Adjuvant and neoadjuvant systemic therapy for soft tissue sarcoma of the extremities

INTRODUCTION — 

Soft tissue sarcomas (STS) are malignant tumors that arise from extraskeletal connective tissues, including the peripheral nervous system. They can arise at any body site, but are most common in the extremities, particularly the lower limbs. (See "Clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Clinical features'.)

Systemic chemotherapy is a standard component of treatment for several sarcomas that occur predominantly in children (eg, rhabdomyosarcoma, Ewing sarcoma, and osteogenic sarcoma). However, the value of adjuvant chemotherapy is controversial for patients undergoing resection of the adult-type localized extremity STS (eg, leiomyosarcoma, liposarcoma, synovial sarcoma).

This topic review will discuss the use of adjuvant and neoadjuvant chemotherapy in the treatment of adult-type extremity STS. The role of chemotherapy in the treatment of retroperitoneal STS, rhabdomyosarcoma, Ewing sarcoma, extraosseous osteogenic sarcoma, and combined modality approaches for patients with recurrent or metastatic STS are discussed in detail separately.

●(See "Initial management of retroperitoneal soft tissue sarcoma".)

●(See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

●(See "Treatment of Ewing sarcoma".)

●(See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma".)

●(See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities".)

●(See "Chemotherapy and radiation therapy in the management of osteosarcoma".)

MULTIMODALITY THERAPY — 

In treating STS of the extremities, the major therapeutic goals are to achieve long-term survival, avoid local recurrence, maximize function, and minimize morbidity.

Surgical resection is the cornerstone of potentially curative treatment. For nearly all patients with extremity sarcomas >5 cm, the addition of radiation therapy (RT) improves local control, and it has also had a significant impact on limb salvage. Preoperative (neoadjuvant) RT is often preferred over adjuvant RT in this setting. These topics are discussed in detail separately. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk" and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities".)

Neoadjuvant and/or adjuvant chemotherapy is routinely incorporated into the management of most pediatric-type sarcomas (eg, rhabdomyosarcoma, Ewing sarcoma). However, its use in STS subtypes that commonly occur in adults is more controversial and the benefit, if any, may be limited to select high-risk patients.

PEDIATRIC-TYPE SARCOMAS — 

The addition of systemic chemotherapy to local therapy significantly improves outcomes for the common pediatric types of sarcoma (rhabdomyosarcoma, osteogenic sarcoma, and Ewing sarcoma). Most modern treatment plans utilize initial (induction or neoadjuvant) chemotherapy followed by local treatment and additional (adjuvant) chemotherapy. Although these types of sarcoma commonly occur in pediatric patients, they can also be diagnosed in adults.

Rhabdomyosarcoma — The routine use of multiagent chemotherapy in addition to surgery and radiation therapy (RT) has contributed significantly toward increasing cure rates among those with localized rhabdomyosarcoma in subtypes more commonly occurring in children such as embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma. The vast majority of patients with rhabdomyosarcoma are children. The rare cases of pediatric-type rhabdomyosarcomas that arise in adults are managed similarly, with the exception of older adults who may not be eligible for multiagent chemotherapy due to age or comorbidities. The most common type of rhabdomyosarcoma in adults, pleomorphic rhabdomyosarcoma, is managed like other high-grade STS of adults. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk".)

Ewing sarcoma — Neoadjuvant chemotherapy is a standard part of Ewing sarcoma treatment, given to reduce local tumor volume, facilitate resection, and treat micrometastatic disease. A reduction in tumor volume may enable limb sparing procedures for extremity lesions, but may also be important for rib, chest wall, and vertebral primaries. Following neoadjuvant chemotherapy patients undergo local therapy (surgery, RT, or both) to the primary lesion, followed by adjuvant chemotherapy.

