Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk

INTRODUCTION — Sarcomas are malignant tumors that arise from skeletal and extraskeletal connective tissues, including the peripheral nervous system. They can arise from mesenchymal tissue at any site. Soft tissue sarcomas (STS) are uncommon. In the United States, over 13,000 cases are diagnosed annually, representing less than 1 percent of all newly diagnosed malignant tumors [1]. Although surgical resection is, in general, a necessary prerequisite for cure, the addition of radiation therapy is recommended for most patients with an STS of the extremities or superficial trunk (chest wall, flank, abdominal wall, paraspinal musculature) to minimize the risk of a local recurrence, and to maximize function and long-term survival.

This topic will provide an overview of multimodality treatment of STS arising in the extremities and superficial trunk. The following issues are discussed separately: the clinical presentation, diagnosis, and staging of STS; radiation-associated sarcomas; STS arising in the head and neck, breast, and retroperitoneum; surgical resection of potentially resectable STS of the extremities; management of locally advanced, unresectable STS; adjuvant as well as neoadjuvant chemotherapy for the types of STS that typically arise in adults; and radiation therapy techniques for STS.

●(See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

●(See "Radiation-associated sarcomas".)

●(See "Head and neck sarcomas".)

●(See "Breast sarcoma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging" and "Breast sarcoma: Treatment".)

●(See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma" and "Surgical resection of retroperitoneal sarcoma" and "Management of locally recurrent retroperitoneal sarcoma".)

●(See "Surgical resection of primary soft tissue sarcoma of the extremities".)

●(See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities" and "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities" and "Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk".)

IMPORTANCE OF MULTIDISCIPLINARY EVALUATION AND MANAGEMENT — Because of their rarity and the frequent need for multimodality treatment, evaluation and management of STS should ideally be carried out in a center with expertise in the treatment of patients with sarcomas, including pathology, surgical oncology, orthopedic surgery, plastic surgery, adult or pediatric medical oncology, radiation oncology, and physical therapy. The multidisciplinary team approach to care of patients with STS optimizes treatment planning, minimizes duplication of diagnostic studies, and reduces the time to implementation of the definitive therapeutic protocol.

Moreover, the expertise gained by dedicated subspecialists improves clinical outcomes. This was illustrated by one study that examined outcomes of 375 patients with STS of the extremities and torso according to the time of referral to a tumor center in the South Sweden Health Care Region [2]. Compared with patients referred preoperatively, local recurrence rates were 2.4-fold higher in patients not referred at any time and 1.3-fold higher in those referred only after definitive surgery.

EXTREMITY SARCOMAS

General approach to treatment — In treating extremity STS, the major therapeutic goals are long-term survival, avoidance of a local recurrence, maximizing function, and minimizing morbidity. There are a wide variety of clinical situations that arise from involvement of a variety of different anatomic sites, the range of histologies, and variability in grade and tumor size. As a result, for most patients, treatment must be individualized. The following suggestions serve as a general guide to therapy:

●Our recommended treatment for most patients with an extremity STS who are medically and deemed operable is combined surgery and radiation therapy (RT). In most instances, the probability of tumor control is higher, and the late functional and cosmetic result is superior following combined modality therapy than with either "radical" or "wide" excisional surgery or radiation alone. (See 'Margin classification systems' below.)

The multidisciplinary management of sarcoma must be individualized, taking into account the patient's functional status, the heterogeneity of tumor behavior, and the location of the tumor. However, in general, surgical excision alone is usually reserved for patients with small (<5 cm), low-grade, and especially superficial (superficial to the fascia) sarcomas. Surgery alone may also be considered for select patients with small intramuscular sarcomas, even if higher grade, provided that adequate surgical margins can be obtained with preservation of function. RT is recommended in addition to resection for the remainder of sarcoma patients. (See 'Radiation therapy' below.)

Preoperative RT is associated with similar oncologic outcomes to postoperative RT, but there is a difference in toxicity profile [3]. The choice between preoperative and postoperative RT is discussed below. (See 'Choosing between preoperative and postoperative RT' below and "Risk factors for impaired wound healing and wound complications", section on 'Radiation'.)

●In addition to oncologic control, sarcoma management must prioritize preservation of function, especially in extremity sarcomas. When "radical" or "wide" resection would compromise a functional extremity, various neoadjuvant approaches have been explored, especially in patients with large, intermediate- or high-grade extremity lesions. There are limited randomized trials comparing various treatments. The optimal chemoradiation approach is not established, and the choice is usually based upon institutional expertise and preferences. Outside of a well-established treatment regimen for specific sarcoma subtypes such as Ewing sarcoma or rhabdomyosarcoma, our approach is to offer chemoradiation as part of a clinical trial. If trial participation is not feasible, chemoradiation may be selectively offered only to medically fit patients with a good performance status and high- to intermediate-grade, large (>5 cm) tumors. (See 'Is there a role for chemoradiation?' below.)

