Wednesday, August 21, 2019

Childhood Soft Tissue Sarcoma Treatment (PDQ®) 3/5 –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 Option Overview for Childhood Soft Tissue Sarcoma






Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas, coordination of treatment by a multidisciplinary team comprising oncologists (pediatric or medical), pathologists, surgeons, and radiation oncologists should be considered for all children, adolescents, and young adults with these tumors. In addition, to better define the tumors' natural history and response to therapy, entry into national or institutional treatment protocols should be considered for children with rare neoplasms. Information about ongoing clinical trials is available from the NCI website.



Surgery

After an appropriate biopsy and pathologic diagnosis, every attempt is made to resect the primary tumor with negative margins before or after chemotherapy and/or radiation therapy. Involvement of a surgeon with special expertise in the resection of soft tissue sarcomas is highly desirable.
The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial operation fails to achieve pathologically negative tissue margins or if the initial surgery was done without the knowledge that cancer was present, a re-excision of the affected area is performed to obtain clear, but not necessarily wide, margins.[1-4] This surgical tenet is true even if no mass is detected by magnetic resonance imaging after initial surgery.[5]; [6][Level of evidence: 3iiA]
Regional lymph node metastases at diagnosis are unusual and are most often seen in patients with epithelioid and clear cell sarcomas.[7,8] Various institutional series have demonstrated the feasibility and effectiveness of sentinel node biopsy as a staging procedure in pediatric patients with soft tissue sarcomas.[9-14]

Radiation Therapy

Considerations for radiation therapy are based on the potential for surgery, with or without chemotherapy, to obtain local control without loss of critical organs or significant functional, cosmetic, or psychological impairment. This will vary according to the following:
  • Patient variables (e.g., age and sex).
  • Tumor variables (e.g., histopathology, site, size, and grade).
  • Use of surgery and margin status.
  • Expectations for radiation-induced morbidities (e.g., impaired bone or muscle development, organ damage, or subsequent neoplasm).
Radiation therapy can be given preoperatively or postoperatively. It can also be used as definitive therapy in rare situations in which surgical resection is not performed.[15] Radiation field size and dose will be based on patient and tumor variables and the surgical procedure.[16] Radiation therapy was associated with improved overall survival (OS) compared with surgery alone when delivered preoperatively or postoperatively.[17]
Preoperative radiation therapy has been associated with excellent local control rates.[18-20] The advantages of this approach include treating smaller tissue volumes without the need to treat a postsurgical bed and somewhat lower radiation doses because relative hypoxia from surgical disruption of vasculature and scarring is not present. Preoperative radiation therapy has been associated with an increased rate of wound complications in adults, primarily in lower extremity tumors; however, the degree of these complications is questionable.[21] Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps because of the smaller treatment volume and dose.[22]
Retroperitoneal sarcomas are unique in that radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable.[23,24] Postoperative adhesions and bowel immobility can increase the risk of damage from any given radiation dose. This contrasts with the preoperative approach in which the tumor often displaces bowel outside of the radiation field, and any exposed bowel is more mobile, which decreases exposure to specific bowel segments.
Radiation therapy can also be given postoperatively. In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[25,26] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[27,28]; [29][Level of evidence: 3iiDiv] With combined R0 (negative margin) surgery and radiation therapy, local control of the primary tumor can be achieved in about 90% of patients with extremity sarcomas, 70% to 75% of patients with retroperitoneal sarcomas, and 80% of patients overall.[30-34]
Brachytherapy and intraoperative radiation may be applicable in select situations.[31,35,36]; [37][Level of evidence: 3iiiDii]
Radiation volume and dose depend on the patient, tumor, and surgical variables noted above, as well as the following:
  • Patient age and growth potential.
  • Ability to avoid critical organs, epiphyseal plates, and lymphatics (but not the neurovascular bundles that are relatively radiation tolerant).
  • Functional/cosmetic outcome.
Radiation doses are typically 45 Gy to 50 Gy preoperatively, with consideration for postoperative boost of 10 Gy to 20 Gy if resection margins are microscopically or grossly positive, or planned brachytherapy if the resection is predicted to be subtotal. However, data documenting the efficacy of a postoperative boost are lacking.[38] The postoperative radiation dose is 55 Gy to 60 Gy for R0 resections, up to 65 Gy for R1 resections (microscopic positive margins), and higher when unresectable gross residual disease exists depending on overall treatment goals (e.g., definitive local control vs. palliation).
Radiation margins are typically 2 cm to 4 cm longitudinally and encompass fascial planes axially.[39,40]