Among children, Ewing sarcoma is much more common in bone than in soft tissue, while in adults, it more often presents in soft tissue. Regardless of whether it arises in bone or soft tissue, the tumor is treated in the same multidisciplinary manner in adults as in children. (See "Treatment of Ewing sarcoma", section on 'Multimodality therapy for localized disease'.)

OTHER SARCOMA SUBTYPES — 

The use of systemic chemotherapy is controversial in patients with several sarcoma subtypes that more commonly occur in adults, including leiomyosarcomas, synovial sarcomas, and some forms of liposarcoma. If used, systemic therapy is largely reserved for patients with higher-risk disease and typically includes a combination of an anthracycline and ifosfamide.

Neoadjuvant systemic therapy

Indications for neoadjuvant approach — The decision of whether to offer neoadjuvant systemic therapy (chemotherapy or immunotherapy) is individualized in patients with more common adult-type STS subtypes, such as liposarcomas, leiomyosarcomas, and synovial sarcomas. Neoadjuvant systemic therapy is given prior to surgery either at the same time as radiation therapy (RT) or sequentially. However, many patients with STS may receive either preoperative or postoperative RT alone. A full discussion of how to integrate different treatment modalities is located elsewhere. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)

Theoretical advantages to neoadjuvant systemic therapy include earlier tumor cytoreduction, immediate treatment of micrometastases, and an early indication as to the effectiveness of therapy. Cytoreduction will occasionally allow for a less radical surgical resection, and this approach is often considered in patients with large extremity sarcomas, particularly if the patient is a borderline candidate for limb salvage surgery. In addition, neoadjuvant therapy may be preferable if there are concerns that the surgery will impair the ability to administer systemic therapy. However, the optimal neoadjuvant regimen and how best to integrate RT, systemic therapy, and surgery remain unknown. If possible, these patients should be evaluated at experienced sarcoma centers and considered for enrollment in clinical trials.

Indications for neoadjuvant chemotherapy and immunotherapy include the following:

●Neoadjuvant chemotherapy and radiation therapy – Neoadjuvant (induction) chemotherapy is most often offered in the setting of a large high-grade primary tumor, particularly if limb salvage is expected to be difficult or in patients with stage III disease. In these situations, RT is also an important component of the treatment approach. If neoadjuvant chemotherapy is chosen, we prefer sequential therapy with chemotherapy administered first, followed by RT, and subsequent surgery. (See 'Chemotherapy for other subtypes' below.)

●Neoadjuvant immunotherapy and radiation therapy for undifferentiated pleomorphic sarcoma – The combination of neoadjuvant immunotherapy and RT has been examined in a phase II trial comprised primarily of patients with one high grade sarcoma subtype, undifferentiated pleomorphic sarcoma [1]. In this trial, three cycles of programmed death 1 (PD-1) inhibition were delivered prior to, concurrent with, and following preoperative RT and then 14 cycles were delivered after surgery. The integration of immunotherapy and chemotherapy with RT has not been examined prospectively. (See 'Neoadjuvant PD-1-based immunotherapy for undifferentiated pleomorphic sarcoma' below.)

●Neoadjuvant chemotherapy as a sole modality – We rarely offer neoadjuvant chemotherapy alone as the benefit without RT is uncertain. There are no adequately powered, randomized phase III trials that demonstrate the benefit of using chemotherapy alone for neoadjuvant therapy [2-5]. A randomized phase II European Organisation for Research and Treatment of Cancer (EORTC) study of 150 patients failed to show improved survival in those who received surgery plus three cycles of neoadjuvant doxorubicin (50 mg/m² per cycle) plus ifosfamide (5 g/m² per cycle) versus surgery alone (although some patients received RT for incomplete resections) [6]. However, standard doxorubicin, ifosfamide, and mesna (AIM) regimens use higher doses of doxorubicin (≥75 mg/m² per cycle) and ifosfamide (≥9 g/m² per cycle), and the low chemotherapy intensity used in this study could have contributed to the negative result.