In addition, for patients with large, locally advanced or recurrent extremity STS, neoadjuvant chemotherapy can be administered systemically in conjunction with regional hyperthermia or regionally (intraarterially), using procedures such as isolated limb infusion and isolated limb perfusion. These treatments are not widely available in the United States, but where available, they represent potentially limb-sparing options. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Chemotherapy with regional hyperthermia' and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Regional chemotherapy'.)

●The benefit of adjuvant chemotherapy for common adult STS of the extremities continues to be debated, and there is little consensus as to the indications or specific benefit. The appropriateness of adjuvant chemotherapy should be addressed 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. The potential for benefit must be discussed in the context of expected treatment-related toxicities, including sterility in younger individuals, cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life. (See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities", section on 'Sarcomas more commonly seen in adults'.)

Our approach parallels consensus-based guidelines for multidisciplinary management of soft tissue tumors of the extremity and trunk, which are available from the American Society for Radiation Oncology (ASTRO) [4], European Society for Medical Oncology (ESMO) [5] and the National Comprehensive Cancer Network (NCCN) [6]. (See 'Society guideline links' below.)

Resection — Wide surgical resection of the primary tumor (total en bloc excision of the primary tumor without cutting into tumor tissue and having an adequate margin of normal tissue completely surrounding the tumor) is the essential component of treatment for virtually all patients with extremity STS. For most patients, resection of the tumor with adequate surgical margins is possible and preserves a functional limb; however, primary amputation may be the best alternative in small subset of patients. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Primary amputation'.)

Surgical technique — Wide local excision of the primary tumor (ie, en bloc tumor removal) should take place through apparently normal uninvolved tissue outside of the tumor pseudocapsule, if one exists.

Violation of the tumor (ie, intralesional surgery) or inadequate resection that results in gross or microscopic residual tumor is associated with a higher local failure rate, even if RT is used. The status of the surgical margins is the most important surgical variable that influences local control; however, the exact width (thickness) of the negative margin that is optimal for local control is not known. What defines an "adequate" margin likely depends on the type of tissue. As an example, a fascial margin can be thinner than a muscle or fatty margin. Most clinicians recommend that, if surgery is used as the sole modality of treatment, the margin should be at least 1 cm in all directions or include a fascial barrier, but this type of margin is seldom achieved in all margins of a tumor, especially around the neurovascular bundle. If surgery is combined with RT, it is generally accepted that the surgical margin may be less thick without compromising local control. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Wide local excision' and "Surgical management of chest wall tumors", section on 'Wide tumor excision'.)

Rotational flaps or free tissue transfers may be necessary to achieve wound closure. Given that the spread of sarcoma to lymph nodes is uncommon, in most cases, regional node dissection is only recommended if there is clinical or radiologic evidence of regional nodal disease. The principles of surgical resection (including issues related to the regional nodes) for extremity STS are discussed in detail separately. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Sarcoma resection and reconstruction' and "Surgical management of chest wall tumors", section on 'Surgical resection and reconstruction'.)

Margin classification systems — There are several classification systems that define surgical margins. The most commonly used are the Enneking classification system [7] and the AJCC residual ("R") classification system. Details of each system are as follows:

Enneking classification system — The Enneking classification system is adopted by the Musculoskeletal Tumor Society and defines radical, wide, marginal, and intralesional margins as follows. This classification systemic applies to both resection and amputation:

•Radical margin – A "radical" margin is complete removal of the anatomic compartment containing the tumor and is almost never performed.

•Wide margin – A "wide" margin is a surgical resection that includes a cuff of normal tissue completely surrounding the tumor.

•Marginal margins – A "marginal" margin is a surgical resection that occurs through the reactive pseudocapsule of the tumor.

•Intralesional margins – An "intralesional" margin is a surgical resection where the tumor was entered.

AJCC residual classification system — The AJCC residual system uses "R" classification to define surgical margins as follows:

•R0 resection – Surgical resection in which the tumor is completely resected with histologically negative margins.

Some experts have promoted the UICC margin "R+ 1" classification and measurement of distance [8]. This means that, for an R0 margin to be truly negative, it must include a minimum of 1 mm between the tumor and the closest inked margin. However, minimal margins around neurovascular structures and bone are usually accepted and probably do not increase the risk of local recurrence [9].

