Surgery_Schwartz

Surgery_Schwartz. genes. The two genes most relevant to soft tissue sarcoma are retinoblastoma (Rb) and p53. Mutations or deletions in Rb can lead to retinoblastoma, the most common malignant ocular neoplasm of childhood. Survi-vors of retinoblastoma are at risk for developing soft tissue and bone sarcomas later in life. Patients with germline mutations in p53 (Li-Fraumeni syndrome) have a high incidence of soft tissue sarcomas Mutant p53 expression is thought to correlate with poor overall survival.23 Strategies to target p53 mutation are being investigated for treatment of some sarcomas.Neurofibromatosis type 1 (von Recklinghausen’s disease) occurs in approximately 1 of every 3000 people and is due to various mutations in the NF-1 tumor suppressor gene, located on chromosome 17. Patients with neurofibromatosis type 1 have an estimated 3% to 15% additional risk of malignant disease compared with the general population lifetime risk, including malignant peripheral nerve sheath tumors (MPNST) and GIST.


Surgery_Schwartz

Surgery_Schwartz. type 1 have an estimated 3% to 15% additional risk of malignant disease compared with the general population lifetime risk, including malignant peripheral nerve sheath tumors (MPNST) and GIST. In turn, 25% to 50% of patients with MPNST have a mutation in NF-1.27INITIAL ASSESSMENTThe clinical behavior of most soft tissue sarcomas is determined by anatomic location (depth in relation to the investing fascia), histologic subtype and grade of aggressiveness, and size. The dominant pattern of metastasis is hematogenous, primarily to the lungs. Lymph node metastasis is rare (affecting <5% of patients) except in a few histologic subtypes, including epi-thelioid sarcoma, pediatric rhabdomyosarcoma, clear cell sar-coma, angiosarcoma, and, more rarely, synovial sarcoma and myxofibrosarcoma.28Clinical PresentationSoft tissue sarcomas most commonly present as an asymptom-atic mass. Extremity sarcomas may present as a deep venous thrombosis, particularly in patients without significant risk


Surgery_Schwartz

Surgery_Schwartz. PresentationSoft tissue sarcomas most commonly present as an asymptom-atic mass. Extremity sarcomas may present as a deep venous thrombosis, particularly in patients without significant risk factors for thrombosis.29 Tumors in the distal extremities are generally smaller, whereas tumors in the proximal extremities and retroperitoneum can grow quite large before becoming apparent. Tumors often grow centrifugally and can compress surrounding normal structures. Infrequently, tumor impinge-ment on bone or neurovascular bundles produces pain, edema, and swelling. Less frequently, tumors cause obstructive gastro-intestinal symptoms or neurologic symptoms related to com-pression of lumbar or pelvic nerves. Often an extremity mass is discovered after a traumatic event that draws attention to a preexisting lesion.The differential diagnosis of a soft tissue mass should include consideration of lipoma (which is 100 times more com-mon than sarcoma), lymphangioma, leiomyoma, neurinoma, primary or


Surgery_Schwartz

Surgery_Schwartz. lesion.The differential diagnosis of a soft tissue mass should include consideration of lipoma (which is 100 times more com-mon than sarcoma), lymphangioma, leiomyoma, neurinoma, primary or metastatic carcinoma, melanoma, and lymphoma. Superficial small lesions (<5 cm) that are new or that are not enlarging as indicated by clinical history can be observed. Figure 36-2. A 55-year-old man with a leiomyosarcoma involving the inferior vena cava. Note the displacement of the inferior vena cava to the right hemiabdomen adjacent to the liver (arrow).Enlarging masses and masses larger than 5 cm or deep to the fascia should be evaluated with a history, imaging, and biopsy.30Diagnostic ImagingDiagnostic imaging of the primary should be performed before any invasive procedure to avoid the possibility of soft tissue swelling or hemorrhage complicating the image interpretation. Pretreatment diagnostic imaging is helpful for defining the size and anatomic location of a tumor and its proximity to


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Surgery_Schwartz. of soft tissue swelling or hemorrhage complicating the image interpretation. Pretreatment diagnostic imaging is helpful for defining the size and anatomic location of a tumor and its proximity to adjacent structures; staging disease with respect to regional or metastatic spread; guiding percutaneous biopsy; and establishing whether a tumor is benign or malignant and low grade or high grade.Radiographs are useful in the evaluation of primary bone tumors but not in the evaluation of soft tissue sarcomas of the extremities unless there is underlying bone involvement from an adjacent soft tissue tumor or mineralization patterns sugges-tive of histologic subtype. Magnetic resonance imaging (MRI) is the preferred imaging technique for soft tissue sarcomas of the extremities, whereas computed tomography (CT) is most use-ful for evaluating retroperitoneal, intra-abdominal, and truncal sarcomas.31 CT of the chest should be performed to assess for lung metastases in patients with high-grade


