INTRODUCTION — Soft tissue sarcomas (STS) are rare malignant tumors that arise from extraskeletal connective tissues, including the peripheral nervous system. They can arise at any body site.
Treatment for locally recurrent and locally advanced, potentially unresectable STS of the extremities will be reviewed here. The clinical presentation, diagnosis, and staging of STS; overview of multimodality treatment options for localized primary STS of the extremities and chest wall; the use of adjuvant (ie, postoperative) and neoadjuvant (ie, preoperative) chemotherapy for extremity STS; and the treatment of STS in locations other than the extremities and chest wall (head and neck, breast, and retroperitoneal sarcomas) are discussed separately.
●(See "Head and neck sarcomas".)
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 sarcomas, including surgical, orthopedic, medical, pediatric, and radiation oncology. The multidisciplinary team approach to the care of STS optimizes treatment planning, minimizes duplication of diagnostic studies, and reduces the time to implementation of the definitive therapeutic protocol, and the expertise gained by dedicated subspecialists improves clinical outcomes.
LOCALLY RECURRENT DISEASE — Approximately 10 to 15 percent of patients with extremity STS who are treated with complete resection and adjunctive radiation therapy (RT) will develop a local tumor failure, the majority within the first two years [1-4]. A local recurrence is associated with a significant worsening of prognosis, although whether the local relapse is causative or simply a marker of worse tumor biology is debated [5-12]. At least in theory, the two mechanisms might coexist and possibly interact, with both contributing to outcomes. On the other hand, if local control can be regained after aggressive management of a local recurrence and there are no metastases, prognosis may not necessarily be adversely impacted.
The approach to the patient with an isolated local recurrence is similar to that for primary disease, with some modification depending on whether the patient has received previous RT.
Overview of the therapeutic approach
●All patients – For most patients with a locally recurrent STS, we recommend reresection rather than nonoperative therapy, if possible. Surgery is an important component of successful therapy for these patients. As with primary treatment, the goal is to salvage the limb with a complete resection and wide margins. (See 'Reresection' below.)
●No prior radiation – For patients who have not been previously irradiated, we recommend external beam RT in addition to surgical resection to improve rates of local control.
•Timing of RT – While we tend to favor neoadjuvant radiation in patients receiving radiation at the time of primary treatment, there are less data available on the optimal sequence of surgery and radiation for patients with locally recurrent tumors. Some of the arguments in favor of neoadjuvant radiation, such as smaller field size with neoadjuvant radiation, may not apply to patients who have a local recurrence because they have already undergone a major resection, and all of the previously manipulated tissues are theoretically at risk and might need to be irradiated, either before or after salvage surgery. Thus, the decision to pursue neoadjuvant or adjuvant radiation must be individualized, taking into account the size and resectability of the recurrence as well as the extent of the prior and planned surgical field. (See 'Radiation therapy' below.)
•Chemoradiation – For most patients, we suggest RT rather than chemoradiation outside the setting of a clinical trial, but there is no consensus on this issue, and institutional practice varies. Initial chemoradiation is an acceptable alternative option to RT alone for medically fit patients with a good performance status and large, initially unresectable or recurrent tumors. The optimal chemoradiation approach is not established, and the choice is usually based upon institutional preference and expertise. (See 'Neoadjuvant chemoradiation' below.)
●Previously irradiated – The decision as to optimal local therapy is more difficult in previously irradiated patients. Options include wide local excision (WLE) alone (if it seems likely that a complete resection can be accomplished with good functional results), limb-sparing surgery with brachytherapy, amputation, or where available, regional chemotherapy or systemic chemotherapy plus regional hyperthermia. This decision must be individualized based upon the location and size of the tumor recurrence, the availability of some of these treatments (such as regional hyperthermia), institutional expertise, and the wishes of a well-informed patient. (See 'Previously irradiated patients' below.)
For patients who are going to receive additional RT to enhance local control, many clinicians favor adjuvant brachytherapy or neoadjuvant or adjuvant intensity-modulated RT (IMRT) to reduce the risk of late radiation-associated toxicity. Potential risks of reirradiation in this setting include wound healing problems, osteonecrosis, nerve damage, fibrosis, poor functional outcome, need for reoperation, and subsequent amputation. Since the most difficult challenge is wound healing, it is helpful to have plastic surgical expertise for rotational and free-vascularized soft tissue flaps to aid wound healing. It may be possible to remove all or part of the irradiated tissue with the tumor. (See 'Reirradiation' below.)
