Medical Care
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. Most of the data have been extrapolated from trials involving adults. The standard of care for most NRSTSs is to achieve local control by complete surgical resection, if possible, preferably limb-preserving. In general, the roles of radiation and chemotherapy depend on tumor resectability, histological grade, and tumor extent (size and stage).
The role of radiation therapy in children with NRSTSs has yet to be fully defined. In the recent Children's Oncology Group (COG) ARST0332 study, radiation therapy was used less frequently and at lower doses with similar or better outcomes compared with historical controls. [50] 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. [51, 52] Radiation is also indicated for use in large, high-grade tumors. [53] Radiation therapy may also have a role in the control and palliative treatment of certain metastatic diseases.
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. [54, 55] Radiation therapy may also have a role in the control and palliative treatment of certain metastatic diseases.
Large and unresectable primary tumors, metastatic disease, and disease of high metastatic potential may require chemotherapy as part of the treatment plan. Neoadjuvant chemotherapy may allow for a less aggressive surgical approach by achieving tumor shrinkage. Adjuvant chemotherapy may aid in local control and treatment of metastatic disease. The chemotherapy agents with the most activity in NRSTSs are doxorubicin and ifosfamide. These agents were the backbone chemotherapy regimen utilized in the most recent COG-ARST0332 study. Other chemotherapeutic agents that have shown activity either alone or in combination are cyclophosphamide, vincristine, etoposide, cisplatin, and dactinomycin.
The role of each component of multimodal therapy in NRSTSs has been studied in prospective clinical trials, and studies are ongoing. The recent COG trial ARST0332 was designed to elucidate a risk-based strategy for treating NRSTSs, with the goals of limiting toxicity in low-risk patients and maximizing efficacy in intermediate- and high-risk patients. Stratification into these risk-based groups was based on tumor grade and extent (size, resectability, and presence of metastatic disease). Patients at low risk were 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 was not excised, received combined neoadjuvant chemoradiotherapy prior to definitive resection. Intermediate and high risk patients in whom the primary tumor was able to be excised, were treated with adjuvant chemotherapy with or without irradiation. The chemotherapeutic regimen for all patients was doxorubicin with ifosfamide. [50] The prognostic ability of the risk classification system used for COG-ARST0332 was validated using data from the Surveillance, Epidemiology, and End Results (SEER) database. [56] The current COG trial ARST1321 is a phase 2/3 study evaluating the efficacy of radiation therapy with or without chemotherapy or pazopanib in surgically resectable NRSTSs (clinical trial identifier NCT02180867). [57]
See the pdf below outlining the experimental design schema and table outlining the risk-stratified therapy approach taken in COG-ARST0332.
COG-ARST0332 experimental design schema.
Table, Risk Based Treatment Stratification used in COG-ARST0332 study. Adapted from Spunt et al., 2014 and Sangkhathat, 2015 [50, 58] (Open Table in a new window)
Risk group |
Tumor characteristics |
Treatment |
|||
Tumor Grade |
Tumor Size |
Tumor Stage |
Upfront Surgical Resectability |
||
Low |
Low |
Any |
Localized |
Gross resection (with negative or positive microscopic margins) |
Surgery + observation |
| Low | High |
< 5 cm |
Localized |
Gross resection with negative microscopic margins |
Surgery + observation |
| Low | High |
< 5 cm |
Localized |
Gross resection with positive microscopic margins |
Surgery + adjuvant radiation therapy |
Intermediate |
High |
>5 cm |
Localized |
Gross resection |
Surgery + adjuvant radiation therapy + adjuvant chemotherapy |
| Intermediate | High |
Any |
Localized |
Unresectable or Planned delayed surgical resection due to high grade, size >5 cm, and anticipate gross resection only possible with positive microscopic margins |
Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy with or without radiation therapy |
High |
Low |
Any |
Metastatic |
Gross resection |
Surgery + observation |
| High | High |
Any |
Metastatic |
Gross resection |
Surgery + adjuvant radiation therapy + chemotherapy |
| High | High |
Any |
Metastatic |
Unresected |
Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy with or without radiation therapy |
For certain subtypes of NRSTSs, molecular targeted therapies have shown promising activity.
