Soft-tissue sarcomas represent rare limb-threatening and life-threatening malignancies of connective tissue origin. They arise within the tissues of mesenchymal origin, such as muscle, tendon, fat, and nerve. Any mass larger than 5 cm, deep to the fascia, or of increasing size over a short interval should be considered as a soft-tissue sarcoma until proven otherwise. Treatment planning is made in a multidisciplinary manner with recommendations made in a tumor-specific and patient-specific manner considering histologic subtype, grade, size, anatomic location, the presence of metastatic disease, and patient factors including physical and social factors. Surgery remains the cornerstone of multimodal treatment along with varying implementation of radiation and chemotherapy. Although surgery can be curative for select patients, many patients will undergo adjuvant therapy in addition to surgery. Despite sophisticated imaging and surgical advancements over the past decades, there is still significant variability in patient outcomes. Outcomes vary significantly for several reasons; perhaps the most frustrating, however, is the physician’s poor adherence to guideline care and oncologic surgical principles. Unfortunately, improper referrals, poor adherence to biopsy and surgical recommendations, and ignorance still exist. These factors are modifiable, and efforts should continue through advocacy and education to the larger medical community where these errors occur. It is important to remember, however, that sarcomas are a very heterogenous group of malignancies and that despite physicians’ best efforts, tumor biology plays a significant role and cannot be altered by even the sharpest scalpel, the keenest eye, or the most skilled hands.

After a specific histologic diagnosis has been made, the next step is staging with appropriate imaging modalities and according to the American Joint Committee on Cancer Staging System for Soft Tissue Sarcoma of the Trunk and Extremities.² Although the overall incidence of nodal metastasis with soft-tissue sarcoma is relatively low, physical examination by palpation of relevant draining regional lymph node basins is recommended in the workup of any patient with a suspected or newly diagnosed soft-tissue sarcoma. Formal evaluation with at least ultrasonography is recommended for those soft-tissue sarcoma subtypes with a higher incidence of nodal metastasis (clear cell sarcoma, angiosarcoma, rhabdomyosarcoma, epithelioid sarcoma). Selected patients with these histologies could also be considered for sentinel node biopsy, but no conclusive evidence or trial exists to confirm its definitive benefit, as discussed in a 2022 study.³

Consensus guidelines provide soft-tissue sarcoma treatment and surveillance guidelines. In addition to surgery, radiation therapy and chemotherapy are important modalities in the management of soft-tissue sarcomas (Table 1) and are considered and implemented based on histology, anatomic location, staging, and patient factors. In addition to consensus guidelines, the American Society for Radiation Oncology convened a multidisciplinary workgroup and has established guidelines for the use of radiation therapy in the treatment of patients with soft-tissue sarcomas, as discussed in a 2021 study.⁴

In general, the treatment of localized, resectable extremity soft-tissue sarcoma begins with the incorporation of grade, size, anatomic location, and risk assessment for local and distant disease recurrence (Figure 1). With respect to American Joint Committee on Cancer stage I and stage II tumors (or those tumors < 5 cm), excluding specific histologies such as Ewing sarcoma and associated sarcomas (eg, CIC-DUX4 tumors), wide resection alone can be considered.⁵ Adjuvant radiation therapy can be selectively considered in cases in which acceptable margins could not be achieved, further surgical excision cannot be completed, and the risk of local recurrence is expected to be high. Radiation therapy in addition to wide margin excision is generally part of the limb salvage strategy for stage IIIA/B disease. After the SR.2 trial⁶ and additional supporting studies, many sarcoma centers and guidelines⁴ advocate for preoperative radiation therapy over adjuvant radiation treatment outside of some specific patient or anatomic location considerations. Some patients in this higher-risk group, stage IIIB, may also be considered for chemotherapy. The decision for chemotherapy in localized disease, even in the setting of high-risk, is nuanced and must be patient and tumor specific. Some histologies, such as synovial sarcoma or myxoid/round cell sarcoma, may be more sensitive to chemotherapy, as discussed in a 2022 study.⁷

As discussed in recent studies, beyond traditional nomograms for prediction of survival, app-based programs have evolved to help inform treatment planning for particular patients, such as Sarculator⁸ and PERSARC (Personalised Sarcoma Care).⁹ With the Sarculator app, those patients with predicted 10-year overall survival worse than 60% may benefit from adjuvant systemic treatment with anthracycline-based chemotherapy, as discussed in a 2022 study¹⁰ (Figure 2). The PERSARC app has also been validated and demonstrated potential benefit to the multidisciplinary treatment planning for patient-specific prediction of local recurrence and survival rates^9,11 (Figure 3). In addition, neoadjuvant chemotherapy or combined neoadjuvant chemotherapy and radiation has been considered for potential local downstaging for those tumors for which resection would result in poor functional outcomes or in which limb salvage surgery may not possible; however, the resultant tumor response may not be as significant as hoped for.¹² If the tumor remains unresectable after neoadjuvant therapy, then amputation surgery versus palliative approaches should be considered.

For those patients who present with stage IV disease, approaches often include upfront systemic treatment. In addition, if the distant disease is in a single organ (ie, pulmonary), then metastatectomy with or without radiation therapy versus stereotactic body radiation therapy may be performed in addition to treatment of the primary tumor as described earlier. For those with disseminated disease, the approach is palliative with chemotherapeutic, radiotherapeutic, and/or interventional treatments, such as radiofrequency ablations, cryoablation, and embolization.

Surgery is the standard treatment for most patients with localized soft-tissue sarcoma of the extremities and should be performed by an appropriately trained surgeon, ideally at a center with significant sarcoma experience.¹³ The goal of surgery is to completely eradicate the primary tumor via excision within a cuff of normal tissue (negative margin). Secondary goals include minimizing morbidity of treatment and maximizing postoperative function.