•R1 resection – Surgical resection in which the ink used to mark the specimen prior to processing is in contact with the tumor.

•R2 resection – Surgical resection in which there is known residual microscopic and usually macroscopic tumor.

In one observational study, the Enneking system performed similarly or better (with higher sensitivity and negative predictive value) versus the AJCC residual classification [10]. This study also suggested that a 1 mm margin is adequate when adjuvant radiation is used and 5 mm or greater if surgery alone is used for high-grade pleomorphic sarcomas of the extremity. Myxofibrosarcomas appear to require wider surgical margins because these tumors have the tendency to invade along fibrous septae.

Radiation therapy — The use of RT in conjunction with resection lessens the necessity for amputation, increases the potential to resect sarcomas, and maintains acceptable functional and cancer outcomes. For the majority of patients with STS, the combination of limb-sparing surgery and RT achieves better local control than either modality alone, although it does not improve survival. Further details on RT techniques for primary STS of the extremities and superficial trunk are discussed separately. (See "Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk".)

Adjuvant RT improves local control and has also had a significant impact on rates of limb salvage for extremity STS. In the 1970s, up to one-half of patients with extremity STS underwent amputation. With the emergence of RT and advanced reconstructive techniques, the rate of amputation has been reduced to approximately 1 percent without any measurable fall in overall survival [11-16].

The benefit of adding RT to limb-sparing surgery has been addressed in two randomized trials, both of which showed that the combination of limb-sparing surgery and RT reduced the absolute risk of local recurrence by 20 to 25 percent when compared with limb-sparing surgery alone but did not improve overall survival [17,18]. However, these trials were not adequately powered to demonstrate any small differences in survival. Although there are many limitations to this type of study, lower level evidence from an analysis of a large number of patients with STS reported to the Surveillance, Epidemiology, and End Results (SEER) database suggests a modest overall survival benefit for the addition of adjuvant RT [19]. When combined with limb-sparing surgery, RT at moderate dose levels (50 to 65 Gy) can effectively eradicate microscopic disease extension beyond the gross lesion, resulting in rates of local control that are comparable to those achieved with amputation or surgical resection with a "radical" margin [11]. With combined therapy, most series report local control rates of approximately 85 to 90 percent for high-grade extremity STS and 90 to 100 percent for low-grade STS, depending upon size [3,11,20-25].

Adjuvant RT at higher doses can also improve outcomes in patients with positive margins [26,27]. The largest experience comes from a retrospective review of 154 patients with resected STS at any anatomic site (105 extremity, nine truncal) who had positive resection margins and who underwent RT with curative intent over a 31-year period [26]. At five years, rates of local control, disease-free survival, and overall survival for the entire cohort were 76, 47, and 65 percent, respectively. Outcomes were most favorable for patients with extremity primaries (five-year local control, disease-free, and overall survival 82, 48, and 66 percent, respectively); those who received an RT dose >64 Gy; and those who had microscopic (rather than grossly visible) margins, tumor size <5 cm, and a superficial rather than deep location. Among patients receiving RT doses >64 Gy, 85 percent achieved local control at five years.

However, because local control is still worse with positive as compared with negative margins, reresection to negative margins is preferred if additional conservative surgery can be performed. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Inadequate initial resection'.)

The optimal timing of RT (ie, preoperative versus postoperative) is discussed in detail below. (See 'Choosing between preoperative and postoperative RT' below.)

Are there patients for whom RT is not needed? — In general, we reserve surgical excision alone for:

●Adult patients with superficial (to the fascia), low-grade tumors that are 5 cm or less in diameter.

●Select patients with small, purely intramuscular tumors (including higher grade tumors) that can be resected with a wide surgical margin of muscle and still preserve function. (See 'Surgical technique' above.)

●For pediatric patients with low-grade nonrhabdomyosarcoma STS (NRSTS), RT can be withheld and reserved for those with recurrent disease. This approach may also be offered to pediatric patients with high-grade nonrhabdomyosarcoma STS up to 5 cm in size excised with negative margins.

While it is well documented that the risk of a local recurrence is higher for high-grade tumors, low-grade tumors do not uniformly carry a low risk of local recurrence. In one randomized trial, the improvement in local control in irradiated patients appeared to be limited to patients with high-grade histopathology [17]. However, in a separate randomized trial, there was a significant reduction in risk for low-grade tumors as well (5 versus 30 percent local recurrence rate for patients treated with surgery alone) [18].