Regimen selection

Neoadjuvant PD-1-based immunotherapy for undifferentiated pleomorphic sarcoma — In patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma (UPS) of the extremity, there are several options for management including neoadjuvant pembrolizumab with RT followed by surgery and then adjuvant pembrolizumab. Another option is neoadjuvant chemotherapy and preoperative radiation. For those not accepting or not appropriate for systemic therapy, preoperative radiation alone followed by surgery is acceptable. (See 'Chemotherapy for other subtypes' below.)

Given the limited follow-up in a study investigating neoadjuvant pembrolizumab and its unknown impact on survival, the decision about whether to use immunotherapy (or any systemic therapy for that matter) should involve shared decision making with the patient. In a phase II study modified intention to treat analysis of 127 patients with UPS including myxofibrosarcoma (114 patients) or liposarcoma (13 patients), the addition of neoadjuvant and adjuvant pembrolizumab to preoperative radiotherapy and surgery improved the two-year disease-free survival (67 versus 52 percent; HR 0.61, 90% CI 0.39-0.96) [1]. Patients in the experimental group received three cycles of pembrolizumab every three weeks given prior to, concurrently with, and after radiation followed by surgery and up to 14 cycles of adjuvant pembrolizumab. Overall survival (OS) data are immature. However, with a median follow-up of 43 months the two-year OS was similar (88 versus 85 percent; HR 0.67, 95% CI 0.33-1.39). The incidence of grade ≥3 adverse events was higher in the pembrolizumab group (56 versus 31 percent). Common toxicities included radiation dermatitis, fatigue, and pain.

Only 13 patients with liposarcoma (dedifferentiated and pleomorphic subtypes) were treated on the SU2C-SARC32 trial. We do not offer immunotherapy in this patient population on the basis of this very limited trial. Liposarcoma encompasses several histologies and grades of tumor with highly divergent biologic behavior. As a result, a prospective trial will be needed before making any decisions about the theoretical utility of immunotherapy in the neoadjuvant setting for specific liposarcoma subtypes.

Chemotherapy for other subtypes — Patients with a high risk of developing metastatic disease may be appropriate candidates for neoadjuvant chemotherapy. There is general consensus supporting the use of a combination regimen that incorporates an anthracycline (either doxorubicin or epirubicin) in addition to ifosfamide plus mesna. If a decision is made to offer neoadjuvant chemotherapy for STS of the extremity, we typically offer three cycles of AIM. Standard AIM regimens use high doses of doxorubicin (usually 75 mg/m² per cycle) and ifosfamide (9 to 10 g/m² per cycle) (table 1 and table 2).

Support for the use of anthracycline plus ifosfamide regimens is based largely on extrapolation of data demonstrating the efficacy of these regimens in the adjuvant and metastatic settings, and is largely consistent with guidelines from other expert groups, including NCCN [7]. The strongest support from a randomized clinical trial comes from the ISG-STS 1001 study, which showed superior overall survival with anthracycline plus ifosfamide chemotherapy over a histotype-selected therapy in common STS subtypes with high risk of recurrence [8-10]. Possible treatment-related toxicities include sterility, cardiomyopathy, kidney or bladder damage, and second cancers. More details regarding this trial and the use of AIM in the metastatic setting are presented separately. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Combination anthracycline-based therapy'.)