Surgery_Schwartz

Surgery_Schwartz. tomography (CT) is most use-ful for evaluating retroperitoneal, intra-abdominal, and truncal sarcomas.31 CT of the chest should be performed to assess for lung metastases in patients with high-grade tumors larger than 5 cm; while chest X-ray is sufficient for smaller or low-grade lesions. Abdominal/pelvic CT should be performed in patients with myxoid round cell liposarcomas, leiomyosarcomas, epi-thelioid sarcomas, or angiosarcomas because of their propensity to metastasize to the abdomen and/or pelvis.1 Total Spine MRI has been advocated for myxoid round cell liposarcoma.1 MRI of the brain should be considered for patients with alveolar soft part sarcomas and angiosarcomas because of their propensity to metastasize to the brain.Ultrasonography. Ultrasonography may have a diagnostic role in patients with soft tissue sarcoma who cannot undergo MRI. Ultrasonography can also be a useful adjunct to MRI when findings on MRI are indeterminate and for delineating adjacent vascular


Surgery_Schwartz

Surgery_Schwartz. role in patients with soft tissue sarcoma who cannot undergo MRI. Ultrasonography can also be a useful adjunct to MRI when findings on MRI are indeterminate and for delineating adjacent vascular structures. Finally, ultrasonography can be used for postoperative surveillance and to guide biopsies.Computed Tomography. Chest CT should be performed to evaluate for lung metastasis at presentation and before any radi-cal treatment. CT is also the preferred imaging technique for evaluating retroperitoneal sarcomas (Fig. 36-2).31 Current CT Brunicardi_Ch36_p1567-p1598.indd 157001/03/19 6:38 PM 1571SOFT TISSUE SARCOMASCHAPTER 36techniques can provide a detailed image of the abdomen and pelvis and can delineate adjacent organs and vascular struc-tures. For extremity sarcomas, CT may be useful if MRI is not available or cannot be used. When histologic assessment of an extremity sarcoma reveals a myxoid liposarcoma, CT of the abdomen and pelvis should be done because this subtype is known to


Surgery_Schwartz

Surgery_Schwartz. MRI is not available or cannot be used. When histologic assessment of an extremity sarcoma reveals a myxoid liposarcoma, CT of the abdomen and pelvis should be done because this subtype is known to metastasize to the abdomen.32Magnetic Resonance Imaging. MRI is the most useful imag-ing modality for extremity sarcomas because of its superior soft tissue contrast resolution and multiplanar capabilities. MRI accurately delineates muscle groups and distinguishes among bone, vascular structures, and tumor. Sagittal and coronal views allow evaluation of anatomic compartments in three dimensions (Fig. 36-3). Soft tissue sarcomas of the extremities usually present on MRI as a heterogeneous mass. Their signal inten-sity tends to be equal to or slightly higher than that of adjacent skeletal muscle on T1-weighted images and heterogeneous and high on T2-weighted images. Hemorrhagic, cystic, or necrotic changes may also be observed in the tumor. If adjacent vas-cular structures must be delineated,


Surgery_Schwartz

Surgery_Schwartz. T1-weighted images and heterogeneous and high on T2-weighted images. Hemorrhagic, cystic, or necrotic changes may also be observed in the tumor. If adjacent vas-cular structures must be delineated, special MRI techniques may be performed, including magnetic resonance angiography. MRI may also be an important adjunct to cytologic analysis in distinguishing benign lesions such as lipomas, hemangiomas, schwannomas, neurofibromas, and intramuscular myxomas from their malignant counterparts. In patients undergoing pre-operative chemotherapy, contrast-enhanced T1-weighted MRI can be useful in evaluating intratumoral necrosis.MRI is also valuable for assessing tumor recurrence after surgery. A baseline image is usually obtained 3 months after surgery. Some clinicians forego routine postoperative imaging of the primary extremity tumor site in asymptomatic patients, citing the difficulties in detecting early recurrence in scarred, irradiated tissue.31 Others advocate routine imaging every 3 to