Nevertheless, based upon these results as well as retrospective and population-based registry series [28-36], there appear to be some patients with low-grade extremity STS who do not require adjuvant RT. The identification of this subset remains challenging, in large part because of the difficulty in quantifying the risk of a local recurrence for individual patients based upon the usual features used to estimate prognosis, such as size, depth, and histologic grade.

In the pediatric population with NRSTS, RT should be avoided whenever possible. Pediatric patients who receive RT may experience negative treatment-related growth consequences (eg, limb length discrepancy and angular deformities) and they are also at risk for late radiation-associated subsequent cancers [37]. As an example, in one Children's Oncology Group study, RT was withheld in patients with low-grade nonrhabdomyosarcoma STS after tumor excision (including those with involved margins) as well as in those with high-grade NRSTS up to 5 cm excised with negative margins [38]. Isolated local recurrence or progression occurred in 4 of 103 low-grade R0 tumors (4 percent), 4 of 22 low-grade R1 tumors (18 percent), and 5 of 80 high-grade R0 tumors of up to 5 cm (6 percent). (See "Radiation-associated sarcomas" and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

Various nomograms are available to estimate the risk of local recurrence in individual patients with sarcoma receiving surgery alone [39]. While these nomograms may be useful tools to estimate the risk of a local recurrence in an individual patient, decisions about omitting adjuvant RT must be made on a case-by-case basis by an experienced multidisciplinary team. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Local' and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Prognostic tools' and 'Prognostic tools' below.)

Choosing between preoperative and postoperative RT — Adjunctive RT can be administered preoperatively (neoadjuvant RT) or postoperatively (adjuvant RT). There are potential advantages of both approaches. Preoperative RT enables the delivery of a lower dose (50 Gy) to a smaller target volume. It might also be expected to reduce tumor burden, theoretically allowing more conservative surgical therapy. Postoperative RT allows histologic examination of the tumor specimen and is also associated with fewer wound complications. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Wound-related complications'.)

In general, for most patients who receive RT, we suggest preoperative rather than postoperative RT. This includes most patients with intermediate- and high-grade tumors as well as those with large, low-grade tumors where the surgeon expects close or positive margins. We favor preoperative RT for such patients with extremity and superficial trunk sarcomas on the basis that acute wound complications can usually be managed and will eventually heal in the long run, while late treatment effects from postoperative radiation are generally irreversible. Specific radiation techniques and schedules for preoperative RT in primary STS are discussed separately. (See "Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Preoperative treatment and doses'.)

Nevertheless, postoperative RT for some patients is still a viable option as part of local control for primary extremity or trunk sarcomas. Specific radiation techniques and schedules for postoperative RT in primary STS are discussed separately. (See "Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Postoperative treatment and doses'.)

Postoperative radiation may be offered to the following groups:

●Patients with infiltrative subcutaneous myxofibrosarcomas for which it is very difficult to define an appropriate preoperative radiation target volume based on preoperative imaging.

●Patients with additional risk factors for acute wound healing problems along with RT (ie, where incised skin/subcutaneous tissues cannot be spared from RT) or for whom acute wound complications may be particularly detrimental. (See "Risk factors for impaired wound healing and wound complications".)

Retrospective observational series of patients who have received either postoperative or preoperative RT have reported local control and disease-specific survival rates that are at least as good with preoperative as compared with postoperative therapy RT [40-44], and possibly better [45,46].

In one phase III clinical trial (the SR2 study) 190 patients with primary (90 percent) or recurrent (10 percent) extremity STS (83 percent intermediate- or high-grade) were randomly assigned to either preoperative or postoperative RT [3]. The 94 patients assigned to preoperative therapy all received 50 Gy prior to surgery with a postoperative boost (16 to 20 Gy) given to the 14 patients with a positive margin. All patients in the postoperative group received 50 Gy to the initial field plus a 16 to 20 Gy boost. Complications were defined as secondary wound surgery, hospital admission for wound care, or the need for deep packing or prolonged wound dressings within 120 days of tumor resection. The study was terminated when a highly significant result was obtained at the time of a planned interim analysis. With a median follow-up of 3.3 years, acute wound complications were significantly more common with preoperative treatment (35 versus 17 percent) [3]. Other factors associated with acute wound complications were the volume of resected tissue and lower limb location of the tumor.

