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Soft Tissue Sarcomas (Excluding Retroperitoneum)

Sarcomas are rare malignancies that arise from the connective tissues in any organ or at any anatomic location of the body. This chapter addresses sarcomas that arise in the extraskeletal, nonvisceral connective tissues of adults, excluding the retroperitoneum. Despite the diversity of tissues and locations of origin, these soft tissue sarcomas are grouped together because of overall similarities in natural history and treatment. Retroperitoneal sarcomas, pediatric sarcomas, osteosarcomas, sarcomas arising in visceral organs, Kaposi's sarcoma, and sarcomas arising in the vasculature are discussed elsewhere in this textbook.

Anatomy

The majority of soft tissue sarcomas occur in the muscle groups of the extremities (Table 81.1). These tumors often remain confined to the muscle compartment of origin. The thigh is the most common subsite of origin and is partitioned into three compartments (37). The muscle compartments of the arm, forearm, and leg are similarly defined (4) (Fig. 81.1). Anatomic knowledge is essential for the radiation oncologist because it allows appropriate positioning of the limb to encompass the portion of the compartment at risk, while avoiding compartments that are not involved.

Epidemiology, Genetics, and Risk Factors

Approximately 9,400 cases of soft tissue sarcoma are diagnosed yearly in the United States, accounting for 0.7% of cancers and an estimated 3,500 deaths (68). Men are more frequently affected than women, and rates are higher among African Americans than whites. Most sarcomas arise in a sporadic fashion, without identifiable etiology. Sarcomas do not appear to develop from pre-existing benign lesions. Associated factors can be identified in certain subsets of sarcomas, including predisposing genetic mutations, previous ionizing radiation or chemical exposures, and chronic soft tissue injury or lymphe-dema.

The Li-Fraumeni syndrome is an autosomal dominant familial cancer predisposition syndrome in which the risk of breast and other invasive cancers, including sarcomas, by age 35 years is almost 50% (88). A germline mutation in the p53 tumor suppressor gene is identifiable in most of the affected families (91). The p53 gene is central in modulating a cell's response to DNA damage by arresting the cell cycle and inducing apoptosis (81). Somatic mutations of p53 are among the most common genetic alterations seen in mesenchymal tumors, occurring in nearly 60% of sarcomas (26). The activity of p53 can also be disrupted by amplification of the MDM2 gene, located at chromosome 12q13-q14 and coding for a nuclear phosphoprotein that inactivates wild type p53. MDM2 amplification has been demonstrated in 10% to 30% of sarcomas (43).

Patients with hereditary retinoblastoma inherit a germline mutation in the RB gene, and a “second hit” in the remaining allele results in malignancy. The RB protein regulates the cell cycle, governing the entrance into the DNA synthesis (S) phase of the cell cycle. In addition to malignant retinoblastomas of the eye, these patients are at increased risk of developing osteosarcomas and soft tissue sarcomas later in life, particularly after exposure to therapeutic radiation (145). Genetic disruption of the RB pathway is observed in over 50% of sarcomas (22).

Patients with neurofibromatosis type 1 (NF1, von Recklinghausen's neurofibromatosis) develop multiple neurofibromas and are at increased risk for gliomas and malignant peripheral nerve sheath tumors (MPNSTs) (155). As in heritable retinoblastoma, a germline mutation in NF1, followed by somatic mutation of the remaining allele, results in malignant degeneration (59).

Ionizing radiation exposure produces a small but detectable risk of both bone and soft tissue sarcoma. Radiation-induced sarcomas were first reported in the 1920s among workers painting radium watch dials (48). Sarcomas arising after therapeutic irradiation, reported since the 1930s (16), develop after a latency period (between 2 and 25 years) within the radiation portal and are histologically distinct from the primary malignancy (17). In one review, 3.3% of 1,089 sarcoma patients met these criteria (94). The median latency period was 14 years, and risk was increased after high radiation doses. In a large Finnish cohort study, the absolute risk of postirradiation sarcoma with long-term follow-up was 0.03% (140). The most commonly observed radiation-induced sarcomas arise after radiation therapy for breast cancer. These aggressive malignancies often involve a large portion of the breast (Fig. 81.2). Among 194,798 women diagnosed with localized or regional invasive breast cancer between 1973 and 1995, the relative risks of angiosarcoma and other sarcoma subtypes were 15.9 and 2.2 for irradiated patients compared with unirradiated patients (66). Despite high relative risks, the absolute risk of developing radiation-induced sarcomas is small, 0.28% and 0.48% at 15 years after in two large series (78,116). Angiosarcoma is also observed in patients with chronic lymphedema (Stewart-Treves syndrome), which may or may not be associated with radiation therapy (73).

Epidemiologic studies of industrial chemical exposures and sarcoma risk are limited by the small numbers of individuals exposed to a variety of different agents. Studies have suggested links between vinyl chloride and hepatic angiosarcoma (36), as well as phenoxy herbicides, particularly those contaminated with chlorinated dioxins, and soft tissue sarcomas (38). Studies of United States veterans exposed to Agent Orange, a dioxin-containing herbicide used extensively during the Vietnam War, have shown no evidence of increased sarcoma risk (133).

Natural History

Extremity soft tissue sarcomas spread directly by local extension along the longitudinal axis of muscular compartments. Fascial planes and bone are rarely violated and constitute barriers
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to local spread. Grossly, lesions appear encapsulated; however, this is a pseudocapsule, representing compressed normal tissue and reactive fibrosis (37). Subclinical disease can infiltrate adjacent tissues, extending 5 to 10 cm beyond the pseudocapsule, “skipping” areas that appear uninvolved. Biopsy procedures can potentially change the pattern of spread if they violate an uninvolved compartment or if an extensive hematoma results (4). In the trunk or head and neck regions, the disease more commonly invades adjacent structures.

