Cancer Management Chapter 21: Bone sarcomas

March 9, 2010

Article

Bone sarcomas are extremely rare neoplasms, which precludes determination of their true incidence. In 2009, approximately 2,570 new cases of cancer of the bones and joints will be diagnosed in the United States, and some 1,470 patients will succumb to 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), comprising 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's sarcoma represents approximately 6% of all primary malignant bone tumors, with an annual incidence of 200 cases. Malignant fibrous histiocytoma (MFH) comprises < 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's 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 the elderly (secondary tumors arising in association with Paget's 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's sarcoma is extremely rare in American and African blacks.

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's sarcoma is classically described as a diaphyseal 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 90% in patients with adequately treated tumors. With regard to high-grade sarcomas, survival has improved dramatically in patients with osteosarcoma or Ewing's sarcoma due to the advent of effective multiagent chemotherapy regimens. Survival has improved with multimodality therapy from historic rates of < 20% to current rates of 50% to 75%.

Etiology and risk factors

For the majority of bone sarcomas, no specific etiology has been established. A few predisposing factors have been identified.

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 such other cancers such as breast, leukemia, soft-tissue sarcoma, brain, and adrenal cortical tumors. Li-Fraumeni syndrome results from a genetic loss of TP53.

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. 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's 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's disease and Maffucci's 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. The short temporal relationship between the traumatic event and the diagnosis of the tumor usually rules out a causal relationship.

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 arising 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 prior to 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's 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 CBC may demonstrate anemia and/or leukocytosis associated with Ewing's sarcoma, but, in general, results of these studies fall within the normal range. Alkaline phosphatase and lactic dehydrogenase (LDH) levels may be elevated in patients with osteosarcoma or Ewing's sarcoma. An abnormal glucose tolerance test may be observed in patients with chondro-
sarcomas.

X-rays
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, 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 CT scans provide further delineation of many of these changes.

MRI
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
A bone scan is performed to screen for distant osseous metastases.

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

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 expert in percutaneous biopsy techniques who are 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's 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 (CD99) that recognizes a cell-surface glycoprotein (p30/32MIC2) in human Ewing's sarcoma and primitive neuroectodermal tumor (PNET) has been developed. There is strong immunoreactivity of CD99 in Ewing's 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's sarcoma and PNET.

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's 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.

Staging and prognosis

Staging system
The staging system of the MTS is currently used (Table 1). This 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.

Prognostic factors
Many studies have demonstrated that tumor response to preoperative chemotherapy, as determined by histologic analysis of the resected specimen, is the most powerful predictor of survival for patients with osteosarcoma. Adverse prognostic indicators, such as an axial primary tumor or elevated LDH and alkaline phosphatase levels, signal an even worse outcome.

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's sarcoma. The translocation t(11;22), which results in the type 1 EWS-FLI1 fusion, is also a significant positive predictor of overall survival in Ewing's 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 (3 to 4 cycles) is followed by surgical extirpation of the primary tumor. Chemotherapy is reinitiated postoperatively after wound healing has occurred (usually 2–3 weeks after surgery).

For patients with Ewing's 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 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. Patients with unresectable tumors or microscopic or macroscopic residual disease following tumor excision clearly require adjuvant radiotherapy to consolidate their local treatment.

Surgical treatment strategy
The MTS recognizes wide excision, either by amputation or 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. Conceptually, this strategy is applicable to all high-grade sarcomas. Wide excision successfully controls local disease in ≥ 90% of patients.

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 (ANC) has recovered to a level of ≥ 1,500/μL and the platelet count ≥ 70,000/μL.

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, 75% to 80% of patients may be treated with conservative 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.

Long-term follow-up is necessary for patients treated for osteosarcoma. Late side 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 side 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 60–75 g/m

of ifosfamide), subclinical renal impairment (48% in those who received > 60 g/m

of ifosfamide), and hearing impairment (40% of those who received cisplatin;

Bacci G et al: J Clin Oncol 28:774–780, 2006)

Types of resection Limb-sparing tumor resection falls into one of three types based 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.

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 problem for the orthopedic oncologist, particularly in patients with substantial projected growth of the involved extremity. The surgical management of bone sarcomas in young patients, with few exceptions, has entailed amputation or rotationplasty.

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%–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

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 < 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 (

) 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 prior to 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 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 versus 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 presenting with localized, primarily extremity osteosarcoma is > 70%. Regardless of the multidrug therapy used, event-free survival correlates with histologic response. Patients with > 90% tumor necrosis have a > 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 > 700 μmol/L. Chemosensitivity also seems to be diminished in patients with metastatic disease at presentation.

