A coordinated, team-based approach to sarcoma management, from core needle biopsy and molecularly integrated pathology to neoadjuvant treatment sequencing and tumor board–driven decision-making, improves outcomes for patients with this disease, according to Breelyn Wilky, MD, and Steven Thorpe, MD, FACS.
In recognition of Sarcoma Awareness Month, which is observed annually in July, OncLive® spoke with Wilky and Thorpe about the questions they most frequently encounter from patients and referring physicians regarding soft tissue and bone sarcomas.
Wilky is an associate professor of medicine-medical oncology, the director of Sarcoma Medical Oncology, the deputy associate director for Clinical Research, and The Cheryl Bennett and McNeilly Family Endowed Chair in Sarcoma Research at the University of Colorado Anschutz in Aurora.
Thorpe is an associate professor of orthopedics and orthopedic surgical oncology, as well as chief of Musculoskeletal Oncology, at the University of Colorado Anschutz School of Medicine.
Q: When should a patient with a suspicious mass be referred to a sarcoma center?
A: Referral should ideally occur before a tissue diagnosis is established rather than after, Thorpe said.
“If there is concern or suspicion of the possibility of a sarcoma based on imaging features, growth of a mass, and location, then I would suggest that even before diagnosis, that patient be referred and seek out their diagnosis, evaluation, and treatment at a sarcoma center with a multidisciplinary group focused on the management of these rare tumors,” he explained.
Consolidating the workup, diagnosis, staging, and treatment at a specialized center directs the appropriate diagnostic workup from the outset and shortens the interval from biopsy to the start of treatment, he added.
As a practical screening rule of thumb, “a mass that’s larger than a golf ball in the extremities or trunk, and especially one that has grown over a short period, raises concern,” Thorpe noted. Such masses warrant an MRI with gadolinium contrast, followed by referral to an appropriate center for further workup.
Q: How should a potential sarcoma biopsy and pathologic workup be approached?
A: For most soft tissue and bone sarcomas, a core needle biopsy is the gold standard, offering a limited, percutaneous approach with high diagnostic yield, Thorpe said. That tissue should be reviewed by a pathologist with dedicated expertise in bone and soft tissue pathology, who evaluates these rare tumors across many histologies to render an accurate diagnosis. Equally important is correlation with molecular pathology, including next-generation sequencing.
Diagnostic entities continue to evolve as groups such as the World Health Organization redefine sarcoma subtypes based on novel genetic translocations and molecular markers, which can also guide targeted treatment. That molecular information must be interpreted in the context of the histologic differential, Thorpe cautioned.
“[It is] even better if that bone and soft tissue pathologist with expertise in sarcoma is closely paired with a molecular program that [is] integrated, because you have to take the molecular information you get about the tumor in [the] context of the possible sarcoma diagnoses…to make sure the final diagnosis makes sense.”
Q: Once a sarcoma diagnosis is confirmed, should surgery be the first intervention?
A: Generally, no, Thorpe said. “We need the right diagnosis, the right name for it, then the right staging based on what that tumor type is—knowing where it can spread—before we start managing it,” he explained.
Proceeding directly to resection risks discovering the diagnosis only after surgery and forgoing the opportunity to optimally sequence systemic therapy and radiation therapy.
Since each modality affects both local tumor control and long-term outcomes, treatment sequencing matters. Neoadjuvant treatment can downstage a tumor locally to facilitate resection, provide insight into the biology of a tumor, inform the type of surgery and the margins required, and reduce the risk of distant spread, all with the goal of maximizing long-term survival, Thorpe noted.
Q: Who should be part of the multidisciplinary sarcoma team?
A: Given the rarity and complexity of these diseases, decisions should be made jointly rather than by any single clinician, Thorpe said.
“With how rare these diseases are, and the complexity of the disease and treatment, it is a team sport, and [these decisions] should be made together,” he explained.
An ideal sarcoma tumor board includes bone and soft tissue pathology expertise; musculoskeletal, thoracic, and abdominal radiology; and treating physicians with substantial sarcoma experience across medical oncology, radiation oncology, and orthopedic or surgical oncology. A thoracic surgeon is also an important expert to consult, particularly when planning treatments for patients with pulmonary spread, Thorpe added.
Sarcoma Diagnosis and Management Need to Knows
- Patients with a mass that is suspicious for sarcoma should ideally be referred to a specialized, multidisciplinary sarcoma center before a tissue diagnosis is established, which streamlines the workup and shortens the time from biopsy to treatment.
- Surgery should rarely be the first intervention, as accurate diagnosis, molecularly integrated pathology, and staging must guide tumor board–driven decisions about neoadjuvant therapy and treatment sequencing.
- Emerging systemic therapy options are expanding beyond traditional chemotherapy, with pembrolizumab added to preoperative radiotherapy improving DFS in stage III extremity disease and afami-cel offering a cell-based therapy for synovial sarcoma.
Q: How is treatment sequenced for a large, localized extremity sarcoma?
A: Sarcoma treatment sequencing is individualized to both the tumor and the patient, Thorpe said. He offered the example of a 14-cm, high-grade undifferentiated pleomorphic sarcoma of the thigh that is resectable with no distant disease. Patient factors, such as age, fitness, and comorbidities, shape the treatment approach as much as the disease histology. The plan for a healthy 50-year-old patient may differ substantially from that for an 80-year-old patient with the same diagnosis, largely depending on their ability to tolerate chemotherapy.
