Bone Sarcomas

November 1, 2015
R. Lor Randall, MD, FACS

,
Matthew G. Cable, MD

,
Nadia N. I. Laack, MD, MS

,
Warren Chow, MD

Overview

Bone sarcomas are extremely rare neoplasms, which precludes determination of their true incidence. It is estimated that in 2015, approximately 2,970 new cases of cancer of the bones and joints were diagnosed in the United States, and some 1,490 patients died of the disease. Population-based tumor registries seldom separate bone sarcomas into various histologic types.

Osteosarcoma is the most common malignant primary bone tumor (excluding multiple myeloma), accounting for 30% of all such malignancies. The annual incidence of osteosarcoma is approximately 800 cases per year in the United States. Chondrosarcoma is the second most common malignant primary tumor of bone; its annual incidence is approximately half that of osteosarcoma. Ewing sarcoma represents approximately 6% of all primary malignant bone tumors, with an annual incidence of 200 cases. Malignant fibrous histiocytoma (MFH) accounts for less than 1% of primary bone sarcomas.

Epidemiology

Gender

The incidence of primary bone sarcomas is higher in males than in females, regardless of histologic type. A low-grade variant of osteosarcoma (parosteal osteosarcoma) is observed more frequently in females.

Age

Osteosarcoma and Ewing sarcoma develop primarily in children and adolescents. A biphasic pattern of incidence of osteosarcoma has been observed; peaks have been noted among adolescents (rapid growth of long bones) and in patients over 60 years of age (secondary tumors arising in association with Paget disease or within previously irradiated tissue). Chondrosarcomas are rarely seen in skeletally immature patients. They usually develop in middle-aged and older adults. MFH is observed in adults.

Race

No predilection has been noted in any particular race. However, Ewing sarcoma is extremely rare in American and African blacks. Recent evidence suggests that polymorphisms in EWS/FLI1-responsive microsatellites correlate with these racial disparities.

Disease Site

Any bone and any site within a given bone may be affected. Most osteosarcomas occur in the metaphyseal region of skeletally immature long bones (ie, distal femur, proximal tibia, and proximal humerus), which have the greatest growth potential. Ewing sarcoma is classically described as a diaphyseal (main or midsection of a long bone) lesion, but it may arise in any region within an involved long bone. It commonly arises in the flat bones of the pelvis and scapula. Primary bone tumors of any histologic type are extremely rare in the spine and sacrum.

Survival

Low-grade sarcomas are associated with the most favorable survival, which approaches and may even exceed 90% in patients with adequately treated tumors. With regard to high-grade sarcomas, survival has improved dramatically in patients with osteosarcoma or Ewing sarcoma because of the advent of effective multiagent chemotherapy regimens. Survival has improved with multimodality therapy, from historic rates of less than 20% to current rates of 60% to 75%, but it has plateaued at this level for well over a decade. Novel agents are certainly necessary for refractory cases.

Etiology and Risk Factors

For the majority of bone sarcomas, no specific etiology has been established. A few predisposing factors have been identified, including genetics, radiation therapy, chemotherapy, preexisting benign tumors and conditions, trauma, and orthopedic implants.

Genetic Factors

Children with familial retinoblastoma have a 13q chromosome deletion and an increased incidence of osteosarcoma. Li-Fraumeni syndrome is also associated with an increased risk of bone sarcomas as well as other cancers, such as breast cancer, leukemia, soft-tissue sarcoma, and brain and adrenal cortical tumors. Li-Fraumeni syndrome results from a genetic loss of TP53. A maternal history of breast cancer or melanoma has been suggested as a risk factor in at least one study. Screening of at-risk families and surveillance of affected individuals for these syndromes may permit earlier diagnosis and more effective treatment in these populations. There is some preliminary evidence that pleomorphisms in the microsatellite region of the promoters for downstream targets of EWS/Fli1 may make certain populations at increased risk for developing Ewing sarcoma.