Surgery_Schwartz

Surgery_Schwartz. imaging of the primary extremity tumor site in asymptomatic patients, citing the difficulties in detecting early recurrence in scarred, irradiated tissue.31 Others advocate routine imaging every 3 to 4 months for the first 2 years, every 6 months in years 3 through 5, and then annually.Positron Emission Tomography. Positron emission tomogra-phy (PET) is a functional imaging modality that measures tumor uptake of the glucose analog [18F] fluorodeoxyglucose (FDG). Figure 36-3. A 62-year-old man presented with right thigh mass. Magnetic resonance imaging demonstrated an 18 × 15 cm2 dedifferentiated liposarcoma within the posterior compartment. Note the atypical fatty mass (left) with a large necrotic and peripherally enhancing nodule (left).PET imaging allows evaluation of the entire body. Although PET/CT may be useful in specific circumstances, FDG-PET is not currently recommended for the initial staging of patients with soft tissue sarcoma.Roberge and colleagues compared FDG-PET/CT


Surgery_Schwartz

Surgery_Schwartz. Although PET/CT may be useful in specific circumstances, FDG-PET is not currently recommended for the initial staging of patients with soft tissue sarcoma.Roberge and colleagues compared FDG-PET/CT versus chest CT alone in the initial staging of 75 patients with soft tissue sarcoma and found that only one patient had disease upstaged as a result of PET, whereas two had false-positive find-ings and three had indeterminate findings with no subsequent development of metastasis.33 Previous studies that reported a marginal benefit of PET/CT for detecting metastasis at the time of sarcoma staging included patients with more heterogeneous tumors, such as osseous tumors, soft tissue osteosarcomas, Ewing’s sarcoma, and rhabdomyosarcoma.34-36In patients with sarcoma, PET has primarily been used to assist with tumor grading and to assess response to chemotherapy.37-40 In 50 patients with resectable high-grade soft tissue tumors scheduled for preoperative chemotherapy and tumor resection, a 35%


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Surgery_Schwartz. with tumor grading and to assess response to chemotherapy.37-40 In 50 patients with resectable high-grade soft tissue tumors scheduled for preoperative chemotherapy and tumor resection, a 35% or greater reduction in tumor FDG uptake following an initial cycle of chemotherapy was associated with histopathologic tumor response defined as pathologic necrosis in 95% or more of the resected specimen.41 While this is helpful in determining response controversy exists as to whether this translates into a predictor of overall survival.Biopsy TechniquesFine-Needle Aspiration. At centers where cytopathologists have experience with evaluation of mesenchymal tumors, fine-needle aspiration is an acceptable method of diagnosing most soft tissue sarcomas, particularly when the results correlate closely with clinical and radiologic findings.42 Fine-needle aspiration of primary tumors has a lower diagnostic accuracy rate (60–90%) than core needle biopsy and is often not sufficient for establish-ing


Surgery_Schwartz

Surgery_Schwartz. with clinical and radiologic findings.42 Fine-needle aspiration of primary tumors has a lower diagnostic accuracy rate (60–90%) than core needle biopsy and is often not sufficient for establish-ing a specific histologic diagnosis and grade.43 However, fine-needle aspiration is the procedure of choice to confirm or rule out the presence of a metastatic focus or local recurrence.44Although fine-needle aspiration of superficial lesions can often be done in the clinic, fine-needle aspiration of deeper tumors may need to be done by an interventional radiologist Brunicardi_Ch36_p1567-p1598.indd 157101/03/19 6:38 PM 1572SPECIFIC CONSIDERATIONSPART IIunder sonographic or CT guidance. Generally, a 21to 23-gauge needle is introduced into the mass after appropriate cleansing of the skin and injection of local anesthetic. Negative pressure is applied, and the needle is moved back and forth several times in various directions. After the negative pressure is released, the needle is withdrawn,


Surgery_Schwartz

Surgery_Schwartz. of local anesthetic. Negative pressure is applied, and the needle is moved back and forth several times in various directions. After the negative pressure is released, the needle is withdrawn, and the contents of the needle are used to prepare smears.45 A cytopathologist then examines the slides to determine whether sufficient diagnostic material is present.Core Needle Biopsy. Core needle biopsy is safe, accurate,46,47 and economical48 and has become the preferred technique for diagnosing soft tissue lesions. Dupuy and colleagues found that core needle biopsy had an accuracy of 93% in 221 patients with musculoskeletal neoplasms.46Image guidance (ultrasound or CT) can prevent sam-pling of nondiagnostic necrotic or cystic areas of the tumor and thus increase the positive yield rate. Image guidance also per-mits biopsy of tumors in otherwise inaccessible locations and tumors located near vital structures with less risk of injury or complication.The tissue sample obtained from core needle


