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Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities

Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities
Literature review current through: May 2024.
This topic last updated: Apr 23, 2024.

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

In treating STS of the extremities, the major therapeutic goals are long-term survival, avoidance of a local recurrence, maximizing function, and minimizing morbidity. Surgical resection is the cornerstone of potentially curative treatment. For nearly all patients with extremity sarcomas >5 cm, the addition of radiation therapy (RT) improves local control, and it has also had a significant impact on limb salvage. There are advantages to preoperative (neoadjuvant) as compared with postoperative (adjuvant) administration of RT, and for neoadjuvant therapy utilizing combinations of RT and chemotherapy, particularly for recurrent and large, high-grade primary tumors. These topics are discussed in detail separately. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk" and "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities".)

Systemic chemotherapy is nearly always a mandatory component of treatment for several STS that occur predominantly in children (eg, rhabdomyosarcoma, Ewing sarcoma, and extraosseous osteogenic sarcoma). However, the value of adjuvant chemotherapy in patients undergoing resection of the adult-type localized extremity STS (eg, leiomyosarcoma, liposarcoma, synovial sarcoma) remains controversial due to the complexity of the group of diagnoses involved.

This topic review will discuss the use of adjuvant and neoadjuvant chemotherapy in the treatment of adult-type extremity STS. The role of chemotherapy in the treatment of retroperitoneal STS, rhabdomyosarcoma and Ewing sarcoma, and neoadjuvant combined modality approaches for patients with large, high-grade or recurrent extremity STS are discussed in detail separately. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment" and "Treatment of Ewing sarcoma" and "Surgical treatment and other localized therapy for metastatic soft tissue sarcoma" and "Initial management of retroperitoneal soft tissue sarcoma".)

ADJUVANT CHEMOTHERAPY

Pediatric-type sarcomas — The addition of systemic chemotherapy to local therapy significantly improves outcomes for the common pediatric types of sarcoma (rhabdomyosarcoma, osteogenic sarcoma, and Ewing sarcoma). Most modern treatment plans utilize initial (induction or neoadjuvant) chemotherapy followed by local treatment and additional (adjuvant) chemotherapy.

Rhabdomyosarcoma — The vast majority of patients with rhabdomyosarcoma are children. The routine use of multiagent chemotherapy (typically vincristine, dactinomycin, and cyclophosphamide, VAC, or regimens used for Ewing sarcoma), in addition to surgery and radiation therapy (RT), has contributed significantly toward increasing cure rates among those with localized disease. The rare cases of rhabdomyosarcoma that arise in adults are managed similarly, with the exception of older adults who may not be eligible for multiagent chemotherapy due to age or comorbidities. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

Ewing sarcoma — Among children, Ewing sarcoma is much more common in bone than in soft tissue, while in adults, it more often presents in soft tissue. Regardless of whether it arises in bone or soft tissue, the tumor is treated in the same multidisciplinary manner in adults as in children. A combination of neoadjuvant and adjuvant chemotherapy using vincristine, doxorubicin, and cyclophosphamide (VAC), with alternating cycles of ifosfamide and etoposide, is a standard of care in addition to local therapy. (See "Treatment of Ewing sarcoma", section on 'Multimodality therapy for localized disease'.)

Extraosseous osteogenic sarcomas — Osteosarcomas rarely arise in the soft tissue rather than bone (image 1 and image 2). In contrast with Ewing sarcoma, when osteogenic sarcomas arise in soft tissue rather than bone, management has, to date, followed the principles established for soft tissue tumors rather than primary bone tumors, although this remains a topic of some controversy.

In particular, while adjuvant chemotherapy is a standard component of treatment for primary bone osteosarcomas in all age groups, it has been thought to be much less effective for tumors of extraosseous origin [1]. However, at least one study suggests that outcomes may be better when children with extraosseous osteosarcoma are treated with the same combination chemotherapy protocols as used for bone-primary osteogenic sarcoma [2]. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis" and "Chemotherapy and radiation therapy in the management of osteosarcoma".)

