General information
A total of 237 patients were reviewed and patients were followed by phone/clinic. Follow-up time ranged from 2 to 144 months. Eventually, 203 patients were identified with the clear status of lung metastasis. The average age at diagnosis of osteosarcoma was 22.8±14.2 (5-77) years. The historical type one included 88 osteosarcoma NOS, 89 conventional osteosarcoma, 7 telangiectatic osteosarcoma, 3 small cell osteosarcoma; type two included 4 low-grade central osteosarcoma, 8 parosteal osteosarcoma and 4 periosteal osteosarcoma. Eighty-eight (43.3%) patients were diagnosed with lung metastasis. Twenty-one pulmonary metastases (10.3%) were identified at the initial diagnosis of osteosarcoma while 67 patients (33%) were found during the following treatment. The detail information about the distribution of osteosarcoma was summarized according to the status of lung metastasis in Table 1.
Overall survival and prognostic factors
The overall survival of all patients was 104.7±5.4 [95%CI Confidence interval (CI) 94.1-115.3] months. The 1-, 3-, 5-year survival rate was 94.4%, 77.3% and 70%, respectively. The survival of patients within different variables were shown in Table 2. For patients without lung metastasis, the average overall survival was 139.2±2.8 (95%CI 133.7-144.6) months. The survival was worse in patients with lung metastasis: 33.3±12.6 (95%CI 8.6-57.9) months for SLM patients and 45.8±7.4 (95%CI 31.3-60.3) months MLM patients. The survival curve was shown in Figure 1A.
Univariable Cox regression identified the grade [III-IV, Hazard ratio (HR)=8.235, 95% CI 0.989-68.574, P=0.051], N1 stage (HR=6.630, 95%CI 1.962-22.401, P=0.002), MBM (HR=3.457, 95%CI 1.756-6.805, P=0.000), SLM (HR=43.82, 95%CI 8.71-220.480, P=0.000), MLM (HR=36.74, 95%CI 11.13-121.32, P=0.000), and elevated ALP more than two times (HR=2.453, 95%CI 1.154-5.214, P=0.020) were the factors correlating with the worse survival. The salvage (HR=0.244, 95%CI 0.081-0.728, P=0.011), amputation (HR=0.283, 95%CI 0.092-0.870, P=0.028), and good tumor necrosis (HR=0.085, 95%CI 0.011-0.633, P=0.016) were the factors correlating with better survival. In multivariable Cox regression analysis, SLM (HR=85.07, 95%CI 8.71-220.480, P=0.000), MLM (HR=73.18, 95%CI 12.42-431.24, P=0.000) and salvage (HR=0.112, 95%CI 0.026-0.478, P=0.003) were related with overall survival. More data about the Cox regression can be checked in supplementary Table 1.
Lung metastasis and risk factors
The median internal time from osteosarcoma diagnosis to lung metastasis in 63 MLM patients was 11 (2-99) months. The distribution of MLM was illustrated in Figure 1B. A total of 37 (58.7%) MLM patients were found in the first year after diagnosis of osteosarcoma, 18 (28.6%) patients in the second year, 8 (12.7%) patients in the later time. Metastasectomy of the pulmonary lesion was performed in five patients. Chemotherapy was routinely scheduled.
The risk factors related with SLM in the univariate Logistic regression included T3 stage [Odds ratio (OR)=9.429, 95%CI 1.144-77.70, P=0.037] and synchronous bone metastasis (SBM) (OR=5.882, 95%CI 1.56-22.14, P=0.009).As to the patients with MLM, histological Group two (OR=0.109, 95%CI 0.014-0.85, P=0.035), good necrosis (≥90%, OR=0.113, 95%CI 0.035-0.364, P=0.000), elevated Ki-67 (≥50%, OR=3.646, 95%CI 1.169-11.373, P=0.026), elevated LDH (OR=2.171, 95%CI 1.125-4.190, P=0.021) and elevated ALP more than two times (OR=2.241, 95%CI 1.074-4.678, P=0.032) were associated with MLM occurrence. Details of the univariate Logistic regression were summarized in the supplementary Table 2. Multivariate Logistic regression confirmed that T3 stage (OR=11.415, 95%CI 1.362-95.677, P=0.025) and SBM (OR=6.437, 95%CI 1.69-24.51, P=0.006) were risk factors of SLM occurrence. Good necrosis (≥90%, OR=0.097, 95%CI 0.028-0.332, P=0.000),elevated Ki-67 (≥50%, OR=4.529, 95%CI 1.241-16.524, P=0.022), were proved to be significantly associated with MLM occurrence.