Although soft tissue sarcomas are a heterogeneous group of neoplasms, their clinical evaluation and treatment follow common principles. This chapter focuses on the clinical evaluation, determinants of prognosis and outcome, and treatment of patients with soft tissue sarcoma.
Anatomically, the extremities are the most common anatomic site for soft tissue sarcoma, accounting for approximately half of all cases. Other important anatomic sites include the retroperitoneum, head and neck, and body wall. The site-specific distribution of histologic subtypes is outlined in Fig. 2.1 . Of note, the distribution of histologic subtypes depends greatly on the anatomic site; for example, in the extremities, undifferentiated pleomorphic sarcoma, liposarcoma, and synovial sarcoma are common. In contrast, in the retroperitoneum, synovial sarcoma and undifferentiated pleomorphic sarcoma are relatively uncommon; other histologic subtypes, particularly leiomyosarcoma and liposarcoma, predominate. The reasons for this regional variation in histologic subtype are not understood.
Anatomic distribution and site-specific histologic subtypes of 7563 consecutive soft tissue sarcomas seen at the University of Texas MD Anderson Cancer Center. UPS, Undifferentiated pleomorphic sarcoma (∗previously, malignant fibrous histiocytoma, MFH).
From MDACC Sarcoma Database, June 1996 to June 2006.
Clinical Evaluation
Clinical Presentation and Assessment
Most patients with suspected soft tissue neoplasms present with a painless mass, although pain is reported in one-third of cases. A delay in diagnosis is common; the most common misdiagnoses include posttraumatic or spontaneous hematoma and lipoma. A late diagnosis of patients with retroperitoneal sarcomas is common because of the large size of the retroperitoneal space, generally slow growth rate, and the tendency of sarcomas to gradually displace rather than to invade and compromise adjacent viscera. Therefore, retroperitoneal sarcomas can reach a considerable size before diagnosis ( Fig. 2.2 ).
Contrast-enhanced CT scan of a 52-year-old patient with retroperitoneal dedifferentiated liposarcoma. The CT findings illustrate features of both well-differentiated and dedifferentiated forms of liposarcoma that frequently coexist. The dedifferentiated component is the more solid-appearing, low-density mass situated in the right retroperitoneum, whereas the well-differentiated component has similar density to the subcutaneous (normal) fat and fills the retroperitoneum, displacing the contrast-filled small bowel to the anatomic left side and posteriorly.
The physical examination should include an assessment of tumor size, relative mobility, and fixation. Patients with extremity soft tissue tumors should be evaluated for tumor-related neuropathy. An examination of regional lymph node basins should also be performed, with the understanding that nodal metastases are relatively uncommon, occurring in less than 15% of patients with extremity soft tissue sarcoma. Functional assessment of the region involved is of paramount importance, as well as complete neurologic and vascular examinations.
The Multidisciplinary Approach.
Transdisciplinary engagement, preferably in the form of a formal tumor board is foundational to caring for patients with STS. At a minimum, compliance with nationally accepted guidelines is strongly encouraged. In fact, lack of concordance may result in worse outcomes in some sarcomas. Obtaining adequate imaging is an essential component in the workup for STS. Expert musculoskeletal radiologists’ interpretation can also add tremendous value in that they can hone the diagnostic process, avoiding unnecessary diagnostic tests and/or biopsies. And of course, as this entire text is dedicated to advancing pathologic consideration in STS, expert pathologic analysis is critical. In addition to all of the oncology disciplines (e.g., surgical, medical, radiation, pediatric), allied professionals including advanced practice providers, social workers, physical therapists, and others, enable optimization of the complex care of these patients, who are often traveling great distances to receive their sarcoma therapies.
Pretreatment Evaluation
The pretreatment evaluation of the patient with a suspected soft tissue malignancy includes a biopsy diagnosis and radiologic staging to establish the extent of the disease. Practical nomograms and algorithms for the evaluation of patients with extremity and retroperitoneal soft tissue masses are outlined in Figs. 2.3 and 2.4 .
A, Nomogram for overall survival. B, Nomogram for distant metastases.
Pretreatment evaluation, staging, and treatment algorithm for assessment of the patient presenting with a retroperitoneal (nonvisceral) mass. Patients should undergo pretreatment cross-sectional imaging by CT or MRI. Localized, radiologically resectable masses believed to be neoplastic can be treated by diagnostic and therapeutic primary tumor resection. In clinical settings, where preoperative treatment protocols are available, pretreatment image-guided core-needle biopsy (CNB) should be used to establish the diagnosis of sarcoma for protocol eligibility. Patients with locally advanced (radiologically unresectable) or metastatic disease should undergo CNB for diagnosis followed by consideration of nonsurgical treatments. In general, CNB is sufficient for diagnosis, and surgery performed exclusively for diagnostic purposes (e.g., laparotomy for incisional biopsy) should be avoided whenever possible.
Biopsy.
A pretreatment biopsy of the primary tumor is essential for most patients presenting with soft tissue masses. In general, any soft tissue mass that is enlarging or is greater than 5 cm should be considered for biopsy. For more anatomically constrained areas such as the forearm and hand, lesions smaller than 5 cm should be considered for biopsy. The preferred biopsy method is generally the least invasive technique that allows for a definitive histologic assessment, including an assessment of grade. Grades are particularly important to clinicians because they impact treatment planning and treatment options. The grading of soft tissue sarcomas is discussed in Chapter 1 .
A percutaneous core-needle biopsy (CNB) provides satisfactory diagnostic tissue for the diagnosis of most soft tissue neoplasms. A CNB can be performed “blindly” in the clinic by clinicians without real-time radiologic control. However, many centers have moved to an image-guided CNB performed by interventional radiologists. Image-guided approaches allow for a biopsy from the areas of the tumor believed to be most likely to harbor viable tumor (i.e., avoiding centrally necrotic areas). The use of real-time imaging also minimizes the risks for biopsy-related vascular or adjacent organ injury. In many centers, image-guided biopsy also allows for real-time pathology quality control by having a pathologist immediately available in the biopsy suite to evaluate the quality of tissue retrieved and its probable suitability for a definitive diagnosis. Studies comparing a CNB to the traditional open surgical biopsy have demonstrated the safety, reliability, and cost-effectiveness of this approach. Additional issues related to the pathologic interpretation of core-needle biopsies are discussed in Chapter 5 .
