Abstract
Objective
This study was performed to explore the relationship between various clinical factors and the prognosis of limb osteosarcoma.
Methods
We retrospectively analyzed the clinical data of 336 patients with limb osteosarcoma treated from June 2000 to August 2016 at 7 Chinese cancer centers. Data on the patients’ clinical condition, treatment method, complications, recurrences, metastasis, and prognosis were collected and analyzed. Kaplan–Meier analysis and Cox regression models were used to analyze the data.
Results
The patients comprised 204 males and 132 females ranging in age from 6 to 74 years (average, 21.1 years). The overall 3- and 5-year survival rates were 65.0% and 55.0%, respectively. The 5-year overall survival rate was 64.0% with standard chemotherapy and 45.6% with non-standard chemotherapy. Cox regression analysis demonstrated that standard chemotherapy, surgery, recurrence, and metastasis were independent factors associated with the prognosis of limb osteosarcoma.
Conclusion
The survival of patients with limb osteosarcoma can be significantly improved by combining standard chemotherapy and surgery. The overall survival rate can also be improved by adding methotrexate to doxorubicin–cisplatin–ifosfamide triple chemotherapy.
Keywords: Osteosarcoma, multicenter analysis, prognosis, chemotherapy, recurrence, metastasis
Introduction
Osteosarcoma is the most common primary malignant tumor of the bone. Two to three people of every 1 million are diagnosed every year, accounting for 0.2% of malignant tumors and 11.7% of primary bone tumors.1–3 Osteosarcoma has a bimodal age distribution, with the first peak occurring during adolescence (about 15 years of age) and the second peak occurring in later adulthood (about 75 years of age).4–5 Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur and tibia.6 Prior to the 1970s, amputation was the standard treatment for osteosarcoma, but the long-term survival rate was low. Since the application of standard chemotherapy and extensive tumor resection, the 5-year overall survival rate has increased from <20% to >60%, and the limb salvage rate among those with osteosarcoma has increased from 10%–20% to 80%–90%.7 However, the 5-year survival rate of patients with bone cancer in China is 17.1%,8 which is lower than that in the United States (66.0%).9 We retrospectively collected patient data from seven cancer centers in China to explore the association of several clinical factors with the prognosis of limb osteosarcoma.
Materials and methods
All patients with osteosarcoma in the present study were treated at seven institutions from June 2000 to February 2016. The inclusion criteria for this study were histologically proven osteosarcoma, localization of the primary tumor to the limbs, surgical treatment for the tumor, and a follow-up time of ≥3 years [the endpoint of follow-up was loss to follow-up or death during the observation period or reaching the end of the study period (June 2019)]. Enneking surgical staging10 was applied to determine the clinical stage of the tumor.
From June 2000 to December 2003, various chemotherapy regimens were used to treat the patients with osteosarcoma. The chemotherapy treatments used from January 2004 to February 2016 consisted of preoperative and postoperative adriamycin–cisplatin–ifosfamide (ADM-CDP-IFO) triple chemotherapy (hereafter referred to as DIA) with or without methotrexate (MTX). Second-line chemotherapy mainly included paclitaxel, vincristine, pemetrexed, and docetaxel. We divided the patients into a standard chemotherapy group and non-standard chemotherapy group according to the chemotherapy cycles and doses. In the standard chemotherapy group, the patients received (1) DIA or DIA combined with second-line chemotherapy (DIA + MTX or DIA + MTX combined with second-line chemotherapy), and the dosages of CDP, IFO, ADM, and MTX were 120 to 140 mg/m2, 15 g/m2, 90 mg/m2, and 8 to 10 g/m2, respectively; (2) two or more chemotherapy cycles preoperatively and four or more cycles postoperatively; and (3) administration of chemotherapy 2 weeks after surgery. If the regimen did not meet any of the above descriptions, the patients were assigned to the non-standard chemotherapy group.
Surgical treatment was divided into limb salvage and amputation. Limb salvage included tumor resection and prosthesis replacement, tumor inactivation with replantation, and other procedures. The surgical method employed depended on the size and location of the tumor, neurovascular involvement, skeletal maturity, patient age, presence of pathological fracture, biopsy results, clinical stage, special patient requirements, economic capacity, and other factors.
