Childhood Soft Tissue Sarcoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Soft Tissue Sarcoma Treatment (PDQ®)–Health Professional Version

Neoplasms with perivascular epithelioid cell differentiation (PEComas)

Risk factors and molecular features

Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas.[272] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[273,274] A small proportion of PEComas have TFE3 rearrangements with fusions involving various genes, including SFPQ/PSF and RAD51B.[275]

Clinical presentation

PEComas occur in various rare gastrointestinal, pulmonary, gynecologic, and genitourinary sites. Soft tissue, visceral, and gynecologic PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex.[276] The disease course may be indolent.

Prognosis

Most PEComas have a benign clinical course, but malignant behavior has been reported and can be predicted based on the size of the tumor, mitotic rate, and presence of necrosis.[277]

Treatment

Treatment options have not been defined. Treatment may include surgery or observation followed by surgery when the tumor is large.[278]

Clinical activity with mTOR inhibitors, such as sirolimus, in tumors with evidence of mTORC1activation and TSC loss has been well documented.[279]

Undifferentiated/Unclassified Sarcoma

From 1972 to 2006, patients with undifferentiated soft tissue sarcoma were eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the COG. The rationale was the observation that patients with undifferentiated soft tissue sarcoma had sites of disease and outcomes that were similar to those in patients with alveolar rhabdomyosarcoma. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated soft tissue sarcoma and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy.

In the COG ARST0332 (NCT00346164) trial, patients with high-grade undifferentiated sarcoma were treated with an ifosfamide and doxorubicin-based regimen and were treated with rhabdomyosarcoma-directed therapies in previous Intergroup Rhabdomyosarcoma Study Group studies, with a 5-year survival estimate for nonmetastatic patients of 72%.[280][Level of evidence: 3iiA]

In a report of 32 patients with undifferentiated soft tissue sarcomas who were enrolled on the ARST0332 (NCT00346164) trial, the median age at enrollment was 13.6 years, and two-thirds of the patients were male. The most common primary sites were the paraspinal region and extremities. Five patients presented with metastatic disease.[281]

The 5-year EFS rate was 71%, and the OS rate was 83%.
Of the nine children with low-risk disease (localized low-grade resected disease or localized high-grade disease <5 cm resected with negative margins) who were treated with surgery or radiation therapy only, the 5-year EFS rate was 65% and the OS rate was 100%, suggesting that patients with recurrent disease can be salvaged with additional therapy.
The remaining 23 patients had either intermediate-risk disease (resected high-grade tumor >5 cm, unresected high-grade tumor >5 cm) or high-risk disease (metastasis to lymph nodes or distant sites) and were treated with chemoradiation therapy and delayed surgery when feasible. The 5-year EFS rate was 73%, and the OS estimate was 77%.
Copy number aberrations were common, most frequently involving loss of 1p (25%), gain of 1q (25%), gain of chromosome 8 (25%), and gain of chromosome 2 (16%). These alterations were more commonly seen in patients with intermediate-risk or high-risk tumors, and there was a strong association between loss of chromosome 1p or gain of chromosome 1q and inferior clinical outcomes. Co-occurrence of 1q gain and 1p loss was associated with a particularly poor clinical outcome (5-year EFS and OS of 20%). Next-generation sequencing identified oncogenic fusions in eight of ten samples, which included BCOR and CIC rearrangements, as well as COL1A1-PDGFB, KIAA1549-BRAF, and SAMD-SASH1 fusions.

Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)

At one time, malignant fibrous histiocytoma was the single most common histotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest WHO classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[4,282]

This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.[283]

Molecular features

Undifferentiated pleomorphic sarcoma was most often called malignant fibrous histiocytoma in the past. Historically, this entity has been difficult to evaluate because of the shifting diagnostic criteria. Analysis of 70 cases diagnosed as malignant fibrous histiocytosis of no specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma, or undifferentiated pleomorphic sarcoma showed a highly complex karyotype with no specific recurrent aberrations.[284]

Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas;[284] the relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined.

Risk factors

These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.

Clinical presentation and treatment

These tumors occur mainly in the second decade of life. In a series of ten patients, the median age was 10 years and the tumor was most commonly located in the extremities. In this series, all tumors were localized and five of nine (for whom follow-up was available) were alive and in first remission.[283] In another series of 17 pediatric patients with malignant fibrous histiocytoma, the median age at diagnosis was 5 years and the extremities were involved in eight cases.[285] All patients with metastatic disease died and two patients experienced a clinical response to a doxorubicin-based regimen.

(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information about the treatment of malignant fibrous histiocytoma of bone.)

Undifferentiated round cell sarcomas with BCOR-CCNB3 rearrangements

(Refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangementsand Genomics of Ewing Sarcoma sections of the PDQ summary on Ewing Sarcoma Treatment for more information.)