Tumor recurrence in the needle track after a percutaneous CNB is extremely rare. Indeed, there are only case reports in the literature. However, these rare cases have led some physicians to advocate tattooing the biopsy site for subsequent excision. Most experienced sarcoma surgeons take a practical approach to this issue and perform an en bloc resection of the needle track and percutaneous entry point when feasible, but not if a resection of the biopsy tract requires a second incision or substantial modification of the surgical plan. The low risk of needle track recurrence does not justify the added morbidity risk imposed by major alterations in the surgical plan.
An incisional biopsy is occasionally required to establish a definitive diagnosis for some soft tissue neoplasms. It has the advantage over CNB of providing more tissue for pathologic analysis and often additional tissue for tumor banking or research purposes. However, the morbidity associated with an incisional biopsy can be considerable, including the risks for anesthesia, bleeding, and wound-healing problems. Furthermore, if additional cores can be obtained, CNB may suffice to facilitate research. Given these considerations and its greater cost, incisional biopsy is generally a secondary technique best reserved for cases where a definitive diagnosis cannot be established by CNB.
An excisional biopsy may be appropriate for some patients who present with small, superficial neoplasms located on the extremities, well away from critical structures, or the superficial body wall, where the morbidity from this procedure is minimal. Although an excisional biopsy may allow for a single diagnostic and therapeutic procedure in some clinical settings, its main disadvantage is that the malignant potential of the neoplasm is unknown at biopsy, and informed decisions on surgical margins are not possible. This leaves the operating surgeon with the choice of narrow or nonexistent surgical margins, with generally lower risks for wound and functional morbidity, or deliberately wide margins, with generally greater risks for wound and functional morbidity. The oncologic appropriateness of the surgical margin cannot be assessed preoperatively and is difficult to assess with precision intraoperatively. This disadvantage makes an excisional biopsy appropriate for only a small subset of patients who have small, superficial neoplasms and for whom a reexcision is feasible, if the final diagnosis indicates a malignant lesion with compromised margins.
A percutaneous fine-needle aspiration (FNA) biopsy can also be used for cytologic assessment of some soft tissue neoplasms. Accurate FNA diagnosis requires the availability of an expert cytopathologist experienced in the diagnosis of soft tissue sarcomas by cytology. From a practical standpoint, most centers (even academic centers) will not have a cytopathologist with sufficient experience to use FNA for routine diagnosis and classification of primary soft tissue neoplasms. Additionally, even with experience, a risk of diagnostic error remains because the histologic architecture is not captured with FNA. Given the frequent difficulty in histopathologic diagnosis and classification of soft tissue sarcoma, the major utility of FNA cytology in most centers is for the diagnosis of patients with suspected recurrent sarcoma. In this setting, there is already an established pathologic diagnosis, such that only confirmation of a recurrence with similar features is required.
Staging.
The relative rarity of soft tissue sarcoma, the anatomic heterogeneity of these lesions, and the presence of more than 100 recognized histologic subtypes of variable grades, have made it difficult to establish a functional system that can accurately stage all forms of this disease. The staging system (ninth edition) of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC; formerly International Union Against Cancer) is the most widely used staging system for soft tissue sarcoma , (see Chapter 1 ). The system is designed for optimal staging of extremity tumors but is also applicable to the torso, head and neck, and retroperitoneal lesions; it should not be used for sarcomas of the gastrointestinal tract or other parenchymal organs.
Social Determinants of Health (SDOH)
Widespread disparities exist in access and outcomes in patients with soft tissue sarcomas. Socioeconomic status (SES) and insurance inequities influence the ability to treat and prognosis. Societal awareness has increased dramatically in recent years and many research funding announcements (RFAs) for clinical research call for consideration of SDOH in their grant programs. Those with higher education and income have lower risk for sarcoma and have better responses to therapy. , Delayed access to care is correlated with advanced STS stage. The impact of SES on insurance types also negatively influences complication rate with higher odds of pulmonary embolism, surgical-site infection, and 90-day hospital death in Medicare Advantage patients. Furthermore, disparities exist across age, insurance, and anatomic sites. , While awareness of disparities in cancer care access and geographical influences is increasing, concentrating efforts to assess the needs of these highly vulnerable populations is necessary to enhance equity to the latest standards in sarcoma care.
Prognostic Factors
Clinicopathologic Factors
Understanding the clinicopathologic factors that affect outcome is essential in formulating a treatment plan for the patient with soft tissue sarcoma. The three major clinicopathologic factors that establish the risk profile for a given patient are tumor size, histologic grade, and extent of disease (nodal or metastatic involvement), as reflected in the ninth edition of the AJCC staging system. The tumor’s size is now especially emphasized, with tumors grouped as 5 cm or less, greater than 5 cm, greater than 10 cm, and greater than 15 cm.
In addition to the previous factors, histologic subtype and margin status are also significant, but this information is not captured by the current staging system. Moreover, unlike other solid tumors, factors that predict local recurrence differ from those that predict distant metastasis and tumor-related death ( Table 2.1 ). In other words, patients with a constellation of adverse prognostic factors for local recurrence are not necessarily at increased risk for distant metastasis or tumor-related death, and vice versa. Therefore, clinicians and pathologists should be careful about using the terminology “high-risk disease” without qualification of the endpoint (i.e., local recurrence or overall survival) for which the patient is believed to be at increased risk.
