Surgical treatment and other localized therapy for metastatic soft tissue sarcoma

INTRODUCTION — Soft tissue sarcomas are a heterogeneous group of uncommon tumors arising from mesenchymal cells at all body sites. The malignant precursor cell(s) differentiate along one or several lineages, such as muscle, adipose, fibrous, cartilage, nerve, or vascular tissue. These tumors arise most often in the limbs (particularly the lower extremity), followed in order of frequency by the abdominal cavity/retroperitoneum, trunk/thoracic region, and the head and neck. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Clinical presentation' and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

While local complications from primary or recurrent sarcomas can cause significant morbidity and occasional mortality, the most life-threatening aspect of sarcomas is their propensity for hematogenous dissemination. The pattern of tumor spread varies according to tumor type:

●For most sarcomas of the extremity, chest wall, and head or neck, the primary metastatic site is the lung [1]. However, there are exceptions. Extrapulmonary metastases to the retroperitoneum, spine, and paraspinous soft tissues predominate with myxoid/round cell liposarcomas, although lung metastases develop eventually in almost all [2]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Pattern of spread'.)

●The primary site of failure is locoregional for retroperitoneal and visceral sarcomas; less commonly, these tumors spread hematogenously to the liver and also the lungs [3].

●Spread to locoregional lymph nodes is rare (≤5 percent), with the exception of clear cell and epithelioid sarcomas, angiosarcomas, and rhabdomyosarcomas [4].

The majority of patients who develop metastatic soft tissue sarcoma are incurable, and palliative systemic treatment is the most appropriate therapy. Judicious use of systemic therapy provides symptom palliation, prevents rapid disease progression, and may, in some cases, prolong survival. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

However, for selected patients with certain histologies (eg, well-differentiated and/or de-differentiated liposarcomas), surgical resection of recurrent and/or metastatic disease can provide durable relapse-free survival and even potential cure in rare cases. The majority of these patients have isolated oligometastatic disease in the lungs.

The role of surgery in the treatment of common adult-type metastatic soft tissue sarcomas will be reviewed here. Surgical management of localized primary soft tissue sarcomas of the extremity, trunk, or retroperitoneum; the approach to locally recurrent extremity and retroperitoneal soft tissue sarcomas; surgical management of specific types of soft tissue sarcoma, including gastrointestinal stromal tumors, rhabdomyosarcoma, uterine sarcomas, desmoids, dermatofibrosarcoma protuberans, and Kaposi sarcoma; and the general principles of surgical management of pulmonary metastases are discussed elsewhere. (Refer to appropriate topic reviews.)

PULMONARY METASTASES — Complete pulmonary metastasectomy is feasible in approximately one-third of patients presenting with isolated oligometastatic disease from soft tissue sarcoma [5].

Criteria for resection — No single criterion can be reliably used to exclude patients from surgery because of a predictably low likelihood of cure. In general, the inability to achieve a complete resection, a large number of pulmonary nodules, and a short interval between surgical resection of the primary tumor and the development of metastases (less than 12 to 18 months) are adverse prognostic factors for survival [5-7]. The most important of these is the ability to completely resect all disease [5,6]. In the setting of asymptomatic disease, surgery in the chest should not be undertaken unless all known deposits of disease are being treated.

The following criteria for pulmonary metastasectomy are generally agreed upon [8-10]:

●No extrathoracic disease (although this is being challenged [11]), pleural effusion, or radiographically suspicious hilar/mediastinal adenopathy

●The primary tumor is controlled or controllable

●The patient is a medically appropriate candidate for intervention and pulmonary resection

●Complete resection of all disease appears possible

There is no consensus among thoracic surgical oncologists or sarcoma specialists as to what disease burden represents an insurmountable obstacle. Some experts consider resection of more than eight pulmonary nodules to be a futile exercise, whereas other highly experienced referral centers will not uncommonly resect as many lesions as surgically feasible (eg, >50 nodules) in a young, otherwise healthy individual with no evidence of disease elsewhere. It is not clear that such an extensive surgical approach provides long-term benefit to patients, and in our view, resection should be limited to patients with a small number of lesions (generally less than five).

Preoperative staging — The most reliable method for assessing metastatic spread is not settled. The majority of pulmonary metastases are detected through helical computed tomography (CT) imaging.

