In this study, we investigated the clinical characteristics and treatment results of osteosarcoma during the past 7 years, and evaluated the role of high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT).
We retrospectively analyzed the clinical data of patients who were diagnosed as osteosarcoma at our center from January, 2000 to December, 2007.
The 5-year overall survival and event-free survival of the patients were 72.6% and 55.9%, respectively. Seventeen (41.5%) patients showed disease progression during treatment or relapse after the end of treatment. The patients who had metastasis at diagnosis or who had a lower grade of necrosis after neoadjuvant chemotherapy showed decreased overall and event-free survival. Four patients received ASCT after HDCT, and 3 of them are alive without disease.
The patients who relapsed or had refractory osteosarcoma or who had metastasis at diagnosis or a lower grade of necrosis after neoadjuvant chemotherapy showed poor prognosis. HDCT with ASCT could be an alternative treatment option for these patients.
Osteosarcoma is the most common primary bone tumor in childhood and adolescence. It occurs preferentially in male, and develops primarily during the puberty undergoing rapid growth. In the past, when surgery was the only treatment, most patients showed relapse after amputation, and the 5-year survival rate was less than 10% (
We analyzed the clinical characteristics, prognostic factors, and treatment outcomes of patients treated for osteosarcoma, and evaluated the role of autologous hematopoietic stem cell transplantation (ASCT) following high dose chemotherapy (HDCT) to improve the treatment outcome of osteosarcoma.
We retrospectively analyzed the medical record of 41 patients who were diagnosed and treated as osteosarcoma at Seoul National University Children's Hospital from January, 2000 to December, 2007.
For diagnosis, simple radiography and magnetic resonance imaging (MRI) were taken on the primary site, and chest radiography, chest computed tomography (CT) and bone scan were taken to assess metastasis. Biopsy of primary site was done for pathologic diagnosis.
Neoadjuvant chemotherapy was administered to all cases except 3 cases which were suspected to be benign tumors such as chondroma or meningioma and thus surgical resections were performed. Neoadjuvant chemotherapy was administered by two methods largely depending on whether intra-arterial chemotherapy was feasible or not. For patients for whom intra-arterial chemotherapy was feasible with primary sites at the distal femur or the proximal tibia, 130 mg/m2 cisplatin was administered for 2 hours through an intra-arterial catheter, and 60 mg/m2 doxorubicin was infused continuously for 72 hours intravenously, which was repeated 4 times at 3 weeks interval. For cases with tumors in the site where the intra-arterial approach was not possible or intra-arterial chemotherapy was no longer feasible because of lesions in the skin or muscles, chemotherapy was administered through the vein. In such cases, cisplatin (120 mg/m2, d0), doxorubicin (25 mg/m2, d1-3), and high dose methotrexate (12 g/m2, d21, d28) were administered two times at 5 weeks interval. After the neoadjuvant chemotherapy, for cases that prosthesis required for surgery was not ready, chemotherapy was administered one cycle more than the planned cycle. Depending on the clinical features after neoadjuvant chemotherapy, limb salvage operation or amputation was conducted. As postoperative adjuvant chemotherapy, cisplatin (120 mg/m2, d0), doxorubicin (25 mg/m2, d1-3), and high dose methotrexate (12 g/m2, d21, d28) were administered 4 times at 5 weeks interval, or cisplatin (120 mg/m2, d0) and ifosfamide (1,800 mg/m2, d0-4) were administered alternately at 5 weeks interval. For some patients, chemotherapy using bleomycin, cyclophosphamide, and dactinomycin was administered additionally 3~6 times. Chest radiography was taken in each cycle to assess cardiomegaly and echocardiography was done when the accumulated dose of doxorubicin exceeded 100 mg/m2, 200 mg/m2 or 300 mg/m2. For cases showing the impairment of cardiac function, chemotherapy was switched to the regimen containing ifosfamide, carboplatin, and etoposide.
For recurred patients, cyclophosphamide, topotecan, etoposide, and high dose methotrexate were used primarily, and surgical treatment for the recurred area was carried out before or after the chemotherapy. From 2006, ASCT with HDCT were performed in patients recurred or patients with pulmonary metastasis at diagnosis.
In all patients, during the treatment, simple radiography on the primary site and chest CT were taken to assess the disease progression at 3 months interval. Survival time was obtained based on the date of diagnosis, and event was defined as disease progression, relapse, or death. Kaplan-Meier analysis and log-rank univariate comparisons were used to evaluate overall survival and event-free survival.