Radiation Therapy

Bone sarcomas constitute a rare, but devastating, consequence of therapeutic irradiation. Radiation-associated sarcomas develop within the radiation field, usually after a latent period of at least 3 years, occurring anytime thereafter. The majority of these tumors are osteosarcomas. MFH and other histologies also can arise within a radiation field.

Chemotherapy

Alkylating agents and anthracyclines administered for unrelated cancers have been implicated as etiologic factors in the development of second malignant neoplasms, particularly osteosarcoma.

Preexisting Benign Tumors/Conditions

Osteosarcomas can arise in association with Paget disease and rarely in association with benign bone tumors (ie, fibrous dysplasia). Chondrosarcomas can develop in the cartilaginous component of osteochondromas (solitary and multiple hereditary exostosis) and in patients with enchondromatosis (Ollier disease and Maffucci syndrome). MFH can arise in association with bone infarcts.

Trauma

A traumatic event often prompts medical intervention, at which time the bone sarcoma is detected. Interestingly, experimental inflammation via wounding in animal models infected with the Rous sarcoma virus led to sarcomagenesis. Such a finding is truly intriguing. Nonetheless, the incidence of trauma relative to that of sarcomas certainly implies inflammation alone is not causative.

Orthopedic Implants

Case reports of bone sarcomas arising in the region in which a metallic prosthetic device has been implanted have been published. The rarity of these clinical situations relative to the vast number of devices implanted makes a causal relationship unlikely.

Signs and Symptoms

Local Symptoms

Localized pain and swelling are the hallmark clinical features of bone sarcomas. The pain, which initially is insidious and transient, becomes progressively more severe and unremitting. Localized soft-tissue swelling, with or without associated warmth and erythema, may be present. A joint effusion may be observed, and range of motion of the adjacent joint may be limited and painful. Movement or weight bearing of the involved extremity may exacerbate local symptoms.

Patients with tumors that arise in the lower extremities can present with a painful limp. The neurovascular examination of the affected extremity is usually normal. Regional lymph nodes are rarely involved.

Pathologic fracture may also be a presenting sign, although a history of pain before fracture usually can be elicited.

Constitutional Symptoms

These are rare in patients with bone sarcoma, but such symptoms as fever, malaise, and weight loss can be observed in those with Ewing sarcoma.

Screening and Diagnosis

Currently, there is no screening test for primary bone sarcomas. The diagnosis must be made by clinical and radiographic evaluations and confirmed by histopathologic analysis of biopsy-obtained tissue.

Physical Examination

Physical examination should include an assessment of the local extent of the soft-tissue mass, if present, and its relationship to the adjacent joint.

Laboratory Studies

A complete blood cell (CBC) count may demonstrate anemia and/or leukocytosis associated with Ewing sarcoma, but in general, results of these studies fall within the normal range. Alkaline phosphatase and lactate dehydrogenase (LDH) levels may be elevated in patients with osteosarcoma or Ewing sarcoma. An abnormal glucose tolerance test may be observed in patients with chondrosarcomas.

Radiographs

Biplanar (anteroposterior and lateral) plain radiographs of the affected extremity provide critical information on the nature of the bone lesion. The specific site of involvement within the bone, the pattern and extent of bone destruction, the type of periosteal changes, and the presence of matrix mineralization within the tumor and of soft-tissue extension may be gleaned from plain films.

CT

Standard computed tomography (CT) scans provide further delineation of many of these changes.

MRI

Magnetic resonance imaging (MRI) is the imaging study of choice for evaluating the extent of an associated soft-tissue mass and the relationship of the tumor to the neurovascular structures, surrounding soft tissues, and the adjacent joint. The intramedullary extent of the tumor and presence of skip metastases within the bone are best demonstrated by MRI.

Bone Scan

At presentation, a bone scan is performed to screen for distant osseous metastases. This may be repeated during surveillance at the discretion of the provider or cooperative study.

Chest Radiographic Studies

A plain film of the chest is required in any patient in whom a bone sarcoma is suspected. Once the diagnosis of malignancy has been established, a CT scan of the chest is a critical part of initial staging.