Increasingly, for certain histopathologic subtypes, integrated fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT is being used for this purpose, particularly to search for otherwise occult extrathoracic involvement. However, the value over helical CT alone is debated [12]. There are several different histologic subtypes of soft tissue sarcoma, many of which are not associated with uptake of the FDG tracer. Furthermore, in general, extrathoracic metastases are rare for most subtypes (although there are exceptions, see below). Guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend a PET scan in this setting [13]. At least some data suggest that PET adds little to diagnostic-quality CT scanning in soft tissue sarcomas of the non-Ewing, non-rhabdomyosarcoma type [14]. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Evaluation for metastatic disease'.)

However, if a PET scan is performed, suspicious positive areas outside of the thorax should be evaluated prior to surgery, due to the possibility of false-positive findings. Confirmation of disease outside of the chest precludes pulmonary metastasectomy, although this tenet is being challenged [11]. This subject is discussed in detail elsewhere. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

Chest CT alone is considered the standard staging method at many institutions. Thin-section, high-resolution helical CT is preferred over conventional CT in order to maximize detection of all sites of intrathoracic disease. The presence of bulky mediastinal or hilar nodal disease on CT (which is a rare finding) is considered by most to represent a contraindication to attempted resection. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

In addition to chest CT, abdomen and pelvic CT is often recommended for patients with myxoid/round cell liposarcoma, epithelioid sarcoma, angiosarcoma, leiomyosarcoma, and sarcomas arising within the abdomen or retroperitoneum to evaluate for intraabdominal and/or retroperitoneal metastases. Spine magnetic resonance imaging (MRI) may also be indicated for round cell and myxoid/round cell liposarcomas, which have a propensity to metastasize to the spine and paraspinous soft tissues.

Intraoperative staging and resection technique — Many thoracic surgeons begin the surgical procedure with mediastinoscopy despite the low likelihood of nodal metastases with soft tissue sarcomas (10 percent in one series [15]). Lymph node dissection provides information on staging and prognosis, but there is no evidence that this has any clinical impact. Although prognosis is worse compared with no lymph node involvement, the discovery of clinically occult hilar or mediastinal lymph node metastases generally does not change the medical management of these lesions. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

Thoracotomy with wedge resection is the standard procedure for resection; lobectomy or pneumonectomy is rarely necessary. Good results have been obtained with less invasive procedures such as video-assisted thoracoscopy (VATS) [16]. Although the VATS procedure is oncologically safe and associated with shorter recovery times, one disadvantage is that the surgeon cannot palpate the entire lung in order to discover radiographically occult ipsilateral metastases (table 1). (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

Considering the greater likelihood of leaving behind undetected tumor with VATS as compared with open thoracotomy, the question of whether VATS should be utilized revolves around the natural history of metastatic disease not detected by preoperative CT scan. Some consider thoracoscopic resection to be a valid approach only for patients with a solitary pulmonary nodule because they have a low likelihood of harboring clinically occult metastases. On the other hand, proponents of VATS argue that initially unresected metastases may be resected once they become detectable on surveillance CT scans, without adversely impacting survival [16]. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

There are no randomized trials addressing this issue. The available retrospective data suggest that patients do at least as well after VATS as after thoracotomy and imply that there is little, if any, clinical significance to skipped nodules. However, because these favorable outcomes from VATS were obtained predominantly in populations with a limited disease extent, many surgeons restrict VATS to patients with a single or very few pulmonary metastases in the lung periphery. For patients with a limited number of bilateral peripheral lung nodules, staged bilateral VATS procedures may be feasible. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

Outcomes — Several reports have summarized the outcomes of soft tissue sarcoma pulmonary metastasectomy from individual institutions and have defined the relevant prognostic factors [7,11,17-22]. The following illustrates the range of findings from the largest series:

●In a single-institution series of 539 patients undergoing 760 therapeutic-intent pulmonary metastasectomies for metastatic soft tissue sarcoma, the median survival was 33 months and the five-year survival was 34 percent [7]. After an R0 pulmonary resection, 74 percent developed a disease recurrence at any site, 63 percent experienced a lung recurrence, and 34 percent had a recurrence that was lung isolated. In multivariate analysis, leiomyosarcoma subtype, primary tumor size ≤10 cm, greater time between primary resection and development of metastases, solitary lung metastases, and minimally invasive resection were all associated with a lower risk of death.