High-grade sarcomas have the potential to metastasize. Because lymph nodes are involved in <10% of sarcoma cases, routine lymph node sampling is usually not performed. Clear cell sarcoma, epithelioid sarcoma, angiosarcoma, rhabdomyosarcoma, and synovial cell sarcoma have higher rates of nodal spread (44), and sampling should be considered for these histologies. Hematogenous metastases occur frequently in patients with high-grade sarcomas; most occur in the lungs (111), with less frequent metastasis to other soft tissue sites, bone, liver or skin (139). The median time to metastasis is approximately 1 year (107). However, metastasis >5 years after initial diagnosis is not uncommon (87).

Clinical Presentation

Soft tissue sarcoma classically presents as a growing, painless mass. Several-month delays in presentation to a physician, establishment of a sarcoma diagnosis, and referral to a sarcoma center are not uncommon (21). Numbness, pain, or edema may be caused by tumor-induced neurovascular compromise. Deep tumors may attain an enormous size before coming to clinical attention. Metastases are noted at the time of diagnosis in <10% of patients (118).

Clinical Evaluation

The history should detail family history and previous radiation exposure. The physical examination must detail the size, location, and depth (superficial or deep) of the mass, as well as its proximity to joints. Evidence of neurovascular compromise and fixation to bone should be sought because the ability to perform a limb-sparing procedure in a patient with these findings is greatly decreased. A careful lymph node examination should always be performed.

Obtaining diagnostic imaging before an attempt to obtain tissue diagnosis may be advantageous because it provides images devoid of biopsy-related changes, and may provide guidance for appropriate biopsy technique. Plain radiographs and ultrasound of the affected area are underused, and often provide valuable information including the presence of a solid versus cystic mass, calcification, or bony invasion. Magnetic resonance imaging (MRI) is increasingly preferred as an imaging modality for soft tissue masses and provides excellent soft tissue detail (Fig. 81.3). Computed tomography (CT) supplements MRI and is particularly helpful in identifying bony invasion or destruction. Although certain soft tissue neoplasms may have characteristic radiographic features, no imaging modality has sufficient specificity to specifically distinguish benign from malignant masses (27). Because the lungs are the predominant site of distant metastasis for soft tissue sarcomas, chest imaging by posterior and lateral chest x-ray or CT is appropriate at initial evaluation and subsequent surveillance for distant metastases, particularly for patients with high-grade disease.

The clinical role of positron emission tomography (PET) in the evaluation of soft tissue sarcomas is an active area of investigation. Uptake of [F-18]-fluorodeoxy-D-glucose (FDG) is somewhat variable in soft tissue neoplasms, but is generally increased in malignant compared with benign, and in high-grade compared with low-grade neoplasms (12). FDG-PET activity may have prognostic significance and may have promise for predicting treatment response (121,123).

A biopsy should be performed on any soft tissue mass that persists or grows, with the exception of subcutaneous lesions that have remained unchanged for years. Ideally, biopsy of a soft tissue mass should be performed by an experienced surgeon. Consideration should be given to biopsy technique and selection of biopsy site, given that all potentially contaminated tissue may need to be removed in a subsequent definitive resection and included in radiation therapy target volumes. Excisional biopsies should be avoided in all but the smallest superficial lesions. Fine-needle aspiration is used by experienced groups for the diagnosis of soft tissue tumors (6), but does not allow for the examination of tissue architecture and is not preferred for diagnosis by most pathologists. Fine-needle aspiration may be most useful to diagnose recurrence or metastasis in patients with an established histologic diagnosis (135). Sufficient tissue for diagnosis is more easily obtained by incisional biopsy or core needle (TruCut) biopsy. The incision for biopsy should be oriented along the longitudinal axis of the extremity such that it can be encompassed in a subsequent resection. Core needle biopsy is minimally invasive as well as easier and cheaper to perform. Although less volume of tissue is obtained by core needle biopsy, it has become standard practice and has been proven to be accurate for diagnosis in the majority of cases (62).

Staging

The American Joint Committee on Cancer staging system (2002 edition) emphasizes grade (G) as the most important prognostic factor for soft tissue sarcoma (Table 81.2) (54). A three- or four-tier system of histologic grading may be used. The prognostic importance of tumor size and depth of invasion is incorporated in the primary tumor (T) stage. The presence of either nodal (N) or distant (M) metastases constitutes stage IV disease. The primary anatomic site of disease is not considered. Comparisons with alternate staging systems developed by investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) and other institutions confirm that tumor depth, grade, and size are the most predictive of systemic relapse (147). However, most systems provide little prognostic information relevant to local recurrence.
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Pathologic Classification

Soft tissue sarcomas are classified according to their presumed tissue of origin, using histologic designations such as liposarcoma (adipose tissue), leiomyosarcoma (smooth muscle), or angiosarcoma (vascular tissue) (41). Tumors without identifiable histogenesis are designated according to morphologic appearance or the presumed “line of differentiation” of the tumor cells. Changes in histologic classification have occurred over time. For example, the category of malignant fibrous histiocytoma (MFH) was established in the 1970s, but subsequently became the most common histologic diagnosis for adult soft tissue sarcomas, coinciding with a reduction in the number of cases classified as pleomorphic rhabdomyosarcoma (Table 81.3). The MFH classification is controversial because neither the tissue of origin nor the line of differentiation is clear. In a review, a specific line of differentiation could be identified in the majority of MFH specimens when reanalyzed histologically, immunohisto-chemically, or ultrastructurally (40), suggesting that the MFH designation is overused.

