Osteosarcoma is a very rare malignant bone tumor with a high predilection for the area surrounding the knee joint [
For those patients with high-grade osteosarcoma around the knee without initial metastases, the surgical margin and the presence of tumor necrosis are generally accepted prognostic factors for local recurrence and overall survival [
We conducted a retrospective, single-center review of patients with osteosarcoma around the knee after limb-salvage surgery between January 2004 and December 2013. During that time, 254 patients were treated for osteosarcoma around the knee. The study was approved by the Institutional Review Board. The exclusion criteria included metastatic disease at initial presentation (28 patients), limb amputation as the primary procedure (17 patients), initial age >=60 years (14 patients), and incomplete follow-up records (13 patients). 182 patients were included in the final analysis.
Age, sex, tumor site, symptom interval, pathological fracture status, previous biopsy history, previous medical history, serum alkaline phosphatase level, preoperative chemotherapy duration, preoperative interval, bone margin length, histologic response (tumor necrosis), tumor size, neurovascular infiltration, postoperative interval, presence of local recurrence, metastatic disease, and overall survival were recorded for each patient (Table
Patient characteristics.
Number of patients (%) | |
---|---|
Gender | |
female | 68(37.4%) |
male | 114(62.6%) |
Age at diagnosis | 21.2±7.6 years, 12-59 |
31-59 years old | 29(15.9%) |
21-30 years old | 50(27.5%) |
10-20 years old | 103(56.6%) |
Site | |
distal femur | 118(64.8%) |
proximal tibia | 64(35.2%) |
Symptom intervals | 68.2±69.7 days, 23-750 |
<60 days | 84(46.2%) |
>=60 days | 98(53.8%) |
Pathologic fracture | |
not occurred | 174(95.6%) |
occurred | 8(4.4%) |
Center performing the biopsy/the tumor resection | |
same | 151(83%) |
different | 31(17%) |
Previous medical history | |
no | 165(90.7%) |
yes | 17(9.3%) |
Elevated initial ALP | |
no | 42(23.1%) |
yes | 140(76.9%) |
Bone margin width | |
>=3 cm | 161(88.5%) |
>=2 cm | 21(11.5%) |
Neurovascular infiltration | |
no | 122(67%) |
yes | 60 (33%) |
Tumor size | |
<10 cm | 106(58.2%) |
>=10 cm | 76(41.8%) |
Histological subtypes | |
osteoblastic | 134(73.6%) |
chondroblastic | 24(13%) |
fibroblastic | 10(5.5%) |
telengiectatic and other | 14(7.9%) |
Tumor necrosis | |
>=90% | 70(38.5%) |
<90% | 112(61.5%) |
Preoperative chemotherapy duration | 10.8 ± 2.1weeks, 4-16 |
8-12 weeks | 110(60.4%) |
>12 weeks | 38(20.9%) |
<8 weeks | 34(18.7%) |
Preoperative interval | 13.1 ± 4.1days, 7-25 |
<14 days | 104(57.1%) |
>=14 days | 78(42.9%) |
Postoperative interval | 23±10.1 days, 7-60 |
<=14 days | 30(16.5%) |
15-21days | 75(41.2%) |
>21 days | 77(42.3%) |
Symptom interval (SI) was defined as the time from the first onset of symptoms or signs to a definitive diagnosis and initiation of treatment [
Previous medical history was defined as the patients having accepted inadequate treatment due to an erroneous diagnosis, including erroneous drug and surgical treatment, before they were referred to professional musculoskeletal oncologists. Patients diagnosed with secondary osteosarcoma were also assessed and included in this group.
At diagnosis, the serum ALP levels were measured in international units (IU), and the activity of ALP was estimated by the p-nitrophenyl phosphate method. ALP ranges of 60.0-300.0 IU/L for patients ≤14 years and 38.0-115.5 IU/L for patients >15 years were considered normal.
Responses to neoadjuvant chemotherapy (tumor necrosis) were graded on the basis of the amount of tumor necrosis in the resected specimen. More than 90% tumor necrosis was regarded as a good response; a cut-off of 90% tumor necrosis is usually used to distinguish good and poor responders [
Standard chemotherapy followed the protocols of IOR/OS-4 [
Neurovascular infiltration was defined as tumor growth outside of the normal compartment and infiltration of soft tissue, such as the nerve and vasculature, which can be inspected by enhanced MRI preoperatively and confirmed during surgery and by pathological examination. Tumors measuring at least 10 cm in length of the involved bone or more were defined as large and all others as small.