Reresection — Surgery is an important component of successful salvage therapy for locally recurrent tumors . As with primary treatment, the goal is to salvage the limb with a limb-sparing resection, if possible. However, approximately 10 to 25 percent of patients with locally recurrent disease will be deemed unsuitable for local resection because of involvement of major nerves and blood vessels, bone or extensive soft tissue invasion, and skin involvement [13-15]. When a complete resection would render the extremity nonfunctional, or if complete tumor control is not achievable with limb-salvage techniques, amputation should be considered. Possible options in this setting include limb-sparing surgery with neoadjuvant or adjuvant RT, initial chemoradiation, or where available and appropriate, systemic chemotherapy with regional hyperthermia and regional chemotherapy, which in Europe includes the use of tumor necrosis factor (TNF), an agent that is not available in the United States. (See 'Chemotherapy with regional hyperthermia' below and 'Regional chemotherapy' below.)
In many cases, a large soft tissue defect will be created from resection of a recurrence, and often this is in a previously irradiated field. A surgical team that includes plastic surgical colleagues with expertise in rotational flap and free-tissue transfers is essential to maximize the chance of wound healing, particularly in previously irradiated patients. A retrospective study of microsurgical outcomes in consecutively treated patients with extremity and trunk sarcoma undergoing free tissue transfer between 2007 and 2012 was conducted from a prospectively collected database . Outcomes in preoperatively (ie, neoadjuvantly) irradiated patients were compared with non-irradiated patients. Microvascular complications (intraoperative revision, flap re-exploration, flap loss) were uncommon and similar between the radiated and non-irradiated groups (4 of 32 and 2 of 14, respectively, p>0.05). Recipient site wound healing complications (ie, not flap related) occurred significantly more frequently in previously irradiated patients (16 events) compared with the control group (two events). There was no significant difference in limb salvage rate or Toronto Extremity Salvage Score (TESS)/Musculoskeletal Tumor Society (MSTS) functional outcome scores between the two patient groups.
Patients without prior radiation therapy
Radiation therapy — Limb-sparing surgery alone for patients with locally recurrent tumors provides long-term local control in only a minority of patients unless wide margins completely around the tumor can be achieved. The optimal amount of uninvolved tissue (thickness) remains controversial, but fascia margins of 2 to 3 mm are probably adequate, whereas 1 cm or more is desirable when the margin is skeletal muscle or fat. For patients whose primary treatment was surgery alone, reexcision is usually combined with RT, either given in the neoadjuvant or adjuvant setting.
We tend to favor neoadjuvant radiation for most patients with primary tumors based on the Canadian randomized trial of neoadjuvant versus adjuvant RT for primary (90 percent of the 190 enrolled patients) or locally recurrent (10 percent) extremity STS, which concluded that efficacy was similar using either approach and that the higher rate of generally reversible acute wound healing complications in neoadjuvantly treated patients was offset by a lower rate of generally irreversible late complications, including grade 3 to 4 fibrosis. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Choosing between preoperative and postoperative RT'.)
However, only 9 percent of the patients in this study had locally recurrent tumors. There are less data available on the optimal sequence of surgery and radiation in these patients. Some of the arguments in favor of neoadjuvant radiation, such as smaller field size with neoadjuvant radiation, may not apply to patients who have a local recurrence because they have already undergone a major resection, and all of the previously manipulated tissues are theoretically at risk and might need to be irradiated, either before or after salvage surgery. Thus, the decision to pursue neoadjuvant versus adjuvant radiation must be individualized.