In a subsequent update with median follow-up of 6.9 years, there was no difference in local control with preoperative versus postoperative RT, with over 90 percent of patients controlled locally [47]. The regional and distant failure rates as well as the progression-free and overall survival rates were also similar. However, patients treated postoperatively developed significantly more grade 2 to 4 late toxicity compared with those treated preoperatively (86 versus 68 percent, respectively). In particular, the incidence of grade 3 (severe induration and loss of subcutaneous tissue or field contracture >10 percent linear measurement) or grade 4 (necrosis) subcutaneous fibrosis was significantly higher in the postoperative group (36 versus 23 percent, respectively).

Although not statistically significant, limb edema (23 versus 16 percent) and joint stiffness (23 versus 18 percent) were both more common in the postoperative treatment group [48]. Fibrosis, edema, and joint stiffness adversely affected functional outcomes.

This study demonstrates that efficacy is similar using preoperative or postoperative RT, and that the higher rate of generally reversible acute wound healing complications in preoperatively treated patients is offset by a lower rate of generally irreversible late complications, including grade 3 to 4 fibrosis. Because very few acute wound-healing complications occurred in either group with tumors located in the upper extremity (a finding that is reported by others [49,50]), these data suggest that these patients preferentially receive preoperative RT.

Preoperative IMRT — Preoperative image-guided intensity-modulated RT (IG-IMRT) with sparing of the proposed surgical flap for resection of lower extremity STS was assessed in a prospective phase II study [51]. The incidence of wound complications (30.5 percent) was lower than the 43 percent risk of wound complications seen with lower extremity sarcomas treated neoadjuvantly in the randomized National Cancer Institute of Canada (NCIC) SR2 trial [3], but in cross trial comparisons, this did not reach statistical significance. Preoperative IG-IMRT significantly diminished the need for tissue transfer. RT chronic morbidities and the need for subsequent secondary operations for wound complications were less than those seen in the NCIC SR2 trial, although not significantly, whereas good limb function was maintained. Further details on IG-IMRT technique are discussed separately. (See "Radiation therapy techniques in cancer treatment", section on 'Image-guided radiation therapy'.)

Similar favorable late toxicity profiles were reported in a Radiation Therapy Oncology Group (RTOG) study of image-guided preoperative RT to a reduced target volume [52]. At two years, 10.5 percent experienced at least one grade 2 toxicity, a value that compares favorably with the 37 percent rate of late grade 2 or higher toxicity reported among patients treated neoadjuvantly in the NCIC SR2 study [3].

Nevertheless, additional strategies are needed for patients with lower extremity sarcomas to further reduce the risk of acute wound healing problems in patients who receive preoperative RT as well as the risk of late treatment-induced effects in patients who receive postoperative RT. As an example, in an observational study of 234 patients with STS, the use of an enhanced recovery after surgery (ERAS) program was associated with reduced morbidity, including fewer wound complications and shorter hospital stays, compared with case-matched controls [53]. (See "Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk".)

Definitive RT — For patients who are medically inoperable, or if a function-preserving resection is not possible and amputation is not accepted, RT alone is a consideration [54-56]. The radiation sensitivity of cell lines derived from sarcomas is not less than that of epithelial cell lines [57]. Myxoid liposarcomas are a particularly radiosensitive subtype [58].

For small sarcomas, good local control rates can be achieved by RT alone. However, local control probabilities of >90 percent for tumors of estimated volume 15 to 65 mL (approximately a sphere of 3 to 5 cm in diameter) require high RT doses (>75 Gy) [13]. As most treatment volumes are relatively large, the late normal tissue changes resulting from these dose levels are clinically important in nearly all patients. In one study, patients who received a dose greater than 68 Gy had a significantly higher complication rate compared with those who received lower doses (26 versus 8 percent) [56]. In animal models, a significantly lower RT dose is required to achieve local control when RT is combined with simple excision as compared with RT alone [59].

Is there a role for chemoradiation? — The optimal approach to chemoradiation in patients with STS of the extremities is not established and is usually based on institutional expertise and preferences. Outside of a well-established treatment regimen for specific sarcoma subtypes such as Ewing sarcoma or rhabdomyosarcoma, our approach is to offer chemoradiation as part of a clinical trial. If trial participation is not feasible, chemoradiation may be selectively offered to medically fit patients with a good performance status and high- to intermediate-grade, large (>5 cm) tumors. (See "Treatment of Ewing sarcoma" and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

Preoperative chemotherapy may potentially improve local control, facilitate surgical resection by reducing tumor burden, and treat early micrometastatic disease. However, the widespread acceptance of chemoradiation into standard clinical practice is limited by lack of randomized trials comparing chemoradiation to RT alone as well as concerns of higher rates of treatment-related toxicity, such as therapy-related myeloid neoplasms (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis", section on 'Causes'.)

