Nonrhabdomyosarcoma Soft Tissue Sarcomas Treatment & Management

General treatment considerations for nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) vary depending on the anatomic site of the tumor, its histologic features, and the extent of local and metastatic disease. The standard of care for high-grade NRSTs is to achieve local control by complete surgical resection, preferably limb-preserving, with radiation therapy. However, most of the data have been extrapolated from trials involving adults. In general, multimodality therapy offers the greatest opportunity for survival.

The role of radiation therapy in children with NRSTSs has yet to be defined and is the future of current Children's Oncology Group (COG) studies. For low-grade NRSTSs the use of radiation therapy after complete surgical excision is controversial. Thus, in these tumors, radiation therapy is generally used adjuvantly only when surgical margins are involved and re-resection is not possible. Radiation is also indicated for use in large, high-grade tumors.

Radiation therapy must be approached differently in children than in adults, who typically require a large treatment volume. This places the adjacent tissues of children at risk for decreased bone growth, loss of joint function, and soft tissue and muscle fibrosis. Devastating lifelong complications, including secondary malignancies, are also a concern. The efficacy of focal limited margin external radiation therapy in patients with high-grade NRSTSs has been tested; preliminary results show a high rate of local control.^[13] Radiation therapy may also have a role in the control and palliative treatment of certain metastatic diseases.

Metastatic disease, disease of high metastatic potential, or large and unresectable primary tumors may require chemotherapy as part of the treatment plan. Chemotherapeutic agents that demonstrate the most activity against NRSTS include ifosfamide, cyclophosphamide, and doxorubicin. Other chemotherapeutic agents that have shown activity either alone or in combination are vincristine, etoposide, cisplatin, and dactinomycin. Ongoing clinical trials are under way to prospectively evaluate the exact role of chemotherapy in managing NRSTSs.

The current COG trial for patients with NRSTSs, COG-ARST0332,^[14] was designed to elucidate a risk-based strategy for treating these patients, with the goals of limiting toxicity in low-risk patients and maximizing efficacy in intermediate and high-risk patients. Stratification into these groups is based on tumor grade and extent. Patients at low-risk are treated with surgery with or without adjuvant radiation therapy, depending on the histologic grade of the tumor and the surgical margin status. Intermediate and high-risk patients in whom the primary tumor has not been excised receive neoadjuvant combined chemoradiotherapy prior to definitive resection. If the primary tumor was able to be excised, they are treated with adjuvant chemotherapy with irradiation. The chemotherapeutic regimen for all patients is doxorubicin with ifosfamide. See the pdf below.

COG-ARST0332 experimental design schema.

For patients with refractory or recurrent NRSTSs, a few newer agents have shown promising activity and are now being evaluated for certain subtypes in clinical trials. Sunitinib is a receptor tyrosine kinase-inhibitor that also has anti-angiogenic properties. It targets the platelet-derived growth factor (PDGF) receptor as well as the vascular endothelial growth factor (VEGF) receptors and has been shown to have effectiveness against alveolar soft part sarcoma (ASPS).^[15] Pazopanib is an oral angiogenesis inhibitor that also targets VEGF and PDGF receptors. It has been found preliminarily to have activity in patients with leiomyosarcomas and synovial sarcomas.^[16]

Wide local excision is the primary therapy for NRSTS. Every attempt is made to obtain negative tumor margins, which can be accomplished in 50-80% of patients. If the initial surgery does not achieve pathologically negative margins, a re-excision should be performed in order to obtain clear margins. The mainstay of local control for sarcomas of the head and neck is aggressive surgical resection. These tumors may be difficult to remove with wide surgical margins. However, modern reconstruction techniques with vascularized flaps, free composite grafts, and rotation flaps assist in complete resection. Lesions in the extremities are usually totally resectable.

Limb-salvage procedures or amputation are the surgical options in patients with limb tumors. Limb or ray amputation may be needed to manage tumors of the hands or feet. In rapidly growing, young children, limb salvage is not always the best option in terms of function because frequent limb-lengthening procedures may be needed. New orthopedic limb-lengthening procedures and prostheses may make limb salvage more feasible than it once was in select patients. For some children with relapsed extremity tumors who were treated with previous radiation therapy, amputation may be the only option.

Dissection of the lymph nodes is not always warranted because of the infrequency of lymph node involvement in association with NRSTSs. The rate of involvement is 6-9% in pediatric cases, usually high-grade NRSTSs. Lymph node resection is warranted if the lymph nodes are enlarged on examination or scanning or if the tumor arises in an area near lymph nodes.

Surgical staging is important in making treatment decisions. Appropriate staging also allows for prognostication. The tumor, node, and metastases (TNM) staging system is useful and takes into account the size of the tumor (>5 cm or < 5 cm), the involvement of lymph nodes, and the presence or absence of metastatic disease. Another staging system, one used by the IRS researchers, is based on the extent of disease after initial surgical resection. See Staging above for definitions of the TNM stages and IRS groups.

In children with metastatic disease involving isolated pulmonary mets, an exploratory thoracotomy should be performed in an attempt to resect all gross disease.^[17] In addition, re-resection of relapsed primary tumors is considered standard treatment.

Patients with sarcomas, particularly children, should be treated at comprehensive cancer centers with devoted multidisciplinary sarcoma programs that involve a pediatric sarcoma oncologist, oncologic surgeons, radiation oncologists, radiologists, and soft tissue pathologists.

For limb salvage procedures or amputation, consultation with a physical therapist and occupational therapist is essential to maximize functional outcome and recovery. The use of these services in certain other patients may be necessary, depending on the site and surgical procedure.