Undifferentiated round cell sarcomas with CIC-DUX4 rearrangements

(Refer to the Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements andGenomics of Ewing Sarcoma sections of the PDQ summary on Ewing Sarcoma Treatmentfor more information.)

Vascular Tumors

Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[286] Malignant vascular tumors include the following subtypes:

Epithelioid hemangioendothelioma

Incidence and outcome

This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[287-293]

The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.[289]

Histopathology and molecular features

A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported.[287] These fusions are not directly targetable with current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.

Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.[289]

The number of pediatric patients reported in the literature is limited.

Clinical presentation and diagnostic evaluation

Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[289,294,295] Clinical presentation depends on site of involvement, as follows:

Liver: Hepatic nodules have central vascularity on ultrasound, contrast-enhancing lesions by computed tomography, and low T1 signal and moderate T2 signal on magnetic resonance imaging.
Lung: Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.
Bone: Bone metastasis may be associated with pathologic fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.
Soft tissue: Thirty percent of soft tissue cases are associated with metastases, and when present, can have a very aggressive course, with limited response to chemotherapy.
Skin: Cutaneous lesions can be raised and nodular or can be warm red-brown plaques.

Treatment of epithelioid hemangioendothelioma

Treatment options for epithelioid hemangioendothelioma include the following:

Observation.
Surgery.
Immunotherapy.
Targeted therapy.
Chemotherapy.

For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[296] The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.[289,297-300]

Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.

Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.

Treatment options under clinical evaluation for epithelioid hemangioendothelioma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

NCT03148275 (Trametinib in Treating Patients with Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery): This is a phase II trial assessing the efficacy of trametinib, with patient-reported outcomes as secondary aims.
NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Angiosarcoma of the soft tissue

Incidence

Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million people; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.[301]

Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[302-305] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.

Risk factors

Established risk factors include the following:[306]

Vinyl chloride exposure.
Radiation exposure.
Chronic lymphedema from any cause, including Stewart-Treves syndrome.

Histopathology and molecular features

Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.[306]

Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).[303]

Treatment of angiosarcoma of the soft tissue

Treatment options for angiosarcoma of the soft tissue include the following:

Surgery (localized disease).
Radiation therapy (localized cutaneous disease in adults).
Surgery, chemotherapy, and radiation therapy (metastatic disease).

Localized disease is cured by aggressive surgery. Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[304,307-309] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[309] Data on liver transplantation for localized angiosarcoma are limited.[310][Level of evidence: 3iiA]

Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.[311]

Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[312] Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months [313] and a median overall survival (OS) rate of 14 months to 18 months.[314] In both adults and children, 5-year OS rates between 20% and 35% are reported.[304,305,315]

In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.[302,312] A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.[316]

Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[303,315]

Treatment options under clinical evaluation for angiosarcoma of the soft tissue

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.
NCT02834013 (Nivolumab and Ipilimumab in Treating Patients With Rare Tumors):This is a phase II study of nivolumab and ipilimumab to treat patients with rare tumors. Immunotherapy with monoclonal antibodies such as nivolumab and ipilimumab may help the body's immune system attack the cancer and may interfere with the ability of the tumor cells to grow and spread.

Current Clinical Trials

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Treatment of Metastatic Childhood Soft Tissue Sarcoma

Standard treatment options for metastatic childhood soft tissue sarcoma include the following:

Multimodality therapy using chemotherapy, radiation therapy, and surgical resection of pulmonary metastases.

For treatment options, refer to the individual tumor type sections of the summary.

The prognosis for children with metastatic soft tissue sarcomas is poor,[1-6] and these children should receive combined treatment with chemotherapy, radiation therapy, and surgical resection of pulmonary metastases. In a prospective randomized trial, chemotherapy with vincristine, dactinomycin, doxorubicin, and cyclophosphamide, with or without dacarbazine, led to tumor responses in one-third of patients with unresectable or metastatic disease. The estimated 4-year survival rate, however, was poor, with fewer than one-third of children surviving.[6-8]

Pulmonary Metastases

Generally, children with isolated pulmonary metastases should be considered for a surgical procedure in an attempt to resect all gross disease.[9] For patients with multiple or recurrent pulmonary metastases, additional surgical procedures can be performed if the morbidity is deemed acceptable. In a retrospective review, patients with synovial sarcoma and pulmonary metastases for whom it was possible to completely resect all metastatic lung lesions had better survival than did patients for whom it was not possible to achieve complete resections.[9][Level of evidence: 3iiiA] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.[10]

An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy), which has been successfully used in adults to control lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies.[11]