Neoadjuvant chemoradiation — Initial chemoradiation is an acceptable alternative option to RT alone for medically fit patients with a good performance status and large, initially unresectable or recurrent tumors, if no prior radiation to the extremity has been administered. The optimal chemoradiation approach is not established, and the choice is usually based upon institutional preference and expertise. Of note, prior receipt of a particular chemotherapy agent during initial treatment of a localized STS may limit its subsequent use for chemoradiation in recurrent tumors (eg, anthracyclines due to the risk of cumulative cardiotoxicity). (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)
Previously irradiated patients — Decisions regarding local therapy are more difficult in patients who underwent RT as a component of primary treatment. For these patients, options include wide or radical resection, limb-sparing surgery plus brachytherapy, limb-sparing surgery plus reirradiation (IMRT or proton therapy), and where available and appropriate, systemic chemotherapy with regional hyperthermia or regional chemotherapy. Amputation is also at times an option that restores function while eradicating the local recurrence. Amputation should not always be viewed as a failure, when at times, it offers good function while avoiding the potential side effects of some of the adjuvant therapies. Some patients may choose this option if it means extending survival and if it offers reasonable function, especially with modern prosthetics. This is related to the location of the tumor in an extremity, as high-thigh amputations, hip disarticulation, and hemipelvectomy have worse function than a more distal-thigh and below-knee amputation.
Reirradiation — For patients who have had prior RT and are going to receive additional RT to enhance local control, many clinicians favor adjuvant brachytherapy or neoadjuvant or adjuvant IMRT to reduce the risk of late radiation-associated toxicity. Proton reirradiation is also another available option.
There are no randomized trials testing the benefits and risks of reirradiation in patients with a recurrent tumor who underwent RT as a component of primary treatment. An additional course of external beam RT may exceed the maximal tolerance for adjacent normal tissues, resulting in problems with wound healing and radiation fibrosis. As an example, in a series of 14 patients undergoing reirradiation (predominantly with external beam RT) for recurrent STS of the extremity or trunk after gross total resection, one-half had serious complications requiring reoperation or leading to permanent functional impairment .
Data for brachytherapy and proton reirradiation are as follows:
●Brachytherapy – However, additional radiation doses can often be safely administered using brachytherapy techniques [13,18,19]. The success of this approach can be illustrated by the following observations:
•One report detailed the outcome of salvage therapy in 23 patients with an isolated locally recurrent STS after limb-sparing surgery and RT . Seven patients had an amputation, while 16 underwent another limb-sparing resection without (n = 11) or with (n = 5) reirradiation. Seven of the 11 who did not undergo additional RT after surgery had a second relapse, five of whom were subsequently treated by limb-sparing reresection and reirradiation.
Of the 10 reirradiated patients, brachytherapy alone was administered to six, brachytherapy plus external beam RT was administered to one, and three received external beam RT alone. The median radiation dose at the time of retreatment was 49.5 Gy, and the median cumulative soft tissue dose was 100 Gy. None of the patients treated with surgery plus reirradiation relapsed with a median follow-up of 24 months. Six (60 percent) experienced significant wound healing complications, but three recovered completely.
•In another series, 26 patients with an STS recurrence in a previously irradiated field underwent margin-negative reresection and perioperative brachytherapy (47.2 Gy) . With a median follow-up of 16 months, the estimated five-year local control and disease-free survival rates were 52 and 33 percent, respectively. Complications developed in five patients; three had wound breakdown, one had osteonecrosis, and one had neuralgia. Operative intervention was required in four.
●Proton reirradiation – Recurrent STS in a previously radiated field is one of the indications for the use of proton reirradiation. A series on the use of proton radiation for 23 patients with previously irradiated STS or sarcomas arising in a previous irradiation field reported no grade 4 to 5 toxicities . One patient (4 percent) experienced acute grade 3 dysphagia. There were two grade 3 late wound infections (10 percent) and one grade 3 late wound complication (5 percent). At a median follow-up of 36 months, the three-year cumulative incidence of local failure was 41 percent.
In patients for whom further WLE is possible, limited observational data suggest that the addition of reirradiation improves local control, but has similar survival and results in high rates of wound complications. A review of the MD Anderson experience included 62 patients who had a sarcoma recurrence in an irradiated field . Treatment consisted of WLE alone (n = 25) or with reirradiation (n = 37, brachytherapy alone in 33). Local control rates were higher in the reirradiated group (39 versus 58 percent at five years), but there were no differences in five-year disease-specific survival (67 versus 66 percent) or distant metastasis-free survival.