Data are also limited for the optimal chemosensitizing agent, and treatment strategies vary widely between different countries and sarcoma centers of excellence. Various approaches have been investigated, including concurrent chemoradiation with various chemosensitizers (eg, doxorubicin [60-65], ifosfamide [66,67], gemcitabine, and hafnium oxide [68-70] which has regulatory approval in Europe) and sequential or "interdigitated" RT with multiagent chemotherapy regimens incorporating anthracyclines and ifosfamide [52,71-81]. While chemoradiation may be an option for select patients (eg, in the context of a clinical trial or for specific histologic subtypes such as Ewing sarcoma or rhabdomyosarcoma), further data are needed before using standardly using this approach for all patients with STS of the extremities and superficial trunk.

The use of chemoradiation as initial therapy for patients with unresectable or locally recurrent extremity STS is discussed separately. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Neoadjuvant chemoradiation'.)

Response assessment — Assessment of response following neoadjuvant therapy is problematic. In many studies, tumor size did not change much by examination or imaging after neoadjuvant therapy, while the degree of necrosis was substantial on histologic review of the surgical specimen. This finding, which is observed repeatedly in the treatment of sarcomas [74,82-85], illustrates that changes in tumor size during preoperative therapy may not accurately reflect treatment efficacy.

The clinical importance of histologic response is unclear. There are conflicting data on whether higher degrees of histologic necrosis predict better outcomes in STS (as they do in patients undergoing neoadjuvant treatment for bone sarcomas) [53,86,87]. Furthermore, as in bone sarcomas, there is no evidence from prospective clinical trials that altering treatment in a patient who has a poor histologic response to initial neoadjuvant therapy improves outcomes, and further prospective studies are necessary. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'The option to change systemic therapy after neoadjuvant chemotherapy and surgery'.)

Some observational studies have suggested the use of fluorodeoxyglucose (FDG)-positron emission topography (PET) or dynamic contrast-enhanced magnetic resonance imaging (MRI) to identify histopathologic treatment response as early as after one cycle of neoadjuvant chemotherapy [84,85,88-91]. However, further data are needed to validate this approach.

Regional approaches — For patients with large, locally advanced, initially unresectable or recurrent extremity STS, neoadjuvant chemotherapy can be administered systemically in conjunction with regional hyperthermia, or regionally (intra-arterially), using procedures such as isolated limb infusion and isolated limb perfusion. These treatments are largely unavailable outside of clinical trials in the United States, but where available, they represent potentially limb-sparing options. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Chemotherapy with regional hyperthermia' and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Regional chemotherapy'.)

Adjuvant chemotherapy — Systemic chemotherapy is a routine component of treatment for several STS that occur predominantly in children (ie, rhabdomyosarcoma, Ewing sarcoma). However, despite many randomized trials, the role of adjuvant chemotherapy for the more common adult subtypes of STS (such as liposarcoma, synovial sarcoma, and leiomyosarcoma) remains uncertain [38]. There is little consensus as to the indications or specific benefit, and it is likely that no single drug regimen is appropriate for all STS histotypes. In keeping with guidelines from the NCCN [6] and ESMO [5], the appropriateness of adjuvant chemotherapy is usually addressed 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. The potential for benefit must be discussed in the context of expected treatment-related toxicities including sterility in younger individuals, cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life. (See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities", section on 'Sarcomas more commonly seen in adults'.)

SUPERFICIAL TRUNK SARCOMAS — Primary STS of the superficial trunk (chest wall, flank, abdominal wall, paraspinal musculature) other than those arising in the breast are rare, accounting for approximately 15 percent of all STS [92]. The differential diagnosis for a superficial trunk STS is broad and includes benign and malignant tumors of the soft tissues, cartilage and bone. (See "Surgical management of chest wall tumors", section on 'Indications for chest wall resection'.)

Clinical presentation — Although patients often present with a mass or pain, some tumors are found incidentally on routine imaging. A core needle biopsy is strongly encouraged to establish the diagnosis prior to resection, particularly since tumors such as Ewing sarcoma and osteosarcoma are often managed by neoadjuvant chemotherapy. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Biopsy'.)

Treatment — Some authors group superficial trunk sarcomas with retroperitoneal (deep trunk) sarcomas [93]. However, the clinical behavior of superficial trunk sarcomas is more similar to extremity STS than to retroperitoneal STS (which, like head and neck sarcomas, have a poorer prognosis). Thus, in our view, these tumors should be treated similarly to extremity sarcomas [94-98]. (See 'Extremity sarcomas' above.)