Sarcomas more commonly seen in adults — The remainder of this discussion will focus on the use of adjuvant chemotherapy for the more common adult-type STS, such as liposarcomas, leiomyosarcomas, and synovial sarcomas.

Over 20 randomized trials and two meta-analyses have addressed the potential benefit of adjuvant chemotherapy for resected extremity STS in adults. Unfortunately, these have yielded conflicting data, and as a result, the benefit of adjuvant chemotherapy remains uncertain.

Early randomized trials — The majority of early trials used doxorubicin alone or with dacarbazine but did not employ ifosfamide, a compound only developed in the mid-1980s. Among the first 14 published randomized trials of adjuvant doxorubicin-based therapy versus surgery alone, two reported a significant survival advantage for combination chemotherapy, three found higher survival in the observation arm, and the remainder showed no difference in outcome in the treated group [3].

SMAC meta-analysis — Individual patient data from these trials, which involved 1568 adults with localized resectable STS (only some of which were localized to an extremity), were analyzed by the Sarcoma Meta-Analysis Collaboration (SMAC) and published in 1997 [4,5]. All evaluated studies randomly assigned patients postoperatively to receive or not receive adjuvant doxorubicin-containing chemotherapy; fewer than 5 percent of patients received a chemotherapy regimen that included ifosfamide. The following benefits were noted in the chemotherapy group:

Significantly longer local recurrence-free interval (hazard ratio [HR] for local recurrence 0.73, 95% CI 0.56-0.94).

Significantly longer distant recurrence-free interval (HR 0.70, 95% CI 0.57-0.85).

Significantly higher overall recurrence-free survival (HR for any recurrence 0.75, 95% CI 0.64-0.87). This corresponded to an absolute 6 to 10 percent improvement in recurrence-free survival at 10 years.

There was a trend towards better overall survival that favored chemotherapy, but it was not statistically significant (HR for death 0.89, 95% CI 0.76-1.03).

There was no consistent evidence of a difference in any endpoint according to age, sex, stage, site, grade, histology (although there was no central pathology review), extent of resection, tumor size, or exposure to RT. However, the strongest evidence of a beneficial effect on survival was shown in the subset of patients with extremity and truncal sarcomas. Among these patients who received adjuvant doxorubicin-containing chemotherapy, there was a modest but statistically significant benefit for chemotherapy (HR for death 0.80, p = 0.029), which translated into a 7 percent absolute benefit in overall survival at 10 years.

The updated meta-analysis from this group, which includes many later trials, is presented below. (See 'Updated meta-analyses' below.)

Later randomized trials — Given the suggestion of a survival benefit for extremity and truncal STS in the SMAC meta-analysis, later randomized trials largely focused on these sites. There are few randomized trials addressing the benefit of adjuvant chemotherapy for visceral or head and neck STS.

Four additional randomized trials explored the benefit of anthracycline and ifosfamide-based combination adjuvant chemotherapy in extremity STS [6-10], two of which suggest a possible survival benefit for adjuvant chemotherapy [6-8]:

In an Italian trial in which 46 percent of the enrolled patients had either synovial sarcoma or liposarcoma (two relatively chemosensitive histologies), 104 patients with high-grade, large (≥5 cm) or recurrent spindle cell sarcomas involving the extremities or girdles were randomly assigned to no postoperative therapy or to five cycles of chemotherapy [6,7]. Chemotherapy consisted of a dose intensive epirubicin/ifosfamide combination (epirubicin 60 mg/m2 on days 1 and 2 plus ifosfamide 1.8 g/m2 on days 1 to 5) with mesna and granulocyte colony-stimulating factor support. Accrual was prematurely discontinued at two years, when a significant difference in the cumulative incidence of distant metastasis was found (45 versus 28 percent), favoring the chemotherapy group.

Four-year overall survival was significantly greater in favor of chemotherapy (69 versus 50 percent), but the difference that favored the chemotherapy group lost statistical significance with median follow-up of over seven years, a finding that was attributed to the limited number of enrolled patients. Curiously, overall relapse rates (local and distant) were similar in the two groups (44 and 45 percent).