●The European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group conducted a multi-institutional retrospective study of 255 patients who underwent pulmonary metastasectomy for soft tissue sarcoma [18]. The three- and five-year overall survival rates following metastasectomy were 54 and 38 percent, and the corresponding disease-free survival rates were 42 and 35 percent, respectively. Favorable prognostic factors included a disease-free interval greater than 2.5 years, microscopically free resection margins, and histologic grade 1 or 2 primary tumors. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)

●In a review of 274 consecutive patients treated at a single institution, the five-year overall survival following pulmonary metastasectomy was approximately 40 percent [17]. Three unfavorable risk factors were identified: metastasis size >2 cm, more than one pulmonary metastasis, and a metastasis-free interval of 18 months or less. Patients with none of these risk factors had a 60 percent five-year survival; the corresponding rates for those with one, two, or three of these factors were 30, 20, and 0 percent, respectively.

●Long-term outcomes may be less favorable for patients who present with synchronous pulmonary metastases [21,23,24].

In the absence of a randomized trial, it is impossible to know whether these results simply reflect careful patient selection and favorable biology (good performance status and relatively indolent disease progression over time following the discovery of pulmonary metastases) rather than a specific benefit of surgery. However, most lung metastases in soft tissue sarcoma derive from high-grade rather than low-grade histologic subtypes, and the clinical behavior of high-grade sarcomas is generally not indolent. The likelihood of patients with metastatic high-grade soft tissue sarcoma surviving five years with no specific therapy is exceedingly low (probably less than 5 percent).

There are no data upon which to base a comparison of outcomes in patients treated with surgery versus systemic chemotherapy alone. Many of the surgical series were published at a time when chemotherapy for soft tissue sarcoma was suboptimal [6]. Whether the results are still valid in patients treated with modern, histology-based chemotherapy is unknown. However, even with the advances in systemic therapy that have occurred over the last 20 years, the likelihood of five-year survival among patients with metastatic high-grade soft tissue sarcoma is still exceedingly low, probably less than 5 percent.

Despite these uncertainties, it is unlikely that clinicians or patients would ever consider a randomized prospective clinical trial (of surgery versus best supportive care or chemotherapy alone) feasible in order to test these hypotheses. Therefore, despite the lack of randomized controlled trials, the retrospective data represent the best available evidence supporting the benefit of surgery as a treatment option for patients with isolated or limited potentially resectable pulmonary metastases.

Adjuvant chemotherapy — Patients with completely resected pulmonary metastases are often referred to medical oncologists to discuss the risks, potential benefits, and uncertainties of postresection chemotherapy. The efficacy of postmetastasectomy adjuvant chemotherapy for soft tissue sarcomas is unproven; there are no randomized controlled trials. Some retrospective reviews suggest a better outcome with postoperative adjuvant chemotherapy [25], while others do not [6,26]. The biases inherent in such retrospective reports preclude drawing any definitive conclusions regarding whether there is any benefit from such chemotherapy.

As a result, the benefit of chemotherapy and its use in this setting remain a matter of clinical judgment weighing a variety of patient-specific variables, such as age, comorbidity, patient preferences, and risk profile, as well as the specific histopathologic subtype of the sarcoma involved and the expected chemosensitivity of the disease. As an example, the rare adult who presents with distant metastases from a primary rhabdomyosarcoma may benefit from postresection combination chemotherapy with or without radiation therapy [27]. (See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

On the other hand, for the more common types of adult soft tissue sarcoma, the role of adjuvant chemotherapy after resection of metastatic disease remains much more uncertain and cannot be routinely recommended. Guidelines from the NCCN do not make a specific recommendation in this regard but, instead, suggest resection of pulmonary metastases "with or without chemotherapy" [13]. Of note, the administration of adjuvant chemotherapy following resection of earlier-stage localized disease is also controversial and is not supported by high-quality evidence. (See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities".)