Pathologic grading is subjective, but the significance of grade as a predictor of metastasis has been demonstrated repeatedly (41). No grading system is uniformly accepted, but most assign tumors to one of three or four categories. The grading system developed by the French Federation Nationale des Centres de Lutte Contre le Cancer assigns a tumor to grade 1 through 3 based on differentiation, mitotic rate, and degree of necrosis (24). The National Cancer Institute system uses histologic type, cellularity, nuclear pleomorphism, frequency of mitoses, and degree of necrosis. There was 34.6% discordance in grading between the two systems in a study of 410 nonmetastatic soft tissue sarcoma cases (58). Although both systems were prognostic, the French Federation Nationale des Centres de Lutte Contre le Cancer system yielded the best correlation with distant metastasis and overall survival. In our current practice, every attempt is made to assign a given tumor into either a high- or low-grade category in order to facilitate clinical decision-making.

Two immunohistochemical stains that are useful for distinguishing sarcomas from more common carcinomas are vimentin (positive in almost all sarcomas, and negative in most carcinomas) and cytokeratin (positive in almost all carcinomas, and negative in most sarcomas). S100 and HMB-45 are positive in melanoma, but may also be positive in specific soft tissue sarcomas. Sarcoma subclassification can be aided by desmin or myoD1 (positive in myogenic tumors), vascular markers (positive in angiosarcomas), and MIC2 (positive in peripheral neuroectodermal tumors). These stains may confirm a diagnosis already considered on morphologic grounds or may raise the possibility of a diagnosis not previously considered.

Metaphase cytogenetics or polymerase chain reaction-based molecular testing may be useful for the identification of chromosomal rearrangements and gene fusions specific to particular subtypes of soft tissue sarcomas (153), such as the t(12;16)(q13;p11) translocation that creates a fusion between adipocyte differentiation gene CHOP and nuclear RNA-binding protein TLS (28), t(X;18)(p11.2;q11.2) that results in a fusion between the SYT gene and either the SSX1 or SSX2 genes in synovial cell sarcoma (20), t(12;22)(q13;q12) (ATF1-EWS) in clear cell sarcoma (42), t(11;22)(p13;q12) (WT1-EWS) in desmoplastic small round cell tumor (50), t(9;22)(q22;q12) (CHN-EWS) in
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extraskeletal myxoid chondrosarcoma (64), t(17;22)(q22;q13) (COL1A1-PDGFB) in dermatofibrosarcoma protuberans (105), or t(X;17)(p11;q25) (ASPL-TFE3) in alveolar soft parts sarcoma (70). Chromosomal and molecular analyses such as gene expression profiling can subclassify sarcomas based on molecular biology, providing insight into tumor biology and identifying potential therapeutic targets (60). Molecular classification may supplement or even supplant traditional histologic classification in the future.

Prognostic Factors

The most important prognostic factor for distant metastasis and survival is grade (24,107,152). For low-grade tumors, the risk of distant metastases at 5 years is <10%, compared with almost 50% for high-grade tumors. Tumor size and depth are also prognostic with respect to distant metastasis. Certain histologic subtypes such as MPNST or leiomyosarcoma may be associated with increased distant metastasis and worse survival (24,107). Nomograms predicting disease-specific survival after resection of localized soft tissue sarcoma have been developed (74,93).

Risk factors for local recurrence are distinct from those for distant metastasis and survival. Multiple prospective and retrospective studies have demonstrated that the presence of tumor cells at the surgical margin and inadequate surgical excision are the most important adverse risk factors for local recurrence (23,56,107,115,119,130,134,143,152). Age >50 years, locally recurrent disease, MPNST or fibrosarcoma histology, the presence of symptoms at presentation, deep location, and withholding of radiation therapy have also been associated with increased local recurrence risk.

No conclusive link has been demonstrated between local control and survival in soft tissue sarcoma. Randomized trials have not detected a survival difference between patient groups with disparate local control (108,112,149). However, Gronchi et al. (56) found that the 10-year rates of distant metastasis and cause-specific mortality were higher for patients with positive margins, compared with patients with negative margins. Although these differences were not large, several studies have suggested this trend (23,35,63,134,142,152). Interestingly, Gronchi et al. reported a cause-specific mortality hazard ratio of 0.7 (p = .032) in favor of patients receiving adjunctive radiation therapy. Whether local recurrence seeds distant metastasis to impact survival, or it is simply a reflection of biologically aggressive disease, remains controversial.

A variety of molecular pathologic factors have been evaluated for prognostic significance. Proliferative activity as assessed by Ki-67 (MIB-1) immunohistochemistry has been shown to be prognostic (61). Increased expression of p53 and MDM2 has been associated with a poor prognosis in some studies (148), but not others (61). In synovial sarcomas, the presence of the fusion gene SYT-SSX2 was shown to associate with higher metastasis-free survival than SYT-SSX1 (75). Despite these preliminary data, routine application of molecular prognostic biomarkers awaits prospective validation in larger patient cohorts. These molecular markers may be most useful for selecting high-risk patients for future trials of adjuvant chemotherapy.

General Management

The majority of soft tissue sarcoma patients require multimodality treatment. Treatment is optimally delivered by a multidisciplinary team of dedicated surgical, orthopaedic, medical and radiation oncologists, plastic and reconstructive surgeons, pathologists, and radiologists with specific interest and expertise in mesenchymal malignancies (51). Given the rarity of soft tissue sarcomas, it is understandable that treatment results are optimized at specialized sarcoma centers.

Surgery

Surgical resection is the primary and only potentially curative treatment for soft tissue sarcomas. The primary goals of sarcoma surgery are to achieve optimal oncologic resection while preserving maximal function with minimal morbidity. Surgical specimens, including all surgical margins, should be thoroughly assessed by expert pathologists. For an optimal oncologic resection, negative surgical margins should be obtained if at all feasible, and often may require re-resection. If these goals cannot be anticipated with primary surgery, strong consideration should be given to preoperative treatment with chemotherapy and/or radiation therapy.