It is difficult to interpret these results since the main expected benefit of adjuvant systemic chemotherapy is to reduce the rate of distant relapse. However, this may have reflected a preponderance of patients with local recurrence later amenable to local surgical salvage approaches.

A follow-up Italian trial randomly assigned 88 patients with high-risk extremity sarcoma to surgery with or without RT (n = 43) or to surgery plus chemotherapy (n = 45, 26 with epirubicin alone and 19 to epirubicin plus ifosfamide) with or without RT [8]. The five-year survival rate of patients treated with chemotherapy was significantly higher than that of patients who did not receive chemotherapy (72 versus 47 percent). However, the large number of treatment variables and the small number of studied patients makes interpretation of this result difficult.

In contrast with these results, a survival benefit from adjuvant doxorubicin and ifosfamide-containing chemotherapy could not be shown in two other trials [9,10]:

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

An Austrian trial of 59 patients assigned to perioperative chemotherapy or surgery alone was also negative, but the small number of patients makes it likely that the study was underpowered to detect a small difference between the arms, if one were present [9].

Updated meta-analyses — An updated 2008 meta-analysis was conducted on published data from 18 randomized trials of 1953 patients with localized and potentially resectable STS that were reported between 1973 and 2002, including the Austrian and both Italian trials discussed above, but not the EORTC trial [11]. Five of the trials used doxorubicin plus ifosfamide, while the others used doxorubicin alone or in combination with other agents.

The odds ratio (OR) for local recurrence was 0.73 (95% CI 0.56-0.94) in favor of chemotherapy; the corresponding value for distant and overall recurrence was 0.67 (95% CI 0.56-0.82), again favoring chemotherapy. These values are nearly identical to those found in the earlier meta-analysis. (See 'SMAC meta-analysis' above.)

However, in contrast with the earlier analysis, the use of doxorubicin with ifosfamide was associated with a statistically significant overall survival benefit (OR for death 0.56, 95% CI 0.36-0.85). The absolute risk reduction for doxorubicin in combination with ifosfamide was 11 percent (30 versus 41 percent risk of death). Benefit could not be shown for doxorubicin alone (OR 0.84, 95% CI 0.68-1.03), implying the fundamental importance of ifosfamide in the adjuvant treatment of sarcomas overall.

Pooled analysis of the EORTC trials — In contrast with this result, a pooled analysis of individual patient data from the two largest adjuvant trials of doxorubicin and ifosfamide-based chemotherapy (both performed by the European Organisation for Research and Treatment of Cancer [EORTC [10,12]] and totaling 819 patients) was negative [13]. Compared with surgery alone, the use of postoperative adjuvant chemotherapy was not associated with a significant survival benefit, except in the subset of patients undergoing incomplete (R1) resection. In multivariate analysis, tumor size, histologic type, and grade were not associated with any progression-free or overall survival benefit from adjuvant chemotherapy.

Impact of histology — Adjuvant clinical trials in adult sarcomas have, out of necessity, included patients with multiple histologies, in contrast with pediatric studies, which focus on one specific sarcoma type. It is well recognized that myxoid/round cell liposarcomas and synovial sarcomas are relatively chemosensitive histologic types of STS, at least in the setting of metastatic disease. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Histologies where non-anthracyclines are preferred'.)

Although it has been proposed that the benefit of adjuvant chemotherapy may be preferentially seen when patients are selected based on tumor histology, grade [14] or tumor size, this hypothesis has never been validated in a prospective clinical trial in adult sarcoma patients, nor in any of the pooled analyses of randomized trial data [11,13].

