Treatment
Primary Treatment of Bone Sarcomas
Surgical excision is the mainstay of treatment for patients with low-grade sarcomas. For high-grade tumors, multimodality therapy is indicated. For most high-grade bone sarcomas, excluding chondrosarcoma, preoperative multiagent chemotherapy (three or four cycles) is followed by surgical extirpation of the primary tumor. Chemotherapy is reinitiated postoperatively after wound healing has occurred (usually 2 to 3 weeks after surgery).
For patients with Ewing sarcoma, the optimal therapy for local tumor control is less well defined. Historically, radiotherapy has been a mainstay of local treatment. However, there has been a recent trend toward surgery, with or without adjuvant radiotherapy, to achieve local tumor control. No prospective randomized studies have been performed to define the relative role of each of these treatment modalities, but several retrospective studies suggest improvements in local tumor control and patient survival when surgery is satisfactorily performed. A recent analysis of patients enrolled in three Children’s Oncology Group (COG) phase III trials attempted to identify the local control modality with the greatest event-free survival. This analysis revealed no significant differences in event-free survival between surgery, radiation, or surgery followed by radiation. Patients with microscopic or macroscopic residual disease following tumor excision clearly require adjuvant radiotherapy to consolidate their local treatment. Patients who have unresectable tumors can be treated with radiotherapy as the sole local treatment modality.
Surgical treatment strategy
The MTS recognizes wide excision, either by amputation or by a limb-salvage procedure, as the recommended surgical approach for high-grade sarcomas. A wide excision removes the primary tumor en bloc along with its reactive zone and a cuff of normal tissue in all planes. While the importance of a negative margin cannot be emphasized enough, it is controversial as to what defines an adequate negative margin. Conceptually, this strategy is applicable to all high-grade sarcomas. Wide excision successfully controls local disease in 90% of patients or more.
The timing of surgery must be coordinated with the patient's chemotherapy schedule and with bone marrow recovery to minimize the period of systemic therapy. Generally, surgical intervention is postponed until the patient's absolute neutrophil count has recovered to a level of 1,500/μL or greater and the platelet count is 70,000/μL or greater.
Limb-salvage procedures
Wide tumor excision with limb preservation has supplanted amputation as the principal surgical method for eradicating local disease in patients with primary sarcomas of bone, regardless of histology or grade. Local tumor control and patient survival have not been compromised by this more conservative operative strategy. Refinements in surgical techniques and advances in bioengineering have increased the number of patients eligible for limb-salvage surgery. Currently, more than 80% of patients may be treated with non-ablative, function-sparing surgery.
Successful limb-salvage surgery for the patient with a high-grade bone sarcoma is predicated on complete extirpation of the tumor, effective skeletal reconstruction, and adequate soft-tissue coverage. Planning for the operative procedure must begin far in advance to permit adequate time to procure the implant for reconstruction.
Types of resection. Limb-sparing tumor resection falls into one of three types depending on the anatomic site and extent of involved bone to be excised. Resection can involve (1) tumor-bearing bone and the adjacent joint (osteoarticular), (2) tumor-bearing bone only (intercalary), or (3) whole bone and adjacent joints (whole bone).
Since most bone sarcomas arise in the metaphysis of the long bone near the joint, the majority of procedures performed for these tumors involve resection of both the segment of tumor-bearing bone and the adjacent joint (osteoarticular resection). Most of these resections are performed through the adjacent joint (intra-articular). When the tumor extends along the joint capsule or ligamentous structures and/or invades the joint, the entire joint should be resected (extra-articular) to avoid violating areas that have tumor involvement.
Reconstruction. Prosthetic arthroplasty is the most common method by which the skeletal defect and adjacent joint are reconstructed. Osteoarticular allografts, intercalary allografts, and vascularized and nonvascularized autografts are also used, depending on the extent of resection and requirements for successful reconstruction. Biologic reconstructions including rotationplasty in the lower extremity and clavicula pro humero for humeral lesions should be considered in the skeletally immature patient.
