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Childhood Soft Tissue Sarcoma Treatment (PDQ®) 4/7 —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 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]
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