Four categories of surgical procedures have been described, based on the surgical plane of dissection (37). An intralesional procedure results in partial tumor removal with violation of the pseudocapsule. Although appropriate for a planned incisional diagnostic biopsy, it is not an appropriate therapeutic procedure. A marginal procedure (simple excision or “shellout”) removes the tumor within the confines of the pseudocapsule with a high likelihood of local recurrence due to residual subclinical disease (156). In wide local excision, the tumor is removed with a margin of normal tissue from within the same muscle compartment without removal of the entire structure of origin. Radical excisions, including compartmental resections and most amputations, remove the entire tumor and the structure of origin (entire anatomic compartment) en bloc. Local recurrence rates after surgery alone range from <10% after radical excision to ≥80% after marginal excision.

Historically, radical resections were performed to maximize local control, but also severely compromised limb function (143). Subsequently, more conservative, limb-sparing surgical procedures have become standard. Surgery alone may be sufficient for selected, small soft tissue sarcomas excised with wide (>1 cm) margins (49,72). However, conservative surgery with adjunctive radiation therapy is required in the majority of cases and results in local control comparable to amputation (89,111,127,144) with superior functional and cosmetic results (114,126). Amputations are now applied to <5% of patients at major sarcoma centers, and are reserved for massive disease in which functional limb-preservation is not feasible. Amputation may also be used for salvage of patients with local recurrence after previous conservative resection and radiation therapy, although limb salvage may still be possible in these cases (18).

Multidisciplinary communication regarding surgical technique can influence the effectiveness of postoperative radiation therapy as well as the incidence of late complications. Surgical scars and drain sites, which are at risk for subclinical disease, should be positioned and oriented such that their inclusion in the radiation treatment portal avoids circumferential (or near-circumferential) limb irradiation. Surgical clip placement at the boundaries of the tumor bed facilitates radiation treatment planning (131). Prophylactic bone stabilization in antici-pation of circumferential bone irradiation may reduce risk of subsequent fracture.

Chemotherapy

The efficacy of chemotherapy for soft tissue sarcoma is difficult to assess because of the heterogeneity of patients and drugs studied and the small sizes of individual trials. There remains no uniform consensus regarding the value of chemotherapy in patients with soft tissue sarcoma. Anthracyclines (doxorubicin and epirubicin) achieve response rates of 15% to 25% in patients with metastatic disease (98). Single-agent ifosfamide achieves similar response rates at conventional doses, and may be more
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active at higher doses (84). Combination chemotherapy regimens may be more active than single-agent regimens, although with increased toxicity (120). Regimens combining ifosfamide with an anthracycline appear to result in higher response rates than those without ifosfamide (146).

Early randomized trials of adjuvant chemotherapy in patients with localized disease showed no significant benefit for treatment (5); however, a meta-analysis found that patients receiving adjuvant doxorubicin had significantly improved local and distant recurrence-free survival (1). A 4% absolute benefit in overall survival at 10 years was not statistically significant, although for patients with extremity sarcomas, an absolute overall survival benefit of 7% at 10 years was statistically significant. Criticisms have centered on the inclusion of patients with visceral soft tissue sarcoma and the lack of central pathology review in this analysis (138). A recent randomized Italian trial randomized 104 patients with ≥5 cm or locally recurrent high-grade extremity sarcomas to five cycles of adjuvant epirubicin and ifosfamide or observation (47). With an updated median follow-up of 90 months, the 5-year survival for the chemotherapy group was 66% compared with 46% for the control group (p = .04) (46). A retrospective analysis of 245 patients with resected high-grade liposarcomas of the extremity treated with or without adjuvant chemotherapy suggested improved disease-specific survival with ifosfamide-based chemotherapy but not doxorubicin-based chemotherapy (34). In 215 patients with resected synovial cell sarcoma, distant metastasis-free survival was improved in patients receiving adjuvant chemotherapy (39). However, when 674 patients treated with neoadjuvant or adjuvant doxorubicin-containing chemotherapy at the MSKCC and the M.D. Anderson Cancer Center were combined for a retrospective analysis, the benefit of chemotherapy in improved disease-free survival was only sustained for 1 year after treatment (25), emphasizing the importance of sufficient follow-up in clinical studies of adjuvant chemotherapy for soft tissue sarcomas.

Chemotherapy given in the neoadjuvant setting allows investigators to judge clinical and pathologic response to treatment, and may provide a basis for identifying patients for whom additional chemotherapy may provide a benefit (106). A retrospective study of patients treated with surgery alone versus those receiving neoadjuvant doxorubicin and ifosfamide before surgery showed improved disease-specific survival for those receiving neoadjuvant chemotherapy, with the benefit mainly seen in patients with tumors >10 cm (55). However, a prospective randomized phase II trial of surgery alone versus neoadjuvant doxorubicin and ifosfamide followed by surgery failed to demonstrate a survival benefit (53). For many institutions, including our own, clinical trials of neoadjuvant and adjuvant chemotherapy in selected patients with high-grade extremity sarcomas are ongoing.

The next generation of systemic treatment strategies for soft tissue sarcoma may arise from current translational research that has identified specific molecular targets for therapy. The development and use of the imatinib mesylate (STI 571) in patients with gastrointestinal stromal tumor provides proof of principle for this type of approach (69). Molecular agents designed to modulate various receptor tyrosine kinases and their downstream signaling pathways governing growth and differentiation, survival and apoptosis, normal and aberrant transcription, invasion and metastasis, and angiogenesis are all being investigated in soft tissue sarcoma (14).

Radiation Therapy

Radiation therapy plays a central role in the treatment of soft tissue sarcoma. Although historically considered to be “radioresistant,” sarcomas have similar radiosensitivity to epithelial neoplasms (117). Multimodality treatment combining conservative surgery and radiation therapy achieves excellent local control rates while minimizing morbidity and maximizing long-term extremity function in comparison to radical surgery. Radiation therapy may be delivered using external beam, brachytherapy, or intraoperative electron beam techniques, and advancing technologies such as intensity-modulated radiation therapy (IMRT) and proton or other charged particle radiation therapy are also being applied to sarcomas (31,108,149).