Follow-up consisted of outpatient visits or telephone interviews once every 3 months for the first 2 years postoperatively, then once every 4 months during the 3rd year, once every 6 months during the 4th and 5th years, and once a year from the 6th to 10th years. Osteosarcoma presents both a local problem and a concern for distant metastasis. The workup included imaging of the primary site (usually X-ray) and chest imaging [computed tomography (CT)]. More detailed imaging (CT or magnetic resonance imaging) of abnormalities identified on primary imaging was required for suspected metastatic disease. (For some patients with local swelling and pain, we found definite osteosarcoma-related changes in the imaging examination, and patients confirmed to have osteosarcoma by local puncture biopsy and immunohistochemistry were diagnosed with postoperative recurrence of osteosarcoma. For some patients with cough and other lung symptoms, the imaging examination showed nodules or lesions in their lungs. With the cooperation of respiratory physicians, local fine-needle aspiration biopsy and immunohistochemistry were applied to confirm the presence of pulmonary metastasis of osteosarcoma; such patients were diagnosed with pulmonary metastasis of osteosarcoma. For patients with multiple metastases, we applied an emission CT bone scan or positron emission tomography–CT for confirmation.)
The Kaplan–Meier method was applied to create survival curves. The multivariate Cox proportional hazards method was applied for multivariate analysis, and meaningful single factors were incorporated into a Cox regression analysis with the forward Wald approach. A P value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA).
Results
Patients and survival
In total, 336 patients with an initial diagnosis of osteosarcoma were included in the present study (204 males and 132 females; mean age, 21.1 years; range, 6–74 years). Patients aged <14 years accounted for 29.47% (n = 99), those aged 15 to 39 years accounted for 61.01% (n = 205), and those aged >40 years accounted for 9.52% (n = 32). The median follow-up time was 45 months (range, 12–201 months), and the mean follow-up time was 53.38 months. The primary tumor locations were mainly around the knee, including the distal femur (n = 176), proximal tibia (n = 89), proximal humerus (n = 26), proximal femur (n = 15), proximal fibula (n = 13), distal tibia (n = 13), distal humerus (n = 3), and radius (n = 1) (Table 1). The 3- and 5-year overall survival rates for all patients were 65.0% (n = 222) and 55.0% (n = 111), respectively, and the 3- and 5-year disease-free survival rates were 52.0% (n = 176) and 45.0% (n = 96), respectively (Figures 1 and 2; survival curve of all 336 patients). The 5-year overall survival rate of male patients (n = 204) and female patients (n = 132) was 54.9% and 55.9%, respectively, and the 5-year overall survival rate of patients aged <14 years (n = 99), 15 to 39 years (n = 205), and >40 years (n = 32) was 47.7%, 59.0%, and 53.7%, respectively. There were no significant differences in sex or age among these groups of patients (χ2 = 0.061 and χ2 = 3.510, respectively).
Table 1.
Primary tumor locations of 336 patients with osteosarcoma.
| Primary tumor site | Number of patients | Percent (%) |
|---|---|---|
| Distal femur | 176 | 52.38 |
| Proximal tibia | 89 | 26.49 |
| Proximal humerus | 26 | 7.74 |
| Proximal femur | 15 | 4.46 |
| Proximal fibula | 13 | 3.87 |
| Distal tibia | 13 | 3.87 |
| Distal humerus | 3 | 0.89 |
| Radius | 1 | 0.30 |
Figure 1.
Disease-free survival curve of all 336 patients.
Figure 2.
Overall survival curve of all 336 patients.
Preoperative biopsy and surgical staging
In total, 215 patients underwent core needle biopsy preoperatively, while the remaining patients did not. The 5-year overall survival rates were 55.3% and 55.1%, respectively, with no significant difference (χ2 = 0.082). In terms of surgical staging, 319 patients had Enneking stage II cancer while 17 patients had Enneking stage III. The 5-year overall survival rates were 57.0% and 22.1%, respectively, with statistical significance (χ2 = 18.301, P = 0.000) (Table 2).
Table 2.