However, interpretation of these results is limited by imbalances in the two groups in terms of histopathologic subtype, grade of differentiation, and tumor site. There was a high incidence of positive resection margins in both groups (14 of 25 versus 12 of 37 in the WLE and reirradiation groups, respectively), as well as a high rate of major wound complications after reirradiation (57 percent). These rates are higher than those reported by others (approximately 13 to 20 percent) [18,21].
Regional chemotherapy approaches — Where available, TNF-based isolated limb perfusion (ILP) can avoid amputation in most patients with recurrent extremity STS in a prior irradiated field. TNF-based therapies are unavailable in the United States outside of a clinical trial.
One report detailed outcomes of ILP in 26 patients who were felt to require amputation for a locally recurrent STS in a previously irradiated field; four required two separate ILP treatments . There were six complete and 15 partial responses (objective response rate 70 percent), and limb salvage was achieved in 17 (65 percent). At a median follow-up of 22 months, the local recurrence rate was higher in those with multiple, as compared with single, tumors (45 versus 27 percent). Ten patients (35 percent) died of systemic metastases, and the remainder remained alive at last follow-up.
A description of the ILP procedure and additional data on the outcomes of ILP (which has most often been performed for patients with a primary unresectable extremity STS) are provided below. The availability of ILP utilizing TNF is limited to specialized centers outside of the United States; TNF is unavailable for patient use in the United States. (See 'Isolated limb perfusion' below.)
Comparable efficacy with less toxicity has been reported with an alternative type of regional chemotherapy treatment called isolated limb infusion (ILI). However, as with ILP, the availability of ILI is limited to specialized centers. (See 'Isolated limb infusion' below.)
Chemotherapy with regional hyperthermia — Systemic chemotherapy combined with regional hyperthermia may represent another potentially limb-sparing technique for patients with a locally recurrent tumor in an irradiated field. This technique is not widely available in the United States. A randomized study from the European Organisation for Research and Treatment of Cancer (EORTC; study 62961) showed better local control for regional hyperthermia plus chemotherapy than for chemotherapy alone for those patients with the highest risk of local recurrence. (See 'Systemic chemotherapy with and without regional hyperthermia' below.)
Adjuvant chemotherapy — As with primary STS, the role of adjuvant chemotherapy for locally recurrent STS is undefined. This topic is addressed in detail separately. (See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities".)
UNRESECTABLE LOCALLY ADVANCED DISEASE — For the relatively uncommon patients with advanced STS in whom the tumor has progressed beyond surgical resectability, treatment options depend upon the site of tumor involvement and the treating center. There are no randomized phase III trials to define the most effective option, and available treatment strategies vary widely between different countries and expert centers. Importantly, the definition of "unresectable" is variable with the surgeon and/or treating center. Surgeons may differ with regard to their willingness to resect major nerves or vessels (with bypass grafting). Experienced treatment centers with a multidisciplinary team experienced with these challenging patients are best suited to deciding on the local control options. (See 'Importance of multidisciplinary evaluation and management' above.)
Overview of the therapeutic approach
●When available, we encourage patients to enroll in a clinical trial testing new strategies. If trial participation is not feasible, we suggest chemoradiation rather than radiation therapy (RT) alone for most patients. For some initially unresectable tumors, there may be a sufficient response to permit later limb-sparing surgery. (See 'Radiation therapy and chemoradiation' below.)
●Where available, isolated limb infusion (ILI) and isolated limb perfusion (ILP) with low-dose tumor necrosis factor (TNF)-alpha plus melphalan represent potentially limb-preserving options, but these procedures are not in widespread use in the United States. (See 'Regional chemotherapy' below.)
●Although not used much in the United States, regional hyperthermia with systemic chemotherapy is another potentially limb-preserving option for high-risk extremity and truncal tumors in other parts of the world where it is available. Whether this approach is superior to ILP, ILI, RT alone, or chemoradiation is not clear. (See 'Chemotherapy with regional hyperthermia' above.)
●In certain cases, amputation with modern prosthetic fitting, especially in the lower extremity, may be the most reasonable option.
●For cases that are not amenable to local therapy, palliative systemic chemotherapy remains an option for treatment of locally advanced disease.
Radiation therapy and chemoradiation — At least in the United States, most patients are offered RT with or without concomitant chemotherapy. Selected patients can achieve local control with external beam RT with or without chemotherapy, especially if the tumor is small [23,24].