Anthracycline plus ifosfamide combination regimens (eg, AIM) remain the standard of care. However, trabectedin has shown efficacy in patients with one specific STS diagnosis (high-grade myxoid liposarcoma). While the data need to be interpreted cautiously, trabectedin may be considered in individual situations using shared decision making. Although it has not been directly compared with AIM, in the ISG-STS 1001 randomized study cited above, trabectedin was similarly effective to the combination of epirubicin plus ifosfamide in the neoadjuvant setting [11]. This trial was closed early after an overall futility analysis demonstrated improved outcomes in patients receiving standard chemotherapy in all arms except for patients with high-grade myxoid liposarcoma. The high-grade myxoid liposarcoma cohort was subsequently expanded to a total of 101 patients. At five years, when compared with standard chemotherapy, trabectedin resulted in similar disease-free survival (86 versus 73 percent; HR 0.6, 95% CI 0.24-1.46) and overall survival (88 versus 90 percent; HR 1.2, 95% CI 0.37-3.93). Grade 3 and 4 toxicities were lower in the trabectedin arm versus standard chemotherapy for anemia (0 versus 15 percent), neutropenia (7 versus 67 percent), and thrombocytopenia (0 versus 20 percent). This study shows encouraging results for neoadjuvant trabectedin. However, caution should be taken in interpreting the results due to the wide confidence intervals and study design.

Additional data from a nonrandomized phase II trial also showed evidence of activity in locally advanced myxoid liposarcoma. In an uncontrolled study of 23 patients, seven had an objective partial response, and at surgery, three had a pathologic complete response after three to six cycles of trabectedin (1.5 mg/m² over 24 hours, once every 21 days) [12]. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Trabectedin (LMS)'.)

Based on these data, trabectedin is a possible alternative to standard anthracycline and ifosfamide chemotherapy in patients with high-grade myxoid liposarcoma, at least those at highest risk. However, further data are still needed to determine the optimal approach for neoadjuvant therapy in this population.

Is there a role for chemotherapy with regional hyperthermia? — Another option employed in some institutions is the neoadjuvant use of regional hyperthermia plus systemic chemotherapy. A European randomized trial reported benefit from the addition of regional hyperthermia to neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone among patients with large high-grade tumors or initially unresectable disease [13]. This approach, which is not widely used outside of Europe, is discussed in detail separately. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Chemotherapy with regional hyperthermia'.)

Adjuvant therapy — Adjuvant systemic therapy can be a component of multimodality therapy with the goal to reduce the risk of a recurrence. However, surgery and radiation are key components of the treatment plan. Adjuvant systemic therapy, which is controversial due its unclear benefit and known toxicity, is not a substitute for an inadequate surgery. All patients being considered for adjuvant therapy should have an adequate surgical excision. (See 'Multimodality therapy' above.)

Patients who received neoadjuvant systemic therapy

Prior neoadjuvant immunotherapy — In patients with grade 2 or 3, stage III resectable UPS of the extremity, it is appropriate to consider neoadjuvant pembrolizumab with RT followed by surgery and then adjuvant pembrolizumab based on an improvement in disease-free survival compared with no pembrolizumab [1]. However, the role of chemotherapy in such patients is unknown since the integration of chemotherapy was not studied in the SU2C-SARC32 trial. We treat as per the study and administer up to 14 cycles of adjuvant pembrolizumab (200 mg every three weeks). However, it is not clear if the benefit in recurrence-free survival seen in a phase III trial is related to adjuvant therapy, neoadjuvant therapy, or both. This is described in detail separately. (See 'Neoadjuvant PD-1-based immunotherapy for undifferentiated pleomorphic sarcoma' above.)

Prior neoadjuvant chemotherapy — In patients who have received neoadjuvant chemotherapy, such as those with large, bulky tumors, we do not routinely administer adjuvant chemotherapy. It is unclear if additional chemotherapy would have benefit. (See 'Chemotherapy for other subtypes' above.)

Patients who did not receive neoadjuvant systemic therapy

Definition of high risk and impact of histology — Tumor size, histologic grade, and histology play an important role in determining the risk of recurrence or probability of distant metastases. A multidisciplinary team should evaluate patients based on these factors to determine if a patient is at high risk for recurrence and whether they should be offered adjuvant chemotherapy. Several nomograms have been developed to help clinicians in this assessment. These are located separately. (See "Clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Prognostic factors'.)