The postoperative interval was defined as the time from primary surgery to the resumption of postoperative chemotherapy.
Diagnosis of osteosarcoma, established by clinical and radiological findings, was confirmed on core needle biopsy or open biopsy instead of fine biopsy. Thereafter, 2 cycles of neoadjuvant chemotherapy were given to patients. The chemotherapy protocol was IOR/OS-4 [
Surgical excision of the primary tumor involved en bloc resection of the overlying biopsy tract with the tumor. Resection of the tumor and reconstruction of the bone defect were performed according to the operating instructions provided by Enneking et al. [
Postoperative chemotherapy was given once the wound healed adequately. The chemotherapy protocol was modified if the tumor response was poor according to IOR/OS-4. Postoperative follow-up was performed every 2-3 months in the first two years, every 4 months until 5 years, and every 6 months in the following years. Imaging modalities included bone scans, chest computed tomography (CT) scans, abdominal ultrasounds, and positron emission tomography (PET) scans.
Seventy patients showed good response to neoadjuvant chemotherapy with tumor necrosis >=90%. The average preoperative chemotherapy duration was 10.8 ± 2.1 weeks, and patients were grouped according to their length of preoperative chemotherapy: 110 patients (60.4%) with a duration of 8-12 weeks, 38 patients (20.9%) with a duration greater than 12 weeks, and 34 patients (18.7%) with a duration less than 8 weeks due to noncompliance or severe drug toxicity. Seventy-eight patients (42.9%) underwent primary surgery after 14 days from the end of preoperative chemotherapy, while 77 patients (42.3%) had a delay of greater than twenty-one days to the resumption of chemotherapy (Table
Kaplan and Meier estimates were used to assess overall survival (OS) and local recurrence-free overall survival (LRFS) [
The 5-year and 10-year overall survival rates were 68.6 ± 6.6% and 59.4 ± 10.6%, respectively (Figure
Overall survival for 182 patients and overall survival for patients with tumor necrosis >=90% and not (
Univariate analysis showed that the prognostic factors for overall survival were young age at diagnosis, prolonged symptom intervals >=60 days, biopsy/tumor resection performed by different centers, previous medical history, elevated ALP at diagnosis, neurovascular infiltration, tumor size >=10 cm, tumor necrosis <90%, incomplete preoperative chemotherapy (<8 weeks), and prolonged postoperative interval >21 days. In the multivariate analysis, the risk factors were young age at diagnosis, biopsy/tumor resection performed by different centers, elevated ALP at diagnosis, tumor size >=10 cm, tumor necrosis <90%, prolonged postoperative interval >21 days, and shorter preoperative chemotherapy (<8 weeks) (Table
Summary of univariate and multivariate Cox proportional hazards model for overall survival. HR: hazards ratio; LRT: likelihood rate testing.
Univariate LRT | Multivariate LRT | |||
---|---|---|---|---|
| | |||
Gender | 0.771 | |||
female | Ref. | |||
male | 0.927(0.557-1.543) | |||
Age at diagnosis | 0.026 | |||
31-59 years old | Ref. | Ref. | ||
21-30 years old | 2.849(0.952-8.530) | 0.038 | 2.268(1.065-10.029) | |
10-20 years old | 3.686(1.322-10.283) | 0.026 | 3.304(1.156-9.447) | |
Site | 0.533 | |||
distal femur | Ref. | |||
proximal tibia | 0.845(0.497-1.437) | |||
Symptom intervals | 0.066 | 0.193 | ||
<60 days | Ref. | Ref. | ||
>=60 days | 1.622(0.969-2.715) | 1.443(0.830-2.509) | ||
Pathologic fracture | 0.248 | |||
not occurred | Ref. | |||
occurred | 0.313(0.043-2.260) | |||
Center performing the biopsy/the tumor resection | 0.044 | 0.001 | ||
same | Ref. | Ref. | ||
different | 1.817(1.017-3.247) | 2.797(1.503-5.207) | ||
Previous medical history | 0.045 | 0.108 | ||
no | Ref. | Ref. | ||
yes | 1.997(1.016-3.927) | 1.928(0.865-4.294) | ||
Elevated ALP at diagnosis | 0.041 | 0.013 | ||
no | Ref. | Ref. | ||
yes | 1.678(1.022-2.756) | 2.001(1.156-3.463) | ||
Bone margin width | 0.701 | |||
>=3 cm | Ref. | |||
>=2 cm | 1.157(0.549-2.436) | |||
Neurovascular infiltration | 0.049 | 0.182 | ||
no | Ref. | Ref. | ||