Perhaps more importantly, as has been seen with locally recurrent tumors that were not previously irradiated, a response to RT and chemotherapy may convert an initially unresectable tumor to one that can be resected and potentially cured. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)
Regional chemotherapy — For patients with unresectable disease limited to the extremity, regional chemotherapy has been applied with marked early success. Two techniques are available, ILP and ILI. A systematic review concluded that ILP and ILI can be safely performed for extremity soft tissue sarcomas with appreciable response rates (aggregate overall 73 percent, with 26 demonstrating a complete response) and significant limb salvage rates (74 percent) .
Despite these encouraging results, regional chemotherapy approaches are not widely available or used in the United States given the labor-intensive nature of the procedures. Furthermore, it is not clear for whom these techniques represent optimal therapy and, especially, whether there are any advantages to ILP or ILI as compared with RT with or without systemic chemotherapy in patients who are either not resectable without amputation or are truly unresectable.
Isolated limb perfusion — ILP involves surgical isolation of the vascular inflow and outflow of an extremity to separate the circulation of the affected limb from that of the remainder of the body. Thus, high concentrations of drugs can be circulated locally without exposing the rest of the body to the same level of toxicity. By excluding the liver and kidney from the perfusion circuit, drug metabolism is minimized, thus leading to sustained high concentrations of drug in the perfused limb. The isolated extremity is usually subjected to mild hyperthermia (target tissue temperature between 38.5°C and 40°C) to improve antitumor effect without subjecting the entire body to the risks of hyperthermia.
Hyperthermic ILP is performed under general anesthesia. ILP of the lower extremities is most commonly performed via cannulation of the external iliac vessels; the axillary vessels are used in the arm. However, ILP can be performed via the femoral or popliteal vessels in the lower extremity and via the brachial vessels in the arm in certain clinical situations. The vessels are cannulated and connected to the inflow and outflow lines of an extracorporeal bypass circuit identical to that used in cardiac surgery. A tourniquet is applied around the root of the extremity to occlude superficial veins that could communicate between the limb circuit and the remainder of the body.
Further details of the procedure are described separately. (See "Cutaneous melanoma: In-transit metastases", section on 'Isolated limb perfusion'.)
Most studies of ILP for locally advanced STS have utilized high-dose TNF-alpha and melphalan with or without interferon. Recombinant TNF-alpha is a highly potent antineoplastic agent, but systemic administration in humans results in a life-threatening septic shock-like syndrome. The regional administration of TNF-alpha via ILP eliminates systemic side effects and permits the delivery of a TNF dose that is 10-fold higher than the maximally tolerated systemic dose. Systemic toxicity is generally moderate and includes fever, chills, and a hyperdynamic circulatory state. Toxicity seems to be reduced and efficacy maintained with lower doses of TNF-alpha (1 mg) .
Acute treatment-related toxicity was addressed in a report of 88 patients in which acute regional toxicity was mild (grade 1 to 2, corresponding to either no toxicity, or mild erythema or edema) in 86 percent, more severe (grade 3 with considerable erythema/edema with slight blistering, with or without impairment of mobility ) in 10 percent, and grade 4 (extensive epidermolysis or obvious damage to the deep tissues causing definite impairment; threatening or manifest compartment syndrome) in 3 percent. There were no grade 5 toxicities (reaction requiring amputation).
Several studies report encouraging results with TNF-alpha-based ILP for unresectable extremity STS (table 1) [22,26,28-44]. Follow-up in nearly all of these series is limited to two years or less (and most of the data on long-term outcomes are from actuarial estimates, with one exception). Long-term outcomes were addressed in a Dutch cohort of 208 patients who were treated with TNF-alpha-based ILP for locally advanced (n = 134) or locally recurrent (n = 97) extremity STS; the median follow-up duration was 12 years, range 5 to 19 . Overall, the limb salvage rate was 81 percent, 30 percent had a local recurrence, and 5- and 10-year overall survival rates were 42 and 33 percent, respectively.