For a fit, younger patient with this presentation, the team might recommend chemotherapy first, followed by radiation and concurrent immunotherapy, and then resection of the primary tumor, Thorpe said. This approach is informed by data including that from the phase 2 SU2C-SARC032 trial (NCT03092323). However, the decision is always tailored to histology and patient-specific factors.
Q: What is the role of radiation in sarcoma management, and why is the preoperative approach often preferred?
A: Radiation reduces local recurrence in limb-preserving resections and, with appropriate planning, allows surgeons to work closer to critical structures, such as nerves, blood vessels, and bone, but also preserving function, Thorpe said. Radiation extends the local treatment effect beyond the surgical margin to address microscopic disease and lower the risk of recurrence.
The timing of radiation involves a trade-off established by the NCIC SR2 trial, which randomly assigned patients to receive preoperative radiotherapy at 50 Gy in 25 fractions or postoperative radiotherapy at 66 Gy in 33 fractions.1 In the trial, major wound complications were more frequently reported with preoperative treatment. Despite this, practice has shifted toward the preoperative approach, Wilky said, which manages the tumor itself rather than the larger postoperative tumor bed, permits a lower radiation dose, and is associated with fewer long-term complications, such as scarring and stiffness. For certain sarcoma subtypes, radiation courses are now being shortened further, reducing patient disease burden and delays to surgery.
Q: What is the efficacy of chemotherapy in sarcoma? Is it as ineffective as patients often believe?
A: This is among the most nuanced and longstanding questions in the field, Wilky said, and the answer depends on the goal of treatment. Unlike some hematologic malignancies, chemotherapy alone rarely eradicates sarcoma, she explained. Nonetheless, specific agents have meaningful activity in sarcoma depending on the disease subtype and treatment intent: whether cytotoxic chemotherapy to shrink or stabilize a tumor toward resection, or systemic therapy in the metastatic setting.
“It’s important for me as a medical oncologist to know what type of sarcoma we’re dealing with, because different sarcoma types respond to treatments differently,” Wilky said.
For example, gastrointestinal stromal tumor (GIST) treatment relies heavily on the tumor’s molecular underpinnings, and includes targeted oral agents that block signaling pathways rather than nonspecifically killing dividing cells. Additionally, risk-adjusted tools, such as the Sarculator nomogram, help identify the subset of patients most likely to benefit from chemotherapy. When cytotoxic therapy is indicated for high-risk disease, doxorubicin and ifosfamide remain the 2 most commonly used agents that produce an overall survival signal, Wilky noted, although which patients require chemotherapy in addition to immunotherapy remains an open question.
Q: Where do immunotherapy and cell-based therapies fit into sarcoma care?
A: “The idea of immunotherapy is that we’re trying to boost the patient’s own immune system to fight the sarcoma, rather than targeting the tumor directly,” Wilky said.
In the SU2C-SARC032 trial, adding the anti–PD-1 agent pembrolizumab (Keytruda) to preoperative radiotherapy and surgery significantly improved disease-free survival (DFS) in patients with grade 3, stage III soft tissue sarcoma of the extremity. At a median follow-up of 43.1 months, the estimated 2-year DFS rate was 67% (90% CI, 58%-78%) with pembrolizumab (n = 64) vs 52% (90% CI, 42%-64%) without pembrolizumab (n = 63; HR, 0.61; 90% CI, 0.39-0.96; 1-sided stratified log-rank P = .035).2 No meaningful DFS difference was observed among patients with grade 2 disease (n = 42; HR, 0.84; 95% CI, 0.26-2.76; P = .78). This regimen is a valuable option for patients who are not ideal chemotherapy candidates, Wilky noted.
Cell-based therapies are also entering the sarcoma treatment landscape. Wilky highlighted engineered T-cell therapy for synovial sarcoma, exemplified by afamitresgene autoleucel (afami-cel; Tecelra), which as of June 2026, is now FDA approved for select patients at least 12 years of age with unresectable or metastatic synovial sarcoma. In the phase 2 SPEARHEAD-1 trial (NCT04044768), findings from which supported the FDA approval, afami-cel produced an overall response rate of 37% (95% CI, 23.62%-51.04%) in the investigational patient cohort (n = 52) and 39% (95% CI, 24.36%-54.50%) among patients with synovial sarcoma (n = 44).3 New treatments in this class are also emerging month by month, Wilky said.
Q: Why do clinical trials matter for patients with newly diagnosed sarcoma?
A: “We used to think of clinical trials as the last-ditch effort in patients with very advanced disease with no other treatment options. That is not the case anymore,” Wilky explained, noting that trials are now available for newly diagnosed patients and are designed to improve on the current standard of care.
Many of the sarcoma field’s recent treatment advances, including immunotherapy plus radiation, cell therapy for synovial sarcoma, and novel agents for GIST, originated in clinical trials. One of the key benefits of evaluating patients at a high-volume sarcoma center is access to these studies, Wilky said. She encouraged patients with newly diagnosed sarcoma to ask whether any trials, locally or nationally, might be appropriate for them, as trial participation is how treatment outcomes for future patients will be improved.
References
- O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359(9325):2235-2241. doi:10.1016/S0140-6736(02)09292-9
- Mowery YM, Ballman KV, Hong AM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. Lancet. 2024;404(10467):2053-2064. doi:10.1016/S0140-6736(24)01812-9
- D’Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. 2024;403(10435):1460-1471. doi:10.1016/S0140-6736(24)00319-2