Soft-tissue coverage. Adequate soft-tissue coverage is critical to the success of any limb-salvage procedure. Local transposition muscle flaps and free-tissue transfers are extremely useful for providing a healthy, well-vascularized soft-tissue envelope to cover the reconstruction and reduce the risk of deep infection.
Tumors in the immature skeleton. Tumors arising in the immature skeleton pose a unique challenge for the orthopedic oncologist, particularly in patients with substantial projected growth of the involved extremity. The surgical management of bone sarcomas in very young patients favors autobiologic reconstructions such as rotationplasty or clavicula pro humero. Amputation can have good long-term outcomes in select patients as well. These options should be strongly considered in children younger than 10 years.
Custom-manufactured expandable metallic joint prostheses can be implanted to allow for skeletal growth in those children deemed candidates for limb-salvage surgery. The long-term outcome of this technique has been promising. However, multiple operative procedures should be anticipated to maintain a functional extremity.
Surgical Treatment of Metastatic Disease
The most common site of metastatic involvement for bone sarcoma is the lungs. Patients who present with pulmonary metastases (10% to 20% of patients with osteosarcoma) have a poor prognosis (5-year survival rate < 15%). Approximately 30% to 40% of patients who present with localized disease and who subsequently develop resectable pulmonary metastases can undergo salvage treatment with reinduction chemotherapy and metastasectomy (see section on "Treatment of advanced osteosarcoma"). Patients with extrapulmonary metastases or unresectable pulmonary metastases have a uniformly poor prognosis. The objective of any surgical intervention in these patients, therefore, would be palliative.
Osteosarcoma
The Instituto Ortopedico Rizzoli/Osteosarcoma-4 protocol for neoadjuvant/adjuvant chemotherapy for osteosarcoma of the extremities, from the Rizzoli Institute, Bologna, Italy.Chemotherapy
The probability of 5-year disease-free survival for patients with osteosarcoma of the extremities treated with either amputation or limb-salvage surgery alone is less than 20%. Although the incidence of local recurrence is low, microscopic dissemination is likely to be present in 80% of patients at the time of diagnosis, leading to distant metastases, mostly in the lungs and bones, within the first 6 to 12 months. The incorporation of chemotherapy as part of the standard therapeutic plan for osteosarcoma (Figure 1) has improved both relapse-free and overall survival.
Neoadjuvant/adjuvant chemotherapy. To achieve better systemic control and decrease the degree of functional defect following surgery, neoadjuvant (presurgical) treatment programs have been developed by several centers. Early trials incorporated high doses of methotrexate(Drug information on methotrexate) given weekly for 4 weeks with leucovorin rescue before surgery. Subsequent modifications included the incorporation of bleomycin, dactinomycin(Drug information on dactinomycin) (Cosmegen), and cyclophosphamide(Drug information on cyclophosphamide) into the regimen, with the further addition of doxorubicin(Drug information on doxorubicin).
The next generation of trials adjusted the adjuvant (postoperative) chemotherapeutic regimen, depending on the degree of tumor necrosis found at the time of surgery. Patients who had a good tumor response (> 90% necrosis) were treated with additional cycles of the neoadjuvant regimen; those who had a poor response received cisplatin(Drug information on cisplatin) and doxorubicin. It remains controversial whether altering the adjuvant chemotherapeutic regimen for patients with poor histologic response truly changes their event-free survival.
The addition of ifosfamide(Drug information on ifosfamide) did not improve survival in pediatric patients with osteosarcoma in one study. A COG study reported no difference in outcome between a three-drug combination of cisplatin, doxorubicin, and high-dose methotrexate and a four-drug regimen of the same drugs plus ifosfamide. The European Osteosarcoma Intergroup (EOI) reported no difference in histopathologic response to preoperative chemotherapy and overall survival in patients randomized to receive a two-drug regimen with doxorubicin and cisplatin or a complex multidrug protocol containing doxorubicin, cisplatin, and high-dose methotrexate, among other agents.