Surgery_Schwartz

Surgery_Schwartz. also per-mits biopsy of tumors in otherwise inaccessible locations and tumors located near vital structures with less risk of injury or complication.The tissue sample obtained from core needle biopsy is usually sufficient for several diagnostic tests, such as electron microscopy, cytogenetic analysis, and flow cytometry. The risk for needle track seeding is negligible, and the reported compli-cation rate for core needle biopsy is less than 1%.46,47Incisional Biopsy. Historically, an open surgical biopsy was the gold standard for achieving adequate tissue for definitive and specific histologic diagnosis of bone or soft tissue sarcomas. Contemporary guidelines recommend incisional biopsy when core needle biopsy cannot produce adequate tissue for diagnosis or when findings on core needle biopsy are nondiagnostic.The disadvantages of incisional biopsy include the need to schedule the procedure, the need for general anesthesia, and high costs. In addition, an inappropriately placed


Surgery_Schwartz

Surgery_Schwartz. biopsy are nondiagnostic.The disadvantages of incisional biopsy include the need to schedule the procedure, the need for general anesthesia, and high costs. In addition, an inappropriately placed incision can necessitate more extensive definitive resection to incorporate the biopsy incision. In a series of 107 patients with soft tissue sarcoma, planned surgical treatments had to be changed because of poorly oriented biopsies in 25% of cases.49 Complication rates up to 17% have been reported after incisional biopsies.45 Potential complications include hematoma, infection, wound dehiscence, and tumor fungation, any of which can delay defini-tive treatment.45Incisional biopsies should be performed only by surgeons experienced in the management of soft tissue sarcoma, ideally in a center specializing in the treatment of sarcoma and by the surgeon who will perform the definitive surgery. The biopsy incision should be oriented longitudinally along the extremity to allow a subsequent wide


Surgery_Schwartz

Surgery_Schwartz. in the treatment of sarcoma and by the surgeon who will perform the definitive surgery. The biopsy incision should be oriented longitudinally along the extremity to allow a subsequent wide local excision that encompasses the biopsy site, scar, and tumor en bloc minimizing the risk for increasing the complexity of the subsequent curative procedure. A poorly oriented biopsy incision often necessitates an exces-sively large surgical defect for a wide local excision, which in turn can result in a larger postoperative radiation therapy field to encompass all tissues at risk. Adequate hemostasis must be achieved at the time of biopsy to prevent dissemination of tumor cells into adjacent tissue planes by hematoma.Excisional Biopsy. Excisional biopsy can be performed for easily accessible (superficial) extremity or truncal lesions smaller than 3 cm. However, excisional biopsy rarely provides benefits over other biopsy techniques. Excisional biopsies should not be performed for lesions


Surgery_Schwartz

Surgery_Schwartz. (superficial) extremity or truncal lesions smaller than 3 cm. However, excisional biopsy rarely provides benefits over other biopsy techniques. Excisional biopsies should not be performed for lesions involving the hands and feet because such biopsies may complicate definitive reexcision. For sarcomas with initial diagnosis confirmed with excisional biopsy, microscopic residual disease has been reported in up to 69% of reexcision specimens50,51; without reexcision, the reported rate of local recurrence is 30% to 40% when margins are positive or uncertain.Wide en bloc excision is seldom performed as a diagnostic procedure. When en bloc excision is done for diagnosis, the mar-gin status is often not adequately evaluated during pathologic assessment of the specimen. Unless detailed descriptions of the surgical procedure and the pathology specimen are provided, the margins should be classified as uncertain or unknown, a classifi-cation associated with the same prognosis as resection


Surgery_Schwartz

Surgery_Schwartz. of the surgical procedure and the pathology specimen are provided, the margins should be classified as uncertain or unknown, a classifi-cation associated with the same prognosis as resection margins that are positive for tumor cells. In patients with uncertain or unknown margins, reexcision should be performed if possible to ensure negative margins. The biopsy site or tract (if applicable) should be included en bloc with the re-resected specimen.Pathologic Assessment and ClassificationSarcoma is generally diagnosed by morphologic assessment based on microscopic examination of histologic sections by an experienced sarcoma pathologist. However, even expert sar-coma pathologists disagree on the specific histologic diagnosis and the tumor grade in 25% to 40% of cases.52Morphologic assessment can be supported by ancillary techniques, including conventional cytogenetics; immunohis-tochemistry; and molecular genetic testing, which is useful for classifying soft tissue sarcoma subtypes with