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deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995. [PUBMED Abstract]
Pappo AS, Rao BN, Jenkins JJ, et al.: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children's Research Hospital experience. Med Pediatr Oncol 33 (2): 76-82, 1999. [PUBMED Abstract]
Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999. [PUBMED Abstract]
Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998. [PUBMED Abstract]
Stanelle EJ, Christison-Lagay ER, Wolden SL, et al.: Pulmonary metastasectomy in pediatric/adolescent patients with synovial sarcoma: an institutional review. J Pediatr Surg 48 (4): 757-63, 2013. [PUBMED Abstract]
Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995. [PUBMED Abstract]
Dhakal S, Corbin KS, Milano MT, et al.: Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. Int J Radiat Oncol Biol Phys 82 (2): 940-5, 2012. [PUBMED Abstract]

Treatment of Progressive/Recurrent Childhood Soft Tissue Sarcoma

With the possible exception of infants with infantile fibrosarcoma, the prognosis for patients with recurrent or progressive disease is poor. No prospective trial has demonstrated that enhanced local control of pediatric soft tissue sarcomas will ultimately improve survival. Therefore, treatment should be individualized for the site of recurrence, biologic characteristics of the tumor (e.g., grade, invasiveness, and size), previous therapies, and individual patient considerations. All patients with recurrent tumors should be considered for clinical trials.

Treatment options for recurrent or progressive disease include the following:

Surgery.
- Surgical excision of local recurrence.
  - An Italian review of 73 patients with recurrent malignant peripheral nerve sheath tumors found that most relapses were local. Multivariate analysis showed that the factors associated with improved survival were no tumor invasiveness at initial diagnosis (T1), time of recurrence more than 12 months after initial diagnosis, and achievement of a second complete response with surgical removal of the recurrence(s). Only 15.8% of patients who had complete surgical excisions of local recurrence(s) were alive at 5 years.[1][Level of evidence: 3iiiA]
- Surgical excision of isolated pulmonary occurrence.
  - Pulmonary metastasectomy may achieve prolonged disease control for some patients.[2] A large, retrospective analysis of patients with recurrent soft tissue sarcoma showed that isolated local relapse had a better prognosis and that resection of pulmonary metastases improved the probability of survival.[3] In 31 children and adolescents younger than 23 years with pulmonary metastases from synovial sarcoma, complete resection of lung metastases appeared to prolong survival when compared with ten other patients who were not considered candidates for metastasectomy.[4][Level of evidence: 3iiiA]
- Surgical excision of local recurrence followed by radiation therapy or brachytherapy (if no previous radiation therapy was given).
- Limb amputation (only for some children with extremity sarcomas that have already received radiation therapy).
Chemotherapy.
- Gemcitabine and docetaxel.[5]
- Trabectedin.[6-8]
- A clinical trial of new chemotherapeutic regimens.
Tyrosine kinase inhibitors.
- Pazopanib. A phase I trial of pazopanib reported one partial response in a patient with desmoplastic small round cell tumor and prolonged disease stabilization in eight patients with recurrent sarcoma.[9][Level of evidence: 2Diii]
  Pazopanib has been approved for use in recurrent soft tissue sarcoma. The clinical trial that was used to obtain approval was limited to adults and demonstrated disease stabilization and prolonged time to progression; it did not demonstrate improved overall survival.[10]
  One 13-year-old boy and one 14-year-old girl with multiply recurrent synovial sarcoma and lung metastases had responses to pazopanib for 14 and 15 months, respectively.[11][Level of evidence: 3iiDi]
Immune checkpoint inhibitors.
- Pembrolizumab. The Sarcoma Alliance for Research through Collaboration conducted a phase II trial of the checkpoint inhibitor pembrolizumab in patients aged 18 years and older with recurrent soft tissue sarcoma.[12][Level of evidence: 3iiDiv] Seven of 40 patients (18%) with soft tissue sarcoma had an objective response, including four of ten patients (40%) with undifferentiated pleomorphic sarcoma, two of ten patients (20%) with liposarcoma, and one of ten patients (10%) with synovial sarcoma. No patients with leiomyosarcoma (n = 10) had an objective response.
Radiation therapy.
- Targeted (stereotactic body) radiation therapy is an option for sites of metastasis, particularly the lung.[13] Targeted radiation therapy is also an option for local control or sites of metastasis, including the lungs, particularly in patients for whom the morbidity of resection is a concern or whose life expectancy is limited.[13]

Resection is the standard treatment for recurrent pediatric nonrhabdomyosarcomatous soft tissue sarcomas. If the patient has not yet received radiation therapy, postoperative radiation should be considered after local excision of the recurrent tumor. Limb-sparing procedures with postoperative brachytherapy have been evaluated in adults but have not been studied extensively in children. For some children with extremity sarcomas who have received previous radiation therapy, amputation may be the only therapeutic option.