The EOI also investigated standard-dose vs increased-dose intensity (dose-dense) cisplatin and doxorubicin for patients with operable osteosarcoma of the extremity. The overall dose intensity was increased by 24% for cisplatin and 25% for doxorubicin. Good histologic response (≤ 10% viable tumor) was significantly higher in the intensified arm (51% vs 36%). Unfortunately, overall survival at 4 years was not significantly different (61% for standard and 64% for intensified).
The actuarial 5-year event-free survival rate in patients who present with localized, primary extremity osteosarcoma is more than 70%. Regardless of the multidrug therapy used, event-free survival correlates with histologic response. Patients with more than 90% tumor necrosis have a more than 80% probability of 5-year event-free survival. Complete responses are more likely to occur in patients with the nonchondroblastic subtype and in those whose peak serum methotrexate levels are greater than 700 μmol/L. Chemosensitivity also seems to be diminished in patients with metastatic disease at presentation.
In June 2011, the European and American Osteosarcoma Study Group (EURAMOS)-1 trial, a joint protocol of four of the world's leading multi-institutional osteosarcoma groups (COG, EOI, Cooperative Osteosarcoma Study Group [COSS], and Scandinavian Sarcoma Group) completed accrual of patients with localized osteosarcoma. All patients will receive induction chemotherapy with two cycles of cisplatin and doxorubicin along with four cycles of high-dose methotrexate (MAP). Patients will then proceed to surgical resection. Postoperative therapy will be determined by histologic response. Good responders will be randomized to continue with MAP or receive MAP with pegylated interferon alfa-2b(Drug information on interferon alfa-2b) as maintenance therapy after MAP. Poor responders will be randomized to continue with MAP or receive the same regimen with the addition of ifosfamide and etoposide(Drug information on etoposide).
Treatment of advanced osteosarcoma
Axial primary tumor. For the 10% to 15% of patients who present with axial primary osteosarcoma, neoadjuvant chemotherapy should be considered to reduce the tumor burden before surgery or radiation therapy. The COSS reported that 11.4% of its patients treated before 1999 had proven metastases at diagnosis. For patients treated with preoperative and postoperative multiagent chemotherapy as well as aggressive surgery for all resectable lesions, actuarial survival at 5 and 10 years was 29% and 24%, respectively. Multivariate Cox regression analysis demonstrated that multiple metastases at diagnosis and macroscopically incomplete surgical resection are significantly associated with inferior outcomes in patients with primary metastatic osteosarcoma.
Pulmonary metastasis. Patients with metastatic disease to the lungs should be evaluated for resection. Following aggressive pulmonary metastasectomy, fewer than 25% of patients will achieve prolonged relapse-free survival. Hence, these patients may also benefit from aggressive "secondary" adjuvant chemotherapy.
Chemotherapy should also be considered for patients whose pulmonary metastases are unresectable, with the intention of performing surgery in those who have a sufficient response; approximately 10% of such patients may become long-term survivors.
Sidebar: For patients who do not have surgically resectable metastatic disease, Results of the randomized, phase III Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus (SUCCEED) study of the oral mammalian target of rapamycin (mTOR) inhibitor, ridaforolimus, vs placebo in patients with metastatic sarcoma who had at least stable disease after standard chemotherapy were reported at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting. A total of 711 patients were enrolled. The primary endpoint was progression-free survival. The median progression-free survival was 17.7 weeks for patients randomized to ridaforolimus vs 14.6 weeks for the placebo group (hazard ratio [HR] = 0.72; P = .0001). However, there was no significant difference in overall survival: 21.4 months for the ridaforolimus group vs 19.2 months for the placebo group (HR = 0.088; P = .2256). These findings suggest that there may be a role for maintenance therapy in patients with chemotherapy-responsive sarcoma (Chawla SP et al: J Clin Oncol 29:abstract 10005, 2011).
Poor-risk patients or patients with recurrent disease. Poor-risk patients or patients with recurrent disease are candidates for clinical trials that evaluate newer therapeutic agents. The COG demonstrated stabilization of disease in patients with recurrent or refractory osteosarcoma when the combination of cyclophosphamide and topotecan(Drug information on topotecan) (Hycamtin) was employed, although objective responses were rare. A team from the University of Michigan reported that the combination of gemcitabine(Drug information on gemcitabine) (Gemzar) and docetaxel(Drug information on docetaxel) (Taxotere) is moderately active in recurrent osteosarcoma, Ewing sarcoma, and other soft-tissue sarcomas.