These results support the view that ILP appears to provide the opportunity to salvage limbs that might otherwise require amputation because of a locally advanced or recurrent tumor. However, the quality of the available studies is limited, with no randomized trials comparing ILP with another treatment regimen, significant methodological heterogeneity in the available studies, and a lack of uniformity in defining potential candidates and response outcomes . Furthermore, ILP with TNF-alpha and melphalan is a complex and time-consuming procedure, and expertise in this technique is not widely available except in selected centers in Europe where the procedure has received regulatory approval and is considered a safe and effective method for limb salvage . There is no access to TNF in the United States. It should also be acknowledged that there are limited data on the function of the limb and quality of life in patients treated by ILP.
Isolated limb infusion — An alternative type of regional chemotherapy treatment is ILI, which was developed at the Sydney Melanoma Unit for treatment of locoregionally advanced melanoma. (See "Cutaneous melanoma: In-transit metastases", section on 'Isolated limb infusion'.)
The artery and vein of an extremity are accessed percutaneously using high flow catheters, and a pneumatic tourniquet is used proximally to isolate the extremity (figure 1). ILI differs from ILP in that it circulates blood in the isolated extremity at a much slower rate than ILP and for only 30 minutes. During ILI, the extremity is hypoxic, which leads to marked acidosis. In contrast, with hyperthermic ILP, the pump oxygenator maintains oxygenation and normal acid/base status of the extremity. In addition, ILI also uses standard chemotherapy drugs and not TNF.
The safety and efficacy of ILI for locally advanced, unresectable extremity STS has been addressed in the following reports:
●A retrospective review included 21 patients with locally advanced extremity STS treated at a single institution with ILI using high-dose chemotherapy (mainly melphalan and dactinomycin) . Fourteen received ILI prior to definitive surgery; seven had either an inoperable recurrence or metastatic disease.
Twelve patients had a complete response to therapy, seven had a partial response, and two had no response for an overall response rate of 90 percent. Nine of the 14 patients treated preoperatively (65 percent) had a pathologic complete response. At a median follow-up of 28 months, there were nine local recurrences (42 percent), and the overall disease-specific survival was 62 percent. Only five patients ultimately required limb amputation for disease progression.
●A second report included 40 patients undergoing preoperative ILI using doxorubicin plus external beam RT for an extremity STS for which amputation was felt to be the only available treatment option . All patients had a single course of ILI with doxorubicin (0.7 and 1.4 mg/kg for the upper and lower limbs, respectively), followed three to seven days later by neoadjuvant external beam RT (35 Gy in 10 fractions); surgery was performed three to seven weeks later.
Local morbidity was limited to edema or erythema (grade 2 ) in eight patients, considerable erythema or edema with some blistering and slightly disturbed mobility (grade 3 ) in four, and no more serious toxicity. A tumor response was seen in 85 percent, rendering most patients resectable. At a median follow-up of 15 months, limb salvage was achieved in 83 percent.
Neither of these studies looked at function of the salvaged limb to determine if the quality of life was comparable or superior to amputation. In addition, in the second study, radiation was used in addition to infusional chemotherapy. Five of 12 in the first study and 17 percent of the second study ultimately resulted in amputation.
Although randomized trials have not been carried out, these reports suggest that ILI can provide locoregional tumor control in highly selected patients with a locally advanced, unresectable extremity STS. This approach is best used within the context of a clinical trial.
Systemic chemotherapy with and without regional hyperthermia — The benefit of induction chemotherapy alone is uncertain. Adequately powered, randomized phase III trials are not available, and the results of uncontrolled studies are conflicting. (See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities", section on 'Neoadjuvant chemotherapy'.)
However, at least some data from Europe suggest that systemic chemotherapy combined with regional hyperthermia may represent an alternative, potentially limb-sparing technique for patients with locally advanced, unresectable, high-grade STS of the extremities and trunk as well as those with a locally recurrent tumor in an irradiated field [49-52].
Benefit for this approach was suggested in a trial (European Organisation for Research and Treatment of Cancer [EORTC] study 62961) in which 341 patients with locally recurrent (n = 37), incompletely resected or resected with a surgical margin <1 cm (n = 142), or grade 2 or 3 primary STS ≥5 cm (n = 162) of the extremity (43 percent) or a non-extremity site (pelvis, abdomen, trunk, head and neck) were randomly assigned to four courses of systemic chemotherapy with or without regional hyperthermia, followed by aggressive local therapy (surgery and/or RT) and four additional courses of chemotherapy with or without regional hyperthermia . Chemotherapy consisted of 21-day cycles of etoposide (125 mg/m2 on days 1 and 4), ifosfamide (1500 mg/m2 per day on days 1 through 4), and doxorubicin (50 mg/m2 on day 1 only), while regional hyperthermia was performed by exposing the affected body part to temperatures between 40 and 43 degrees for 60 minutes on days 1 and 4 of each chemotherapy course.