Surgery_Schwartz

Surgery_Schwartz. can be supported by ancillary techniques, including conventional cytogenetics; immunohis-tochemistry; and molecular genetic testing, which is useful for classifying soft tissue sarcoma subtypes with multiple genetic aberrations. Other molecular diagnostic techniques include cytogenetic analysis, fluorescence in situ hybridization, and polymerase chain reaction–based methods.53 However, molecu-lar genetic techniques are associated with significant technical limitations and should be interpreted in the context of the sar-coma’s morphologic features.Some experts have suggested that pathologic classification of soft tissue sarcomas has more prognostic significance than does tumor grade when other pretreatment variables are taken into account. Tumors with limited metastatic potential include des-moid, atypical lipomatous tumor (also called well-differentiated liposarcoma), dermatofibrosarcoma protuberans, and solitary fibrous tumor. Tumors with an intermediate risk of metastatic spread


Surgery_Schwartz

Surgery_Schwartz. des-moid, atypical lipomatous tumor (also called well-differentiated liposarcoma), dermatofibrosarcoma protuberans, and solitary fibrous tumor. Tumors with an intermediate risk of metastatic spread usually have a large myxoid component and include myx-oid liposarcoma, myxofibrosarcoma, and extraskeletal myxoid chondrosarcoma. Among the highly aggressive tumors with sub-stantial metastatic potential are angiosarcoma, clear cell sarcoma, pleomorphic and dedifferentiated liposarcoma, leiomyosarcoma, MPNST, rhabdomyosarcoma, and synovial sarcoma.It has recently been noted that malignant fibrous histio-cytoma is not associated with a distinct gene cluster, suggest-ing that malignant fibrous histiocytoma is not a separate tumor entity but rather a common morphologic appearance of various sarcoma subtypes.54,55 For example, most tumors initially diag-nosed as malignant fibrous histiocytoma in the retroperitoneum have been reclassified using genomic profiling as dedifferenti-ated


Surgery_Schwartz

Surgery_Schwartz. sarcoma subtypes.54,55 For example, most tumors initially diag-nosed as malignant fibrous histiocytoma in the retroperitoneum have been reclassified using genomic profiling as dedifferenti-ated liposarcomas,56 whereas those in the extremities have been reclassified as leiomyosarcoma, myxofibrosarcoma, or pleo-morphic undifferentiated sarcoma.Guidelines for the pathologic reporting of sarcoma have been established.1 Included in the report should be the primary diagnosis, anatomic site, depth, size, and histologic grade, pres-ence or absence of necrosis, status of excision margins and lymph nodes, TNM stage, and additional features of the tumor (i.e., mitotic rate and presence or absence of vascular invasion).Brunicardi_Ch36_p1567-p1598.indd 157201/03/19 6:38 PM 1573SOFT TISSUE SARCOMASCHAPTER 36Staging and Prognostic FactorsSoft tissue sarcoma is most commonly staged using either the American Joint Committee on Cancer (AJCC) system (generally used in the United States) or the World


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Surgery_Schwartz. 36Staging and Prognostic FactorsSoft tissue sarcoma is most commonly staged using either the American Joint Committee on Cancer (AJCC) system (generally used in the United States) or the World Health Organization sys-tem. A unique aspect of sarcoma staging is the inclusion of tumor grade, which is one of the most important prognostic factors.57The seventh edition of the AJCC staging system for soft tissue sarcomas is based on histologic grade of aggressive-ness, tumor size and depth, and the presence of nodal or distant metastases.58 This system does not apply to GIST, fibromatosis (desmoid tumor), Kaposi’s sarcoma, or infantile fibrosarcoma.Histologic Grade of Aggressiveness. Histologic grade is the most important prognostic factor for patients with soft tissue sarcoma. For accurate determination of grade, an adequate tis-sue sample must be appropriately fixed, stained, and reviewed by an experienced sarcoma pathologist. The features that define grade are cellularity, differentiation


Surgery_Schwartz

Surgery_Schwartz. of grade, an adequate tis-sue sample must be appropriately fixed, stained, and reviewed by an experienced sarcoma pathologist. The features that define grade are cellularity, differentiation (good, moderate, or poor/anaplastic), pleomorphism, necrosis (absent, <50%, or ≥50%), and number of mitoses per high-power field (<10, 10–19, or ≥20). Tumor grade has been shown to predict metastasis and overall survival.59 Metastasis has been estimated to occur in 5% to 10% of low-grade lesions, 25% to 30% of intermediate-grade lesions, and 50% to 60% of high-grade lesions.The number of grades varies according to the classifica-tion system used. The most common classification systems, those of the National Cancer Institute and the French Federation of Cancer Centers, use three-tier tumor grades.60 The National Cancer Institute system is based primarily on histologic sub-type, location, and amount of necrosis. The French Federation of Cancer Centers system is based on tumor differentiation (good,