yes | 1.654(1.003-2.727) | 1.479(0.832-2.628) | ||
Tumor size | 0.034 | 0.003 | ||
<10 cm | Ref. | Ref. | ||
>=10 cm | 1.708(1.041-2.802) | 2.199 (1.311-3.690) | ||
Histological subtypes | 0.654 | |||
osteoblastic | Ref. | |||
chondroblastic | 0.765(0.347-1.688) | |||
fibroblastic | 0.458(0.111-1.884) | |||
telengiectatic and other | 0.800(0.289-2.216) | |||
Tumor necrosis | <0.001 | 0.001 | ||
>=90% | Ref. | Ref. | ||
<90% | 3.504(1.827-6.720) | 3.287(1.665-6.491) | ||
Preoperative chemotherapy duration | 0.019 | |||
8-12 weeks | Ref. | Ref. | ||
>12 weeks | 1.081(0.556-2.099) | 0.434 | 0.745(0.357-1.556) | |
<8 weeks | 2.210(1.251-3.903) | 0.008 | 2.249(1.232-4.105) | |
Preoperative interval | 0.701 | |||
<14 days | Ref. | |||
>=14 days | 0.906(0.547-1.501) | |||
Postoperative interval | 0.051 | |||
<=14 days | Ref. | Ref. | ||
15-21days | 1.965(0.749-5.153) | 0.051 | 2.687(0.998-7.236) | |
>21 days | 2.913(1.139-7.451) | 0.036 | 2.844(1.068-7.572) |
The 5-year overall survival for patients with tumor necrosis >=90% and patients with tumor necrosis <90% was 84.2±8.6% and 58.9±9.2% (
Overall survival for 182 patients with different symptom interval (
The 5-year overall survival rates for patients with different postoperative intervals (PSIs) were 83.3±13.3% (PSI, <14 days), 69.3±10.4% (PSI, 14-21 days), and 62.3±10.8% (
Overall survival for patients with different duration of preoperative chemotherapy (74.5±8.2% (8-12 weeks), 68.4±14.7% (>12 weeks), and 49.6±16.9% (<8 weeks),
The incidence of local recurrence (LR) in this study was 13.7% (25/182), and the 5-year LR-free survival was 85.3 ± 5.3% (Figure
Local recurrence-free survival for 182 patients and overall survival for patients with and without local recurrence (
Univariate analysis showed that prognostic factors for LR-free survival were biopsy/tumor resection performed by different centers, neurovascular infiltration, tumor size >=10 cm, and tumor necrosis <90%. Patients with a previous medical history or a larger tumor size were inclined to develop local recurrence, although it was not significant. However, in the multivariate analysis, only biopsy/tumor resection performed by different centers and tumor necrosis <90% were independent predictors of local recurrence. There was no significant difference in the probability regarding sex, age, bone margin width, elevated ALP level at diagnosis, preoperative chemotherapy duration, preoperative interval, and postoperative interval (Table
Summary of univariate and multivariate Cox proportional hazards models for LR. HR: hazards ratio; LRT: likelihood rate testing.
Univariate LRT | Multivariate LRT | |||
---|---|---|---|---|
| | |||
Gender | 0.241 | |||
female | Ref. | |||
male | 0.625(0.285-1.370) | |||
Age at diagnosis | 0.544 | |||
31-59 years old | Ref. | |||
21-30 years old | 1.947(0.527-7.194) | |||
10-20 years old | 1.366(0.389-4.794) | |||
Site | 0.678 | |||
distal femur | Ref. | |||
proximal tibia | 0.837(0.361-1.940) | |||
Symptom intervals | 0.480 | |||
<60 days | Ref. | |||
>=60 days | 1.334(0.599-2.971) | |||
Pathologic fracture | 0.464 | |||
not occurred | Ref. | |||
occurred | 0.046(0-171.359) | |||
Center performing the biopsy/the tumor resection | <0.001 | 0.002 | ||
same | Ref. | Ref. | ||
different | 4.601(2.082-10.169) | 4.099(1.649-10.192) | ||
Previous medical history | 0.060 | 0.931 | ||
no | Ref. | Ref. | ||
yes | 2.561(0.960-6.835) | 0.951(0.308-2.942) | ||
Initial raised ALP | 0.301 | |||
no | Ref. | |||
yes | 1.517(0.688-3.344 ) | |||
Bone margin width | 0.895 | |||
>=3 cm | Ref. | |||
>=2 cm | 1.084(0.325-3.624) | |||
Neurovascular infiltration | 0.007 | 0.163 | ||
no | Ref. | Ref. | ||
yes | 4.140(1.826-9.388) | 1.838(0.782-4.320) | ||
Tumor size | 0.070 | 0.152 | ||
<10 cm | Ref. | Ref. | ||
>=10 cm | 2.080(0.043-4.589) | 1.871(0.795-4.405) | ||
Histological subtypes | 0.340 | |||
osteoblastic | Ref. | |||
chondroblastic | 0.261(0.035-1.944) | |||
fibroblastic | 1.922(0.571-6.470) | |||
telengiectatic and other | 0.477(0.064-3.555) | |||
Tumor necrosis | 0.014 | 0.022 | ||
>=90% | Ref. | Ref. | ||
<90% | 3.802(1.304-11.087) | 3.536(1.198-10.438) | ||
Preoperative chemotherapy duration | 0.783 | |||