Univariate analysis of 336 patients with osteosarcoma.
| Number of patients | Overall survival rate (%) |
Disease-free survival rate (%) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| 3-year | 5-year | χ2 | P value | 3-year | 5-year | χ2 | P value | ||
| All | 336 | 65.0 | 55.0 | – | – | 52.0 | 45.0 | – | – |
| Sex | |||||||||
| Male | 204 | 65.2 | 54.9 | 0.061 | 0.805 | 52.0 | 45.1 | 0.025 | 0.875 |
| Female | 132 | 65.2 | 55.9 | 51.5 | 43.7 | ||||
| Age in years | |||||||||
| ≤14 | 99 | 58.6 | 47.7 | 3.510 | 0.173 | 46.5 | 38.6 | 0.963 | 0.618 |
| 15–39 | 205 | 67.3 | 59.0 | 53.2 | 48.6 | ||||
| ≥40 | 32 | 71.9 | 53.7 | 59.4 | 36.8 | ||||
| Tumor site | |||||||||
| Around the knee | 265 | 62.2 | 51.8 | 4.504 | 0.034 | 48.7 | 40.8 | 6.570 | 0.010 |
| Outside of the knee | 71 | 74.6 | 68.8 | 63.4 | 59.2 | ||||
| Preoperative puncture | |||||||||
| Yes | 215 | 65.1 | 55.3 | 0.082 | 0.775 | 53.0 | 45.2 | 0.114 | 0.736 |
| No | 121 | 65.3 | 55.1 | 49.6 | 43.5 | ||||
| Surgical staging | |||||||||
| Enneking stage II | 319 | 67.1 | 57.0 | 18.301 | 0.000 | 54.5 | 47.0 | – | – |
| Enneking stage III | 17 | 29.4 | 22.1 | – | – | ||||
| Chemotherapy | |||||||||
| Standard | 176 | 72.3 | 64.0 | 14.928 | 0.000 | 59.9 | 52.8 | 9.898 | 0.002 |
| Non-standard | 160 | 57.2 | 45.6 | 42.8 | 35.5 | ||||
| Preoperative chemotherapy | |||||||||
| DIA | 84 | 54.8 | 42.4 | 4.451 | 0.035 | 46.4 | 38.8 | 0.684 | 0.408 |
| DIA + MTX | 79 | 67.1 | 61.4 | 55.7 | 47.5 | ||||
| Postoperative chemotherapy | |||||||||
| DIA | 84 | 57.1 | 48.0 | 1.783 | 0.182 | 44.0 | 36.8 | 1.096 | 0.295 |
| DIA + MTX | 116 | 67.2 | 59.1 | 51.7 | 47.9 | ||||
| Uniformity | |||||||||
| Yes | 131 | 58.8 | 52.3 | 0.004 | 0.949 | 51.1 | 43.9 | 1.211 | 0.271 |
| No | 143 | 63.6 | 49.6 | 45.5 | 39.4 | ||||
| Surgery | |||||||||
| Limb salvage | 308 | 67.9 | 57.4 | 10.690 | 0.001 | 53.9 | 46.0 | 9.033 | 0.003 |
| Amputation | 28 | 35.7 | 32.1 | 28.6 | 28.6 | ||||
| Tumor cell necrosis rate | |||||||||
| ≥90% | 19 | 89.5 | 89.5 | 11.652 | 0.001 | 84.2 | 78.2 | 13.400 | 0.000 |
| <90% | 48 | 54.2 | 33.6 | 29.2 | 21.2 | ||||
| Recurrence and metastasis | |||||||||
| None | 162 | 95.7 | 92.7 | 239.047 | 0.000 | 95.7 | 92.7 | 374.240 | 0.000 |
| Only recurrence | 32 | 59.4 | 40.7 | 15.6 | 0 | ||||
| Only lung metastasis | 96 | 38.5 | 17.8 | 11.5 | 1.3 | ||||
| Multiple metastases | 46 | 17.4 | 8.7 | 6.5 | 2.2 | ||||
Chemotherapy, standard: (1) DIA or DIA combined with second-line chemotherapy preoperatively, DIA + MTX or DIA + MTX combined with second-line chemotherapy postoperatively, (2) more than two chemotherapy cycles preoperatively and more than four cycles postoperatively; (3) chemotherapy was applied 2 weeks after surgery. Non-standard: If the regimen did not meet the above descriptions, it fit into the non-standard chemotherapy group. DIA, doxorubicin-cisplatin-ifosfamide. MTX, methotrexate. Uniformity: yes, chemotherapy is uniform preoperatively or postoperatively; no, chemotherapy is diverse preoperatively or postoperatively. Multiple metastases, pulmonary metastasis and recurrence were simultaneous; χ2, chi-square goodness-of-fit test).