FDG-PET

Recent reports suggest that the majority of bone sarcomas are fluorodeoxyglucose (FDG)-avid. In a prospective, multi-institutional trial utilizing FDG positron emission tomography (PET) in pediatric sarcomas, FDG-PET was superior compared with CT and bone scan in detection of osseous as well as lymph node and non-osseous metastasis. In this report, treatment was modified in 32% of patients based on FDG PET data. Utility of FDG-PET in staging and response is currently being evaluated in the ongoing Children’s Oncology Group localized Ewing sarcoma study (trial AEWS1031).

Biopsy

With few exceptions, a biopsy must be obtained to confirm the diagnosis. Tissue may be obtained by percutaneous (closed) or surgical (open) techniques. The biopsy should be performed by personnel who are expert in percutaneous biopsy techniques and familiar with bone tumors and their treatment.

Biopsies performed at referring institutions have been reported to be associated with a higher incidence of misdiagnosis and complications, which may affect patient outcome. Optimally, the biopsy should be performed at the institution where definitive treatment will be given.

Pathology

Histologic Subtypes

Current histopathologic classification of bone neoplasms is based on the putative cell of origin. Malignant tumors may arise from any cellular constituent present in bone, including osteogenic (osteosarcoma), chondrogenic (chondrosarcoma), hematopoietic (multiple myeloma, lymphoma), vascular (angiosarcoma, hemangioendothelioma, leiomyosarcoma), lipogenic (liposarcoma), neurogenic (neurofibrosarcoma, chordoma), and histiocytic and fibrohistiocytic (MFH, Ewing sarcoma) elements. Histologic subtyping is based on the predominant cellular pattern present within the tumor, the degree of anaplasia, and the relationship of the tumor to the bone (intramedullary vs surface).

A monoclonal antibody that recognizes a cell-surface glycoprotein, CD99 (p30/32MIC2), in human Ewing sarcoma and primitive neuroectodermal tumor (PNET) is helpful for diagnosis. There is strong immunoreactivity of CD99 in Ewing sarcoma and PNET that aids in distinguishing these tumors from other small, round-cell tumors of childhood and adolescence. Additional experience with CD99, however, demonstrates that it is not exclusively specific for Ewing sarcoma and PNET. Verification of the t(11;22) EWS/FLI1 translocation via fluorescent in situ hybridization or polymerase chain reaction should be performed.

Dedifferentiation

Primary bone sarcomas can exhibit the phenomenon of “dedifferentiation.” These neoplasms demonstrate a dimorphic histologic pattern, which is characterized by the presence of a borderline malignant or low-grade malignant tumor juxtaposed against a high-grade, histologically different sarcoma. Enchondromas, low-grade chondrosarcomas, low-grade variants of osteosarcoma (surface and intramedullary), and chordomas may all develop an area of high-grade spindle-cell tumor, usually MFH.

Metastatic Spread

Approximately 10% to 20% of patients with osteosarcoma and 15% to 35% of patients with Ewing sarcoma have evidence of metastatic disease at initial presentation. In approximately 90% of patients with bone sarcomas, the initial site of distant metastasis is the lungs. Distant osseous sites, bone marrow, and viscera may also be involved as a manifestation of advanced disease, but involvement of these sites is less common and usually occurs after the development of pulmonary metastases. Regional lymph node involvement is rare in most bone tumors. Ewing sarcoma historically has been associated with slightly higher rates of lymph node spread (5% to 9%). FDG-PET staging can identify occult lymphadenopathy, and the incidence of detected lymph node involvement is increasing.

Staging and Prognosis

TABLE 1: Surgical staging of bone sarcomas

Staging System

The staging system of the Musculoskeletal Tumor Society (MTS) has been used historically (Table 1). The MTS system is based on tumor grade (I = low or II = high); tumor extent (A = intraosseous involvement only or B = extraosseous extension); and presence of distant metastases, regardless of the extent of local disease (III). Patients with a localized tumor may have stage IA, IB, IIA, or IIB disease. A more universally and now relevant staging system has been developed for bone sarcomas by the American Joint Committee on Cancer (Table 2). This system has four stages and incorporates tumor size (T), lymph node involvement (N), metastasis (M), and histologic grade.