Table 2.1
Multivariate Analysis of Prognostic Factors in Patients With Extremity Soft Tissue Sarcoma
From Pisters PW, Leung DH, Woodruff J, et al. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14(5):1679–1689.
| End Point | Adverse Prognostic Factor | Relative Risk (%) |
|---|---|---|
| Local recurrence | Fibrosarcoma | 2.5 |
| Local recurrence at presentation | 2.0 | |
| Microscopically positive margin | 1.8 | |
| Malignant peripheral nerve sheath tumor | 1.8 | |
| Age >50 years | 1.6 | |
| Distant recurrence | High grade | 4.3 |
| Deep location | 2.5 | |
| Size 5.0 to 9.9 cm | 1.9 | |
| Leiomyosarcoma | 1.7 | |
| Nonliposarcoma histology | 1.6 | |
| Local recurrence at presentation | 1.5 | |
| Size >10.0 cm | 1.5 | |
| Disease-specific survival | High grade | 4.0 |
| Deep location | 2.8 | |
| Size >10.0 cm | 2.1 | |
| Malignant peripheral nerve sheath tumor | 1.9 | |
| Leiomyosarcoma | 1.9 | |
| Microscopically positive margin | 1.7 | |
| Lower-extremity site | 1.6 | |
| Local recurrence at presentation | 1.5 |
Adverse prognostic factors identified are independent by Cox regression analysis.
Prognostic and Predictive Indicators
Prognostic and predictive indicators in the treatment of STS provide critical background characteristics that may offer additional insights into evaluation and planning for cancer patients. Lymph node involvement, age over 60, and tumors larger than 7 cm were identified as significant risk factors for local recurrence and distant metastasis in a study of UPS, an analysis of 386 cases. Deep tumor location and a grade higher than 2 have been correlated with an increased rate of local recurrence. Additionally, Houdek et al. described the incidence of local recurrence and distant disease following wide excision of STS in the foot and ankle. They noted worse overall survival in tumors ≥3 cm. Iqbal et al. noted that low serum albumin levels were associated with poor event-free survival, as well as tumor size >10 cm and single-modality treatment demonstrating reduced overall survival. Furthermore, imaging techniques and histological analysis have been incorporated into prognostic evaluations, where CT chest imaging measurements of sarcopenia demonstrate higher skeletal muscle density correlation with improved survival and invasion beyond the subcutaneous fat was associated with increased risk of recurrence. While the incidence of STS often makes the study of prognostic factors complicated, additional research in the area will be pivotal toward improving outcomes for the aggressive nature of STS.
Classification and Prognostic Significance of Surgical Margins
Surgeons should use the UICC resection (designated by the letter R ) classification system for integration of the operative findings and the final microscopic surgical margins. Under this system, an R0 resection is defined as a macroscopically complete sarcoma resection with microscopically negative surgical margins; an R1 resection is a macroscopically complete sarcoma resection with microscopically positive surgical margins, and an R2 resection is a macroscopically incomplete (i.e., with gross residual disease) sarcoma resection with microscopically positive surgical margins. See Fig. 2.5 for a comparison of resection margins in surgery and radiology.
Surgical and radiographic margins to guide treatment planning for soft tissue sarcoma of the extremities. CC, Craniocaudal; CTV, clinical target volume; GTV, gross tumor volume; LM, lateromedial; RT, radiotherapy.
All therapeutic surgical procedures should be described in medical records using the R classification. To do so, surgeons must await the final pathology report, including margin assessment, and then integrate the observed operative findings, including the presence or absence of a residual gross tumor, with the final assessment of microscopic surgical margins. The operative report, discharge summary, and related medical records should describe the procedure using the R classification. As an example, a surgical procedure that involved a wide local resection of a left anterior thigh soft tissue leiomyosarcoma with satisfactory gross tumor margins, no operatively defined residual gross tumor, and negative microscopic surgical margins would be described as “R0 resection of left anterior thigh leiomyosarcoma.”
Microscopically positive surgical margins also appear important. For example, an R1 resection for a low-grade liposarcoma or an R1 after preoperative radiation treatment in which a microscopically positive margin is anticipated (and accepted) in order to preserve critical structures has a relatively low risk (<10%) for local recurrence. , Furthermore, an anticipated positive margin on a critical structure does not increase local recurrence rates, as described in the Toronto Margin Context Classification (TMCC). Using the TMCC, positive margins are separated into planned close but positive margins at critical structures, positive after an unplanned surgical resection or reexcision, and inadvertent positive margins.
Patients undergoing “unplanned” excision followed by a reexcision with positive margins (i.e., R1 reresection) or patients with unanticipated positive margins after primary resection are at increased risk for local recurrence, with rates approaching 30%. Therefore, the specific clinical setting needs to be considered when interpreting the relative risk for local recurrence after an R1 resection.
A recent paper emphasized that while achieving a negative oncologic margin is of extreme importance, the quantitative width of that margin has not been associated with oncologic outcomes. The authors do recommend reresection of non-R0 unplanned resections given that these patients are at increased risk of recurrence. The prognostic significance of surgical resection margins for local recurrence, distant metastasis, and overall survival in sarcoma of over 200 soft tissue sarcoma cases revealed that while margin width did not have a significant impact on prognosis, local relapse did predict a significantly worse distant relapse-free survival rate.
Nomograms for Assessment of Individual Patient Prognosis
The results of a study of 2163 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) were used to construct and internally validate a nomogram to predict sarcoma-specific death ( Fig. 2.6 ). Since the release of this, several prognostic nomograms have been developed for patients with soft tissue sarcomas in the extremity and retroperitoneum. These nomograms match a patient’s prognostic score against those of previously treated patients with comparable tumor and clinical factors to estimate individual patient risk for sarcoma-related death based on overall survival and disease-free survival (see Figs. 2.3 and 2.6 ).
(A) Nomogram for sarcoma-specific deaths. (B) Dynamic nomogram for 5-year overall survival.
More recently, PERSARC and Sarculator have gained widespread use and can help teams navigate multimodal care. These tools should not supplant comprehensive tumor board discussions. Decision making at times can be quite nuanced and the implications of SDOH and SES factors must also be considered.