Chemotherapy
The 5-year overall survival rate in the standard chemotherapy group (n = 176) and non-standard chemotherapy group (n = 160) was 64.0% and 45.6%, respectively, and the 5-year disease-free survival rate in the standard and non-standard chemotherapy groups was 52.8% and 35.5%, respectively; this difference was statistically significant (χ2 = 14.928, P = 0.000) (Figures 3 and 4; survival curve of chemotherapy). Before surgery, the difference between the DIA group and DIA + MTX group was statistically significant (χ2 = 4.451, P = 0.035); after surgery, however no significant difference was found (χ2 = 1.783). The difference between the groups regardless of whether the preoperative and postoperative chemotherapy regimens were consistent was not statistically significant (χ2 = 0.004). Additionally, the 5-year overall survival rate with a tumor cell necrosis rate of ≥90% (n = 19) and <90% (n = 48) was 89.5% and 33.6%, respectively. The difference between these two rates was statistically significant (χ2 = 11.652, P = 0.001).
Figure 3.
Overall survival curve of patients who underwent chemotherapy.
Figure 4.
Disease-free survival curve of patients who underwent chemotherapy.
Surgery
Among all patients, 308 patients underwent limb salvage (including tumor resection and prosthesis replacement in 228 patients, inactivation of the tumor and replantation in 39 patients, and other procedures in 41 patients) and 28 patients underwent amputation (Table 3). The 5-year overall survival rate in the limb salvage group and amputation group was 57.4% and 32.1%, respectively; this difference was statistically significant (χ2 = 10.690, P = 0.001). The proportion of patients who underwent standard chemotherapy with limb salvage surgery was much higher than that of patients who underwent amputation. Among 308 patients who underwent limb salvage procedures, 159 (51.62%) received standardized chemotherapy while only 10 of 28 (35.71%) who underwent amputation received such therapy. Among the total study population, 39 patients developed various complications. The complication with the highest incidence was infection, accounting for 43.59% (Table 4).
Table 3.
Correlation between surgical approach and prognosis.
| Surgery | Number of patients | Overall survival (%) |
χ2 | P | |
|---|---|---|---|---|---|
| 3-year | 5-year | ||||
| Limb salvage | 308 | 67.9 | 57.4 | – | – |
| Tumor resection and prosthesis replacement replacement | 228 | 68.9 | 55.6 | 4.997 | 0.082 |
| Tumor inactivation and replantation | 39 | 56.4 | 49.6 | ||
| Other approaches | 41 | 73.2 | 73.2 | ||
| Amputation | 28 | 35.7 | 32.1 | – | – |
Table 4.
Non-tumor postoperative complications.
| Number of patients | Percent (%) | |
|---|---|---|
| All | 39 | 100 |
| Infection | 17 | 43.59 |
| Prosthesis-related | 14 | 35.90 |
| Wound nonunion | 8 | 20.51 |
Prosthesis-related: mainly included prosthetic loosening and leg-length discrepancy.