Neoadjuvant chemotherapy — There are theoretical advantages to preoperative (neoadjuvant) chemotherapy (ie, chemotherapy administered prior to surgical resection of pulmonary metastases). While there are no data to support a survival benefit for the addition of neoadjuvant chemotherapy to surgery alone, one of the benefits of initial chemotherapy is the ability to assess the efficacy of the specific regimen through evaluation of posttreatment radiographs and the resection specimen. If administration of chemotherapy resulted in a significant response with a high level of tumor necrosis, this might prompt consideration of additional courses of postoperative chemotherapy, if the patient's medical condition can tolerate it. However, there are no data that provide prospective validation of the selective benefit of postoperative chemotherapy in this setting.

Perhaps more importantly, patients who rapidly develop extrapulmonary metastases or new lesions in other lung lobes during neoadjuvant chemotherapy may be spared the morbidity of unnecessary surgery. In asymptomatic patients with low volume disease, an alternative strategy is to withhold chemotherapy and simply delay the surgery for six to eight weeks in order to evaluate the natural history of untreated disease through repeat radiographic evaluation.

The use of neoadjuvant chemotherapy prior to resection of pulmonary metastases is not a widespread practice, and the decision to pursue this strategy must be made on a case-by-case basis or in the context of a clinical trial. For most adult-type soft tissue sarcomas, if there are concerns as to the natural history of newly diagnosed untreated metastatic disease, an alternative option is radiographic reassessment of disease status after an interval of six to eight weeks to allow the disease biology to declare itself and to spare patients with aggressive disease unnecessary surgery. The choice of approach may vary significantly depending upon the histologic subtype and grade of the sarcoma and the symptomatology and performance status of the patient. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

Second metastasectomy — Despite a potentially curative operation, the majority of patients undergoing pulmonary metastasectomy will eventually exhibit recurrence of metastatic sarcoma. A subset of these patients may be considered for repeat surgical intervention as long as extrathoracic metastatic disease is absent. The decision to pursue a second metastasectomy also depends upon the disease-free interval, the extent of metastatic spread, and an evaluation of the available systemic therapies that may be relevant to the specific histologic subtype. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Overview of the initial treatment of metastatic soft tissue sarcoma".)

The success of this approach in metastatic soft tissue sarcoma is illustrated by uncontrolled reports [28-31]. For example:

●In a report of 43 patients treated at the National Cancer Institute, 72 percent could be rendered free of disease at the second thoracotomy, and the median survival for resectable compared with unresectable patients was 25 versus 10 months [28]. This type of analysis is prone to several sources of bias since the patients who had reresection might not have been directly comparable with those who did not in terms of disease burden or extent, and performance status. Therefore, it cannot be assumed that the resection procedure itself necessarily improved the outcomes.

●In a series of 86 patients undergoing reoperation for recurrence of pulmonary metastases, the median disease-specific survival was 43 months and the estimated five-year survival was 36 percent [30]. Prognostic factors for a more favorable outcome included the ability to achieve clear margins, one or two versus three or more nodules, the largest size of metastases ≤2 cm, and low-grade rather than high-grade primary tumor histology.

●The relationship between disease extent at the time of recurrence and outcomes was further shown in a series of 39 patients from MD Anderson Cancer Center who underwent reoperation for a second pulmonary metastasis after an initial successful metastasectomy [29]. The median survival for the 19 patients who had complete resection of a single recurrent focus of metastatic disease was 65 months, compared with 14 months for the 15 patients who had complete resection of two or more sites of recurrent disease.

HEPATIC METASTASES — Isolated hepatic metastases may also be amenable to potentially curative resection, although there are less available data than with pulmonary metastasectomy [32-36].

In a series of 11 patients undergoing hepatic resection for isolated metastases from leiomyosarcoma originating in either the retroperitoneum or gastrointestinal tract, the median survival was 39 months [33]. Five of six patients undergoing complete resection were alive with a median follow-up of 53 months.

OTHER THERAPEUTIC OPTIONS — There are some situations in which surgery is not a viable option (eg, due to patient comorbidities) but there is still the desire to treat a local site of tumor progression. In these settings, local interventional therapies are increasingly being used, such as radiofrequency ablation [35,37], cryoablation [38], and focal radiation techniques such as stereotactic body radiation therapy [39-44]. In addition, for liver metastases, other interventional techniques include hepatic arterial embolization, with or without chemotherapy, and radioembolization.