Prognostic Factors

Many studies have demonstrated that tumor response to preoperative chemotherapy is a powerful predictor of survival for patients with osteosarcoma. This is determined by histologic analysis of the resected specimen, with 90% necrosis as a commonly chosen cutoff. Adverse prognostic indicators, such as an axial primary tumor or elevated LDH and alkaline phosphatase levels, signal an even worse outcome. Older age at diagnosis has been associated with worse prognosis, but recent reports suggest that adults treated with modern pediatric regimens (regimens using more than two agents [cisplatin and doxorubicin]) may have similar prognosis.

Tumor size (low volume) and anatomic site (peripheral), absence of metastases at initial presentation, and good histologic response to chemotherapy are prognostic variables associated with better outcome in patients with osteosarcomas and Ewing sarcoma. Recent work has suggested that certain microRNA signatures are associated with the pathogenesis of osteosarcoma and may serve as potential pretreatment biomarkers of metastasis and response to chemotherapy. Lymph node involvement has recently been identified as an unfavorable prognostic factor in Ewing sarcoma.

For low-grade malignant tumors, adequacy of surgery is the most significant predictor of outcome.

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. Novel bone-fixation devices for megaprostheses are demonstrating good early to intermediate results. 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.

Bone graft substitutes and tissue engineering. The large resections required in musculoskeletal oncology frequently require use of bone allograft or bone substitute materials. Graft incorporation is inherently difficult, given the frequent use of perioperative adjuvant therapies including radiation and chemotherapy. Autograft or donor allograft bone augmented with bone marrow aspirate remains the gold standard, however development of improved bone substitute options remains important. Recent developments have included the incorporation of “additive manufacturing” techniques into bone tissue engineering (ie, 3-D printing), progressing beyond older subtraction methods of manufacturing. These techniques were initially used in designing prosthetic implants, but are now being used for designing bone tissue scaffolds. Commonly used materials include tricalcium phosphate and polycaprolactone, but recently investigation of new materials, such as graphene, has been pursued. Greater control at the macroscopic and microscopic levels allows a scaffold to have improved osteoconductive properties. Translation to actual clinical applications has been slow, with cost of manufacturing being the most prohibitive factor impeding progress.

Limb prostheses. Custom prostheses for the lower extremity remain hampered by socket fit around the residual limb. Cost continues to be prohibitive with the introduction of newer designs and materials. Elastomeric liners have led to improved activity levels and patient satisfaction, with total surface–bearing sockets faring better than patellar tendon–bearing sockets. Vacuum-assisted suction sockets have shown decreased pistoning and improved gait symmetry, and have the potential for improved wound healing and decreased residual limb volume loss, however given the modernity of this design, there is a paucity of literature about this option in comparison to total surface–bearing sockets.

Potential socket-fit issues can be avoided with osseointegrated implants, which are in limited use outside of the United States, predominantly with transfemoral amputees. There are still many hurdles to overcome with osseointegration, including loosening at the bone–implant interface, implant breakage, infection of the skin–implant interface, and prolonged rehabilitation times.

The majority of upper-extremity prostheses for above-elbow amputees remain body-powered via cables and pulleys, or often patients opt to not use a prosthesis. Advancements are being made with myoelectric arms employing rudimentary sensory feedback designs, such as the DEKA Arm System currently being developed by the Pentagon’s Defence Advanced Research Projects Agency (DARPA), but none are close to being commercially available.

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.

Functional outcomes

With improved endoprostheses and patient survival, long-term outcomes can now be reported for primary bone sarcomas in the vicinity of the knee. Revision-free survival is equivalent between custom and modular cemented endoprostheses of the distal femur, with implant survival being documented beyond 25 years in some cases. Although the rate of limb salvage is high, revision surgery (most commonly for infection) is a frequent occurrence, with a rate well above that of traditional joint replacement. Newer implants with uncemented press-fit porous coatings are showing similar implant survival rates at 5 and 10 years. Implants with compression-based osseous integration are increasingly being used, but long-term studies are not yet available. Implant survival in patients who have undergone revision surgery is signifcantly higher than that of primary implants.