Recurrence and metastasis
Among all patients, recurrence alone occurred in 32 patients, lung metastasis alone occurred in 96, and multiple metastases occurred in 46 (pulmonary metastasis and recurrence occurred simultaneously). The total recurrence rate was 23.21%, and the lung metastasis rate was 42.26%. The 5-year overall survival rate with no recurrence and no metastasis, only recurrence, only metastasis, and multiple metastases was 92.7%, 40.7%, 17.8%, and 8.7%, respectively (χ2 = 239.047, P = 0.000) (Table 2). Among all patients, 78 developed recurrence after surgery, 54 were part of the reoperation group, 11 were in the chemotherapy group, and 13 were in the untreated group. Amputation was performed in 28 patients, accounting for 51.85% of all patients with recurrence who agreed to undergo reoperation, confirming that amputation was the main treatment for postoperative recurrence. Additionally, 142 patients developed lung metastasis (including lung metastasis at the initial diagnosis and postoperative pulmonary metastasis), among whom 83 were in the chemotherapy group, 26 were in the surgery (lung operation) combined with chemotherapy group, 16 were in the radiotherapy combined with chemotherapy group, and 17 were in the untreated group. The differences in survival among the various treatments after lung metastasis were statistically significant (χ2 = 15.401, P = 0.002). The overall survival of patients who underwent pulmonary lobectomy combined with chemotherapy after lung metastasis was higher than that of patients who underwent other treatments and was far higher than that of untreated patients.
Multiple-factor analysis
The single-factor analysis showed that standard chemotherapy, the preoperative chemotherapy regimen, the tumor cell necrosis rate, surgery, the Enneking stage, recurrence, and metastasis were significantly correlated with the prognosis of patients with limb osteosarcoma. Factors such as patient sex, patient age, tumor location, postoperative chemotherapy regimen, and preoperative puncture were not significantly correlated with the prognosis of limb osteosarcoma (Table 2). Additionally, after entering standard chemotherapy, the tumor cell necrosis rate, surgery, the Enneking stage, recurrence, metastasis, and demographic factors (sex and age) into the multivariate Cox regression, the results showed that standard chemotherapy, surgery, recurrence, and metastasis were independent predictive factors for the prognosis of limb osteosarcoma (Table 5).
Table 5.
Cox multivariate analysis of 336 patients with osteosarcoma.
| Cox regression analysis | ||||||
|---|---|---|---|---|---|---|
| B | SE | Wald | df | Sig. | Exp(B) | |
| Standard chemotherapy | −0.412 | 0.177 | 5.412 | 1 | 0.020 | 0.662 |
| Recurrence and metastasis | 1.071 | 0.084 | 160.791 | 1 | 0.000 | 2.918 |
| Surgery | 1.122 | 0.263 | 18.299 | 1 | 0.000 | 3.070 |
B, regression coefficient; SE, standard error; Wald, test statistic; df, degrees of freedom; Sig, significance; Exp(B), index of B coefficient.
The results of the separate analyses of the seven centers involved in this study showed that standard chemotherapy, surgery, recurrence, and metastasis were statistically significant in the single-factor analysis and that recurrence and metastasis were the strongest independent predictive factors for the prognosis of limb osteosarcoma.
Discussion
Chemotherapy
In the 1960s, Jaffe11 used multiagent chemotherapy comprising high-dose MTX, ADM, CDP, bleomycin, cyclophosphamide, and dactinomycin to treat patients who had undergone postoperative amputation. The author concluded that postoperative chemotherapy increased survival. In the 1970s, Rosen et al.12 designed a preoperative chemotherapy regimen called T5, which comprised methotrexate (200 mg/kg), vincristine (16 mg/m2), and ADM (45 mg/m2). The authors analyzed 31 patients who had been diagnosed with osteosarcoma and treated with the T5 regimen with a follow-up period of 30 to 52 months. During that time, 23 of 31 patients (75%) survived, with 21 of 23 showing no evidence of disease. This finding confirmed that preoperative chemotherapy had a more complete effect against primary tumors.