The following drugs have been approved by the US Food and Drug Administration (FDA) for NRSTS subtypes:
Atezolizumab, a PD-1/PD-L1 inhibitor, was approved in December 2022 as a single agent for unresectable or metastatic alveolar soft part sarcoma in adults and pediatric patients aged 2 years and older. [59]
Pazopanib, a tyrosine kinase inhibitor with activity against multiple tyrosine kinases including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and c-kit, is FDA approved for soft tissue sarcomas. Specifically, it has been found to have activity in patients with leiomyosarcomas and synovial sarcomas. [60] The COG trial ARST1321 is a phase 2/3 study that is evaluating pazopanib in NRSTSs (clinical trial identifier NCT02180867). [57]
Phase 1 and 2 trials of tazemetostat, an enhancer of zeste homolog 2 (EZH2) inhibitor involved in the INI1 pathway, have shown promising anti-tumor activity in epithelioid sarcoma and malignant rhabdoid tumors (clinical trial identifiers NCT02601937 and NCT02601950). [35, 36, 37, 38, 39] Tazemetostat received accelerated approval in January 2020 for patients aged 16 years or older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. Approval was based on a phase 2 trial (n=62). The overall response rate was 15%; 1.6% of patients had a complete response, and 13% had a partial response. Of the 9 patients who had a response, 6 patients (67%) had a response that lasted 6 months or longer. [61]
Olaratumab, a monoclonal antibody that targets platelet-derived growth factor receptor α (PDGFR-α), gained accelerated approval in 2016 for adults with soft tissue sarcomas. The drug was withdrawn from the US market in April 2019. In a press release, Eli Lilly and Company reported that the results of ANNOUNCE, a phase 3 trial of olaratumab in combination with doxorubicin in patients with advanced or metastatic soft tissue sarcoma, did not confirm the clinical benefit of olaratumab in combination with doxorubicin compared with doxorubicin. [62]
The following drugs continue to be evaluated in clinical trials:
Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor, has been found to have marked and durable antitumor activity in children and adults with TRK fusion–positive cancers, including infantile fibrosarcoma. Given these promising results, the standard treatment approach to TRK fusion–positive tumors may change. [4, 3] Nirogacestat (previously called PF-03084014), an inhibitor of γ-secretase which is involved in the NOTCH pathway, has had encouraging results in phase 1 and 2 trials of adults with desmoid tumors and a phase 3 trial is planned. [20, 19]
Sunitinib is a receptor tyrosine kinase inhibitor that also has anti-angiogenic properties. It targets the PDGF receptor as well as the VEGF receptors and has been shown to have effectiveness against alveolar soft part sarcoma (ASPS). [63]
Surgical Care
Wide local excision is the primary therapy for most 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 most NRSTSs. The rate of involvement is 6-9% in pediatric cases, usually high-grade NRSTSs although it is higher in certain subtypes of NRSTSs, most notably epithelioid sarcoma. 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 metastases, an exploratory thoracotomy should be performed in an attempt to resect all gross disease, if feasible. [64] In addition, re-resection of relapsed primary tumors is considered standard treatment.
Consultations
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.
-
COG-ARST0332 experimental design schema.
Tables
|
Primary Tumor |
Regional Lymph Nodes |
Distant Metastasis |
Histologic Grade |
Stage I |
Any tumor size, superficial or deep |
N0 |
M0 |
G1 or G2 |
Stage II |
T1a (tumor < 5 cm, superficial) |
N0 |
M0 |
G3 |
T1b (tumor < 5 cm, deep) |
N0 |
M0 |
G3 |
|
T2a (tumor >5 cm, superficial) |
N0 |
M0 |
G3 |
|
Stage III |
T2b (tumor >5 cm, deep) |
N0 |
M0 |
G3 |
Stage IV |
Any tumor size, superficial or deep |
N1 |
M0 or M1 |
G1, G2, or G3 |
Any tumor size, superficial or deep |
N0 or N1 |
M1 |
G1, G2, or G3 |
Risk group |
Tumor characteristics |
Treatment |
|||
Tumor Grade |
Tumor Size |
Tumor Stage |
Upfront Surgical Resectability |
||
Low |
Low |
Any |
Localized |
Gross resection (with negative or positive microscopic margins) |
Surgery + observation |
| Low | High |
< 5 cm |
Localized |
Gross resection with negative microscopic margins |
Surgery + observation |
| Low | High |
< 5 cm |
Localized |
Gross resection with positive microscopic margins |
Surgery + adjuvant radiation therapy |
Intermediate |
High |
>5 cm |
Localized |
Gross resection |
Surgery + adjuvant radiation therapy + adjuvant chemotherapy |
| Intermediate | High |
Any |
Localized |
Unresectable or Planned delayed surgical resection due to high grade, size >5 cm, and anticipate gross resection only possible with positive microscopic margins |
Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy with or without radiation therapy |
High |
Low |
Any |
Metastatic |
Gross resection |
Surgery + observation |
| High | High |
Any |
Metastatic |
Gross resection |
Surgery + adjuvant radiation therapy + chemotherapy |
| High | High |
Any |
Metastatic |
Unresected |
Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy with or without radiation therapy |
