miércoles, 8 de mayo de 2019

Childhood Soft Tissue Sarcoma Treatment (PDQ®) 7/7 —Health Professional Version - National Cancer Institute

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

National Cancer Institute



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

Treatment of Metastatic Childhood Soft Tissue Sarcoma

Standard treatment options for metastatic childhood soft tissue sarcoma include the following:
  1. 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]
References
  1. Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 9 (4): 765-85, 1995. [PUBMED Abstract]
  2. Elias A, Ryan L, Sulkes A, et al.: Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7 (9): 1208-16, 1989. [PUBMED Abstract]
  3. Edmonson JH, Ryan LM, Blum RH, et al.: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11 (7): 1269-75, 1993. [PUBMED Abstract]
  4. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec. [PUBMED Abstract]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995. [PUBMED Abstract]
  11. 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:
  1. 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).
  2. Chemotherapy.
    • Gemcitabine and docetaxel.[5]
    • Trabectedin.[6-8]
    • A clinical trial of new chemotherapeutic regimens.
  3. 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]
  4. 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.
  5. 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

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 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 3,000 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 ClinicalTrials.gov website for APEC1621 (NCT03155620).

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.
References
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. 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]
  14. 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]
  15. 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 (04/18/2019)

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.
General Information About Childhood Soft Tissue Sarcoma
Revised text to state that of 530 suspected soft tissue masses in patients who underwent core-needle biopsies, 426 were proven to be soft tissue tumors, 225 of which were malignant. Core-needle biopsy was able to differentiate soft tissue sarcomas from benign lesions with a sensitivity of 96.3% and a specificity of 99.4%. Tumor subtype was accurately assigned in 89.5% of benign lesions and in 88% of soft tissue sarcomas. The complication rate was 0.4%.
Added text to state that the utility of sentinel node biopsy is limited to epithelioid sarcoma, clear cell sarcoma, and trunk and extremity rhabdomyosarcoma (cited Wagner et al. as reference 49).
Added Schaefer et al. as reference 57.
Histopathological Classification of Childhood Soft Tissue Sarcoma
Added Le Guellec et al. as reference 6.
Revised text to state that undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas; the relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined.
Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma
Revised text to state that after complete surgical resection of well-differentiated or myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90% (cited La Quaglia et al. as reference 11). Also added Lee et al. and Beane et al. as references 12 and 13, respectively.
Added text to state that the median age of patients was 38 years in one Japanese study of patients with extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma.
Revised text to state that evaluation of the benefit of interventions for treatment of desmoid-type fibromatosis has been extremely difficult, because desmoid-type fibromatosis has a highly variable natural history, with partial regressions seen in up to 20% of patients (cited Gounder et al. as reference 43).
Added hydroxyurea as a treatment option for desmoid-type fibromatosis. Also added text to state that a retrospective analysis reported the results of 16 children with previously treated desmoid tumors who were treated with hydroxyurea. Seven patients had tumor progression, two patients had increased pain, and seven patients had both before treatment with hydroxyurea. Tumor shrinkage occurred in 37.5% of patients, and symptom improvement occurred in 68.7% of patients.
Added text to update the outcome data for patients with unresectable progressive or symptomatic desmoid tumors who were treated with sorafenib in an international prospective phase III double-blind study conducted through the National Clinical Trials Network, including the objective response rate and progression-free survival rate.
Added text to state that hypercalcemia secondary to elevated levels of parathyroid hormone–related protein has been reported as a presenting feature of infantile fibrosarcoma in newborns (cited Hirschfeld et al. as reference 101).
Added targeted therapy as a treatment option for infantile fibrosarcoma.
Added text to state that five of the seven patients in a single-institution retrospective review of malignant ectomesenchymoma were healthy and free of disease at the time of reporting.
Added Recurrent synovial sarcoma NOS as a new subsection.
Added text about the NCT02683148 trial as a treatment option under clinical evaluation for synovial sarcoma.
Added text to state that in a phase I trial of the EZH2 inhibitor tazemetostat, two patients with INI1-negative epithelioid sarcoma had prolonged stable disease for more than 20 months after starting therapy (cited Italiano et al. as reference 209).
Added text to state that in patients with alveolar soft part sarcoma, presentation with metastases is common and often has a prolonged indolent course. In a series of patients treated on consecutive studies from Germany, 15 of 61 patients presented with metastases, often miliary in nature. Despite lack of response to chemotherapy, the 5-year OS was 61%, with an EFS of 20%.
Added text to state that in a series of patients treated on consecutive studies from Germany, progression-free survival for patients without metastases on presentation appeared to improve with complete resection of the primary tumor; the 5-year EFS was 100% for patients with completely resected tumors, compared with 50% for patients with microscopic or gross residual disease.
Added text to state that in a study by the European Organization for Research and Treatment of Cancer, 26 patients with clear cell sarcoma who had metastatic disease and documented EWSR1 rearrangements were treated with crizotinib. One patient achieved a partial response, and 17 patients had stable disease (cited Schöffski et al. as reference 236).
Added Subbiah et al. as reference 254.
Added text about the results of 32 patients with undifferentiated soft tissue sarcomas who were enrolled on the ARST0332 trial, including demographics, clinical presentation, EFS and OS rates, and genomic information (cited Laetsch et al. as reference 279).
Added Molecular features as a new subsection for undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade).
Added text to state that most of the tumors in series of patients who had sarcomas with BCOR-CCNB3 fusions arose in the bone.
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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
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]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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  • Updated: April 18, 2019
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