Furthermore, the results from observational studies evaluating adjuvant chemotherapy in patients with the more chemotherapy-sensitive histologic types are conflicting [15-19]. While some contemporary studies suggest a potential survival benefit for adjuvant chemotherapy in patients with the liposarcoma and synovial sarcoma types of extremity STS [15,16,18], others do not [17,19,20]. Interpretation of these studies is also limited because subset data for the three forms of liposarcoma (well differentiated/dedifferentiated, myxoid/round cell, and pleomorphic) are not available. As examples:

Benefit for adjuvant chemotherapy was suggested in a single-center Italian report of 251 patients (aged 5 to 87 years) with localized synovial sarcoma [16]. Adjuvant chemotherapy was administered to 61 of 215 patients who had a macroscopically complete resection (28 percent), while the remainder received no adjuvant systemic therapy. Five-year metastasis-free survival was greater for those treated with chemotherapy (60 versus 48 percent), and benefit appeared to be greatest for patients aged 17 or older who had tumors measuring >5 cm (five-year metastasis-free survival 47 versus 27 percent, respectively).

On the other hand, a lack of long-term benefit from adjuvant chemotherapy was suggested in a report of the combined experience of two major cancer centers (Memorial Sloan Kettering Cancer Center [MSKCC] and MD Anderson) that included 674 consecutive adults who underwent resection of a high-grade, ≥5 cm extremity STS between 1984 and 1999 [17]. Adjuvant doxorubicin-based chemotherapy was administered to 336 (50 percent), while the remainder received local therapy only.

Although not a randomized trial, there were no statistically significant differences between the chemotherapy and local therapy alone groups with respect to tumor size, anatomic site, histopathologic type, or resection margin status. With a median follow-up of 6.1 years, the effect of chemotherapy appeared to vary over time. During the first year, the HR for disease-specific survival for chemotherapy versus no chemotherapy was 0.37 (95% CI 0.20-0.69); thereafter, the HR was 1.36 (95% CI 1.02-1.81) and did not vary according to histology or tumor size.

These data can be interpreted positively or negatively; the negative view is that overall survival was not improved with the use of chemotherapy. The positive view is that patients with inferior prognosis had their survival improved to that of lower risk patients with the use of systemic chemotherapy in the adjuvant setting.

Summary — The role of adjuvant chemotherapy for patients with a resected extremity STS remains uncertain and controversial [21,22]. The updated meta-analysis from the Sarcoma Meta-Analysis Collaboration [11] suggests that use of an optimal, adequately dosed anthracycline/ifosfamide-containing regimen significantly prolongs survival in patients with resected extremity STS [11] with the ifosfamide component as the more important of the two drugs. However, the analysis did not include data from the single largest negative trial [12]. A pooled analysis of this trial and another European trial, both of which tested the value of an anthracycline and ifosfamide-containing regimen, indicated no benefit from adjuvant anthracycline-ifosfamide chemotherapy [13].

Taken together, despite positive meta-analysis, it is difficult to recommend adjuvant chemotherapy as a standard practice for all patients with extremity STS. If there is a survival benefit for doxorubicin-based adjuvant chemotherapy, it appears to be small, no more than a 5 percent absolute increase in survival at 5 to 10 years [11]. Conversely, the positive meta-analysis from 2008 is arguably the strongest evidence in support of the use of adjuvant chemotherapy. The approach of treating many different sarcoma types with one therapeutic plan has not worked in other cancers and should be not be expected to apply to what are 50 or more sarcoma types.

In keeping with the consensus-based guidelines of the National Comprehensive Cancer Network (NCCN) [23] and the European Society of Medical Oncology (ESMO) [24], which endorse adjuvant chemotherapy as an option for high-risk patients, our present approach is to individualize therapy, taking into consideration the patient's performance status, comorbid factors (including age), site of disease, and histologic types which may be more likely to benefit from adjuvant therapy (eg, younger patients with high-risk synovial sarcoma or myxoid liposarcoma). The potential for benefit from adjuvant chemotherapy must be discussed in the context of expected treatment-related toxicities, including potential sterility, cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life.

