard ratios; CI: confidence interval. |
We then compared the MST by extent of metastasis sites (Fig. 1D). In general, patients with more metastasis sites had poorer survival. However, there was no survival difference for those with two or three extra-bone metastasis sites (P = 0.336). Then, we further compared the MST by subtype as stratified by tumor location and ascertained the extent of systemic disease (Table 4). We also found that the presence of bone metastases at initial diagnosis was associated with shorter survival time compared with patients presenting with 1 metastatic site without baseline bone involvement, except in RCC with brain metastasis (Table 4). There was no survival difference for single brain metastasis (MST = 8.9) and both brain and bone metastasis (MST = 9.0). Notably, for RSC with single brain metastasis, the MST was 14.0 months and then suddenly decreased to 1 month.
Table 4
The median survival of metastasis CRC with single metastatic site and multiple-sites
Subtype | Survival, Median (IOQ), month |
Extra bone metastasis Disease Only | Extra bone metastasis and Bone Metastases |
All cohort | | |
Subsite of metastasis | | |
0 | 45.8 (45.67–45.93) | 13.98 (11.74–16.21) |
Brain | 12.62 (9.25-16) | 6.5 (1.19–11.81) |
Lung | 24.04 (22.92–25.15) | 14.31 (11.26–17.35) |
Liver | 21.30 (20.94–21.66) | 11.28 (9.97–12.58) |
Two sites | | |
Lung and liver | 14.78 (14.22–15.31) | 9.53 (8.43–10.64) |
Lung and brain | 7.75 (5.25–10.25) | 5.82 (1.96–9.66) |
Liver and brain | 7.79 (4.98–10.60) | 8.02 (2.75–13.29) |
Three sites | | |
Lung, liver, and brain | 6.10 (3.74–8.26) | 6.98 (4.27–9.69) |
Other sites | 16.63 (18.21–18.21) | 9.54 (4.75–14.32) |
RCC | | |
Subsite of metastasis | | |
0 | 43.96 (43.76–44.16) | 10.37 (7.33–13.41) |
Brain | 8.94 (4.43–13.44) | 9 (0-18.02) |
Lung | 19.81 (17.86–21.78) | 12.13 (8.27–15.99) |
Liver | 17.06 (16.55–17.57) | 7.85 (6.54–9.15) |
Two sites | | |
Lung and liver | 11.41 (10.65–12.17) | 6.79 (5.50–8.09) |
Lung and brain | 9.15 (2.48–15.83) | 6.43 (1.34–11.50) |
Liver and brain | 6.65 (3.52–9.78) | 7.14 (0.62–13.66) |
Three sites | | |
Lung, liver, and brain | 6.93 (4.93–8.83) | 6.5 (2.72–10.28) |
Other sites | 14.04 (11.84–16.25) | 7.46 (2.59–12.33) |
LCC | | |
Subsite of metastasis | | |
0 | 47.00 (46.77–47.24) | 12.78 (8.69–16.87) |
Brain | 13.99 (8.11–19.88) | 1 (0–1) |
Lung | 25.01 (22.71–27.31) | 14.11 (7.14–21.08) |
Liver | 24.29 (23.61–24.96) | 13.02 (10.10-15.93) |
Two sites | | |
Lung and liver | 15.47 (14.44–16.49) | 11.33 (8.78–13.87) |
Lung and brain | 8.04 (3.83–12.25) | 9 (0-20.76) |
Liver and brain | 13.03 (6.89–19.16) | 2.5 (0.39–4.61) |
Three sites | | |
Lung, liver, and brain | 2.56 (1.67–3.45) | 1.67 (1.01–2.33) |
Other sites | 18.76 (15.66–21.87) | 9.88 (0-22.41) |
RSC | | |
Subsite of metastasis | | |
0 | 47.24 (47.03–47.46) | 15.16 (12.02–18.30) |
Brain | 15.39 (10.16–20.61) | 3.8 (0-7.89) |
Lung | 26.06 (24.44–27.68) | 15.56 (10.98–20.15) |
Liver | 24.49 (23.77–25.21) | 13.72 (11.21–16.22) |
Two sites | | |
Lung and liver | 17.31 (16.32–18.31) | 10.15 (8.53–11.78) |
Lung and brain | 7.39 (3.94–10.84) | 7.01 (5.06–8.94) |
Liver and brain | 15 (3.80–26.20) | 11.98 (4.98–18.99) |
Three sites | | |
Lung, liver, and brain | 9.77 (5.98–13.56) | 9.82 (5.33–14.29) |
Other sites | 18.61 (15.56–21.65) | 11.15 (4.91–17.39) |
Abbreviations: CRC, colorectal cancer; RCC, right-sided colon cancer; LCC, left-sided colon cancer; RSC, Rectosigmoid cancer. |
When patients had metastasis at two sites, such as liver and lung metastasis, other bone metastasis was associated with poorer survival except in those with LCC. Patients with liver, brain, and bone metastasis in the LCC, had a MST of 2.5 months but the MST increased to 13.0 months when bone metastasis was not present.
For patients with three organs affected by metastasis, survival difference was independent of bone metastasis.