Chemotherapy

The role of postoperative chemotherapy remains unclear.[41]
Evidence (lack of clarity regarding postoperative chemotherapy):
  1. A meta-analysis of data from all randomized trials of adults with soft tissue sarcoma observed the following:[42]
    • Recurrence-free survival was better with postoperative chemotherapy for patients with high-grade tumors larger than 5 cm.
  2. In a European trial, adults with completely resected soft tissue sarcoma were randomly assigned to observation or postoperative chemotherapy with ifosfamide and doxorubicin.[43][Level of evidence: 1iiA]
    • Postoperative chemotherapy was not associated with improved event-free survival (EFS) or OS.
    • It is difficult to extrapolate this trial to pediatric patients because the trial included: 1) a wide variety of histologies; 2) a relatively low dose of ifosfamide; 3) patients assigned to chemotherapy had definitive radiation delayed until completion of chemotherapy; and 4) almost one-half of the patients in the trial had intermediate-grade tumors.
    • In the discussion section, the authors merged their patients with previously published series, including those from the European meta-analysis, and concluded that the results suggested a benefit for postoperative chemotherapy.
  3. The largest prospective pediatric trial failed to demonstrate any benefit with postoperative vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[30]
  4. Doxorubicin and ifosfamide were used in the risk-based COG ARST0332 (NCT00346164) trial.[44][Level of evidence: 3iiiA]
    • Although this was not a randomized study, results at 2.6 years showed that patients with high-risk (>5 cm and high grade), grossly resected, nonmetastatic tumors who were treated with radiation therapy and postoperative doxorubicin and ifosfamide had a 3-year EFS of 68% and OS of 81%.
    • In patients with metastatic disease treated with preoperative chemotherapy and radiation therapy, the estimated 3-year failure-free survival was 52% and OS was 66%.

Targeted Therapy

The use of angiogenesis and mammalian target of rapamycin (mTOR) inhibitors has been explored in the treatment of adult soft tissue sarcomas but not in pediatrics.
Evidence (targeted therapy in adults with soft tissue sarcoma):
  1. In a trial of 711 adult patients who achieved a response or stable disease after chemotherapy, patients were randomly assigned to receive ridaforolimus or placebo.[45]
    • The administration of ridaforolimus was associated with a 3-week improvement in progression-free survival (PFS) when compared with placebo.
  2. In another trial of 371 randomly assigned adult patients with metastatic soft tissue sarcoma that progressed after chemotherapy, pazopanib was compared with placebo.[46]
    • The median PFS for the pazopanib arm was 4.6 months compared with 1.6 months for the placebo arm. OS was not different between the two arms.
  3. In a study of 182 previously treated adult patients with recurrent liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas, patients were randomly assigned to receive regorafenib or placebo.[47]
    • Patients with nonadipocytic tumors who were treated with regorafenib had significant improvements in PFS when compared with patients who were treated with placebo.

Special Considerations for the Treatment of Children With Soft Tissue Sarcoma

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[48] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
  • Primary care physicians.
  • Pediatric surgical specialists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[49] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Multidisciplinary evaluation in pediatric cancer centers that have surgical and radiotherapeutic expertise is of critical importance to ensure the best clinical outcome for these patients. Although surgery with or without radiation therapy can be curative for a significant proportion of patients, the addition of chemotherapy might benefit subsets of children with the disease; therefore, enrollment into clinical trials is encouraged. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Many therapeutic strategies for children and adolescents with soft tissue tumors are similar to those for adult patients, although there are important differences. For example, the biology of the neoplasm in pediatric patients may differ dramatically from that of the adult lesion. Additionally, limb-sparing procedures are more difficult to perform in pediatric patients. The morbidity associated with radiation therapy, particularly in infants and young children, may be much greater than that observed in adults.[50]
Improved outcomes with multimodality therapy in adults and children with soft tissue sarcomas over the past 20 years has caused increasing concern about the potential long-term side effects of this therapy in children, especially when considering the expected longer life span of children versus adults. Therefore, to maximize tumor control and minimize long-term morbidity, treatment must be individualized for children and adolescents with nonrhabdomyosarcomatous soft tissue sarcoma. These patients should be enrolled in prospective studies that accurately assess any potential complications.[51]