The objective response rate for neoadjuvant chemotherapy was significantly higher in the hyperthermia group (29 versus 13 percent), although the number of patients who had definitive tumor resection as a component of local treatment was similar (two-thirds of both groups), as were amputation rates (5 versus 6 percent). At a median follow-up of 34 months, disease-free survival (median 32 versus 18 months) and two-year local progression-free survival (76 versus 61 percent) significantly favored the regional hyperthermia arm. However, the trial was heavily weighted towards retroperitoneal sarcomas, which have a higher local recurrence rate than do extremity sarcomas. In fact, the higher rate of two-year local progression-free survival with hyperthermia was significant in those with non-extremity primary tumors (64 versus 45 percent) but not in those with an extremity sarcoma (92 versus 80 percent).
Overall survival was not significantly better in the hyperthermia group in this initial report when all patients were analyzed (59 versus 57 percent); however, in a later analysis with a median follow-up of 11.3 years, patients randomized to chemotherapy plus hyperthermia had significantly better disease-specific survival (counting deaths due to sarcoma or its treatment) at both 5 (62.7 versus 51.3 percent) and 10 years (52.6 versus 42.7 percent) . The survival advantage was consistent across all subgroups (age, site, surgical extent, use of RT, size, grade, and histologic subtype).
Quality assurance guidelines for regional hyperthermia are available . Although not used much in the United States, regional hyperthermia with systemic chemotherapy is an option for high-risk extremity tumors in other parts of the world where it is available. Whether this approach is superior to ILP with low-dose TNF-alpha and melphalan, ILI, or RT with or without chemotherapy will require a randomized trial.
If neoadjuvant chemotherapy is chosen, the choice of regimen is empiric; we generally prefer the AIM regimen (doxorubicin, ifosfamide, mesna). In Europe, epirubicin, ifosfamide, and mesna are used in some institutions. (See "Treatment protocols for soft tissue and bone sarcoma".)
Palliative chemotherapy — For cases that are not amenable to local therapy, palliative systemic chemotherapy remains an option for treatment of locally advanced disease. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)
Guidelines from expert groups — Consensus-based guidelines for treatment of unresectable, locally advanced STS are available from the National Comprehensive Cancer Network (NCCN)  and the European Society for Medical Oncology (ESMO):
●NCCN guidelines  for management of patients with locally advanced, unresectable extremity STS include initial RT, chemotherapy, chemoradiation, or regional limb therapy (at institutions with experience with this approach) followed by surgical resection if the patient becomes resectable.
For patients who remain unresectable after neoadjuvant therapy, options include definitive RT (in patients who have not had a prior course of irradiation), chemotherapy, palliative surgery, amputation, observation (for an asymptomatic patient), or best supportive care. The guidelines do not address the use of ILP, ILI, or chemotherapy with regional hyperthermia.
Links to additional society guidelines can be found elsewhere. (See 'Society guideline links' below.)
POSTTREATMENT SURVEILLANCE — The main purpose of posttreatment surveillance is the detection of local recurrences and pulmonary metastases. Isolated, limited metastatic tumor to the lung is frequently asymptomatic and potentially resectable for cure. Limited pulmonary metastases can also be treated with curative intent using stereotactic body radiation therapy. (See "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma" and "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Soft tissue sarcoma'.)
We recommend frequent follow-up, particularly in the first two years after treatment, given that two-thirds of recurrences will be detected during this period.
Posttreatment cancer surveillance guidelines have not been established through rigorous clinical investigation. We generally follow the consensus-based recommendations of the National Comprehensive Cancer Network (NCCN) , which are discussed in more detail separately. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Posttreatment sarcoma surveillance'.)