Even for those patients in whom the decision has been made to administer adjuvant chemotherapy, the optimal regimen is undefined. We prefer five to six cycles of doxorubicin (usually 75 mg/m2 per cycle in split bolus doses or continuous infusion over three days), ifosfamide (9 to 10 g/m2 in split doses over three hours per day for three to four days), and mesna (AIM (table 1 and table 2)) rather than MAID (mesna, doxorubicin, ifosfamide, and dacarbazine [25]) since this permits the administration of maximal doses of the two most active drugs for sarcoma (doxorubicin and ifosfamide), rather than adding myelotoxicity with dacarbazine. Three cycles of chemotherapy may suffice, although the data supporting this statement are limited to a single trial of three versus five cycles of chemotherapy in 328 patients with high-risk (deeply seated, high-grade, or large [≥5 cm] primary, or locally recurrent) extremity sarcomas [26]. Given the limitations of the available data, with the understanding that microscopic metastatic disease may ultimately require more, rather than fewer, cycles of chemotherapy, we still consider that five or six cycles of chemotherapy represents the preferred approach. (See "Treatment protocols for soft tissue and bone sarcoma".)

Given that the benefit of chemotherapy appears to be dependent on the use of ifosfamide, at least from one meta-analysis, and the known age-dependent toxicities of ifosfamide, it makes the decision to use adjuvant chemotherapy in older patients even more difficult. In view of the uncertainty of long-term benefit for patients with most sarcoma types, extreme caution is indicated in treating older adult patients with adjuvant chemotherapy.

NEOADJUVANT CHEMOTHERAPY

Indications and approach — Neoadjuvant (induction) therapy is most often offered in the setting of a large high-grade primary tumor, particularly if limb salvage is expected to be difficult. In these situations, radiation therapy (RT) is also an important component of the treatment approach, before or after anthracycline/ifosfamide-based chemotherapy for most subtypes of sarcoma. The optimal neoadjuvant regimen and how best to integrate RT, chemotherapy, and surgery remain unknown. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)

The benefit of neoadjuvant chemotherapy alone in this setting is uncertain. However, National Comprehensive Cancer Network (NCCN) guidelines indicate that preoperative RT alone, preoperative chemotherapy (with postoperative RT), or preoperative chemotherapy and radiation are all acceptable options. If used, we prefer sequential chemotherapy administered first, followed by RT, followed by surgery, rather than adjuvant RT. Where available, some centers prefer neoadjuvant chemotherapy combined with regional hyperthermia. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Chemotherapy with regional hyperthermia'.)

The specific neoadjuvant approach chosen typically depends on institutional expertise and experience. If possible, we prefer that these patients be treated in the context of a clinical trial, the data of some of which are described below.

Theoretical advantages to neoadjuvant approaches to therapy include tumor cytoreduction, immediate treatment of micrometastases, and an early indication as to the effectiveness of chemotherapy/RT. Cytoreduction may allow less radical surgical resection to be performed, and this approach is often considered in patients with large extremity sarcomas, particularly if the patient is a borderline candidate for limb salvage surgery.

Most often, when neoadjuvant therapy is considered for a patient with a large extremity sarcoma, particularly if limb salvage is an issue, RT is chosen with or without chemotherapy. This approach is discussed in detail separately. (See "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)

Regimen selection — The optimal neoadjuvant regimen and how best to sequence RT, chemotherapy, and surgery remain unknown. If a decision is made to offer neoadjuvant chemotherapy for soft tissue sarcoma of the extremity, we typically offer three cycles of doxorubicin, ifosfamide, and mesna (AIM (table 1 and table 2)) based largely on extrapolation of data demonstrating the efficacy of AIM in the adjuvant and metastatic settings. This preference is largely consistent with guidelines from other expert groups, including NCCN [23].

Data regarding the use of AIM in the adjuvant and metastatic setting are presented separately. (See 'Summary' above and "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Combination anthracycline-based therapy'.)

There are no adequately powered, randomized phase III trials that demonstrate a benefit of using chemotherapy alone for neoadjuvant therapy. The results of uncontrolled studies are conflicting [27-30]. A randomized phase II European Organisation for Research and Treatment of Cancer (EORTC) study in which 150 patients were randomly assigned to three cycles of neoadjuvant doxorubicin (50 mg/m2 per cycle) plus ifosfamide (5 g/m2 per cycle) versus surgery alone failed to show better survival in the chemotherapy arm, and the trial was stopped before expansion into a phase III study [31]. However, the low chemotherapy intensity used in this study could have contributed to the negative result.