References
  1. Sugiura H, Takahashi M, Katagiri H, et al.: Additional wide resection of malignant soft tissue tumors. Clin Orthop (394): 201-10, 2002. [PUBMED Abstract]
  2. Cecchetto G, Guglielmi M, Inserra A, et al.: Primary re-excision: the Italian experience in patients with localized soft-tissue sarcomas. Pediatr Surg Int 17 (7): 532-4, 2001. [PUBMED Abstract]
  3. Chui CH, Spunt SL, Liu T, et al.: Is reexcision in pediatric nonrhabdomyosarcoma soft tissue sarcoma necessary after an initial unplanned resection? J Pediatr Surg 37 (10): 1424-9, 2002. [PUBMED Abstract]
  4. Paulino AC, Ritchie J, Wen BC: The value of postoperative radiotherapy in childhood nonrhabdomyosarcoma soft tissue sarcoma. Pediatr Blood Cancer 43 (5): 587-93, 2004. [PUBMED Abstract]
  5. Kaste SC, Hill A, Conley L, et al.: Magnetic resonance imaging after incomplete resection of soft tissue sarcoma. Clin Orthop (397): 204-11, 2002. [PUBMED Abstract]
  6. Chandrasekar CR, Wafa H, Grimer RJ, et al.: The effect of an unplanned excision of a soft-tissue sarcoma on prognosis. J Bone Joint Surg Br 90 (2): 203-8, 2008. [PUBMED Abstract]
  7. Daigeler A, Kuhnen C, Moritz R, et al.: Lymph node metastases in soft tissue sarcomas: a single center analysis of 1,597 patients. Langenbecks Arch Surg 394 (2): 321-9, 2009. [PUBMED Abstract]
  8. Mazeron JJ, Suit HD: Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 60 (8): 1800-8, 1987. [PUBMED Abstract]
  9. Neville HL, Andrassy RJ, Lally KP, et al.: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35 (6): 961-4, 2000. [PUBMED Abstract]
  10. Neville HL, Raney RB, Andrassy RJ, et al.: Multidisciplinary management of pediatric soft-tissue sarcoma. Oncology (Huntingt) 14 (10): 1471-81; discussion 1482-6, 1489-90, 2000. [PUBMED Abstract]
  11. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008. [PUBMED Abstract]
  12. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014. [PUBMED Abstract]
  13. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012. [PUBMED Abstract]
  14. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013. [PUBMED Abstract]
  15. Haas RL, Gronchi A, van de Sande MAJ, et al.: Perioperative Management of Extremity Soft Tissue Sarcomas. J Clin Oncol 36 (2): 118-124, 2018. [PUBMED Abstract]
  16. Crompton JG, Ogura K, Bernthal NM, et al.: Local Control of Soft Tissue and Bone Sarcomas. J Clin Oncol 36 (2): 111-117, 2018. [PUBMED Abstract]
  17. Nussbaum DP, Rushing CN, Lane WO, et al.: Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database. Lancet Oncol 17 (7): 966-975, 2016. [PUBMED Abstract]
  18. Virkus WW, Mollabashy A, Reith JD, et al.: Preoperative radiotherapy in the treatment of soft tissue sarcomas. Clin Orthop (397): 177-89, 2002. [PUBMED Abstract]
  19. Zagars GK, Ballo MT, Pisters PW, et al.: Preoperative vs. postoperative radiation therapy for soft tissue sarcoma: a retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol Phys 56 (2): 482-8, 2003. [PUBMED Abstract]
  20. Dickie C, Parent A, Griffin AM, et al.: The value of adaptive preoperative radiotherapy in management of soft tissue sarcoma. Radiother Oncol 122 (3): 458-463, 2017. [PUBMED Abstract]
  21. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002. [PUBMED Abstract]
  22. Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005. [PUBMED Abstract]
  23. Baldini EH, Wang D, Haas RL, et al.: Treatment Guidelines for Preoperative Radiation Therapy for Retroperitoneal Sarcoma: Preliminary Consensus of an International Expert Panel. Int J Radiat Oncol Biol Phys 92 (3): 602-12, 2015. [PUBMED Abstract]
  24. Bishop AJ, Zagars GK, Torres KE, et al.: Combined Modality Management of Retroperitoneal Sarcomas: A Single-Institution Series of 121 Patients. Int J Radiat Oncol Biol Phys 93 (1): 158-65, 2015. [PUBMED Abstract]
  25. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997. [PUBMED Abstract]
  26. Delaney TF, Kepka L, Goldberg SI, et al.: Radiation therapy for control of soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol Biol Phys 67 (5): 1460-9, 2007. [PUBMED Abstract]