Adjunctive radiation therapy may be effectively and safely delivered either before or after surgery. Postoperative radiation therapy allows for examination of resected specimen, including assessment of the surgical margins, to aid in treatment planning. Preoperative radiation therapy may allow for smaller radiation treatment volumes and may reduce the risk of local and distant dissemination at the time of resection. A phase III Canadian trial randomized 190 patients to preoperative (50 Gy preoperative radiation therapy with 16 to 20 Gy postoperative boost for positive margins) versus postoperative radiation therapy (50 Gy to large field and 16 to 20 Gy cone down boost) with a primary end point of acute wound complications (102). At a median follow-up of 3.3 years, there was a 35% incidence of wound complications in patients treated with preoperative radiation therapy, compared with 17% of patients treated with postoperative radiation therapy (p = .001). Interestingly, increased wound complications were only observed for lower extremity tumors. Updated results with a median follow-up of 6.9 years reveal that local and distant control rates as well as survival are equivalent between the two arms; however, a higher rate of late complications including fibrosis was observed with postoperative radiation therapy (29,103).

Preoperative radiation therapy (44 Gy in split-course) interdigitated with MAID chemotherapy (mesna, doxorubicin, ifosfamide, and dacarbazine) was developed as a strategy to enhance local control and limb preservation (30). Of the 66 patients treated with this regimen as part of a Radiation Therapy Oncology Group trial, 83% experienced grade 4 toxicities and there were three treatment-related deaths (79). Only 22% of patients had partial responses; however, 91% of patients were able to have complete tumor resection, and 27% of resected tumors showed no residual viable tumor. Regional delivery of intraarterial doxorubicin with concurrent preoperative radiation therapy has been shown to result in excellent local control rates, but was also associated with a substantial incidence of wound complications (90,141).

Although many sarcoma centers use preoperative radiation as standard treatment, at our own institution we use mainly postoperative radiation therapy because of concerns about acute wound complications and the fact that many patients are treated on clinical trials of neoadjuvant chemotherapy. If attempted resection will clearly result in gross residual disease and limb-sparing treatment is still desired, preoperative radiation therapy should be considered in an attempt to avoid amputation. The current National Comprehensive Cancer Network practice guidelines include each radiation treatment strategy (preoperative external beam, brachytherapy, and postoperative external beam) because all are effective at achieving excellent local control rates, and there are no data to suggest that one approach has greater efficacy (33). The optimal sequencing for surgery, radiation therapy, and chemotherapy remains unknown.

Retrospective series of highly selected soft tissue sarcoma patients treated with wide local excision with generous margins alone have reported high local control rates (3,7). Interestingly, size and depth were not associated with local relapse in these series. The subset of patients that may be adequately treated with radiation therapy alone has not been well defined; however, for lesions that have been properly excised with wide negative margins (all margins >1 cm), it is reasonable to consider observation, particularly if local recurrence in the tumor
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bed could be re-excised with preservation of function. These criteria are met in fewer than 10% of patients. Current strategies place less emphasis on grade because data from randomized trials of adjuvant brachytherapy (108) and external-beam irradiation (149) show similar incidence of local recurrence for both low- and high-grade tumors. Adjuvant radiation therapy appears to improve local control for both low- and high-grade tumors.

Radiation therapy can also be delivered with radical intent for patients who refuse surgery or have unresectable sarcomas (124,132). However, the local failure rate remains unacceptably high. Several alternative approaches have been investigated for these patients, including preoperative radiation therapy with concurrent chemotherapy (discussed earlier), preoperative radiation therapy with concurrent hyperthermia (113), the use of iododeoxyuridine or other radiosensitizers (125), high linear energy transfer radiation (fast neutrons) (122), and isolated limb perfusion with tumor necrosis factor-α, melphalan, and interferon-γ (86). If these strategies or others could improve local control rates in patients with unresectable disease, consideration could then be given to limb-sparing procedures in the 5% to 10% of patients with extremity sarcomas who otherwise would still require amputation to achieve clear proximal margins.

Radiation Therapy Techniques

Radiation therapy techniques for treatment of sarcomas of the extremity, trunk, and head and neck are described here; retroperitoneal sarcomas are discussed in Chapter 73.

Compartmental Nature of Soft Tissue Sarcomas

Before commencing a course of radiation therapy, the radiation oncologist must evaluate the extent of tumor involvement in the muscle compartment, understand the anatomy of the compartment, and be able to assess the risk of extracompartmental involvement based on MRI and CT imaging. For patients treated in the postoperative setting, attendance in the operating room at the time of resection and surgical clip placement is invaluable in this regard.

Volume at Risk

The radiation target volume is determined based on physical examination, radiologic studies, and knowledge of anatomy and the natural history of sarcomas. Normal structures and organs in proximity to the targeted region must be identified, and appropriate dose constraints for each must be considered. In the postoperative setting, details from the surgeon regarding the extent of dissection or observations from the resection itself must be considered. Some authorities recommend treating the entire compartment (origin to insertion) because hematoma can theoretically track cells to the farthest reaches of a muscle compartment (150). Others recommend margins around the tumor or tumor bed ranging from less than 5 cm up to 15 cm (in the long axis of the extremity), based on the grade and size of the tumor (128). One retrospective analysis of patients treated with postoperative radiation therapy demonstrated that an initial margin of <5 cm was associated with a significantly higher rate of local failure, compared with ≥5 cm (99). Our general practice is to include the resection bed with a 5-cm margin, the incision, and any drain sites in the initial treatment volume. However, the MSKCC brachytherapy experience calls this into question because excellent local control is achieved with a technique that does not cover the surgical scar, the drain sites, or the wide margins discussed previously (108). Clearly, margins should not extend beyond natural barriers of spread (i.e., fascial planes, bone). Regional lymph nodes are rarely at risk in extremity sarcomas, and there are no convincing data that prophylactic lymph node irradiation is beneficial.

