Treatment of Childhood Soft Tissue Sarcoma with Low Potential for Metastasis
        Infantile fibrosarcoma and hemangiopericytoma (in infants and young children)
        Desmoid tumors
Treatment of Childhood Soft Tissue Sarcoma with Adult-like Soft Tissue Sarcoma Biologic Characteristics
        Alveolar soft part sarcoma
        Clear cell sarcoma of soft parts
        Desmoplastic small round cell tumor
        Extraosseous osteosarcoma
        Hemangioendothelioma
        Malignant peripheral nerve sheath tumor
        Synovial sarcoma
        Vascular tumors: angiosarcoma and lymphangiosarcoma
Current Clinical Trials

Standard treatment options for nonmetastatic pediatric nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs) include the following:

• Complete surgical resection alone (if margins were tumor-free) or followed by re-excision if margins were positive.
• Surgical excision followed by postoperative radiation therapy or brachytherapy (if tumor margins were positive and further resection is not possible).

For nonmetastatic pediatric NRSTSs, treatment with surgery alone is often curative.[1-6] If the initial surgery was performed without suspicion of malignancy, re-excision by a surgeon experienced in the treatment of soft tissue sarcoma is essential, even if imaging studies do not suggest the presence of residual tumor. Postoperatively, tumor-free margins must be confirmed through pathologic evaluation, and re-excision must be performed if the margins are positive. If further resection is not feasible, postoperative radiation therapy or, if possible, brachytherapy should be used.[7,8]

The tumors discussed in this section are clinically less aggressive and rarely metastasize.[1,9-11] These tumors include the following:

• Infantile fibrosarcoma.
• Hemangiopericytoma (in infants and young children).
• Desmoid tumors.
• Aggressive fibromatosis.
• Dermatofibrosarcoma.
• Angiomatoid malignant fibrous histiocytoma.

The standard treatment for these tumors is complete surgical excision followed by re-excision if tumor margins were positive or, radiation therapy or brachytherapy if re-excision is not possible. Several of these clinically less aggressive soft tissue sarcomas have been treated with other therapies and these tumors and treatments are discussed below.

In children with infantile fibrosarcoma, preoperative chemotherapy has made possible a more conservative surgical approach; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[1,12] Responses to presurgical chemotherapy with similar agents have been reported in cases of infantile hemangiopericytoma.[1]

Desmoid tumors are well-differentiated fibrous lesions that rarely metastasize, but they have a significant potential for local invasiveness and recurrence. The treatment of choice is resection to achieve clear margins. If postoperative margins are positive, 70% of patients will have a recurrence of disease. When complete surgical excision is not feasible and the tumor poses significant potential for mortality or morbidity, preoperative strategies that include external-beam radiation therapy, postoperative interstitial iridium I 192, nonsteroidal anti-inflammatory agents, antiestrogens, vinblastine, and methotrexate should be considered.[13,14] Evaluation of the benefit of chemotherapy for treatment of desmoid tumors has been extremely difficult because desmoid tumors have a highly variable natural history. Large adult series and a single pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[15,16] A small series of mainly adult patients (n = 19) with desmoid tumors were treated with imatinib mesylate and showed infrequent objective responses.[17] A series of mainly adult familial adenomatous polyposis patients with unresectable desmoid tumors that were unresponsive to hormone therapy, showed that doxorubicin plus dacarbazine followed by meloxicam (a nonsteroidal anti-inflammatory agent) can be safely administered and can induce responses.[18] There are reports of objective responses to systemic chemotherapy in children with desmoid tumors. Combination chemotherapy using vinblastine and methotrexate has been used for the treatment of progressive desmoid tumor in children.[13] These should be interpreted cautiously in light of the variable natural history of the disease. Partially excised or recurrent lesions that do not pose a significant danger to vital organs may be monitored closely if other treatment alternatives are not available.[16,19-22] Whenever possible, however, the treatment of choice is complete resection.

The pediatric neoplasms listed below exhibit similar biologic behavior that is similar to lesions in adults:

• Alveolar soft part sarcoma (ASPS).
• Clear cell sarcoma of soft parts.
• Desmoplastic small round cell tumor.
• Epithelioid sarcoma.
• Extraosseous osteosarcoma.
• Fibrosarcoma in older children and adolescents.
• Hemangioendothelioma.
• Hemangiopericytoma in older children and young adults.
• Leiomyosarcoma.
• Liposarcoma.
• Malignant fibrous histiocytoma.
• Malignant peripheral nerve sheath tumor (MPNST).
• Mesenchymal chondrosarcoma.
• Synovial sarcoma.
• Vascular tumors: angiosarcoma and hemangiosarcoma.

Much of what is known about treating these tumors is derived from studies in adults. Standard treatment options for these tumors include the following:

• Complete surgical resection alone (if margins were tumor-free) or followed by re-excision if margins were positive.
• Surgical excision followed by postoperative radiation therapy or brachytherapy if tumor margins were positive and further resection is not possible.

Every attempt should be made to resect the primary tumor locally with negative margins.[23,24] If the original operation failed to achieve pathologically negative tissue margins, a second surgery may be indicated.[2] Although combined surgery and radiation therapy have dramatically improved outcome in adults and children with soft tissue sarcomas over the past 20 years,[7] the morbidity of high-dose radiation therapy should be considered in infants and young children with these tumors.[25] The use of brachytherapy and intraoperative radiation therapy is under study.[8,26] Preoperative radiation therapy has been associated with excellent local control rates in adults;[27,28] this approach has not been used extensively in pediatric patients.