The survival rate of patients with osteosarcoma treated with amputation alone is only 10% to 20%, while that of patients treated with neoadjuvant chemotherapy combined with extensive tumor resection ranges from 60% to 80%.13 In our patient cohort, the survival rate with standard chemotherapy was much higher than that with non-standard chemotherapy, which is consistent with the data in the study by Jaffe.14 However, most patients did not receive standard chemotherapy, which had a serious negative impact on survival, resulting in a survival rate lower than that in other reports from other countries.15
We divided the patients into the DIA group, DIA + MTX group, and other group according to the chemotherapy regimen that they received. We found that the overall survival rate in the DIA + MTX group was significantly higher than that in the DIA group both preoperatively and postoperatively, while there was a significant difference between the two groups only in preoperative chemotherapy (χ2 = 4.451, P = 0.035). Therefore, the overall survival rate was greatly increased by adding MTX to the DIA group. The Rizzoli Orthopaedic Institute in Italy16 and the Cooperative Osteosarcoma Study Group in Germany17 conformed that IFO combined with ADM, CDP, and MTX can definitely improve the effect of chemotherapy. Additionally, Lin et al.18 analyzed 185 patients with osteosarcoma treated with the four above-mentioned drugs, revealing that the optimization of MTX, CDP, ADM, and IFO based on Chinese patients’ physiology increased the tolerance and efficacy of the treatment of osteosarcoma.
Surgery
Prior to the 1970s, amputation was the most common method for treatment of osteosarcoma. With the development of medical imaging, surgical technology, artificial joint material, and especially the emergence of neoadjuvant chemotherapy, the safety of limb salvage surgery has improved enough to become the mainstream treatment of choice. The limb function outcomes after limb salvage surgery have been confirmed to be superior to those after amputation (especially femoral amputation), and the benefits to patients’ mental health and appearance are prominent.19,20
In the present study, the limb salvage rate was 83.93%, which is accordance with the treatment rates of 80% to 90% reported in the literature.21,22 There were three main categories of limb salvage surgery in our study: tumor resection and prosthesis replacement, tumor inactivation and replantation, and others. Tumor resection and prosthesis replacement was the most common therapeutic approach. The 5-year overall survival rate of patients who underwent limb salvage and amputation was 57.4% and 32.1%, respectively. Additionally, a significant difference was seen within the limb salvage surgery approach (P < 0.05); one possible reason is that patients who underwent limb salvage surgery had less severe clinical conditions. The cancer recurrence rate after limb salvage and amputation was 24.03% and 14.29%, respectively, and the lung metastasis rate after limb salvage and amputation was 40.58% and 60.71%, respectively. The reasons for such differences in clinical outcomes can be summarized as follows: (1) patients who underwent limb salvage had a small tumor load, no neurovascular involvement, and no metastasis; (2) the performance of standard chemotherapy with limb salvage surgery was more common than amputation; (3) patients who underwent limb salvage had a good response to chemotherapy; and (4) the range of tumor resection was larger in the amputation group and the resulting recurrence rate was lower.
The physical outcome was also included in the follow-up of the present study. The patients who survived for 5 years after their operation reported having adjusted well to their physical limitations. Our conclusion confirms that reported by Ottaviani et al.23
Recurrence and metastasis
In our dataset, recurrence and metastasis were the main causes of death and were independent factors affecting the prognosis of osteosarcoma. Our data also demonstrated a significant difference in survival between patients with recurrence and metastasis (χ2 = 239.047, P = 0.000). According to our study, among 78 patients with recurrence, the main treatment was reoperation combined with chemotherapy. Surgical eradication of recurrence with wide margins may be critical to maximizing the chances for survival, although chemotherapy does not have a significant effect on survival.24 Several novel methods have been introduced for the treatment of osteosarcoma recurrence. For example, Yu et al.25 applied high-intensity focused ultrasound to 27 patients with local unresectable recurrence of osteosarcoma, and the 1-, 2-, and 3-year local disease control rates were 59.2%, 40.7%, and 33.1%, respectively. The authors conformed that high-intensity focused ultrasound is a safe and noninvasive treatment for local unresectable recurrence of osteosarcoma, with good local control and without severe complications.