Positioning the Extremity

The extremity should be positioned so as to treat the region of the affected compartment with minimal treatment of uninvolved tissue. The anterior compartment of the thigh can be treated in the “frog-leg” position, with external hip rotation, separating the anterior compartment from the medial and posterior compartments. A lateral decubitus position, with the affected thigh closest to the couch with flexion of the uninvolved extremity, allows treatment of the posterior compartment (Fig. 81.4A). The anterior compartment of the arm (biceps) can be treated by having the shoulder abducted approximately 90 degrees and maximally internally rotated (Fig. 81.4B). Positioning of extremities can be difficult for patients because of effects of tumor or surgery. If the extremity is placed at too extreme an angle, CT scanning may be more difficult. It is often necessary to assess multiple limb positions to discover the optimal setup. The body part must be immobilized with a device such as a foam cradle, plaster mold, or thermoplastic cast (Fig. 81.4), with the limb secured above and below the treatment area to reduce the possibility of rotation in the cradle. Cradle material can be removed from the region to be treated, if it will not compromise the immobilization, to reduce skin toxicity due to bolus effect.

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Treatment Planning

It is common practice to use a “shrinking-field technique” for treatment of sarcomas. For postoperative radiation therapy, the initial treatment fields are designed to encompass the resection bed with generous margins. Subsequently, reduced fields encompassing the preoperative tumor volume can be boosted with smaller margins. For preoperative radiation therapy, the gross tumor itself with a margin is treated. Usually, no field reduction is made prior to surgery, but a postoperative boost can be delivered in case of a positive margin.

For either CT-based, three-dimensional planning, or conventional fluoroscopic simulator-based, two-dimensional planning, it is useful to construct a clinical target volume (CTV) that encompasses any gross disease as well as a volume to account for potential subclinical (microscopic) disease. In the postoperative setting, the initial CTV can be constructed based on the volume of the resection bed (defined by placement of surgical clips and consultation with the surgeon), the preoperative tumor volume (based on preoperative imaging), and additional volume for extension of potential subclinical disease. This initial CTV should be generous, covering the resection bed with a 3- to 6-cm margin, as well as the surgical scar and drain sites. If the scar is being struck tangentially by the irradiation fields, no bolus is necessary. However, if the scar is being irradiated with a direct perpendicular field, bolus should be applied to ensure a brisk skin reaction and full dose over the scar itself. The “boost” CTV usually is limited to the preoperative tumor volume only with smaller 2- to 3-cm margins. In preoperative cases, the CTV can be derived by expansion of the visible gross tumor volume, again with generous 3- to 6-cm margins. The planning target volume should be an expansion of the CTV accounting for potential variation in daily setup, easily 1 cm or more for extremity targets.

A ≥1 cm strip of soft tissue in the circumference of the extremity should be spared to avoid subsequent edema. Attempts should be made to avoid circumferential bone radiation, if possible, to reduce fracture risk, and to minimize joint irradiation, if possible. Three-dimensional conformal radiation therapy and IMRT treatment planning may be useful in achieving the desired dose distribution in selected extremity cases (Fig. 81.5). Although these techniques are useful to spare normal tissues and bone to reduce morbidity (65), extra caution must be used with steep dose gradients to ensure adequate dose coverage of target volumes.

Treatment of thin regions of anatomy (e.g., hand, foot, and forearm) presents additional technical concerns. Skin-sparing by high-energy photon beams can produce underdosed regions inside the tumor volume, and bolus to the entire treatment volume may be necessary. Treatment of the involved region inside a water bath ensures uniform dosage to the affected area, although the complete loss of skin-sparing can produce marked skin reactions. With meticulous technique, limb-sparing surgery with adjuvant radiation therapy can be safely applied (95,129).

Radiation Energy and Dose

Lower energy (6-MV) photons are usually used because higher energies could potentially spare too much superficial tissue. However, higher energy (10- to 16-MV) photons are occasionally
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required for thigh or buttock lesions to produce reasonable dose homogeneity. Sarcomas are usually treated to high doses, even in the adjuvant setting. In postoperative therapy, the initial volume is usually treated to 45 to 50 Gy, with subsequent cone downs to a final dose of 60 to 66 Gy, using 1.8- or 2.0-Gy daily fractions. For preoperative irradiation, 45 to 50 Gy is often delivered 2 to 4 weeks before resection with an intraoperative or postoperative boost as indicated by the surgical margin. Brachytherapy or intraoperative radiation therapy may be used in combination with either preoperative or postoperative external-beam radiation therapy. Doses of 12 to 25 Gy may be given by intraoperative electron beam, or perioperative low dose rate (LDR) or high dose rate (HDR) afterloading brachytherapy, with 36 to 50 Gy external beam (2,19,32,80). Brachytherapy may be used as the sole radiation therapy mode of treatment, using doses of 42 to 50 Gy. For unresectable sarcomas, doses above 70 Gy are used, limiting the high-dose volume to the tumor plus a minimal margin.

Truncal and Head and Neck Sarcomas

Tumors arising in the trunk are usually more superficial than extremity sarcomas, but have similar clinical behavior (57). Tumors on the chest wall and abdominal wall often can be treated with oblique tangential fields. After 45 Gy of photon irradiation, a direct electron boost to the surgical bed can be use to minimize dose to underlying lung or bowel.

In the head and neck, target volumes and sensitive normal tissues are often in close proximity, and toxicity is a significant concern. Treatment planning techniques with three-dimensional conformal radiation therapy and IMRT are particularly useful in these locations. Treatment planning must account for the different patterns of spread that distinguish sarcomas from squamous cell carcinomas in the head and neck region, including the substantially lower risk of nodal spread for sarcomas. Several techniques for entire scalp irradiation have been described, and may be used for the treatment of angiosarcomas, which are infiltrative and prone to local recurrence after surgery alone (77,96,136).