●High-risk tumors – We define high-risk STS based on the presence of one or more of the following high-risk features:

•≥5 cm

•Grade 2 or 3 on the biopsy specimen

•Tumors located deep to fascia

•Locally recurrent tumors

•Having inadequate or positive margins at surgery

These high-risk features are associated with an increased risk of local or distant recurrence. As an example, in one series of 220 patients with STS, the risk of distant metastases increased with tumor size from 38 percent among those with a tumor between 5 and 10 cm to 83 percent among those with a tumor >20 cm [14]. Nomograms can be used to define higher and lower risk extremity sarcomas incorporating these and other factors [15]. Some consider a ≥40 percent risk of developing metastatic disease as high risk [16]. (See "Clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Prognostic tools'.)

●Impact of histology – Histology plays a minor role in the decision of whether to offer adjuvant chemotherapy in adult-type sarcomas. Although it has been proposed that the benefit of adjuvant chemotherapy may be preferentially seen when patients are selected based on tumor histology, this hypothesis has never been validated in a prospective clinical trial in patients with sarcomas more commonly seen in adults, nor in any of the pooled analyses of randomized trial data [17,18]. Adjuvant clinical trials in adults with STS have, out of necessity, included patients with multiple histologies, in contrast with pediatric studies, which focus on one specific sarcoma type. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

It is well recognized that myxoid-round cell liposarcomas and synovial sarcomas are relatively chemosensitive histologic types of STS, at least in the setting of metastatic disease, but it is unclear how this should impact a decision to offer therapy. The results from observational studies evaluating adjuvant chemotherapy in patients with the more chemotherapy-sensitive histologic types are conflicting [19-23]. While some contemporary studies suggest a potential survival benefit for adjuvant chemotherapy in patients with the liposarcoma and synovial sarcoma subtypes of extremity STS [19,20,22], others do not [21,23,24]. Interpretation of these studies is also limited because subset data for the three forms of liposarcoma (well differentiated/dedifferentiated, myxoid-round cell, and pleomorphic) are not available.

Adjuvant therapy for selected high-risk tumors — In patients treated with initial surgery, we decide whether to offer adjuvant chemotherapy to selected patients with high-risk tumors on a case-by-case basis, taking into consideration performance status, comorbid factors (including age), disease location, tumor size, and histologic subtype. While the goal of adjuvant chemotherapy is to reduce the risk of both local and distant recurrence, its use in adult-type STS is controversial given its unclear benefit in this population [25,26].

Over 20 randomized trials and multiple meta-analyses have yielded conflicting data, and as a result, the benefit of adjuvant chemotherapy remains uncertain. A possible, yet unproven, benefit from adjuvant chemotherapy must be discussed in the context of expected treatment-related toxicities, including potential sterility, cardiomyopathy, kidney damage, second cancers, and overall impairment of quality of life. Toxicities may be particularly challenging for older adults. Our approach is consistent with the consensus-based guidelines of the NCCN [7] and the European Society of Medical Oncology [27], which endorse adjuvant chemotherapy as an option for high-risk tumors.

Despite numerous trials, it is still unclear if and how much of a benefit there is with the addition of adjuvant doxorubicin-based chemotherapy. If there is a survival benefit, it appears to be small [17]. However, interpreting the existing clinical trial data is difficult as the different trials included a mix of histologies with varying degrees of chemosensitivity; employed different doses and schedules of chemotherapy; and used different inclusion criteria.

The best support for the use of adjuvant chemotherapy is from a 2008 meta-analysis that included data from 18 randomized trials of 1953 patients with localized and potentially resectable STS conducted from 1973 to 2002 (the Sarcoma Meta-Analysis Collaboration [SMAC] meta-analysis) [17]. Five of the included trials used doxorubicin plus ifosfamide, while the others used doxorubicin alone or in combination with other agents. The use of adjuvant chemotherapy was associated with a reduction in local recurrence (odds ratio [OR] 0.73, 95% CI 0.56-0.94) and distant and overall recurrence (OR 0.67, 95% CI 0.56-0.82). In addition, the use of doxorubicin with ifosfamide was associated with an overall survival benefit (OR for death 0.56, 95% CI 0.36-0.85). The absolute risk reduction for doxorubicin in combination with ifosfamide was 11 percent (30 versus 41 percent risk of death). Benefit could not be shown for doxorubicin alone (OR 0.84, 95% CI 0.68-1.03), implying the fundamental importance of ifosfamide in the adjuvant treatment of sarcomas overall. Limitations of this meta-analysis include the heterogeneity of the patient population and treatments administered. In addition, this meta-analysis did not include a large European Organisation for Research and Treatment of Cancer (EORTC) trial with a negative result [28].