During the study period, 42 patients were diagnosed as osteosarcoma. Among them, one patient was diagnosed as periosteal osteosarcoma and thus excluded from the analysis, and total 41 patients were analyzed. The clinical characteristics of patients were summarized in
Total 38 patients received neoadjuvant chemotherapy, and 3 patients were suspected to have benign tumors initially and thus tumor resections were carried out without neoadjuvant chemotherapy. Among the 38 patients, 21 patients received intra-arterial cisplatin. Two patients developed dermatitis and myositis after receiving intra-arterial chemotherapy, hence, chemotherapy was switched to intravenous injection. Amputations were carried out on 3 patients, and 2 of them underwent amputation at a later time after limb salvage operation because of poor blood circulation or non-union.
The degree of necrosis level is shown in
Seventeen patients (41.5%) showed disease progression during the treatments or relapse after the completion of treatments (
The HDCT followed by ASCT was performed on 4 patients (
The follow up duration of the entire patients was average 46 months (4~98 months). The 5-year overall survival was 72.6% and event-free survival was 55.9%. The 5-year overall survival and event-free survival of the group treated with intraarterial chemotherapy were 82.0% and 63.8%, respectively, which were higher than the survival rates of the intravenous chemotherapy group (63.5% and 50.2%, respectively), but the differences were not significant (p=0.208, p=0.385). The 5-year overall survival (43.8%) and event-free survival (11.1%) of patients with metastasis at diagnosis were lower than the overall survival (80.0%) and event free survival (69.7%) of the patients without metastasis (p=0.014 and p=0.000) (
The use of chemotherapy has significantly changed the treatment outcome of osteosarcoma. The long term survival rate was less than 20% when patients received surgery only (
In our study, the 5-year survival rate of the entire patients did not differ from the survival rate reported previously. But the rate of recurrence or progression during the treatment with conventional drugs was 41.5%, and the mortality rate was high in these patients. In addition, the long term prognosis was poor in patients with metastasis at the time of diagnosis and patients poorly responded to neoadjuvant chemotherapy. Therefore, for the improvement of the treatment outcome of osteosarcoma, alternative therapeutic options are required for relapsed patients, unresponsive patients, patients with metastasis at the time of diagnosis, and patients with poor response to neoadjuvant chemotherapy.
We performed ASCT following HDCT from the year of 2006 for patients with recurred osteosarcoma or patients with metastasis at the time of diagnosis. Until now, 4 patients received ASCT, and 3 of them are alive without disease. Two of them are alive with long term disease-free survival of longer than 2 years and 6 months. For osteosarcoma, ASCT following HDCT has been attempted by several groups previously, and it has been reported that many patients showed disease remission after HDCT and their survival time was prolonged (
We administered intra-arterial cisplatin in cases intra-arterial chemotherapy was feasible. From the 1990s, intra-arterial chemotherapy with cisplatin has been attempted, and the effect on the long term survival rate is controversial in comparison with the intravenous administration. But, the tumor necrosis rate was found to be superior to the intravenous injection (
With the introduction of chemotherapy, treatment outcome of osteosarcoma showed a remarkable improvement. However, the long term survival rate is still low in the recurrent patients, refractory patients, patients with metastasis at the time of diagnosis, and patients with poor response to neoadjuvant chemotherapy. Therefore, to improve the treatment outcome of osteosarcoma, more aggressive treatments for such patients are required, and HDCT with ASCT could be one of the alternative approaches.
This study was supported by a grant of the
The 5-year overall survival (43.8%) and event-free survival (11.1%) of patients with metastasis at diagnosis were lower than the overall survival (80.0%) and event free survival (69.7%) of the other patients (p=0.014 and p=0.000).
The 5-year overall survival (51.6%) and event-free survival (29.2%) of patients who showed necrosis less than 90% after the neoadjuvant chemotherapy were lower than the overall survival (94.7%) and event free survival (84.4%) of the other patients (p=0.012 and p=0.002).
Patient characteristics
*Four patients underwent tumor excision first suspecting benign or other diseases. †One patient could not receive an operation because rapid progression before surgery. ‡This included only the patients who received neoadjuvant chemotherapy and surgery. §intraarterial, ∥intravenous, ¶necrosis.
Characteristics of patients who showed relapse or disease progression during treatment
*intraarterial cisplatin with intravenous doxorubicin, †intravenous cisplatin with intravenous doxorubicin, ‡is consisted of cisplatin, doxorubicin and high-dose methotrexate, §is consisted of cisplatin, doxorubicin, ifosfamide and high-dose methotrexate, ∥no evidence of disease. CCG: Children's Oncology Group.
Characteristics of patients who underwent high-dose chemotherapy
*mononuclear cell, †topotecan, ‡melphalan, §carboplatin, ∥etoposide, ¶no evidence of disease, **stem cell transplantation.