Treatment of Localized Primary Extremity Sarcomas
Surgery
Surgical resection remains the cornerstone of therapy for localized primary soft tissue sarcoma. This discussion focuses on soft tissue sarcoma in the limbs, the most common anatomic site of origin, but the principles of treatment are generally applicable for patients with sarcomas at other anatomic sites.
While historically regarded as the primary treatment of extremity soft tissue sarcoma, amputation has now become much less common. Improvements in advanced imaging have also enabled a better understanding of the anatomic extent of the tumor and its viability in relation to critical structures. With the widespread application of multimodal treatment strategies, most patients with localized soft tissue sarcoma of the extremities undergo limb-sparing treatment, and less than 10% of patients presently undergo amputation.
Satisfactory local resection involves resection of the primary tumor with a margin of normal tissue around the lesion. Dissection along the tumor pseudocapsule ( enucleation or “shelling out”) is historically associated with local recurrence rates ranging between 33% and 63%. In contrast, wide local excision with a margin of normal tissue around the lesion is associated with lower local recurrence rates in the range of 10% to 31%, as demonstrated in the surgery-alone control arms of randomized trials evaluating postoperative radiotherapy (RT) and in single-institution reports.
The issue of what constitutes an acceptable gross surgical margin is complex, with limited prospective data specifically addressing surgical margins in soft tissue sarcoma surgery. The ongoing Children’s Oncology Group prospective study investigating neoadjuvant chemotherapy in children and young adults with nonrhabdomyosarcoma soft tissue sarcoma hopes to address this using data collected on the quantity and quality of the margin. Nonetheless, circumferential margin assessment in sarcomas is imprecise because of the complex anatomy of each tumor, as well as the tendency of soft tissue around the tumor to collapse and adopt its inherent shape when not under the continuous tension that is applied to the tissues as part of modern soft tissue surgery. This can result in significant discordance between the intraoperative perception and the pathologic evaluation of the gross surgical margin.
At sarcoma centers with experienced surgeons, to do limb-sparing resections in particularly challenging cases and in the setting of preoperative RT, occasionally a “planned positive margin” is accepted. This occurs intentionally when the surgeon dissects along critical neurovascular structures to maintain a functioning limb, anticipating a possible microscopic positive margin. Recurrence rates with this attentive technique approach those of true R0 resections.
Unlike resections for cutaneous melanoma in which gross surgical margins can be measured with a ruler at surgery, a gross margin assessment for soft tissue sarcoma cannot be measured so precisely. In addition, it is likely that not all soft tissues provide an equivalent barrier to tumor extension. For example, it is believed that a smaller gross margin that includes a fascial barrier is generally a more secure margin than a comparable gross margin that does not include fascia. For these reasons, a margin assessment for sarcomas by both surgeons and pathologists will continue to have an unavoidable degree of imprecision that probably exceeds the inherent imprecision in the assessment of gross margins of other solid tumors.
Combined-Modality Limb-Sparing Treatment.
Currently, more than 90% of patients with localized extremity sarcomas undergo limb-sparing treatment. The use of limb-sparing multimodal treatment approaches for extremity sarcoma was based on an important phase III trial from the U.S. National Cancer Institute (NCI) in which patients with extremity sarcomas amenable to limb-sparing surgery were randomly assigned to receive amputation or limb-sparing surgery with postoperative RT.
Both arms of this trial included postoperative chemotherapy with doxorubicin, cyclophosphamide, and methotrexate. With more than 9 years of follow-up data, this study established that for patients for whom limb-sparing surgery is an option, limb-sparing surgery combined with postoperative RT and chemotherapy yielded disease-related survival rates comparable to those for amputation and simultaneously preserved a functional extremity.
This trial established limb-sparing treatment as the standard treatment for patients with localized extremity soft tissue sarcoma. Amputation is used in clinical settings where local tumor anatomy precludes limb-sparing approaches, most often due to tumor involvement in functionally significant neurovascular structures.
The role of chemotherapy nonetheless remains elusive. Despite a lack of data demonstrating efficacy, systemic chemotherapy utilization has not decreased in the United States. Decision making remains nuanced and must consider the age of the patient, histologic tumor subtype and proclivity or realization of spread.
Currently, discussion of limb-preserving approaches must be linked to the role of adjuvant therapies, most frequently radiation treatment. It is now considered part of the central treatment dogma for extremity STS to employ radiotherapy in an adjuvant setting based upon randomized controlled trials. More recently, however, the role of radiotherapy has been reaffirmed as a key modality in improving local control, with multivariate analysis demonstrating improved relapse-free survival and overall survival. While the use of radiation does increase the risk of major wound complications, long-term functional effects have been reported to be relatively low.
Adjuvant radiation using brachytherapy (BRT) has also been evaluated. High-dose-rate brachytherapy (HDR BRT) can yield acceptable results when there is a high risk of a compromised surgical margin and no planned complex soft tissue reconstruction.
In one study, patients with localized extremity and superficial trunk sarcomas undergoing surgery were randomly assigned to be treated by surgery alone or by a combination of surgery and BRT. BRT was administered postoperatively through an iridium-192 implant that delivered 42 to 45 Gy over 4 to 6 days. At 5 years, the local control rate for high-grade tumors was 91% with BRT compared to 70% in surgery-alone controls ( P < .04). Of note, no improvement in local control with BRT was evident for patients with low-grade tumors. The local control rate was 74% with surgery alone and 64% with BRT. The full explanation for grade-specific differences in local control with BRT remains unresolved, although one suggestion implicates the relatively long cell cycle of low-grade tumors; low-grade tumor cells may not enter the radiosensitive phases of the cell cycle during the relatively short BRT time.
These studies have provided the evidence to support surgery plus radiation as the standard approach for most patients with operable extremity and superficial trunk sarcomas. At this time, there are no controlled trials evaluating the use of radiation treatment for patients with sarcomas in nonextremity sites. However, most multidisciplinary groups have extrapolated from the foregoing data and have assumed that radiation improves local control for patients with nonextremity sarcomas as well.