Wide excision is the standard treatment with adjuvant radiation therapy used for those lesions that have been resected incomplete (R1, R2) margins. As with extremity sarcomas, preoperative radiation will generally allow the use of smaller radiation fields and lower doses and is therefore usually preferred.

Five-year overall survival rates are 63 to 89 percent [94,97,98]. Outcomes are less favorable with high-grade histology and with incomplete (R1, R2) as compared with complete (R0) resections. Outcomes are also less favorable for secondary (radiation-induced) chest wall sarcomas [93]. (See "Radiation-associated sarcomas".)

Surgical resection is also the treatment of choice for locally recurrent tumors, although rates of local control are lower than those seen after primary resection [97]. (See "Surgical management of chest wall tumors".)

Management of sarcomas arising in the breast is discussed separately. (See "Breast sarcoma: Treatment".)

PROGNOSIS

Prognostic tools — Prognostic nomograms have been developed to more accurately predict postoperative survival. Further details on these prognostic tools are discussed separately. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Prognostic tools'.)

Several prognostic factors have also been identified for both local and distant recurrence. (See "Surgical resection of primary soft tissue sarcoma of the extremities", section on 'Recurrence'.)

Stage — Tumor stage is classified according to the eighth edition of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system (table 1). (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Staging'.)

POSTTREATMENT SARCOMA SURVEILLANCE — After treatment completion for STS of the extremities or superficial trunk, we recommend frequent follow-up, particularly in the first two years after treatment, since a majority of recurrences will be detected during this period [99]. Isolated limited metastatic tumor to the lung are frequently asymptomatic and can be resected or treated with stereotactic body radiation therapy (SBRT) or other ablative techniques. One exception to this general rule is synovial sarcomas which are associated with a high incidence of late metastases, even after a decade [100]. Patients who experience a local recurrence of their tumor also appear to be at higher risk for late metastases [101]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

Posttreatment cancer surveillance guidelines have not been established through rigorous clinical investigation [99,102]. The most appropriate surveillance frequency and modality for posttreatment management remains undefined. Further studies are necessary to address whether early detection of metastases using surveillance imaging impacts overall survival.

Consensus-based surveillance guidelines after treatment of an extremity sarcoma from the National Comprehensive Cancer Network (NCCN) [6] include the following:

●Stage I disease:

•History and physical examination every three to six months for two to three years, then annually.

•Consider chest imaging every 6 to 12 months.

•Periodic imaging of the primary site (magnetic resonance imaging [MRI], computed tomography [CT]), based on estimated risk of locoregional recurrence.

●Stage II and III:

•History and physical examination and chest imaging every three to six months for two to three years, then every six months for the next two years, then annually.

•Periodic imaging of the primary site, based on estimated risk of locoregional recurrence.

In general, we follow these guidelines.

Alternative guidelines are available from the European Society of Medical Oncology (ESMO) [5]:

●For surgically treated intermediate/high-grade tumors, follow every three to four months for the first two to three years, then twice a year to year 5, and once yearly thereafter.

●For low-grade tumors, follow for local relapse every four to six months, with chest radiographs or CT scan at longer intervals in the first three to five years, then annually.

Some investigators suggest that routine imaging of the primary site detects few local recurrences in patients with low-risk extremity sarcomas (ie, primary tumor resected with negative margins) whose tumor beds are amenable to physical examination. Instead, they reserve imaging of the primary site for patients with high risk of local recurrence (eg, those with positive margins or who are not easily examined because of deep tumors or fibrosis in the treated area) or those with new symptoms or findings on physical examination [103,104]. In such patients, we image the primary site at approximately six-month intervals for the first two years and then yearly out to five years.

Imaging of the primary site can be accomplished using MRI or CT. For patients at high-risk for local recurrence, we generally prefer MRI over CT scanning. When planning the posttreatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for subsequent cancers. (See "Radiation-related risks of imaging" and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

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 5th to 6th 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 10th to 12th 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

●Multidisciplinary treatment approach – The management of soft tissue sarcomas (STS) is ideally carried out in a center with appropriate expertise. Such centers should have expertise in pathology, surgical oncology, orthopedic surgery, plastic surgery, adult or pediatric medical oncology, radiation oncology, and physical therapy. (See 'Importance of multidisciplinary evaluation and management' above.)

●Superficial trunk sarcomas – The management of patients with superficial trunk sarcomas is similar to those with extremity STS, as the clinical behavior of these tumors are comparable. This approach is consistent with guidelines from the National Comprehensive Cancer Network (NCCN). (See 'Superficial trunk sarcomas' above.)