A patient with osteosarcoma presenting with lung metastases is recommended to undergo the following chemotherapy regimen: (1) first-line chemotherapy: high-dose IFO, ADM, CDP, MTX; (2) second-line chemotherapy: vincristine, etoposide phosphate, bleomycin, cyclophosphamide, and arsenic trioxide. Many methods of osteosarcoma treatment have been reported to date, including targeted therapy (apatinib), radiotherapy, immunotherapy, and gene therapy. Kimura et al.26 treated pulmonary metastases of osteosarcoma using caffeine combined with chemotherapy, which achieved a satisfactory outcome. In the present study, the overall survival rate of patients who underwent pulmonary lobectomy combined with chemotherapy after lung metastasis was higher than that of patients treated with other methods. Harting et al.27 reported that 93 patients with osteosarcoma had a mean 33.6-month survival time after pulmonary lobectomy for lung metastasis, while 38 patients who did not undergo pulmonary lobectomy had a mean survival time of only 10.1 months. Further studies have confirmed that the time of lung metastasis and time to treatment after metastasis are important prognostic factors. Once a lung metastasis is found and if clinical conditions permit, the tumor should be surgically treated quickly thereafter.28
A significant difference was found between independent risk factors for the prognosis of osteosarcoma.29,30 The response to chemotherapy, alkaline phosphatase concentration, patient age, tumor size, recurrence, and metastasis each had a direct impact on prognosis.31
This study was retrospective in nature and thus has certain limitations. First, the clinical data were limited. The follow-up time was ≥3 years; therefore, the 5-year survival rate in this study was and estimated survival rate, and the follow-up time was not uniform; this resulted in a large gap between the overall survival and disease-free survival rates. Additionally, no questionnaires were conducted because the patients chose non-standard chemotherapy with provision of detailed rational reasons. However, the findings of this study far outweigh its shortcomings. Multicenter studies provide strong evidence of the future clinical diagnosis and treatment standards, and some new findings (e.g., adding MTX to DIA can improve the overall survival rate) might also inspire doctors to perform further research.
Conclusion
The survival of patients with limb osteosarcoma can be significantly improved by combining standard chemotherapy and surgery. Additionally, the overall survival rate can be improved by adding MTX to DIA.
Acknowledgement
We thank the patients, and their families for their invaluable contributions to this study.
Authors’ contributions
All authors drafted and critically revised the manuscript. All authors read and approved the final manuscript.
Availability of data and materials
Data are available upon request to the authors.
Declaration of conflicting interest
The authors declare that there is no conflict of interest.
Ethics
This study was approved by the Ethics Committee of PLA 960th Hospital (because this study was initiated by PLA 960th Hospital, the ethics committees of all seven centers reached an agreement on the decision made by the Ethics Committee of PLA 960th Hospital). Written informed consent was obtained from every patient. We de-identified the patients’ details such that their identity cannot be ascertained in any way.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD
References
- 1.Picci P. Osteosarcoma (osteogenic sarcoma). Orphanet J Rare Dis 2007; 2: 6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Chou AJ, Geller DS, Gorlick R. Therapy for osteosarcoma: where do we go from here? Paediatr Drugs 2008; 10: 315–327. [DOI] [PubMed] [Google Scholar]
- 3.Ta HT, Dass CR, Choong PF, et al. Osteosarcoma treatment: state of the art. Cancer Metastasis Rev 2009; 28: 247–263. [DOI] [PubMed] [Google Scholar]
- 4.Gurney JG, Swensen AR, Bulterys M, et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. Bethesda, MD: National Cancer Institute, 1999. [Google Scholar]
- 5.Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the surveillance, Epidemiology, and End Results program. Cancer 2009; 115: 1531–1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res 2009; 152: 3–13. [DOI] [PubMed] [Google Scholar]
- 7.Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. Clin Oncol 2005; 23: 2004–2011. [DOI] [PubMed] [Google Scholar]
- 8.Zeng H, Zheng R, Guo Y, et al. Cancer survival in China, 2003-2005: a population-based study. Int J Cancer 2015; 136: 1921–1930. [DOI] [PubMed] [Google Scholar]