Attempting to prognosticate based upon response to upfront neoadjuvant therapy has a long history in soft tissue sarcoma. In a recent series of 694 patients with localized resectable myxofibrosarcoma and undifferentiated pleomorphic sarcoma of the extremities and chest wall Danieli et al. demonstrated that percent residual viable tumor <5% had a trend for improved survival ( P = .9) with the use of neoadjuvant chemotherapy.
Given the high risk of wound complications with neoadjuvant therapy, particularly RT, investigators have looked at broadening the spectrum of perioperative antibiotic coverage. The addition of anaerobic coverage such as with metronidazole has been shown to decrease major wound issues.
Treatment by Surgery Alone—Without Radiotherapy.
Radiation provides the unquestioned clinical benefit of decreasing local recurrence for most patients with soft tissue sarcoma. However, the known secondary adverse effects of radiation, which include edema, fibrosis, and radiation-induced second malignancies, have also prompted clinicians to try to identify a subset of patients who could be treated by surgery alone without compromising local disease control. Because of these adverse side effects associated with RT, some authors continue to espouse consideration of resection without its use.
Careful patient selection for unimodality treatment by surgery alone is essential. Important criteria include an R0 resection in clinical settings where the anatomic site clearly allows for adequate surgical margins. The importance of anatomic site in considering treatment by surgery alone is illustrated by the hypothetical cases of two patients with 4-cm, high-grade sarcomas: one in the anterior thigh and the second case with an identically sized tumor located in the wrist. Clearly, the first patient could undergo satisfactory treatment by surgery alone because the surgical margins can and should be satisfactory. However, this is not the case for the second patient because the wrist or other anatomically similar site is not amenable to wide margins without amputation and sacrifice of neurovascular structures.
Limb Reconstruction.
Soft tissue sarcoma surgery can be a highly complex intervention involving extensive dissections and tissue rearrangements. , Collaboration with plastic and oncologic surgeons has a strong historical precedent. Recently a study by the U.S. Sarcoma Collaborative demonstrated that involvement of plastic surgeons led to a significantly higher rate of R0 resections, which in turn were associated with local-regional recurrence-free survival and overall survival.
Optimizing functional outcomes is also another important consideration, having evolved substantially since ablative therapies were the norm a few decades ago. The literature, however, lacks methodologic consistency.
With the advent of negative pressure dressings, the ability to coordinate staged soft tissue reconstruction has been greatly enhanced, affording plastic surgeons the ability to perform complex coverage procedure at a potentially more appropriate time at a later date. This protracted surgical intervention does not seem to adversely affect the patient’s perceived outcomes.
Amputation.
Although sparingly used, amputation is still the appropriate treatment for a subset of patients who present with locally advanced primary tumors. The criteria for patient selection for amputation include the following:
-
•
Radiologically defined major vascular, bony, or nerve involvement, such that a “limb-sparing” primary tumor resection will result in critical loss of function or tissue viability.
-
•
Localized nonmetastatic disease (amputation is usually not considered for patients with established metastatic disease).
-
•
When a sarcoma extensively involves the foot and ankle, a below-knee amputation may lead to a more ideal functional result than a limb-sparing surgery, especially if radiation is involved. This decision is certainly discretionary.
For patients without limb-sparing surgical options, amputation offers excellent local tumor control and the prospect of prompt rehabilitation; therefore, a small but well-defined role remains for amputation in the management of patients with extremity soft tissue sarcoma.
Management of Regional Lymph Nodes
There is no role for routine regional lymph node dissection in most patients with localized soft tissue sarcoma, given the low (2% to 5%) incidence of lymph node metastasis in adults with sarcomas. , , However, patients with angiosarcoma, embryonal/alveolar rhabdomyosarcoma, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and epithelioid sarcoma are at increased risk for lymph node metastasis and should be carefully examined for lymphadenopathy. These patients should be considered for either positron emission tomography (PET) scan or sentinel lymph node biopsy as part of definitive treatment. A therapeutic lymph node dissection should be considered for patients with pathologically proven lymph node involvement who do not have radiologically defined metastatic disease. A therapeutic lymph node dissection may result in survival rates as high as 34%.
The prognosis of patients with pathologically positive metastatic disease to lymph nodes has been generally regarded as like patients with visceral metastatic disease. However, one study described a series of patients with isolated lymph node metastasis treated intensively with combined-modality treatment showing somewhat better outcomes, approaching those of patients with localized, high-risk (stage III) disease. Nevertheless, controversy remains because lymph node involvement has also been shown to confer a poor prognosis. Accordingly, in the latest AJCC staging system, N1 is designated stage IV.
Radiotherapy
Rationale for Combining Radiotherapy With Surgery.
Historically, the use of RT in combination with surgery for soft tissue sarcoma is supported by a series of clinical trials (see Table 2.2 for a literature summary). , The rationale for these is based on two premises: (1) microscopic foci of residual disease can be destroyed by RT, and (2) less radical surgery can be performed when surgery and RT are combined. Although the traditional belief was that soft tissue sarcoma is resistant to RT, radiosensitivity assays performed on sarcoma cell lines grown in vitro have confirmed that the radiosensitivity of sarcomas is like that of other malignancies; this confirmation supports the first premise. The second premise stresses the philosophy of preservation of form (including cosmesis where possible) and function as a goal for many patients with extremity, truncal, breast, and head and neck sarcomas. Similar principles govern the frequent use of RT for sarcomas at anatomically challenging sites, such as the retroperitoneum, head and neck, or paravertebral regions. The literature continues to support the utilization of RT to discretionarily tailor back surgical resection to optimize function.