●General treatment approach – In treating STS of the extremities and superficial trunk, the major therapeutic goals are patient survival, avoidance of a local recurrence, maximizing function, and minimizing morbidity. There are a wide variety of clinical situations that arise from involvement of a variety of different anatomic sites, the range of histologies, and variability in grade and tumor size. As a result, for most patients with either an extremity or superficial trunk sarcoma, treatment must be individualized.

The following suggestions serve as a useful guide to therapy and are generally consistent with consensus-based guidelines for multidisciplinary management of extremity and truncal sarcomas from the European Society for Medical Oncology (ESMO), NCCN, and the American Society for Radiation Oncology (ASTRO). (See 'General approach to treatment' above.).

●Principles of surgical resection – Surgical resection of the primary tumor is an essential component of treatment for virtually all patients. The guiding principle is wide excision (ie, total en bloc excision) of the primary tumor with an intact margin of normal surrounding tissue and avoidance of violating the tumor plane. (See 'Resection' above.)

●Indications for surgery alone – Other than in the pediatric setting, indications for surgical excision alone are not entirely clear, and this approach is usually reserved for the following patients (see 'Are there patients for whom RT is not needed?' above):

•Adult patients with superficial (to the fascia) low-grade tumors that are 5 cm or less in diameter.

•Select patients with small purely intramuscular sarcomas, including higher grade tumors that can be resected with a wide surgical margin of muscle and still preserve function.

•For pediatric patients with low-grade nonrhabdomyosarcoma STS, radiation therapy (RT) can be withheld and reserved for those with recurrent disease. This approach may also be offered to pediatric patients with high-grade nonrhabdomyosarcoma STS up to 5 cm in size excised with negative margins. (See 'Are there patients for whom RT is not needed?' above.)

●Indications for definitive RT – For patients who are medically inoperable, or if a function-preserving resection is not possible and amputation is not accepted, definitive RT is appropriate. (See 'Definitive RT' above.)

●Approach to combined modality therapy – For all other sarcomas without indications for surgery or radiation therapy alone, we recommend the addition of RT to surgical excision to improve local control (Grade 1B). RT can be administered either preoperatively or postoperatively. Preoperative RT is associated with similar oncologic outcomes to postoperative RT, but there is a difference in toxicity profile. (See 'Choosing between preoperative and postoperative RT' above and "Radiation therapy techniques for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Preoperative treatment and doses'.)

•Indications for preoperative RT – For most patients with intermediate- or high-grade tumors either of the extremities or the superficial trunk, as well as those with large, low-grade tumors where the surgeon expects close or positive margins, we suggest preoperative rather than postoperative RT (Grade 2A). (See 'Choosing between preoperative and postoperative RT' above.)

•Indications for postoperative RT – Postoperative radiation may be offered to the following groups:

-Patients with infiltrative subcutaneous myxofibrosarcomas where it is very difficult to define an appropriate preoperative radiation target volume based on preoperative imaging.

-Those with additional risk factors for acute wound healing problems from RT (ie, where the incised skin/subcutaneous tissues cannot be spared from RT).

●Is there a role for chemoradiation? – The optimal approach to chemoradiation in patients with STS of the extremities is not established and is usually based on institutional expertise and preferences. Outside of a well-established treatment regimen for specific sarcoma subtypes such as Ewing sarcoma or rhabdomyosarcoma, our approach is to offer chemoradiation as part of a clinical trial. If trial participation is not feasible, chemoradiation may be selectively offered to medically fit patients with a good performance status and high- to intermediate-grade, large (>5 cm) tumors. (See 'Is there a role for chemoradiation?' above and "Treatment of Ewing sarcoma" and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

●Posttreatment surveillance – Our approach to posttreatment surveillance is as follows (see 'Posttreatment sarcoma surveillance' above):

•For patients with stage I disease (table 1), we obtain a history and physical examination at three- to six-month intervals for the first two years, and yearly thereafter.

•For patients with stage II or III disease (table 1), we obtain a history and physical examination and chest imaging every three to six months for two to three years, then every six months for the next two years, then annually.

•For patients at higher risk of local recurrence (such as those with positive margins or whose primary tumor site is not easily examined) we perform periodic imaging of the primary site at approximately six-month intervals for the first two years and then yearly out to five years. For such patients, we generally prefer magnetic resonance imaging (MRI) over computed tomography (CT) scanning to reduce radiation exposure and the risk for subsequent cancers.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David Harmon, MD, and Thomas F DeLaney, MD, who contributed to earlier versions of this topic review.