- 9.DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014; 64: 252–271. [DOI] [PubMed] [Google Scholar]
- 10.Wolf RE, Enneking WF. The staging and surgery of musculoskeletal neoplasms. Orthop Clin North Am 1996; 27: 473–481. [PubMed] [Google Scholar]
- 11.Jaffe N. Adjuvant denotherapy in osteosarcoma: an odyssey of rejection and vindication. Cancer Treat Res 2009; 152: 219–237. [DOI] [PubMed] [Google Scholar]
- 12.Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery. Cancer 1979; 43: 2163–2177. [DOI] [PubMed] [Google Scholar]
- 13.Ferrari S, Ruggieri P, Cefalo G, et al. Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without fosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1. Clin Oncol 2012; 30: 2112–2118. [DOI] [PubMed] [Google Scholar]
- 14.Jaffe N. Osteosarcoma: review of the past, impact on the future. The American experience. Cancer Treat Res 2009; 152: 239–262. [DOI] [PubMed] [Google Scholar]
- 15.Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. Clin Oncol 1988; 6: 329–337. [DOI] [PubMed] [Google Scholar]
- 16.Longhi A, Pasini E, Bertoni F, et al. Twenty-year follow-up of osteosarcoma of the extremity treated with adjuvant chemotherapy. J Chemotherapy 2004; 16: 582–588. [DOI] [PubMed] [Google Scholar]
- 17.Kempf-Bielack B, Bielack SS, Jurgens H, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005; 23: 559–568. [DOI] [PubMed] [Google Scholar]
- 18.Lin F, Wang Q, Yu W, et al. Clinical analysis of Chinese limb osteosarcoma patients treated by two combinations of methotrexate, cisplatin, doxorubicin and ifosfamide. Asia Pac J Clin Oncol 2011; 7: 270–275. doi: 10.1111/j.1743-7563. [DOI] [PubMed] [Google Scholar]
- 19.Ayerza MA, Farfalli GL, Aponte-Tinao L, et al. Does increased rate of limb-sparing surgery affect survival in osteosarcoma? Clin Orthop Relat Res 2010; 468: 2854–2859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Robert RS, Ottaviani G, Huh WW, et al. Psychosocial and functional outcomes in long-term survivors of osteosarcoma: a comparison of limb-salvage surgery and amputation. Pediatr Blood Cancer 2010; 54: 990–999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hogendoorn PC, Athanasou N, Bielack S, et al. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21: v204–v213. [DOI] [PubMed] [Google Scholar]
- 22.Bacci G, Ferrari C, Longhi A, et al. Second malignant neoplasm in patients with osteosarcoma of the extremities treated with adjuvant and neoadjuvant chemotherapy. Pediatr Hematol Oncol 2006; 28: 774–780. [DOI] [PubMed] [Google Scholar]
- 23.Ottaviani G, Robert RS, Huh WW, et al. Socio-occupational and physical outcomes more than 20 years after diagnosis for osteosarcoma in children and adolescents: limb salvage versus amputation. Cancer 2013; 119: 3227–3236. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Takeuchi A, Lewis VO, Satcher RL, et al. What are the factors that affect survival and relapse after local recurrence of osteosarcoma? Clin Orthop Relat Res 2014; 472: 3188–3195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Yu W, Tang L, Lin F, et al. High-intensity focused ultrasound: noninvasive treatment for local unresectable recurrence of osteosarcoma. Surg Oncol 2015; 24: 9–15. [DOI] [PubMed] [Google Scholar]
- 26.Kimura H, Tsuchiya H, Shirai T, et al. Caffeine-potentiated chemotherapy for metastatic osteosarcoma. J Orthop Sci 2009; 14: 556–565. [DOI] [PubMed] [Google Scholar]
- 27.Harting MT, Blakely ML, Jaffe N, et al. Long-term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma. Pediatr Surg 2006; 41: 194–199. [DOI] [PubMed] [Google Scholar]
- 28.Briccoli A, Rocca M, Salone M, et al. High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005. Surg Oncol 2010; 19: 193–199. [DOI] [PubMed] [Google Scholar]
- 29.Lee JA, Kim MS, Kim DH, et al. Risk stratification based on the clinical factors at diagnosis is closely related to the survival of localized osteosarcoma. Pediatr Blood Cancer 2009; 52: 340–345. [DOI] [PubMed] [Google Scholar]
- 30.Harting MT, LaUy KP, Andrassy RJ, et al. Age as a prognostic factor for patients with osteosarcoma: an analysis of 438 patients. Cancer Res Clin Oncol 2010; 136: 561–570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Smeland S, Müller C, Alvegard TA, et al. Scandinavian sarcoma group osteosarcoma study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 2003; 39: 488–494. [DOI] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
Data are available upon request to the authors.