In contrast to results of the SMAC meta-analysis, a benefit from adjuvant chemotherapy was not shown in a pooled analysis of individual patient-level data from 819 patients with STS enrolled on the two largest randomized trials of adjuvant doxorubicin and ifosfamide-based chemotherapy (both performed by the EORTC) [18,28,29]. Compared with surgery alone, the use of postoperative adjuvant chemotherapy was not associated with a survival benefit, except in the subset of patients undergoing incomplete (R1) resection. In multivariate analysis, tumor size, histologic type, and grade were not associated with any progression-free or overall survival benefit from adjuvant chemotherapy.

One of the trials included in the pooled EORTC data included 351 patients with completely resected STS (67 percent extremity tumors, 60 percent high-grade, 40 percent ≥10 cm) who were randomly assigned to observation versus five cycles of adjuvant chemotherapy (doxorubicin 75 mg/m² and ifosfamide 5 g/m² per cycle) [28]. The estimated five-year relapse-free survival was similar in both arms as was overall survival (67 versus 68 percent; HR 0.94, 95% CI 0.68-1.31). However, interpretation of these results is limited by the inclusion of patients with nonextremity, small, and low/intermediate-grade primaries, as well as the relatively low ifosfamide dose.

Regimen selection — For patients receiving adjuvant chemotherapy, the optimal regimen is undefined. We prefer doxorubicin, ifosfamide, and mesna (AIM) The combination of epirubicin plus ifosfamide is an acceptable alternative used by other experts; it has not been directly compared with AIM in this setting. We prefer AIM as it has been used in most of the randomized trials. Standard AIM regimens use high doses of doxorubicin (≥75 mg/m² per cycle) and ifosfamide (≥9 g/m² per cycle) (table 1 and table 2).

If a patient with a good performance status and high-risk tumor (eg, ≥40 percent risk of metastatic disease) did not receive neoadjuvant chemotherapy, we offer three to five cycles of AIM. Three cycles of chemotherapy may suffice, although the data supporting this statement are limited to a single trial of three versus five cycles of chemotherapy in 328 patients with high-risk extremity sarcomas [30]. (See "Treatment protocols for soft tissue and bone sarcoma".)

For patients who have already received neoadjuvant therapy, there are limited data to guide the use of adjuvant therapy. In patients who had three neoadjuvant cycles of AIM, we do not offer further adjuvant chemotherapy based on ISG-STS 1001 [8].

No role for adjuvant therapy in low-risk tumors — We do not offer adjuvant chemotherapy to low-risk tumors given the lack of proven benefit and considerable toxicity associated with adjuvant chemotherapy. Many define a low-risk tumor as having a <40 percent risk of developing metastatic disease. These patients were excluded from most trials of adjuvant chemotherapy. (See "Clinical presentation, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Prognostic tools'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Multimodality approach – Surgery is the cornerstone of treatment for virtually all patients with an extremity soft tissue sarcoma (STS). The combination of surgery and radiation therapy (RT) achieves better outcomes than either treatment alone for most STS more than 5 cm in greatest dimension. (See 'Multimodality therapy' above.)

●Pediatric-type sarcomas – Systemic chemotherapy is a standard component of treatment for several types of sarcoma that occur predominantly in children, some of which occur in soft tissue such as embryonal or alveolar rhabdomyosarcoma, Ewing sarcoma, and osteogenic sarcoma of bone. (See 'Pediatric-type sarcomas' above.)