From a functional standpoint, at a mean of 13.2 years after reconstruction, patients who underwent endoprosthestic reconstruction for primary lower-extremity bone sarcoma were found to have decreased strength but similar O2 consumption and walking speed, compared with control groups. Intercalary tibial allografts have shown survivorship of 79% at 10 years, with an average Musculoskeletal Tumor Society (MSTS) functional score of 29 in a recent study.

Pelvic primary bone sarcomas continue to be difficult, with individualized cases managed at the surgeon’s discretion, selecting from multiple reconstruction options. Massive allograft reconstructions have been fraught with complications, and hemipelvic endoprosthetic reconstructions and saddle prostheses have faired poorly, as evidenced by low quality-of-life and functional outcome scores using the Toronto Extremity Salvage Score (TESS), MSTS, and the Short Form 36 Health Survey (SF-36). Currently some surgeons favor a “minimalist” approach using spinal rod-and-screw instrumentation, “cement and rebar” constructs, or forgo instrumentation entirely.

When amputation is performed, these patients are similar functionally and psychosocially to matched limb-salvage controls. However, complications with amputation such as stump overgrowth, ulceration, infection, and phantom limb pain still need to be addressed.

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

FIGURE 1: 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 given weekly for 4 weeks with leucovorin rescue before surgery. Subsequent modifications included the incorporation of bleomycin, dactinomycin (Cosmegen), and cyclophosphamide into the regimen, with the further addition of 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 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 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.

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) reported their initial results for patients with localized osteosarcoma. All patients received induction chemotherapy with two cycles of cisplatin and doxorubicin along with four cycles of high-dose methotrexate (MAP). Patients then proceeded to surgical resection. Postoperative therapy was determined by histologic response. Good responders were randomized to continue with MAP or receive MAP with pegylated interferon alfa-2b as maintenance therapy after MAP. Poor responders were randomized to continue with MAP or receive the same regimen with the addition of ifosfamide and etoposide. Results for good and poor responders were recently reported. Poor response was detected in 1,059 of 2,260 patients (46.9%). A total of 618 of the poor responders consented to randomization. There was no event-free survival benefit to the addition of ifosfamide and etoposide (hazard ratio [HR] = 1.01; 95% CI, 0.75–1.26). Toxicity was greater, and there were more secondary malignancies with the addition. Accordingly, ifosfamide and etoposide should not be added to the adjuvant treatment of patients with localized osteosarcoma who demonstrate poor response to MAP. Good response was detected in 1,041 of 2,260 patients (46.1%), with 716 of the good responders consenting to randomization. With a median follow-up of 44 months there was no event-free survival benefit with the addition of pegylated interferon alfa-2b to MAP therapy, and many patients developed grade > 3 toxicity associated with pegylated interferon alfa-2b treatment (HR = 0.83; 95% CI, 0.61–1.12). In addition, OS2006, a randomized phase III trial of the addition of zoledronic acid injections (4 mg/dose) given neoadjuvantly (four doses) and adjuvantly (six doses) along with standard chemotherapy was recently reported by a French multicenter osteosarcoma group. The risk of treatment failure was not reduced by the addition of zoledronic acid with an HR for disease-free survival of 1.31 (95% CI, .79–2.18; P = .17) and for death of 1.42 (0.70–2.88; P = .21). Accordingly, zoledronic acid should not be given as neoadjuvant/adjuvant therapy with chemotherapy for localized osteosarcoma.

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, less 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, it is useful to consider the results of the randomized, phase III SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) 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. The findings were reported at the 2013 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 those in the placebo group (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 outcomes suggest that there may be a role for maintenance therapy in patients with chemotherapy-responsive sarcoma (Demetri GD et al: J Clin Oncol 31:2485, 2013).

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 was employed, although objective responses were rare. A team from the University of Michigan reported that the combination of gemcitabine and docetaxel 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.