Interstitial Brachytherapy

Interstitial brachytherapy can be used to deliver all or part of the radiation dose (8). After surgical excision of the tumor, hollow plastic afterloading catheters are inserted using sharp metal trocars in a single plane at approximately 1-cm intervals within the tumor bed (Fig. 81.6). Surgical clips placed at the margin of the tumor bed permit the target volume to be delineated for planning purposes, and the catheters are secured in place. Orthogonal localization films are obtained 2 to 4 days after surgery, and catheter positions may be digitally recorded into a radiation therapy planning system. In contrast to the wide margins typically employed for external-beam irradiation, the MSKCC experience demonstrates that a brachytherapy CTV encompassing only the clipped tumor bed with a 2-cm margin resulted in adequate local control (108). The dose is prescribed to 5 to 10 mm from the implant plane. Catheters are loaded with wired LDR 192Ir seeds or connected for HDR treatments no sooner than the sixth postoperative day to reduce the risk of wound complications. After completion of the treatment, sources are removed and catheters are cut at one end for removal by pulling through the skin.

For LDR implants, a dose of 42 to 45 Gy has been shown to be adequate adjuvant treatment when used alone for high-grade lesions (108). If brachytherapy is to be used in combination with external-beam radiation therapy, a dose of 15 to 25 Gy is used with 45 to 50 Gy external beam (2,32). HDR implants allow for more customization of the treatment plan because the dwell times of the single HDR source at each position can be manipulated. HDR treatments are usually given twice daily at 2 to 5 Gy per fraction to 35 to 50 Gy when used alone, or 15 to 20 Gy when to be used with postoperative external beam (19). HDR treatments can be delivered using conventional interstitial catheters as already described; a technique for intraoperative HDR treatment has also been described (80). A detailed list of recommendations for brachytherapy has recently been published by the American Brachytherapy Society (100).

Results of Standard Treatment

Retrospective reports and a prospective randomized trial have demonstrated conclusively that limb-sparing surgery plus adjunctive radiation therapy produces local control and survival rates similar to those achieved with amputation (89,112,115,127,151). The value of adjuvant radiation therapy after limb-sparing surgery has been demonstrated in randomized trials (108,149). Local control rates for patients with intermediate and high-grade sarcomas treated with surgical resection and adjunctive radiation therapy are generally in the 80% to 90% range, and representative series are presented in Table 81.4. The brachytherapy literature is limited in comparison to the extensive literature supporting the local control benefits of external-beam radiation therapy. Nonetheless, investigators from MSKCC and a limited number of other institutions have demonstrated that brachytherapy achieves comparable local control benefits for intermediate and high-grade disease when used alone or in combination with external irradiation (2,32,108). That these different techniques produce similar and excellent local control further validates the basic concept that radical treatment can be achieved with limb preservation. Even for patients with large high-grade lesions, a local control rate of approximately 85% can be achieved with the use of limb-sparing, wide local excision, and meticulous radiation therapy techniques.

Local control rates for low-grade lesions are also excellent with either postoperative or preoperative external-beam irradiation. In a series of patients treated at the National Cancer Institute, adjuvant external-beam irradiation significantly decreased local recurrence rates, primarily in patients with positive margins (92). Importantly, a randomized trial from MSKCC revealed
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that brachytherapy does not improve local control compared with surgery alone in low-grade lesions (109). Therefore, external beam is preferred over brachytherapy for treatment of low-grade soft tissue sarcoma. Unlike the high- and inter-mediate-grade lesions, low-grade tumors have almost no metastatic potential. Therefore, local control is tantamount to cure in this group.

Despite the increased technical demands, similar local control rates with limb-sparing procedures have been described for sarcomas of the distal extremities. Local recurrences can be salvaged with additional surgery (amputation) with no apparent decrement in survival (15,95,129). Although the head and neck represents another technically challenging site because of the difficulty obtaining negative margins, local control rates have been reported in the 75% to 90% range when radiation therapy is combined with wide local excision (11,85,104).

Overall survival for patients with soft tissue sarcoma closely relates to the development of distant metastases. This is related to the current American Joint Committee on Cancer stage, as can be seen in Fig. 81.7.

Unresectable Sarcomas

In patients who are not eligible for surgical resection, radiation therapy alone can be considered but results in relatively low rates of durable local control. In one series, local control was related to radiation dose and tumor size (76). Neutron radiation, carbon ion beam or photon radiation in combination with radiosensitizing iododeoxyuridine, or isolated limb perfusion with tumor necrosis factor-α, melphalan, and interferon-γ have also been used (52,71,122,124,125,132). Although the optimal treatment of sarcomas clearly involves complete excision, high-dose irradiation may at least achieve palliative benefits.

Treatment of Metastatic Disease

For patients with metastatic disease and controlled primary tumors, complete surgical resection of pulmonary metastases may be potentially curative and can result in disease-free survival rates of 40% at 3 years (13,137). The role of radiation therapy in treatment of metastatic disease is mainly limited to palliation of sites of disease causing local symptoms, although the possibility of using extracranial stereotactic radiation techniques for patients with solitary or oligometastasic disease in unresectable locations may be an area for future investigation.