Surgery_Schwartz

Surgery_Schwartz. National Cancer Institute system is based primarily on histologic sub-type, location, and amount of necrosis. The French Federation of Cancer Centers system is based on tumor differentiation (good, moderate, or poor/anaplastic), number of mitoses per high-power field (<10, 10–19, or ≥20), and amount of tumor necrosis (absent, <50%, or ≥50%). A comparative analysis of the two systems suggested that the French Federation of Can-cer Centers system has better prognostic capability, predicting 5-year survival rates of 90%, 70%, and 40% for grade 1, 2, and 3 tumors, respectively.60Following the recommendation of the College of American Pathologists, the committee that developed the 2008 AJCC staging system changed the system from a four-grade to a three-grade system in which the grades are well differentiated (grade 1), moderately differentiated (grade 2), and poorly differentiated (grade 3).61 Grade 1 is considered low grade, and grades 2 and 3 are considered high grade.Tumor Size and


Surgery_Schwartz

Surgery_Schwartz. differentiated (grade 1), moderately differentiated (grade 2), and poorly differentiated (grade 3).61 Grade 1 is considered low grade, and grades 2 and 3 are considered high grade.Tumor Size and Location. Tumor size is an important prog-nostic variable in soft tissue sarcomas. Sarcomas have classi-cally been stratified into two size groups; T1 lesions are 5 cm or smaller, and T2 lesions are larger than 5 cm. The staging of soft tissue sarcomas has changed considerably in the eighth edition of the AJCC Cancer Staging Handbook.62 Previously, all soft tissue sarcoma sites were staged as one. In the new edi-tion, subsites have been created, and they include head and neck; extremity and trunk; gastrointestinal tract; genitourinary tract; viscera and peritoneum; gynecological sites; breast lung, pleura and mediastinum; and other histologies. Size criteria for head and neck tumors have been reduced from the classic cri-teria because of a worse prognosis at smaller sizes. Trunk and extremity


Surgery_Schwartz

Surgery_Schwartz. pleura and mediastinum; and other histologies. Size criteria for head and neck tumors have been reduced from the classic cri-teria because of a worse prognosis at smaller sizes. Trunk and extremity sarcoma has been reclassified relative to size criteria for tumor stage, changing the four categories: T1 tumors are smaller than 5 cm; T2 tumors are 5 to 10 cm; T3 tumors are 10 to 15 cm; and T4 tumors are larger than 15 cm.62Figure 36-4. A 74-year-old man with a history of an extraskeletal myxoid chondrosarcoma of the gluteal region developed multiple lung metastases.Anatomic tumor location was incorporated into the AJCC staging system in 1998. Soft tissue sarcomas above the superfi-cial investing fascia of the extremity or trunk are designated “a” lesions within the T category, whereas tumors invading or deep to the fascia and all retroperitoneal, mediastinal, and visceral tumors are designated “b” lesions. However, in this most recent AJCC staging system, the superficial versus deep


Surgery_Schwartz

Surgery_Schwartz. invading or deep to the fascia and all retroperitoneal, mediastinal, and visceral tumors are designated “b” lesions. However, in this most recent AJCC staging system, the superficial versus deep distinction is less important and has been eliminated.62Nodal Metastasis. Overall, lymph node metastases arising from soft tissue sarcomas are rare,28 but the incidence of nodal involvement is higher for epithelioid sarcoma, pediatric rhab-domyosarcoma, clear cell sarcoma, synovial sarcoma, myxo-fibrosarcoma, and angiosarcoma. In the seventh edition of the AJCC staging system, sarcoma associated with nodal metas-tases was reclassified as stage III rather than stage IV because several studies reported better survival for patients with isolated regional lymph node metastases treated with radical lymphad-enectomy than for patients with distant metastases.28,63-65 How-ever, in the eighth edition of the AJCC, nodal disease has been revisited: N1 disease behaves similarly between stages III and IV