Table 2.2
Summary of Outcomes for Major Studies on Radiotherapy and Surgery for Soft Tissue Sarcomas
| References | Study Design | Setting | No. of Patients | Median F/U (years) | 5-year LC (%) | 5-year DFS (%) | 5-year OS (%) | ||
|---|---|---|---|---|---|---|---|---|---|
| Yang et al. | Randomized | LSS alone | 71 | 17.9 | 78 (10-year) | High grade | 68 (10-year) |
Low grade
Not reported |
74 (10-year) |
| LSS + postop EBRT | 70 | 100 (10-year) | 95 (10-year) | 75 (10-year) | |||||
| O’Sullivan et al. | Randomized | Preop EBRT | 94 | 3.3 | P = .791 | Not reported | P = .791 | ||
| Postop EBRT | 96 | ||||||||
| Jebsen et al. | Retrospective | LSS alone | 598 | 5 | 28 (Intralesional margins) | 74 (marginal margins) | 87 (marginal margins) | Not reported | Not reported |
| LSS + EBRT (pre or post) | 381 | 62 (Intralesional margins) | 81 (marginal margins) | 93 (marginal margins) | |||||
| Pisters et al. | Prospective randomized | LSS alone | 86 | 6.3 | 69 | 81 | Not reported | ||
| LSS 4- BRT | 78 | 82 | 84 | ||||||
| Sampath et al. | Retrospective | Preop EBRT | 293 | 5.3 | 93 | Not reported | 65 | ||
| Postop EBRT | 528 | 87 | 60 | ||||||
| Wang et al. | Prospective phase II | Preop EBRT + LSS | 79 | 3.6 | 94 (2-year) | 61.5 (2-year) | 80.6 (2-year) | ||
| Koshy et al. | Retrospective | LSS alone | 3.689 | Not reported | Not reported | Not reported | 73 (3-year) | ||
| LSS + EBRT (pre or post) | 3.271 | 63 (3-year) | |||||||
| Alektiar et al. | Retrospective |
LSS
+
EBRT
(pro or post) |
41 | 3 | 84 | Not reported | 64 | ||
BRT, Brachytherapy; DFS , disease-free survival; EBRT, external beam radiotherapy; LSS, limb-sparing surgery; OS , overall survival
Sequencing of Radiotherapy and Surgery.
There remain tradeoffs of benefits and risk factors in terms of sequencing of RT relative to surgery. Advantages of preoperative radiation include a generally lower radiation dose (50 Gy), small field size, and reduced risks for long-term treatment sequelae, including edema and fibrosis. These advantages occur at the cost of increased risk for surgical wound complications resulting from radiation-related impairment in wound healing. Advantages of postoperative radiation treatment include the ability to treat pathologically diagnosed and staged patients with known margin status. However, postoperative radiation is usually administered at a higher dose (65 Gy) and is associated with greater risks for treatment-related, long-term complications, including edema and fibrosis. Therefore, treatment sequencing involves complicated trade-off issues that need to be individualized and carefully discussed with the patient.
The NCI of Canada/Canadian Sarcoma Group SR2 clinical trial ( Fig. 2.7 ) provided a prospective randomized comparison of preoperative versus postoperative RT. Patients were randomly assigned to be treated by surgery with either preoperative or postoperative radiation (with a radiation boost dose for patients with microscopically positive surgical margins). The primary endpoint of the trial was major wound complications. The SR2 trial demonstrated that wound complications were twice as common with preoperative RT as they were with postoperative RT (35% vs. 17%, respectively), although the increased risk was almost exclusively confined to patients with sarcomas of the lower extremity. Other studies have supported these findings. , The SR2 trial also provided important data on long-term, treatment-related complications. Patients randomized to postoperative radiation had significantly greater rates of generally irreversible fibrosis and edema. This observation is potentially important because patients with significant fibrosis, joint stiffness, or limb edema had significantly lower-limb function scores at these later time points.
A–D, Kaplan–Meier plots for probability of local recurrence, metastasis (local and regional recurrence), progression-free survival, and overall survival in the Canadian Sarcoma Group randomized trial of the National Cancer Institute of Canada Clinical Trials Group comparing preoperative and postoperative radiotherapy.
The analysis of late treatment effects demonstrated that the radiation field size was associated with greater degrees of fibrosis and joint stiffness and also may be related to edema. The SR2 trial was neither designed nor statistically powered to compare traditional oncologic endpoints such as local control and overall survival (these were secondary endpoints in the trial). The 5-year results for preoperative versus postoperative radiation, respectively, were as follows: local control, 93% versus 92%; metastatic relapse-free, 67% versus 69%; recurrence-free survival, 58% versus 59%; overall survival, 73% versus 67% ( P = .48); and cause-specific survival, 78% versus 73% ( P = .64). Cox modeling showed only resection margins as significant for local control. Tumor size and grade were the only significant factors for metastatic relapse, overall survival, and cause-specific survival. Grade was the only consistent predictor of recurrence-free survival.
For now, decisions about preoperative versus postoperative RT should be individualized, considering tumor location, tumor size, RT field size, comorbidities, and risks. In general, preoperative RT provides some advantages over postoperative RT but exposes the patient to significantly increased risks of serious (generally reversible) postoperative wound complications. Table 2.3 summarizes the relative indications that can be used to select patients for preoperative RT.
Table 2.3
Relative Indications for Preoperative Radiotherapy (RT), Despite Consents Related to Wound Complications
From O’Sullivan B, et al. The local management of soft tissue sarcoma. Semin Radiat Oncol. 1999;9(4):32S–34S. Berkely FJ. Managing the adverse effects of radiation therapy. Am Fam Physician . 2010;82(4):381–388.