Although AIM remains the standard of care, trabectedin has shown efficacy in patients with high-grade myxoid liposarcoma. Although it has not been directly compared with AIM, in one report, trabectedin appears to be similarly effective to the combination of epirubicin plus ifosfamide in the neoadjuvant setting. This was demonstrated in a randomized phase III trial that investigated the use of neoadjuvant, histotype-driven therapy versus standard chemotherapy in multiple sarcoma subtypes [32]. Although this trial was closed early after an overall futility analysis demonstrated improved outcomes in patients receiving standard chemotherapy in all arms except for high-grade myxoid liposarcoma patients, the high-grade myxoid liposarcoma cohort was subsequently expanded to a total of 101 patients. At five years, when compared with standard chemotherapy, trabectedin resulted in similar disease-free survival (86 versus 73 percent; HR 0.6, 95% CI 0.24-1.46) and overall survival (88 versus 90 percent; HR 1.2, 95% CI 0.37-3.93). Grade 3 and 4 toxicities were lower in the trabectedin arm versus standard chemotherapy for anemia (15 versus 0 percent), neutropenia (67 versus 7 percent), and thrombocytopenia (20 versus 0 percent). This study shows encouraging results for neoadjuvant trabectedin. However, caution should be taken in interpreting the results due to the wide confidence intervals and study design. We feel trabectedin may be considered in individual situations using shared decision making, but AIM is still considered the standard of care for most patients. (See 'Histotype-driven therapy' below.)

Additional data from a nonrandomized phase II trial also support the use of trabectedin as neoadjuvant therapy in locally advanced myxoid liposarcoma. In an uncontrolled study of 23 patients, seven had an objective partial response, and at surgery, three had a pathologic complete response after three to six cycles of trabectedin (1.5 mg/m2 over 24 hours, once every 21 days) [33]. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Trabectedin (LMS)'.)

Based on these data, trabectedin is a reasonable alternative to standard chemotherapy in patients. However, further data are still needed to determine the optimal approach for neoadjuvant therapy in patients with high-grade myxoid liposarcoma.

Investigational approaches

Histotype-driven therapy — Despite increasing interest in histotype-driven treatment for advanced STS, the benefits of this approach for neoadjuvant treatment are not established. (See "Overview of the initial treatment of metastatic soft tissue sarcoma", section on 'Histologies where non-anthracyclines are preferred'.)

An international, open-label, randomized, phase III, multicenter trial evaluated histotype-driven versus standard anthracycline-based therapy in 287 patients with high-risk (deep-seated, high-grade, or ≥5 cm) extremity or truncal STS [34-36]. Patients with five different histologic subtypes of STS were randomly assigned to standard chemotherapy (full-dose epirubicin plus ifosfamide) or histotype-tailored therapy (trabectedin for high-grade myxoid liposarcoma, high-dose ifosfamide alone for synovial sarcoma, etoposide plus ifosfamide for malignant peripheral nerve sheath tumor, gemcitabine plus dacarbazine for leiomyosarcoma, and gemcitabine plus docetaxel for undifferentiated pleomorphic sarcoma).

At a median follow-up of approximately 52 months, histotype-tailored therapy resulted in similar disease-free survival relative to standard chemotherapy with epirubicin and ifosfamide (five-year disease-free survival 47 versus 55 percent, hazard ratio [HR] 1.23, 95% CI 0.88-1.73) but inferior overall survival (five-year overall survival 66 versus 76 percent, HR 1.77, 95% CI 1.10-2.83) [35]. However, in patients with myxoid liposarcoma histotype-tailored therapy was not inferior to epirubicin-ifosfamide. A further discussion of high-grade myxoid liposarcoma is discussed elsewhere. (See 'Regimen selection' above.)

Incidentally, this trial reported favorable disease-free survival for the anthracycline-based regimen among all histologies, including leiomyosarcoma and malignant peripheral nerve sheath tumor, for which data regarding the neoadjuvant use of anthracyclines had been lacking. It is not clear how the use of epirubicin, rather than doxorubicin, affected the results in this trial, particularly given that doxorubicin has been more commonly used in other trials and based on comparative trials of doxorubicin versus epirubicin in metastatic sarcomas [37].