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Surgery_Schwartz. than for patients with distant metastases.28,63-65 How-ever, in the eighth edition of the AJCC, nodal disease has been revisited: N1 disease behaves similarly between stages III and IV and is now captured as stage IV.62 Patients with clinically or radiologically suspicious regional nodes should have metastases confirmed or ruled out by either fine-needle aspiration or core biopsy before radical lymphadenectomy.Distant Metastasis. Distant metastases occur most often in the lungs (Fig. 36-4). Selected patients with pulmonary metas-tases may survive for long periods after surgical resection and chemotherapy. Other potential sites of metastasis include bone (Fig. 36-5), brain (Fig. 36-6), and liver (Fig. 36-7). Visceral and retroperitoneal sarcomas have a higher incidence of liver and peritoneal metastases.Prognostic Factors. Prognostic variables in soft tissue sar-coma include primary tumor size, grade, and depth, all of which are incorporated into the staging system, as well as


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Surgery_Schwartz. peritoneal metastases.Prognostic Factors. Prognostic variables in soft tissue sar-coma include primary tumor size, grade, and depth, all of which are incorporated into the staging system, as well as histology, Brunicardi_Ch36_p1567-p1598.indd 157301/03/19 6:38 PM 1574SPECIFIC CONSIDERATIONSPART IIFigure 36-5. A 36-year-old woman with history of multifocal sclerosing osteosarcoma of the humerus developed diffuse bony metastases 2 years after diagnosis.Figure 36-6. A 64-year-old man with a history of a T2 high-grade pleomorphic sarcoma of the thigh who developed brain metastases 14 months after diagnosis.Figure 36-7. A 33-year-old woman with osteosarcoma of the sternum who presented with a liver metastasis 3 years after diagnosis.tumor site, and presentation (local recurrence or initial diagno-sis). Patient factors such as older age and gender have also been associated with recurrence and mortality in several studies.66 A positive microscopic margin and early recurrence after


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Surgery_Schwartz. diagno-sis). Patient factors such as older age and gender have also been associated with recurrence and mortality in several studies.66 A positive microscopic margin and early recurrence after resection of an extremity sarcoma have been shown to be associated with decreased survival.67Several groups have reported that Ki-67, a proliferation marker, is correlated with a poor clinical outcome in high-grade extremity sarcomas.68,69 E-cadherin and catenins, proteins essen-tial for intercellular junctions, have been associated with poor outcome in patients with soft tissue sarcoma.68 Similarly, higher CD100 expression has been shown to correlate with higher pro-liferative potential and poorer outcome.69Prognostic Nomograms. Prognostic nomograms for soft tis-sue sarcoma have been introduced for use in patient counsel-ing, selecting appropriate surveillance strategies, and selecting patients for clinical trials.70 One such nomogram, developed by Kattan and colleagues at Memorial


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Surgery_Schwartz. for use in patient counsel-ing, selecting appropriate surveillance strategies, and selecting patients for clinical trials.70 One such nomogram, developed by Kattan and colleagues at Memorial Sloan-Kettering Cancer Center, considers age, histology, grade, location, depth, and size to determine the likelihood of 12-year sarcoma-specific survival.70 Two validation studies using the nomogram demon-strated good predictive value.71 More recently, the same group of investigators developed histology subtype-specific nomo-grams for patients with liposarcoma, synovial sarcoma, and GIST72 and demonstrated that they were accurate in predicting disease-specific survival. Other investigators have just devel-oped a site-specific nomogram for patients with retroperitoneal sarcoma, demonstrating an accurate prediction of survival and disease recurrence.73TREATMENT OF EXTREMITY AND TRUNK WALL SARCOMAThe goals of treatment of soft tissue sarcoma are to maxi-mize the likelihood of long-term


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Surgery_Schwartz. an accurate prediction of survival and disease recurrence.73TREATMENT OF EXTREMITY AND TRUNK WALL SARCOMAThe goals of treatment of soft tissue sarcoma are to maxi-mize the likelihood of long-term recurrence-free survival while minimizing morbidity and maximizing function. In the past two decades, a multimodality treatment approach with optimal sequencing of treatments for individual patients has been shown to improve survival.74 Furthermore, patients with soft tissue sarcoma treated at high-volume centers have been shown to have improved survival and functional outcomes.75 Care at such centers is particularly important for patients with high-risk and advanced disease.The overall 5-year survival rate for patients with all stages of soft tissue sarcoma is 50% to 60%. For patients with extremity sarcomas, a multidisciplinary treatment approach has resulted in local control rates exceeding 90% and 5-year survival rates exceeding 70%. Most patients who die of soft tissue sarcoma die of