| Treatment Consideration/Sarcoma Site | Issues of Concern | Comments |
|---|---|---|
| Head and neck Paranasal sinus | Proximity to optic apparatus (eye, orbit, chiasma) | Major visual functional deficit can be minimized |
| Cheek and face | Proximity to spinal cord, brainstem | Other “lesser” morbidities (dental, xerostomia) may also be less due to reduced doses and volumes |
| Neck | Proximity to voice box, spinal cord | Consideration for the larynx and thyroid |
| Thoracic wall-pleura | Proximity to lung or cardiac structures | Lung may be displaced by chest wall or pleural tumor and can be avoided with preoperative RT, or permits GTV to be treated before operative contamination |
| Retroperitoneum | Proximity to bowel, liver, kidney | Critical organs may be displaced by tumor or not fixed or adherent as is likely in postoperative setting |
| Large-volume GTV or CTV’ occupying coelomic cavities | Entire tumor treated before possible contamination of cavity | |
| Small bowel lesions | Proximity to critical anatomy, especially intestine with side-wall adherence | Contamination of abdominal cavity renders postoperative RT unsuitable |
|
Abdominal trunk walls
Pelvic side wall |
Proximity to kidney, bowel, liver, ovaries | Avoid CTV encroachment on vulnerable anatomy. GTV adjacent to dose-limiting critical anatomy |
| Thoracic inlet-upper chest | Proximity to brachial plexus |
Dose limitation of critical anatomy lends itself to preoperative low-dose neck RT
Additional volume considerations |
| Medial thigh | Proximity to reproductive organs | May avoid erectile dysfunction, vaginal dryness, or permanent infertility |
| Split-thickness skin graft reconstruction (especially lower limb) | Skin graft breakdown and consequent infection | Many months to years of recreational and/or vocational disability may occur during healing (rare) |
| Central limb tumor | Proximity to other compartments | Permits partial circumferential sparing, which would not be feasible in postoperative setting |
CTV, Clinical target volume; GTV, gross tumor volume.
In a different approach, tailoring extremity STS surgery to histologic subtype after preoperative radiotherapy has been entertained by some. , In one study, margin status was not predictive in 198 cases for recurrence-free, metastasis-free, and overall survival. The authors suggest that marginal excision may be adequate. Intermuscular extremity myxoid liposarcoma can be managed by marginal resection following neoadjuvant radiotherapy.
Radiation Treatment Techniques.
External beam radiation therapy (EBRT) and brachytherapy (BRT) are used for patients with soft tissue sarcoma. No prospective trials have directly compared EBRT and BRT, but each of these techniques has been compared with surgery alone. ,
EBRT is the most common radiation treatment technique for patients with soft tissue sarcoma. EBRT is widely available and can be administered by all radiation oncologists. It is also effective for patients with both high-grade and low-grade sarcomas. Treatment is usually administered on an outpatient basis in daily fractions of 1.8 to 2.0 Gy (Monday to Friday) to total doses of 50 Gy (preop dose; 5-week duration) or 60 to 66 Gy (postop dose; 6½ weeks). Adjuvant radiotherapy has shown durable local control at 20 years of follow-up. The authors do note lymphedema, functional deficit, and wound complications.
In contrast, BRT for soft tissue sarcoma is available in only specific centers where there are trained radiation oncologists and appropriate facilities for radiation isotope storage and handling, but BRT offers several advantages. Because of the shorter treatment time (4 to 6 days) compared to EBRT, it is usually administered on an inpatient basis during the same hospital stay and is more easily integrated into treatment protocols that include systemic chemotherapy. Because irradiated tissue volume is less, BRT may confer long-term functional advantages. BRT also costs less than EBRT.
One specific limitation of BRT is that it should be used for patients with only high-grade sarcomas (as well as R0 cases) because the only randomized trial that evaluated this technique demonstrated that BRT does not appear to be effective for patients with low-grade sarcomas. , , Retrospective data also suggest that BRT may not provide optimal local control for R1 cases. BRT may also have an advantage in the following situations where normal tissue tolerance to conventional external beam radiation has been compromised: (1) a postoperative boost in patients who have received preoperative RT or (2) radiation for local recurrence in a previously irradiated field.
Intraoperative RT remains contentious and is used only at select centers. A systematic review based on small prospective and retrospective studies concluded that discretionary use can decrease toxicity while affording high local control rates . A more recent study has also been supportive .
Intensity-modulated radiation therapy is a radiation delivery technique that allows external beams designed with variable intensity to be delivered across their profiles, in contrast to the uniform flat profile used in traditional external beam RT. These variable-intensity beams are not only shaped according to the needs of the target, but also consider the dose provided by the others. This allows the beams to conform closely to the target while avoiding other structures. It may be particularly valuable for tumors of complex shapes, such as sarcomas, and has recently been used to treat large intraabdominal targets, including retroperitoneal sarcomas. Clinical results are anticipated from studies of these improvements in RT planning and delivery.
Hypofractionated and Dose Reduction Radiotherapy
To make neoadjuvant RT more convenient and to diminish the surgical extirpation of the tumor, hypofractionated regimens have begun to appear. A single-institution, single-arm, open-label phase II trial of 3-week preoperative radiation delivered 42.75 Gy in 15 fractions. The primary endpoint was wound complication at 120 days. In 120 patients they noted a minor wound complication rate of 31% and a reoperation rate of 10%. The authors concluded that this regiment was safe and convenient.
For myxoid liposarcoma, dose reduction has been proposed. One study decreased the neoadjuvant total dose from 50 to 36 Gy into 18 episodes of 2 Gy. A pathologic response rate of 70% or more of the resection specimens showed extensive treatment response was considered a success. Of 77 evaluable patients, 70 demonstrated extensive pathological treatment response. The local control rate was 100%. The rate of wound complication requiring intervention was 17%, and the rate of grade 2 or higher toxic effects was 14%. The authors conclude that this method is effective, safe, and decreases morbidity in myxoid liposarcoma. Conversely, lattice radiotherapy is a technology that may have relevance in the future to impart increased dosing to areas at the highest risk of physical aspects of a spatially fractionated radiotherapy technique for large soft tissue sarcomas.
A current study underway incorporates the use of hypofractionated proton beam therapy (PBT) for extremity and truncal STS. The regimen involves 30 Gy in 5 fractions every other day with resection occurring 2 to 12 weeks later with the primary outcome being rate of major wound complication. PBT is also now a consideration in children with nonrhabdomyosarcoma STS although the authors call for an international comprehensive collaborative approach to further define its role. They recommend establishing guidelines for PBT indications.
Chemotherapy
Chemotherapy is the mainstay of therapy for patients with metastatic (stage IV) STS. The use of chemotherapy in the (neo)adjuvant setting remains controversial but is gaining increased acceptance when used selectively for certain subtypes, such as synovial sarcoma. For advanced STS, doxorubicin monotherapy is still considered the mainstay.