Aggressive Fibromatosis and Dermatofibrosarcoma Protuberans

Aggressive fibromatosis (desmoid tumor) and dermatofibrosarcoma protuberans (DFSP) are soft tissue neoplasms that almost never metastasize but can be very invasive locally. Desmoids arise within the muscle or its fascial coverings, and DFSPs arise within the dermis. Microscopically, bundles of spindle-shaped fibroblasts are surrounded by abundant fibrous stoma devoid of mitotic figures. Complete surgical excision alone is usually curative for these tumors, but is not always possible because of their size and location. Local recurrence is common. For desmoid tumors, postoperative radiation therapy improved local control for patients with positive margins or gross residual disease (10,97,101,154). It should be noted that some authorities prefer to observe surgically resected patients with microscopically positive margins if the disease site can be readily followed and a local recurrence could be re-excised with minimal morbidity. Primary radiation therapy achieves high rates of local control when surgery is not feasible. Little evidence exists for a dose–response relation, and doses of 50 to 55 Gy are used for either subclinical or gross disease. Tumor responses are rarely seen in <6 months, but can occur after 1 to 2 years. Nonsteroidal antiinflammatory agents, hormonal agents, cytotoxic chemotherapy, and imatinib have activity against desmoid tumors (67). For
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DFSP, radiation therapy enhances local control in patients with positive margins after surgery, or as sole treatment (9).

Sequelae of Treatment

The most significant short-term toxicity of radiation therapy for sarcomas is usually moist desquamation in the high-dose volume. This can be very uncomfortable in patients with proximal thigh tumors who receive significant dose to the perineum. Patients treated for truncal and head and neck sarcomas experience toxicity similar to breast cancer and head and neck squamous cell carcinoma patients. Major wound complications (delayed wound healing or need for surgical intervention) occur in approximately 5% to 15% of patients after surgical resection with postoperative irradiation, and perhaps more commonly with preoperative irradiation.

The long-term sequelae after conservative surgery and irradiation for extremity lesions must always be considered because they may significantly limit the function of the preserved limb. They include decrease in range of motion related to fibrosis, contracture of the joint, edema, pain, and bone fracture. In centers treating high volumes of patients with soft tissue sarcoma, the incidence of moderate-to-severe late effects is <10% (110). The risk of these complications may be reduced by sparing a strip of normal tissue (to allow lymphatic drainage from the extremity) and a portion of the circumference of uninvolved bone. If possible, joint spaces should be excluded after a dose of 40 to 45 Gy to avoid fibrotic constriction of joint capsules. Collaboration with physical therapy specialists is essential in minimizing disabilities after treatment of soft tissue sarcomas. Mobility of the extremity should be stressed, and patients should be on an exercise and range-of-motion program early in the course of therapy. In the treatment of patients with truncal sarcomas, it is particularly important to use cone down fields to limit the dose to normal tissues deep to the target volume (e.g., lung and bowel). In contrast to acute wound complications, late limb morbidity may be reduced with preoperative radiation, likely due to the lower doses and smaller volumes used with preoperative treatment (29). With attention to these details, a high local control rate can be achieved with minimum sequelae.

High-dose irradiation does not appear to compromise the viability of skin grafts used to repair defects after sarcoma surgery if adequate time is allotted for healing (at least 3 weeks) (83). Fertility can be preserved in men undergoing irradiation for lower extremity sarcomas through the use of a gonadal shield to decrease testicular dose (45). The risk of a second malignancy associated with adjuvant irradiation must also be considered, particularly in young patients with low-grade tumors in which an otherwise normal life expectancy is anticipated.

Future Directions

The most significant challenge in the management of soft tissue sarcomas is to reduce the mortality related to systemic disease in patients who present with M0 disease. Further investigation into the benefits of conventional cytotoxic chemotherapy, as well as new molecularly targeted agents, will ultimately determine whether mortality rates can be reduced. Molecular characterization of individual patients and tumors will improve patient selection in future trials. Many clinical trials in soft tissue sarcoma currently use neoadjuvant chemotherapy. Earlier systemic treatment may have a greater capacity to influence occult micrometastases, and allows the assessment of in vivo response. Unfortunately, given the rarity of the disease and the small size of many trials, statistical power will continue to be limited in power to resolve the current controversies regarding the value of chemotherapy. Ultimately, these questions must be addressed in multi-institutional cooperative group studies.

The local treatment of soft tissue sarcomas is markedly different today than it was 25 years ago. Most patients with extremity lesions are now treated with limb-preserving methods, achieving local control rates of ≥90%. Although we prefer wide local excision followed by postoperative irradiation for resectable extremity tumors, excellent results can be obtained with preoperative irradiation or brachytherapy. Wide local excision and meticulous shrinking-field radiation therapy given either before or after surgery have improved the local control rates for patients with truncal and head and neck sarcomas almost to that of extremity lesions. Because wide local excision alone would lead to approximately a 50% local failure rate, radiation therapy appears to permit organ preservation without a significant sacrifice in control rates.

Several issues remain important with respect to local control. Although it has become less common, some patients with advanced extremity sarcomas still require amputation to achieve clear proximal margins, or have unresectable tumors. Continued innovations in the use of combined-modality therapy or radiosensitizers may lead to further improvements in this area. The Radiation Therapy Oncology Group is building on its previous study of preoperative chemotherapy and radiation therapy with another phase II trial investigating interdigitated MAID with combined thalidomide and radiation therapy for high-grade disease, and combined thalidomide and radiation therapy for low-grade disease (see http://www.clinicaltrials.gov/ct/show/NCT00089544). The issues of acute and late treatment morbidity also remain active areas of investigation. The results of the Canadian trial comparing preoperative and postoperative irradiation have further emphasized the relation between field size and radiation dose to toxicity. The necessity of large 5- to 7-cm margins compared with the more conservative 2- to 3-cm margins successfully used in brachytherapy may be an area for randomized study. Currently, Canadian investigators are running a prospective trial investigating the potential benefit of IMRT in reducing wound complications (see http://www.clinicaltrials.gov/ct/show/NCT00188175). Finally, it will be important to develop methods to prospectively identify those patients who may be managed adequately with wide local excision alone. Although adjuvant irradiation can often be delivered without significant acute or late toxicity, selective elimination of its use without loss of local control would represent an additional success in the management of these patients.