The use of neoadjuvant histotype-driven therapy in the primary management of STS remains controversial, and the decision to use this approach must be addressed on a case-by-case basis. Nevertheless, these data provide some of the strongest support for the early administration of anthracycline-based chemotherapy regimens in patients with STS.

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

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

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

Systemic chemotherapy is nearly always a mandatory component of treatment for several STS that occur predominantly in children (ie, rhabdomyosarcoma, Ewing sarcoma, extraosseous osteogenic sarcoma). (See 'Pediatric-type sarcomas' above and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment" and "Chemotherapy and radiation therapy in the management of osteosarcoma" and "Treatment of Ewing sarcoma" and "Treatment of Ewing sarcoma", section on 'Neoadjuvant chemotherapy'.)

However, despite many randomized trials, the role of adjuvant chemotherapy for the more common adult histologic types of STS (such as liposarcoma, synovial sarcoma, and leiomyosarcoma) remains uncertain. Thus, in our view, this approach cannot be adopted as a standard treatment for all extremity STS, regardless of histology, but can be discussed on a patient-by-patient basis. (See 'Sarcomas more commonly seen in adults' above.)

An analysis from the Sarcoma Meta-Analysis Collaboration (SMAC) suggests a significant 11 percent improvement in survival for doxorubicin and ifosfamide-based adjuvant chemotherapy compared with resection alone. (See 'SMAC meta-analysis' above.)

However, a pooled analysis of individual patient data from the two largest adjuvant trials of doxorubicin and ifosfamide-based chemotherapy (both performed by the European Organisation for Research and Treatment of Cancer [EORTC], only one of which was included in the SMAC meta-analysis) was completely negative. (See 'Pooled analysis of the EORTC trials' above.)

Surprisingly, there is limited evidence that adjuvant chemotherapy is relatively more beneficial for the chemotherapy-sensitive types of STS. (See 'Impact of histology' above.)

In keeping with the guidelines of the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), we suggest that the appropriateness of adjuvant chemotherapy 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 type. The potential for benefit must be discussed in the context of expected treatment-related toxicities, including sterility, cardiomyopathy, renal damage, second cancers, and overall impairment of quality of life.

For patients who decide to undergo adjuvant chemotherapy despite the uncertainty of benefit and the potential for treatment-related toxicity, we recommend using a regimen that contains both ifosfamide and an anthracycline (Grade 1A). In the United States, AIM (doxorubicin, ifosfamide, and mesna (table 2 and table 1)) is typically used, whereas epirubicin plus ifosfamide is more commonly used in Europe. (See 'Summary' above and "Treatment protocols for soft tissue and bone sarcoma".)

Neoadjuvant therapy can be offered in the setting of a large high-grade primary tumor, particularly if limb salvage is expected to be difficult. In these situations, RT is most commonly selected, with or without chemotherapy. The optimal neoadjuvant regimen and how best to sequence RT, chemotherapy, and surgery remain unknown. (See 'Neoadjuvant chemotherapy' above and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk", section on 'Is there a role for chemoradiation?'.)

The benefit of neoadjuvant chemotherapy alone in this setting is uncertain. However, NCCN guidelines indicate that preoperative RT alone, preoperative chemotherapy (with postoperative RT), or preoperative chemotherapy and radiation are all acceptable options. If used, we prefer a sequential approach with chemotherapy administered first, followed by RT and subsequent surgery, rather than adjuvant RT. Where available, some centers prefer neoadjuvant chemotherapy combined with regional hyperthermia. (See "Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities", section on 'Chemotherapy with regional hyperthermia'.)

There are no data to support one sequence over the other at the present time, and the specific neoadjuvant approach chosen typically depends on institutional expertise and experience. If possible, we prefer that these patients be treated in the context of a clinical trial.

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

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Topic 7720 Version 44.0

References

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