8-12 weeks | Ref. | |||
>12 weeks | 0.694(0.234-2.063) | |||
<8 weeks | 0.818(0.275-2.432) | |||
Preoperative interval | 0.336 | |||
<14 days | Ref. | |||
>=14 days | 1.469(0.670-3.220) | |||
Postoperative interval | 0.761 | |||
<=14 days | Ref. | |||
15-21days | 0.934(0.288-3.034) | |||
>21 days | 1.278(0.412-3.964) |
For patients who underwent biopsy by different centers, their 5-year LR-free survival was 58.1±19.6% and was much worse than that of those whose biopsy was performed in the same center (
Local recurrence-free survival for patients classified with tumor necrosis (
In this study, we presented a long-term assessment of overall survival and local recurrence in relation to prognostic factors among patients with nonmetastatic high-grade osteosarcoma around the knee. We found an overall cumulative 5- and 10-year survival rate of 68.6 ± 6.6% and 59.4 ± 10.6%, respectively, with a mean follow-up of 73.4 months. The overall survival in our study is on par with most data [
In this study, we found that several factors are significant for an unfavorable prognosis after rigorous statistical analysis. These independent factors are listed as follows and coincide with reports from previous literature: young age [
Although there is a tendency towards worse overall survival for patients with symptom delays of longer than 60 days, we are unable to find a positive correlation (
Incomplete preoperative chemotherapy and prolonged preoperative chemotherapy may incur poorer prognosis compared to standard preoperative chemotherapy in our study. Shorter or incomplete preoperative chemotherapy correlates with poor chemotherapy response [
Similar to the results of Imran et al. [
The local recurrence rate in this study is 13.7%, which is slightly higher than the current international standard (4-10%). Neurovascular infiltration [
Due to the lack of uniformity in patient analyses and methods and statistics that were calculated on study populations whose minimum follow-up was often less than 3 years, a number of clinical and pathologic features show bias in different studies and present with contradictory prognostic significance. However, our present analysis evaluated a large number of patients according to the previously mentioned prognostic variables, followed up for at least 5 years. In our study, data about the variables evaluated were available for almost all patients. The main shortcoming is that data were not derived from a randomized study, but we collected information from each patient prospectively. The tumors of the patients included in this study were somehow heterogeneous in terms of biological behavior and stage, but we rigorously set and executed inclusion and exclusion criteria. We believe that our data provide a meaningful contribution to the previous literature.
For localized osteosarcoma treated with limb-salvage surgery, it is necessary to optimize timely standard chemotherapy and to resume postoperative chemotherapy to improve survival rates. Biopsies should be performed at experienced institutions in cases of developing local recurrence.
The data used to support the findings of this study and the datasets used and/or analyzed during the current study are available from the corresponding author upon request (Chunlin Zhang, shzhangchunlin123@163.com).
The study received ethical approval from the Institutional Review Board of Shanghai Tenth People’s Hospital affiliated to Tongji University.
Written informed consent was obtained from all patients before surgical treatment including the fact that the data may be included in future publications.
Jianping Hu, Chunlin Zhang, and Kunpeng Zhu are co-first authors. The IRB and ethical committee of the Shanghai Tenth Peoples’ Hospital would review the requests because of the patients’ information. After the approval of the committee with confirmation of the reasonable requests, the dataset would be freely available.
The authors declare that they have no conflicts of interest.
This project was supported by grants from the National Natural Science Foundation of China (no. 81572630 and no. 81872174) and Shanghai science and technology talents program (no. 19XD1402900).