The role of adjuvant (postoperative) chemotherapy remains controversial. Virtually all trials of adjuvant chemotherapy in adults with soft tissue sarcoma report the results of treatment for all patients in aggregate. This may obscure important differences in chemosensitivity among histologic subtypes of soft tissue sarcoma. A retrospective analysis of neoadjuvant chemotherapy in adults with soft tissue sarcoma suggested a benefit for patients with larger tumors.[29] The largest prospective pediatric trial failed to document any benefit of adjuvant chemotherapy with vincristine, dactinomycin, cyclophosphamide, and doxorubicin in children with grossly resected tumors.[30] This trial also reported results in aggregate for a variety of soft tissue sarcomas. In patients with unresectable or metastatic disease treated with vincristine, dactinomycin, and cyclophosphamide, the overall survival (OS) and disease-free survival rates were 31% and 10%, respectively.[31] Achieving complete responses after aggressive chemotherapy, radiation therapy, and surgery is possible in most patients with more advanced NRSTS.[32]

Some of these tumors have been treated with other therapies and these selected tumors and treatments are discussed below.

The standard approach is complete resection of the primary lesion.[6] If complete excision is not feasible, radiation therapy should be administered. The value of adjuvant chemotherapy in completely resected ASPS remains unproven, particularly because patients with unresected or metastatic tumors failed to respond to chemotherapeutic agents frequently used to treat soft tissue sarcomas.[33] Patients with ASPS may relapse several years after a prolonged period of apparent remission.[34] The role of adjuvant chemotherapy in children with this malignancy has not been tested. Because these tumors are rare, all children with ASPS should be enrolled in prospective clinical trials.

• COG-ARST0332 ¹ is a prospective study for children and young adults with soft tissue sarcomas other than rhabdomyosarcoma. Patients are stratified by tumor grade and extent. Patients with lower-grade tumors and patients with small, completely resected high-grade tumors are observed after surgical resection alone. Patients with positive microscopic margins receive adjuvant radiation. Patients with high-grade tumors larger than 5 cm undergo resection and receive adjuvant chemotherapy and radiation. Patients with unresectable or metastatic disease receive neoadjuvant chemotherapy. Chemotherapy for all eligible patients is ifosfamide and doxorubicin.[35]

Treatment for clear cell sarcoma of soft parts is primarily surgical with radiation therapy for uncertain or involved margins. Antisarcoma chemotherapy is rarely effective.[36]

Complete resection of this tumor is rarely possible, thus effective treatment must rely on chemotherapy and radiation therapy. Treatment for individuals with desmoplastic small round cell tumor following surgery requires aggressive chemotherapy with agents used for treatment of sarcoma combined with appropriate radiation treatment. Prognosis is dependent on the extent and aggressiveness of the tumor and its treatment.[37-39] Whole abdominopelvic radiation therapy is feasible but has not significantly improved the outcome for this diagnosis.[40,41]

Chemotherapy for extraosseous osteosarcoma has not been well studied. Treatment has previously been recommended to follow soft tissue sarcoma guidelines rather than guidelines for osteosarcoma of bone.[42] Extraosseous osteosarcoma may be more chemosensitive in young patients than in adults.[42] A retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraskeletal osteosarcoma treated with surgery and conventional osteosarcoma chemotherapy.[43] (Refer to the PDQ summary on Osteosarcoma/Malignant Fibrous Histiocytoma of Bone ² for more information.)

Treatment of asymptomatic liver hemangioendothelioma in a child younger than 1 year may compromise close observation because some tumors will regress. Symptomatic lesions require urgent medical or surgical management, especially if coagulopathy is present.[44-47] Epithelioid hemangioendothelioma of the liver should be managed surgically; some patients may need orthotopic liver transplantation because this disease does not respond to radiation therapy or chemotherapy.[48]

A large retrospective analysis of the German and Italian experience with MPNST identified incomplete resection, large tumor size, tumor invasiveness, nonextremity primary site, and clinical diagnosis of neurofibromatosis as unfavorable prognostic findings.[23] There was a trend toward improved outcome with adjuvant radiation therapy. While 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, the analysis did not conclusively demonstrate improved survival for chemotherapy.[23] A series of 37 young patients with MPNST and neurofibromatosis type 1 (NF1) showed that most patients had large invasive tumors that were poorly responsive to chemotherapy; progression-free survival was 19% and 5-year OS was 28%.[49] Another series of older patients with MPNST found that those with NF1 had a worse prognosis than those without NF1.[50]

Synovial sarcoma appears to be more sensitive to chemotherapy than many other NRSTSs. Children with synovial sarcoma have a higher probability for both event-free survival (EFS) and OS than children with other types of NRSTS.[51,52] A German randomized trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma.[53] A meta-analysis also suggested that chemotherapy may improve EFS but could not confirm improvement in OS.[24] Many treatment centers advocate adjuvant chemotherapy following resection of synovial sarcoma in children and young adults; unequivocal proof of the value of this strategy from prospective, randomized clinical trials is lacking. A study of 21 patients with small (<1 cm), localized synovial sarcomas showed an excellent survival rate with no metastatic events; only one patient received chemotherapy.[54] A retrospective analysis of synovial sarcoma in children treated in Germany and Italy identified tumor size (>5 cm or <5 cm in greatest dimension) as an important predictor of EFS.[55] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins did not predict outcome.

Vascular tumors vary from hemangiomas, which are considered always benign, to angiosarcomas, which are highly malignant.[56] Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients in response to local therapy.[57-59]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with nonmetastatic childhood soft tissue sarcoma ³. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁴.

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