A joint protocol of four of the world's leading multi-institutional osteosarcoma groups (COG, EOI, COSG, and Scandinavian Sarcoma Group) is currently accruing patients with localized osteosarcoma (EURA-MOS). 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 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.

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 prior to surgery or radiation therapy. The COSG reported that 11.4% of its patients treated before 1999 had proven metastases at diagnosis. Actuarial survival at 5 and 10 years was 29% and 24%, respectively, when treated with preoperative and postoperative multiagent chemotherapy as well as aggressive surgery for all resectable lesions. 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, < 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.

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 employing the combination of cyclophosphamide and topotecan (Hycamtin), although objective responses were rare. A team from the University of Michigan reported that the combination of gemcitabine (Gemzar) and docetaxel (Taxotere) is moderately active in recurrent osteosarcoma, Ewing's 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 MSKCC reported that in a small subset of patients who developed metachronous osteosarcoma at 24 months or more from 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%, versus 40% for patients receiving monotherapy (usually surgery) only. These results refute an earlier pessimistic sentiment.

Radiotherapy
Although the 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 lesions located adjacent to radiosensitive structures such as the spinal cord. The use of radiosensitizing chemotherapy has been studied by investigators at MDACC; 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 30mCi/kg were studied. Nonhematologic side 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.

Ewing's sarcoma

Chemotherapy
Prior to the availability of effective chemotherapeutic agents, < 10% of patients with Ewing's sarcoma survived beyond 5 years. The first intergroup Ewing's 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 a trial of chemotherapy intensification via interval compression in localized osteosarcoma, the EOI found that dose-dense cisplatin plus doxorubicin did not improve overall survival. However, the COG reported that dose-dense chemotherapy using alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VAC) and ifosfamide plus etoposide (IE) significantly improved event-free survival in patients with localized Ewing's sarcoma and primitive neuroectodermal tumor. In all, 587 patients under 50 years of age were randomized to standard VAC and IE every 3 weeks vs every 2 weeks. Event-free survival at a median of 3 years was 65% in the group treated every 3 weeks and 76% in the group treated every 2 weeks (

= 0.028). Importantly, the occurrence of specific toxicities and days of hospitalization were similar for the two regimens

(Womer RB et al: J Clin Oncol 26:10504a, 2008 [abstract])

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's 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.

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 1–5) results in high response rates of > 80%. Unfortunately, late recurrences are not uncommon.

Dose intensification of active chemotherapeutic compounds, including those employing autologous stem-cell rescue, has not been definitively shown to significantly improve survival of patients with poor-risk and metastatic Ewing's sarcoma and PNET. However, dose-dense chemotherapy is postulated to improve outcome in localized Ewing's sarcoma and is the focus of a randomized phase III trial by COG. The arms studied were standard chemotherapy with growth factor support given every 3 weeks versus every 2 weeks. Newer therapeutic agents should be tested.

In patients with recurrent or refractory Ewing's sarcoma, the combination of cyclophosphamide and topotecan was shown to possess significant antitumor activity by COG.

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 20%, compared with 4% to 10% with surgery or surgery plus radiotherapy. 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.

The prognosis for patients with recurrent, chemotherapy-refractory Ewing's sarcoma is poor. Signaling through the insulin-like growth factor 1 receptor (IGF-1R) is important for the growth, survival, and migration potential for many cancers, including Ewing's sarcoma. In a phase I dose escalation study, up to 9 mg/kg of R1507, a human anti-IGF-1R monoclonal antibody, was given on a weekly schedule to patients with advanced malignant solid tumors. An early report noted that 2 of 8 evaluable Ewing's sarcoma patients had confirmed, ongoing, partial responses for at least 12 weeks, and 2 others had stable disease. Moreover, no dose limiting toxicities were identified in the weekly schedule up to 9 mg/kg

(Leong S et al: Molecular Targets and Cancer Therapeutics, Oct. 22–26, 2007; San Francisco, CA [abstract 78])

When microscopic or gross positive margins remain following resection, post-operative radiotherapy is indicated. 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 Cooperative Ewing's Sarcoma Study trials. If gross disease is left, total doses similar to those used for definitive radiotherapy are utilized.

Metastatic disease Patients with lung metastases at presentation should be considered for “consolidative,” low-dose, whole-lung irradiation following chemotherapy. Doses in the range of 15 to 18 Gy are typically utilized 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.