Published results of two studies addressed the outcomes of children with relapsed synovial sarcoma. Most patients in one study had distant relapse (29 of 44 patients),[14] while most patients in the second study had local relapse (27 of 37 patients).[15] Distant recurrence was a poor prognostic variable, while tumor resectability at relapse (as manifested by extremity recurrence) was associated with a better outcome in both studies.

Treatment Options Under Clinical Evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Current Clinical Trials

References

Bergamaschi L, Bisogno G, Manzitti C, et al.: Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors. Pediatr Blood Cancer 65 (2): , 2018. [PUBMED Abstract]
Belal A, Salah E, Hajjar W, et al.: Pulmonary metastatectomy for soft tissue sarcomas: is it valuable? J Cardiovasc Surg (Torino) 42 (6): 835-40, 2001. [PUBMED Abstract]
Zagars GK, Ballo MT, Pisters PW, et al.: Prognostic factors for disease-specific survival after first relapse of soft-tissue sarcoma: analysis of 402 patients with disease relapse after initial conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 57 (3): 739-47, 2003. [PUBMED Abstract]
Stanelle EJ, Christison-Lagay ER, Wolden SL, et al.: Pulmonary metastasectomy in pediatric/adolescent patients with synovial sarcoma: an institutional review. J Pediatr Surg 48 (4): 757-63, 2013. [PUBMED Abstract]
Maki RG, Wathen JK, Patel SR, et al.: Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 25 (19): 2755-63, 2007. [PUBMED Abstract]
Le Cesne A, Cresta S, Maki RG, et al.: A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer 48 (16): 3036-44, 2012. [PUBMED Abstract]
Garcia-Carbonero R, Supko JG, Maki RG, et al.: Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol 23 (24): 5484-92, 2005. [PUBMED Abstract]
Garcia-Carbonero R, Supko JG, Manola J, et al.: Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 22 (8): 1480-90, 2004. [PUBMED Abstract]
Glade Bender JL, Lee A, Reid JM, et al.: Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's oncology group phase I consortium report. J Clin Oncol 31 (24): 3034-43, 2013. [PUBMED Abstract]
van der Graaf WT, Blay JY, Chawla SP, et al.: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379 (9829): 1879-86, 2012. [PUBMED Abstract]
Casanova M, Basso E, Magni C, et al.: Response to pazopanib in two pediatric patients with pretreated relapsing synovial sarcoma. Tumori 103 (1): e1-e3, 2017. [PUBMED Abstract]
Tawbi HA, Burgess M, Bolejack V, et al.: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18 (11): 1493-1501, 2017. [PUBMED Abstract]
Dhakal S, Corbin KS, Milano MT, et al.: Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. Int J Radiat Oncol Biol Phys 82 (2): 940-5, 2012. [PUBMED Abstract]
Ferrari A, De Salvo GL, Dall'Igna P, et al.: Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma. Eur J Cancer 48 (18): 3448-55, 2012. [PUBMED Abstract]
Soole F, Maupain C, Defachelles AS, et al.: Synovial sarcoma relapses in children and adolescents: prognostic factors, treatment, and outcome. Pediatr Blood Cancer 61 (8): 1387-93, 2014. [PUBMED Abstract]

Changes to This Summary (08/16/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma

The Desmoid-type fibromatosis subsection was extensively revised.

Added text to state that two pediatric patients enrolled in a clinical trial responded to treatment with ceritinib; one patient had a complete response that was durable for multiple years on continuing therapy, and one patient had a partial response when the drug was discontinued for severe liver and renal toxicity (cited Brivio et al. as reference 94).

Added Drilon et al. as reference 109. Also added text to state that pediatric-specific pharmacokinetics and toxicities of larotrectinib were described in a phase I pediatric trial (cited Laetsch et al. as reference 111).

Added text to state that a rare case of a child with documented neurofibromatosis type 2 and a benign neurofibroma had five recurrences; during this time, the lesions progressively lost markers and acquired clear-cut signs of malignant transformation to malignant peripheral nerve sheath tumor, documented by multiple markers, including the first example of NOTCH2 in this disease (cited Agresta et al. as reference 136).

Added Smolle et al. as reference 177.

Added text about the results of a German Cooperative Weichteilsarkom Studiengruppe retrospective analysis of 67 children, adolescents, and young adults with epithelioid sarcoma (cited Sparber-Sauer et al. as reference 209 and level of evidence 3iiA).

Added text about the results of an international, double-blind, placebo-controlled, randomized, phase II trial of cediranib in adolescent and adult patients with alveolar soft part sarcoma (cited Judson et al. as reference 227 and level of evidence 1iA).

Added text about the NCT02834013 trial as a treatment option under investigation for angiosarcoma of the soft tissue.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Soft Tissue Sarcoma Treatment are:

Denise Adams, MD (Children's Hospital Boston)
Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
Holcombe Edwin Grier, MD
Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
R Beverly Raney, MD (Consultant)
Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Soft Tissue Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389361]

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