●Other sarcoma subtypes – The use of systemic therapy remains controversial in patients with several sarcoma subtypes that more commonly occur in adults, such as liposarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors, undifferentiated pleomorphic sarcoma, and synovial sarcomas. If used, systemic therapy is largely reserved for patients with higher-risk disease and involves shared decision making.

●Neoadjuvant therapy – The decision of whether to offer neoadjuvant chemotherapy is individualized in patients with more common adult-type STS subtypes.

•Immunotherapy for UPS – In patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma (UPS) of the extremity, neoadjuvant pembrolizumab with RT followed by surgery and adjuvant pembrolizumab is an option. However, given the limited follow-up in trials investigating this regimen and unknown impact on survival, the decision about whether to use immunotherapy should involve shared decision making with the patient. (Grade 2B)UPS is the only histology in which neoadjuvant immunotherapy has been adequately studied. We do not know if chemotherapy should also be utilized in such patients, nor do we know if immunotherapy is useful in patients who receive neoadjuvant chemotherapy. (See 'Neoadjuvant PD-1-based immunotherapy for undifferentiated pleomorphic sarcoma' above.)

•Chemotherapy – Neoadjuvant chemotherapy can be offered in the setting of a large high-grade primary tumor, particularly if limb salvage is expected to be difficult. If a neoadjuvant approach is used, we suggest sequential treatment with chemotherapy, followed by RT, followed by surgery (Grade 2C), rather than either modality on its own. However, other experts may use alternative approaches. (See 'Neoadjuvant systemic therapy' above and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)

●Adjuvant therapy

•Prior systemic neoadjuvant therapy – In patients with grade 2 or 3, stage III UPS or liposarcoma of the extremity who received neoadjuvant pembrolizumab and RT prior to surgery, we administer up to 14 cycles of adjuvant pembrolizumab (200 mg every three weeks). In patients who have received neoadjuvant chemotherapy, such as those with large, bulky tumors, we do not routinely administer adjuvant chemotherapy or immunotherapy (See 'Patients who received neoadjuvant systemic therapy' above.)

•No prior neoadjuvant systemic therapy – In patients treated with initial surgery, we decide whether to offer adjuvant chemotherapy to patients with selected higher-risk tumors on a case-by-case basis, taking into consideration the patient's performance status, comorbid factors (including age), disease location, tumor size, and histologic subtype. While the goal of adjuvant chemotherapy is to reduce the risk of both local and distant recurrence, its use in STS, which more commonly occur in adults, is controversial and a benefit, if any, may be limited to select high-risk patients. (See 'Adjuvant therapy for selected high-risk tumors' above.)

We define higher-risk STS as the following: ≥5 cm, grade 2 or 3 on the biopsy specimen, tumors located deep to fascia, locally recurrent tumors, or having inadequate or positive margins at surgery. Nomograms can be used to define higher- and lower-risk extremity sarcomas incorporating these and other factors. Some consider a ≥40 percent risk of developing metastatic disease as high risk. (See 'Definition of high risk and impact of histology' above.)

For patients with a good performance status who have high-risk STS and have not undergone neoadjuvant therapy, adjuvant chemotherapy is an option. We do not offer adjuvant chemotherapy to low-risk tumors given the lack of proven benefit and considerable toxicity associated with adjuvant chemotherapy.

For those who undergo systemic chemotherapy, we suggest doxorubicin, ifosfamide, and mesna (AIM; (table 2 and table 1)) (Grade 2C), although we consider epirubicin plus ifosfamide to be an acceptable alternative. Epirubicin plus ifosfamide is more commonly used in Europe. (See 'Regimen selection' above.)

Postoperative RT is appropriate in select groups, as discussed elsewhere. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Choosing between preoperative and postoperative RT'.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.