Chemotherapy Following Primary Surgical Resection.
Although local or locoregional recurrence is a problem for a small subset of patients after primary therapy, the major risk to life in sarcoma patients is uncontrolled microscopic or macroscopic systemic disease. Increasingly, major sarcoma centers are taking a histology-specific approach to selecting patients for consideration of adjuvant treatment.
Neoadjuvant or adjuvant chemotherapy is an appropriate standard of care for Ewing sarcoma and rhabdomyosarcoma. However, for more common soft tissue sarcomas such as leiomyosarcoma, liposarcoma, and high-grade undifferentiated pleomorphic sarcoma, the benefit for chemotherapy, if present, is small. Because adjuvant therapy is used by many practitioners for more common diseases where the benefit is relatively small, such as stage I breast cancer and stage II colon cancer, this small potential benefit must be discussed with the individual patient. Certainly, the lack of available effective agents for metastatic sarcoma has impeded progress in this area. However, the utility of imatinib in a gastrointestinal stromal tumor, with the subsequent availability of other biotargeting agents (such as pazopanib), gives hope that new agents will contribute to the ultimate goal of increasing the cure rate of new patients. Further, if a cure is not attainable, then at least these agents may push metastatic disease status to that of a chronic, less life-threatening disease. ,
Numerous studies of anthracycline-based adjuvant chemotherapy for soft tissue sarcoma have been done, dating back almost to the initial development of doxorubicin. , These are not reviewed here because anthracycline/ifosfamide-based therapy constitutes a better standard of care in patients offered adjuvant chemotherapy, and only one of the studies had used ifosfamide.
Table 2.4 summarizes the results of a recent meta-analysis of monotherapy doxorubicin versus an experimental arm of doxorubicin-based or other chemotherapy regimens. In total, this study comprised 6156 patients from 27 studies, showing that the overall survival at 1 year was significantly improved in the experimental arm but was lost by 2 years. Progression-free survival was not significantly different between the two groups. Additionally, although the overall adverse event profile was not different between the two groups, patients in the experimental arm had more severe nausea and vomiting. The authors conclude that doxorubicin monotherapy is suitable for front-line therapy in advanced STS.
Table 2.4
Description of RCTs That Compare Standard Doxorubicin With Other First-Line Chemotherapies for Soft Tissue Sarcomas
| Study | No. of Patients | Experimental Regimen | Study Phase | Primary Endpoint | ITT Analysis | Postprotocol Treatment |
|---|---|---|---|---|---|---|
| RCTs Comparing DOX and DOX-Based Combination Chemotherapy | ||||||
| Chang (1976) | 33 | DOX+Streptozotocin | Not specified | Not specified | Not specified | Not specified |
| Schoenfeld (1982) | 221 |
VCR+DOX+CPA
VCR+Act-D+CPA |
Not specified | Not specified | Not specified | Crossover |
| Omura (1983) | 315 | DOX+DTIC | Not specified | Not specified | Not specified | Not specified |
| Muss (1985) | 132 | DOX+CPA | III | Not specified | Not specified | Not specified |
| Borden (1987) | 361 | DOX+DTIC | Not specified | Not specified | Not specified | Not specified |
| Borden (1990) | 347 | DOX+Vindesine | Not specified | Not specified | Not specified | Not specified |
| Edmonson (1993) | 279 |
DOX+IFM
DOX+MMC+CDDP |
III | Not specified | Not specified | Not specified |
| Santoro (1995) | 663 |
DOX+IFM
CYVADIC |
III | Not specified | Not specified | Not specified |
| Maurel (2009) | 132 | DOX+IFM | II | PFS | Not specified | IFM, DTIC, GEM+DTIC |
| Demetri (2012) | 128 | DOX+Conatumumab | II | PFS | Not specified | Roll over |
| Judson et al. (2014) | 455 | DOX+IFM | in | os | + | DOX, EPI, IFM, TRAB, PAZ, ERIB, DTIC, GEM +DOC, etc |
| Tap et al. (2016) | 133 | DOX+Olaratumab | II | PFS | + | DOX, GEM+DOC, TRAB, PAZ, ERIB, GEM, DTIC, DOC, etc |
| Martin-Broto (2016) | 115 | DOX+TRAB | II | PFS | + | Not specified |
| Tap (2017) | 640 | DOX+Evofosfamide | III | OS | + | DOX, IFM, TRAB, GEM+DOC, PAZ, ERIB, GEM, DTIC, etc |
| RCTs Comparing DOX and Other Chemotherapy Without DOX | ||||||
| Cruz (l979) | 117 |
Act-D+LPAM
Act-D+LPAM+VCR Act-D+LPAM +NSC1026 |
III | Not specified | Not specified | Crossover |
| Savlov (1981) | 208 | Cycloleucine | Not specified | Not specified | Not specified | Crossover |
| Bramwell (1983) | 71 | Carminomycin | II | Not specified | Not specified | Crossover |
| Mouridsen (1987) | 210 | EPI | II/III | Not specified | Not specified | Crossover |
| Nielsen (1998) | 334 | EPI | III | Not specified | Not specified | Not specified |
| Verweij (2000) | 86 | DOC | II | Not specified | Not specified | Crossover |
| Judson (2001) | 95 | Liposomal doxorubicin | II | RR | + | Not specified |
| Lorigan (2007) | 326 | IFM | III | PFS | Not specified | Not specified |
| Gelderblom (2014) | 118 | Brostallicin | II | 26-week PFR | Not specified | DOX-based, IFM, etc |
| Blay (2014) | 121 | TRAB | III | PFS | + | TRAB, etc |
| Bui-Nguyen (2015) | 133 | TRAB | II | PFS | + | Not specified |
| Chawla (2015) | 123 | Aldoxorubicin | II | FFS | + | Not specified |
| Seddon et al. (2017) | 257 | GEM+DOC | in | 24-week PFR | + | DOX, IFM, TRAB, PAZ, GEM+DOC, GEM, etc |
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