Zoledronic acid has also been shown to be tolerated in the pediatric osteosarcoma patient population. As noted previously in this chapter, the results of OS2006, a randomized phase III trial reported by Brugieres et al, showed that the risk of treatment failure was not reduced by zoledronic acid.

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 g/m2to 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, less 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 alone or in combination with 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 incorporation of cyclophosphamide and topotecan into 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 bone 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. Recent reports suggest suggest definitive treatment of metastatic sites is associated with improved survival. 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 Gy 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.

Chondrosarcoma

More than 90% of chondrosarcomas are classified as conventional chondrosarcomas. Approximately 90% of these are low-grade to intermediate-grade tumors (grade 1 or 2), which have an indolent behavior and low metastatic potential. Only 5% to 10% of conventional chondrosarcomas are grade 3 lesions, which have high metastatic potential. Chondrosarcoma variants are rare; they include dedifferentiated chondrosarcoma (discussed earlier), mesenchymal chondrosarcoma, clear cell condrosarcoma, and myxoid chondrosarcoma. Mesenchymal chondrosarcoma is a highly malignant tumor that is histologically similar to Ewing sarcoma with foci of cartilaginous differentiation. Clear cell chondrosarcoma is a low-grade malignant tumor that principally involves the epiphyseal ends of the long bones. Finally, myxoid chondrosarcoma is characterized by prominent myxoid degeneration histologically. It is now considered distinct from extraskeletal myxoid chondrosarcoma (EMC) of soft-tissue, in which the translocation (9;22) is considered pathognomonic. T(9;22) is generally absent in myxoid chondrosarcoma of bone. Thus, they represent two different entities, and myxoid chondrosarcoma of bone is now regarded as a myxoid variant of intermediate- or high-grade conventional chondrosarcoma.

Chemotherapy

Conventional chemotherapy for metastatic conventional chondrosarcomas and the rare clear cell variant is generally ineffective. A recent report from Tel-Aviv University, however, has shown the combination of the oral mammalian target of rapamycin (mTOR) inhibitor, sirolimus, and oral cyclophosphamide was well tolerated and demonstrated a disease control rate of 70% in their single-institutional case series review for conventional chondrosarcomas. Because of its rarity, the effectiveness of chemotherapy for mesenchymal chondrosarcomas is debatable. The role of adjuvant chemotherapy in dedifferentiated chondrosarcoma remains similarly unclear. However, reports of two large patient series from the Rizzoli Institute and the European Musculo Skeletal Oncology Society have cast doubt on its usefulness.

Giant-Cell Tumor

Giant-cell tumor (GCT) of bone is an unusual (representing 4% to 5% of all bone tumors), benign but locally aggressive neoplasm that typically affects the ends of long bones. The peak incidence of GCT is in individuals between 20 and 45 years of age. It is a primary osteolytic bone tumor that contains cells of the osteoclast lineage in addition to stromal cells. Driver mutations were discovered in the Histone H3.3 genes H3F3A and H3F3B only in the stromal compartment, which confirms that the neoplastic component of these tumors is represented by the stromal cells and not by cells of the osteoclast lineage. Surgery remains the definitive therapy for GCT. Despite this, surgical intervention may lead to substantial morbidity, and recurrence varies from 10% to 75% depending on the size and location of the lesion and the surgical intervention. The cells of osteoclast lineage express receptor activator of nuclear factor kappa-B (RANK), and some of the stromal cells express RANK ligand (RANKL). Denosumab (Xgeva, Prolia) is a fully human monoclonal antibody that specifically inhibits RANKL, thereby inhibiting osteoclast-mediated bone destruction. An international, open-label, phase II study of densosumab was conducted in 37 patients with recurrent or unresectable GCT. A total of 86% of patients had a tumor response defined as elimination of at least 90% of giant cells or no radiographic progression of the target lesion up to week 25. Based upon these results, denosumab was approved by the Food and Drug Administration (FDA) on June 13, 2013 for GCT that is unresectable or where surgical resection is likely to result in severe morbidity.

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