The prognosis for patients who develop metachronous skeletal osteosarcoma has been considered grave compared with that for patients with relapse limited to the lungs. Investigators at Memorial Sloan-Kettering Cancer Center reported that in a small subset of patients who developed metachronous osteosarcoma at 24 months or more following the initial diagnosis (11 of 23 patients with osteosarcoma), combined-modality therapy with surgery and aggressive chemotherapy resulted in a 5-year postmetachronous survival rate of 83%, compared with a survival rate of 40% for patients who received monotherapy (usually surgery) only. These results refute an earlier pessimistic sentiment about the benefit of combined-modality treatment for this patient subgroup.
Radiotherapy
Although routine use of adjuvant radiotherapy for osteosarcoma is unnecessary, certain patients may benefit from treatment. Patients with positive margins and poor response to chemotherapy are particularly at risk for local recurrence. Primary lesions in the axial skeleton are more likely to be difficult to resect with wide margins. DeLaney et al have reported a local control rate of 78% in patients with subtotal resections followed by radiotherapy. Doses in the range of 60 Gy or more are recommended. Patients who have unresectable disease should be considered for high-dose radiotherapy following chemotherapy. Local tumor control may be achieved in 40% to 55% of patients. Sophisticated planning with intensity-modulated radiotherapy and/or proton therapy may be required for unresectable lesions in the pelvis or those located adjacent to radiosensitive structures, such as the spinal cord. The use of radiosensitizing chemotherapy has been studied by investigators at the University of Texas MD Anderson Cancer Center; it may improve the chances of controlling locally advanced disease.
Investigators at the Mayo Clinic reported significant palliation of pain in patients with osteosarcoma and symptomatic bone metastases who were treated with high doses of samarium 153 ethylene diamine tetramethylene phosphonate (153Sm EDTMP), a bone-seeking radiopharmaceutical, in conjunction with stem-cell rescue. Escalating doses up to 30 mCi/kg were studied. Nonhematologic adverse effects were minimal. 153Sm at a dose of 1 mCi/kg has been used for palliation of bone pain from skeletal metastases without the need for stem-cell support. Investigators at the Johns Hopkins Hospital have determined that a 1.21-mCi/kg dose can be administered to heavily pretreated patients without significant toxicity.
Long-term follow-up. Long-term follow-up is necessary for patients treated for osteosarcoma. Late adverse effects of neoadjuvant chemotherapy for osteosarcoma were assessed in a retrospective review performed by investigators at the Rizzoli Institute in Italy. Of the 755 patients with localized osteosarcoma treated with six subsequent protocols, the following adverse effects were noted: symptomatic cardiomyopathy (1.7%), second malignant neoplasms (2.1% after a median of 7 years), permanent azoospermia (100% in men who received 60 to 75 g/m2 of ifosfamide), subclinical renal impairment (48% in those who received > 60 g/m2 of ifosfamide), and hearing impairment (40% of those who received cisplatin).
Ewing Sarcoma
Chemotherapy
Before the availability of effective chemotherapeutic agents, fewer than 10% of patients with Ewing sarcoma survived beyond 5 years. The first Intergroup Ewing sarcoma study demonstrated an improved survival rate for patients receiving systemic therapy with the VAC regimen (vincristine, Actinomycin D [dactinomycin], cyclophosphamide), for those receiving the VACA regimen (the VAC regimen plus Adriamycin [doxorubicin]), and for patients receiving VAC plus bilateral pulmonary irradiation. In the future, selection of a specific therapeutic regimen may be influenced by the presence of molecular markers in addition to standard clinical criteria.
In the second Intergroup study, the addition of doxorubicin to VAC, when given on an intermittent schedule and at a higher dose, improved the 5-year relapse-free survival rate to 73%; this rate was almost double that of the cohort of patients not receiving doxorubicin as part of their treatment. The worst results were observed in patients with pelvic, proximal extremity, and lumbar vertebral lesions.