These techniques may control a single focus of disease that is progressing while other sites of disease involvement are stable or responding to therapy. However, none of these forms of local therapy has been proven to improve patient survival. Nonsurgical local ablative techniques and stereotactic radiation therapy for the treatment of liver metastases, as well as radiofrequency ablation, stereotactic radiation therapy, and cryoablation approaches for treatment of lung lesions, are discussed in more detail elsewhere. (See "Image-guided ablation of lung tumors" and "Stereotactic body radiation therapy for lung tumors", section on 'Lung metastases'.)

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

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

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

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

SUMMARY AND RECOMMENDATIONS

●Surgical resection for metastatic soft tissue sarcoma — Soft tissue sarcomas are a heterogeneous group of rare tumors arising from mesenchymal cells at all body sites. For the majority of patients, treatment of metastatic disease is palliative and consists of systemic therapy. However, surgical resection of oligometastatic disease can provide long-term relapse-free survival and the potential for cure in selected patients, the majority of whom have isolated pulmonary metastases. (See 'Introduction' above and "Overview of the initial treatment of metastatic soft tissue sarcoma".)

●Pulmonary metastasectomy — For appropriately selected patients with isolated, limited pulmonary metastases from soft tissue sarcoma, we suggest pulmonary metastasectomy rather than palliative systemic chemotherapy alone (Grade 2B). There is no consensus as to the optimal selection of surgical candidates; however, the following criteria are generally agreed upon [8] (see 'Criteria for resection' above):

•No extrathoracic disease, pleural effusion, or mediastinal/hilar adenopathy

•The primary tumor is controlled or controllable

•The patient is a medically appropriate candidate for thoracotomy and pulmonary resection

•Complete resection appears feasible

There is also no consensus among thoracic surgical oncologists or sarcoma specialists as to what disease burden represents an insurmountable obstacle, and this must be decided on a case-by-case basis. In our view, outcomes are best when resection is limited to patients with a small number of pulmonary lesions and at least a 12- to 18-month metastasis-free interval.

Issues related to surgical technique and preoperative as well as intraoperative evaluation are discussed elsewhere. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques", section on 'Surgery'.)

●Adjuvant chemotherapy — There is no evidence to support a survival benefit from adjuvant chemotherapy following complete pulmonary metastasectomy for patients with metastatic soft tissue sarcoma, and we suggest not pursuing this approach outside of the context of a clinical trial (Grade 2C). An exception to this general rule is rhabdomyosarcoma, for which multimodality treatment is a standard approach and the role of surgery for metastatic disease is less clear. (See 'Adjuvant chemotherapy' above and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)

●Neoadjuvant chemotherapy — For most patients, we do not suggest the administration of neoadjuvant chemotherapy prior to resection of pulmonary metastases (Grade 2C), although for certain chemosensitive subtypes of sarcoma, this approach may be reasonable, with the goal of gaining a sense of the pace of change of disease and the responsiveness to systemic therapy. If there are concerns as to the natural history of newly diagnosed untreated metastatic disease, another option is to reevaluate disease status radiographically after an interval of six to eight weeks. (See 'Neoadjuvant chemotherapy' above.)

●Second metastasectomy — For patients who develop a recurrence of pulmonary metastatic disease, repeat pulmonary resection is reasonable, providing extrathoracic metastatic disease is absent. The decision to pursue a second metastasectomy also depends upon the disease-free interval, the extent of metastatic spread, and an evaluation of the available systemic therapies that may be relevant to the specific histologic subtype. (See 'Second metastasectomy' above.)

●Hepatic metastasectomy — Although far less data are available, isolated hepatic metastases may be amenable to resection. There is no consensus as to appropriate eligibility requirements, and the decision to operate must be made on a case-by-case basis. In addition, as with pulmonary lesions, it is critical to consider the underlying histology of the tumor, the expected natural history, and the expected responsiveness to systemic therapy when considering surgery as a component of the treatment plan for metastatic disease. (See 'Hepatic metastases' above.)

●Other local treatment options — Other local interventional options for limited sites of metastatic disease include radiofrequency ablation, cryoablation, image-guided radiation therapy, and for liver metastases, hepatic arterial embolization, with or without chemotherapy, and radioembolization. The role of all of these therapies compared with surgery or chemotherapy remains to be defined. (See 'Other therapeutic options' above.)