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 evaluation of soft tissue sarcoma – Soft tissue sarcomas (STS) are rare malignant tumors that arise from extraskeletal connective tissues at any body site. 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 sarcomas, including surgical, orthopedic, medical, pediatric, and radiation oncology. (See 'Introduction' above and 'Importance of multidisciplinary evaluation and management' above.)
●Treatment goals – In treating both primary and recurrent STS of the extremities, the major therapeutic goals are 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. (See 'Overview of the therapeutic approach' above.)
●Locally recurrent, resectable soft tissue sarcomas – For patients with a locally recurrent STS, we recommend reresection rather than nonoperative therapy, if possible (Grade 1B). (See 'Reresection' above.)
•Patients without prior radiation therapy – For patients who have not been previously irradiated, in addition to limb-sparing surgery, we recommend external beam radiation therapy (RT) (Grade 1B). In this setting, neoadjuvant (ie, preoperative) or adjuvant (ie, postoperative) RT can be employed, with the choice tailored to the individual patient, considering the size and resectability of the recurrence, as well as the extent of the prior and planned surgical field (Grade 2B). (See 'Patients without prior radiation therapy' above.)
-Radiation versus chemoradiation – We suggest RT rather than chemoradiation for most patients (Grade 2C), but there is no consensus on this issue, and institutional practice varies. Initial chemoradiation is an acceptable alternative option to RT alone for medically fit patients with a good performance status. The optimal chemoradiation approach is not established, and the choice is usually based upon institutional preference and expertise. (See 'Radiation therapy' above and 'Neoadjuvant chemoradiation' above.)
•Patients with prior radiation therapy – The decision as to optimal local therapy is more difficult in previously irradiated patients. Options include wide local excision (WLE) alone, limb-sparing surgery with brachytherapy, limb-sparing therapy with reirradiation (intensity-modulated RT [IMRT] or proton therapy), amputation, or where available, regional chemotherapy or systemic chemotherapy plus regional hyperthermia. This decision must be individualized based upon the location and size of the tumor recurrence, institutional expertise, and the wishes of a well-informed patient. (See 'Previously irradiated patients' above.)
For patients who have had prior RT and are going to receive additional RT to enhance local control, many clinicians favor adjuvant brachytherapy or neoadjuvant or adjuvant IMRT to reduce the risk of late radiation-associated toxicity. Proton reirradiation is also another available option. For these patients, it is helpful to have plastic surgical expertise for rotational and free-vascularized soft tissue flaps to help with wound healing. It may be possible to remove all or part of the irradiated tissue with the tumor. (See 'Reirradiation' above.)
●Unresectable, locally advanced soft tissue sarcomas – For patients with advanced STS in whom the tumor has progressed beyond surgical resectability, treatment options depend upon the site of tumor involvement and the treating center. There are no randomized phase III trials to define the most effective option, and treatment strategies vary widely between different countries and expert centers. (See 'Unresectable locally advanced disease' above.)
•When available, we encourage patients to enroll in a clinical trial testing new strategies.
•If trial participation is not feasible, in order to give the patient the best chance to reduce tumor burden, we suggest alternating chemotherapy/RT or concurrent chemotherapy and radiation, rather than RT alone for most patients with intermediate- or high-grade tumors larger than 5 cm (Grade 2C). For some initially unresectable tumors, there may be a sufficient response to permit later limb-sparing surgery. (See 'Radiation therapy and chemoradiation' above.)
•Where available, isolated limb infusion (ILI) and isolated limb perfusion (ILP) with low-dose tumor necrosis factor (TNF)-alpha plus melphalan represent potentially limb-preserving options, but these procedures are not in widespread use in the United States. (See 'Regional chemotherapy' above.)
•Although not used much in the United States, regional hyperthermia with systemic chemotherapy is another potentially limb-preserving option for high-risk extremity and truncal tumors in other parts of the world where it is available. Whether this approach is superior to ILP, ILI, RT alone, or chemoradiation is not clear. (See 'Systemic chemotherapy with and without regional hyperthermia' above.)
•In certain cases, amputation with modern prosthetic fitting, especially in the lower extremity, may be the most reasonable option.
•For cases that are not amenable to local therapy, palliative systemic chemotherapy remains an option for treatment of locally advanced disease. (See 'Palliative chemotherapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.
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