In a phase III study, the addition of ifosfamide and etoposide to standard VACA chemotherapy for patients with Ewing sarcoma and PNET of the bone significantly improved overall survival for patients with localized disease (72% vs 61%), but it did not affect the outcome for patients with metastatic disease (overall survival, 34% vs 35%). In addition to biologic adverse features at presentation (male sex, age, high LDH levels, anemia, fever, axial locations, non–type 1 fusion transcripts, and lack of feasibility of surgical resection), independent prognostic factors also include the type of chemotherapy and degree of tumor necrosis.
Therapy may be intensified by keeping the dosing interval stable while escalating chemotherapeutic doses or shortening the interval between cycles. In a phase II trial conducted by the COG, dose-intensification of alkylating agents with similar cumulative doses between the two arms did not demonstrate a significant difference between a standard regimen and an intensified regimen in terms of 5-year event-free survival. In contrast, a trial by Womer et al of dose intensification via interval compression in patients with localized Ewing sarcoma demonstrated a significant improvement in 3-year event-free survival (P = .028) between the experimental arm of VAC alternating with ifosfamide plus etoposide every 2 weeks (75%) and the standard arm of the same regimen every 3 weeks.
Advanced disease. Aggressive combination chemotherapy and irradiation can lead to prolonged progression-free survival, even in patients with metastatic disease. The combination of ifosfamide (1.6 g/m2) and etoposide (100 mg/m2) given on days 1 to 5 results in high response rates of greater than 80%. Unfortunately, late recurrences are not uncommon.
Autologous stem cell rescue has not been definitively shown to significantly improve survival of patients with poor-risk, metastatic, and recurrent Ewing sarcoma and PNET. Newer therapeutic agents should continue to be tested in this population of patients.
In patients with recurrent or refractory Ewing sarcoma, the combination of cyclophosphamide and topotecan was shown to possess significant antitumor activity by COG. Alternatively, protracted, low-dose administration of irinotecan(Drug information on irinotecan) alone or in combination with temozolomide(Drug information on temozolomide) has significant activity in Ewing sarcoma patients with either progressive disease during initial therapy or patients with early (< 2 years) or late (≥ 2 years) relapsed disease.
Because of its activity in the setting of advanced disease, the COG is currently investigating cyclophosphamide and topotecan into its upfront therapy for localized disease. Subjects are randomized to VAC alternating with ifosfamide plus etoposide every 2 weeks or the same drugs with the addition of cyclophophosphamide and topotecan.
Radiotherapy
Local control. Definitive radiotherapy is recommended for patients with unresectable primary tumors or in those for whom morbidity from resection is judged to be excessive. Patients treated with radiotherapy alone tend to have larger, less favorable tumors. In modern series of patients treated without surgery, local failure rates are on the order of 10% to 20%, compared with 4% to 10% with surgery or surgery plus radiotherapy, although emerging data suggest that similar local control rates are achieved with each modality. Patients treated definitively with chemotherapy and radiation therapy alone generally receive 45 Gy to the initial prechemotherapy volume plus a 2-cm margin, followed by a 10.8-Gy boost to a smaller volume, including the site of the original lesion plus any residual soft-tissue disease after chemotherapy.
Postoperative radiotherapy is indicated for microscopic or gross positive margins after resection or when more than 10% of tumor is viable in the pathologic specimen. A dose of 45 Gy is recommended for microscopic positive margins. Lower doses appeared to be associated with higher recurrence rates, based on data from two European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) trials. If gross disease is left, total doses on the order of 55.8 Gy, similar to those used for definitive radiotherapy, are used.
Metastatic disease. Patients with lung metastases at presentation should be considered for "consolidative," low-dose, whole-lung irradiation following completion of chemotherapy. Doses in the range of 15 to 18 Gy are typically used in 1.5-Gy fractions. Radiotherapy may also be used to treat isolated bone metastases following chemotherapy. Patients with painful bone metastases can benefit from palliative radiotherapy for pain control, with up to 55% achieving complete pain relief and an additional 30% achieving partial relief.