  27. Blakely ML, Spurbeck WW, Pappo AS, et al.: The impact of margin of resection on outcome in pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Pediatr Surg 34 (5): 672-5, 1999. [PUBMED Abstract]
  28. Skytting B: Synovial sarcoma. A Scandinavian Sarcoma Group project. Acta Orthop Scand Suppl 291: 1-28, 2000. [PUBMED Abstract]
  29. Hua C, Gray JM, Merchant TE, et al.: Treatment planning and delivery of external beam radiotherapy for pediatric sarcoma: the St. Jude Children's Research Hospital experience. Int J Radiat Oncol Biol Phys 70 (5): 1598-606, 2008. [PUBMED Abstract]
  30. 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]
  31. Merchant TE, Parsh N, del Valle PL, et al.: Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 46 (2): 427-32, 2000. [PUBMED Abstract]
  32. Karakousis CP, Driscoll DL: Treatment and local control of primary extremity soft tissue sarcomas. J Surg Oncol 71 (3): 155-61, 1999. [PUBMED Abstract]
  33. 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]
  34. Raut CP, Miceli R, Strauss DC, et al.: External validation of a multi-institutional retroperitoneal sarcoma nomogram. Cancer 122 (9): 1417-24, 2016. [PUBMED Abstract]
  35. Schomberg PJ, Gunderson LL, Moir CR, et al.: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79 (11): 2251-6, 1997. [PUBMED Abstract]
  36. Nag S, Shasha D, Janjan N, et al.: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49 (4): 1033-43, 2001. [PUBMED Abstract]
  37. Viani GA, Novaes PE, Jacinto AA, et al.: High-dose-rate brachytherapy for soft tissue sarcoma in children: a single institution experience. Radiat Oncol 3: 9, 2008. [PUBMED Abstract]
  38. Al Yami A, Griffin AM, Ferguson PC, et al.: Positive surgical margins in soft tissue sarcoma treated with preoperative radiation: is a postoperative boost necessary? Int J Radiat Oncol Biol Phys 77 (4): 1191-7, 2010. [PUBMED Abstract]
  39. Wang D, Bosch W, Kirsch DG, et al.: Variation in the gross tumor volume and clinical target volume for preoperative radiotherapy of primary large high-grade soft tissue sarcoma of the extremity among RTOG sarcoma radiation oncologists. Int J Radiat Oncol Biol Phys 81 (5): e775-80, 2011. [PUBMED Abstract]
  40. Bahig H, Roberge D, Bosch W, et al.: Agreement among RTOG sarcoma radiation oncologists in contouring suspicious peritumoral edema for preoperative radiation therapy of soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys 86 (2): 298-303, 2013. [PUBMED Abstract]
  41. Ferrari A: Role of chemotherapy in pediatric nonrhabdomyosarcoma soft-tissue sarcomas. Expert Rev Anticancer Ther 8 (6): 929-38, 2008. [PUBMED Abstract]
  42. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350 (9092): 1647-54, 1997. [PUBMED Abstract]
  43. Woll PJ, Reichardt P, Le Cesne A, et al.: Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 13 (10): 1045-54, 2012. [PUBMED Abstract]
  44. Spunt SL, Million L, Anderson JR, et al.: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients under 30 years of age: Children’s Oncology Group study ARST0332. [Abstract] J Clin Oncol 32 (Suppl 15): A-10008, 2014. Also available onlineExit Disclaimer. Last accessed April 18, 2019.
  45. Demetri GD, Chawla SP, Ray-Coquard I, et al.: Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 31 (19): 2485-92, 2013. [PUBMED Abstract]
  46. 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]
  47. Mir O, Brodowicz T, Italiano A, et al.: Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17 (12): 1732-1742, 2016. [PUBMED Abstract]
  48. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  49. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]
  50. Suit H, Spiro I: Radiation as a therapeutic modality in sarcomas of the soft tissue. Hematol Oncol Clin North Am 9 (4): 733-46, 1995. [PUBMED Abstract]
  51. Spunt SL, Million L, Coffin C: The nonrhabdomyosarcoma soft tissue sarcoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 827-54.
Posted by at

No comments:

Post a Comment

Subscribe to: Post Comments (Atom)