3.1 Demographic and clinical characteristics of study patients
Of the 378 study patients, 271 were male (71.70%) and 107 were female (28.30%).The demographic and clinical characteristics of entire cohort and patients grouped by different patterns of metastatic sites are summarized in Table 1.
3.2 Distribution of the metastatic sites
The number of patients with one, two, three, and four site metastases was 219 (57.94%), 115 (30.42%), 38 (10.05%), and 6 (1.59%), respectively.The most common pattern of metastases at one site was lung metastases (33.86%), followed by bone metastases（17.46%）, liver metastases（4.76%）, and brain metastases（1.85%）.The most common pattern of metastases at multiple sites was "lung + bone" (15.61%)，followed by "lung+ liver" (7.14%) and "lung+bone+liver" (7.14%), the proportions of other patterns were less than 5%. Detailed distributions of distant metastatic sites are shown in Table 2.
172 (45.50%) patients received surgery,with radical nephrectomy as the primary surgical type (n=132,76.74%), Partial or subtotal nephrectomy as the secondary surgical type (n=36,20.93%), and 4 (2.33%) had only a biopsy of renal tumor tissue.Among the other treatment methods, 103 (27.25%) patients received regional lymphatic dissection, 209 (55.30%) patients received chemotherapy ,130 (34.40%) patients received radiotherapy.In addition, 40 patients (10.58%) patients did not receive any of above treatments.
3.4 The impact of site-specific distant metastases on overall survival
By the last one follow-up at the end of December 2016，376 patients were effectively followed up and 2 patients were lost to follow-up.At the follow-up endpoint, 348 (92.06%) patients died, 334 (88.36%) died from sRCC, and another 14 (3.70%) died from other causes.The median OS for the entire cohort was 4 months,and the 6,12,18 ,24 months survival rates were 35.45%, 18.25%,9.52%, 7.41% , respectively.
The median OS of patients with one site and multiple sites of distant metastases was 5 and 3 months, respectively, and the difference of OS was statistically significant (χ2=15.544, P <0.001).Compared to patients with one site of metastases, the death hazard ratio（HR) for patients with multiple sites of distant metastases was 1.494(95%CI: 1.205～1.852).Survival curves are shown in Figure 1.
Among the patients with one site of distant metastases ,the median OS of patients with bone, brain, liver, and lung metastases were 6,5,3, and 5 months, respectively, and the difference of OS was not statistically significant (χ2=4.643，P=0.200）.It indicates that for patients with one site of metastases, the specific type of distant metastatic site did not affect the OS.Survival curves are shown in Figure 2.
3.5 Prognostic factors for site-specific distant metastases
In the entire cohort (n=378), univariate Cox analysis showed that age, N stage, lymph node dissection,metastatic sites, chemotherapy and surgery were significant factors affecting OS (P <0.05). The above variables were included in multivariate Cox analysis, which showed that metastatic sites, chemotherapy and surgery were independent prognostic factors affecting OS (P <0.05).Detailed data are shown in Tables 3 and 4.
We used the same approach to identify the independent predictors for OS in patients with one site and multiple sites of distant metastases .Given the low sample size of brain and liver metastases only, therefore, patients with lung metastases only (n=128) and bone metastases only (n=128) were chosen for prognostic analysis.The results showed that: for patients with lung metastases only , surgery and chemotherapy were independent prognostic factors (Tables 3、4), the risk of mortality for patients receiving surgery was significantly lower than that in patients not receiving surgery (HR=0.528, 95%CI: 0.360~0.775, P <0.001),and the patients receiving chemotherapy had lower risk of mortality compared to those who had not receive chemotherapy(HR=0.499, 95%CI: 0.338~0.737, P <0.001).For patients with bone metastases only, surgery was an independent prognostic factor, and the risk of mortality for patients receiving surgery was significantly lower than in those without surgery (HR=0.360, 95%CI: 0.204~0.634, P <0.001).For patients with multiple sites of distant metastases, surgery and chemotherapy were independent prognostic factors. Compared with patients who had not received surgery and chemotherapy, the patients receiving surgery (HR=0.490, 95%CI: 0.347~0.693)and chemotherapy (HR=0.377, 95%CI: 0.270~0.527) had a lower risk of mortality (P <0.001).The above statistical results show that nephrectomy of the primary tumor side reduced the risk of mortality in patients with lung metastases only, bone metastases only and multiple sites of distant metastases; chemotherapy reduced the risk of mortality in patients with lung metastases only and multiple sites of distant metastases, but it was not found to reduce the risk of mortality in patients with bone metastases only.