Surgery_Schwartz

Surgery_Schwartz. sarcomas, a multidisciplinary treatment approach has resulted in local control rates exceeding 90% and 5-year survival rates exceeding 70%. Most patients who die of soft tissue sarcoma die of metastatic disease, which becomes evident within 2 to 3 years of initial diagnosis in 80% of cases.Recommendations for evaluation and treatment of patients presenting with soft tissue masses are summarized in Table 36-3.Brunicardi_Ch36_p1567-p1598.indd 157401/03/19 6:38 PM 1575SOFT TISSUE SARCOMASCHAPTER 36Table 36-3Recommendations for the management of soft tissue masses1. Soft tissue tumors that are enlarging or greater than 3 cm should be evaluated with radiologic imaging (ultrasonography or computed tomography [CT]), and a tissue diagnosis should be made using core needle biopsy.2. Once a sarcoma diagnosis is established, obtain imaging (magnetic resonance imaging for extremity lesions and CT for other anatomic locations) and evaluate for metastatic disease with chest CT for


Surgery_Schwartz

Surgery_Schwartz. a sarcoma diagnosis is established, obtain imaging (magnetic resonance imaging for extremity lesions and CT for other anatomic locations) and evaluate for metastatic disease with chest CT for intermediateor high-grade (grade 2 or 3) or large (T2) tumors.3. A wide local excision with 1to 2-cm margins is adequate therapy for low-grade lesions and T1 tumors.4. Radiation therapy plays a critical role in the management of large (T2), intermediateor high-grade tumors.5. Patients with locally advanced high-grade sarcomas or distant metastases should be evaluated for chemotherapy.6. An aggressive surgical approach should be taken in the treatment of patients with an isolated local recurrence or resectable distant metastases.SurgeryPrimary tumors with no evidence of distant metastasis are managed with surgery alone or, when wide pathologic margins cannot be achieved because of anatomic constraints and/or the grade is high, surgery plus radiation therapy. The type of surgical resection is


Surgery_Schwartz

Surgery_Schwartz. with surgery alone or, when wide pathologic margins cannot be achieved because of anatomic constraints and/or the grade is high, surgery plus radiation therapy. The type of surgical resection is determined by several factors, including tumor location, tumor size, depth of invasion, involvement of nearby structures, need for skin grafting or autogenous tissue reconstruction, and the patient’s performance status. In 1985, the National Institutes of Health developed a consensus statement recommending limb-sparing surgery for most patients with high-grade extremity sarcomas.76 However, for patients with primary or recurrent tumors that cannot be grossly resected with a limb-sparing procedure and preservation of function (<5% of patients), amputation remains the treatment of choice.Margin status after surgical resection has been shown to be an independent prognostic factor.77,78 The goal of surgical resec-tion is to achieve a complete resection because microscopically positive or grossly


Surgery_Schwartz

Surgery_Schwartz. after surgical resection has been shown to be an independent prognostic factor.77,78 The goal of surgical resec-tion is to achieve a complete resection because microscopically positive or grossly positive resection margins are associated with increased risk of local recurrence and death.79 If an unex-pected positive margin is found on pathologic examination of the resection specimen, reexcision should be performed if fea-sible. In patients with a positive margin, particularly in patients with macroscopic residual disease, local control is unlikely even with the addition of postoperative radiation therapy, emphasiz-ing the importance of a well-planned initial operation.80Wide Local Excision. The preferred treatment for extrem-ity sarcomas is wide local excision that includes resection of the biopsy site. The goal of wide local excision is to remove the tumor with approximately 1 to 2 cm of surrounding nor-mal soft tissue,77 but narrower margins may be necessary to preserve uninvolved


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Surgery_Schwartz. the biopsy site. The goal of wide local excision is to remove the tumor with approximately 1 to 2 cm of surrounding nor-mal soft tissue,77 but narrower margins may be necessary to preserve uninvolved critical neurovascular structures and may be adequate for patients undergoing radiation therapy.81 Dis-section should proceed through grossly normal tissue planes not abutting the tumor. Soft tissue sarcomas are generally sur-rounded by a zone of compressed reactive tissue that forms a pseudocapsule; this pseudocapsule should not be used to guide resection (enucleation) as microscopic disease exists within this reactive zone. If the tumor is adjacent to or displacing major neurovascular structures, these do not need to be resected, but the adventitia or perineurium should be removed.1 For some massive tumors of the extremities, wide local excision entails a radical or complete anatomic compartment resection. Surgical clips should be placed to delineate the extent of the resection bed for


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Surgery_Schwartz. massive tumors of the extremities, wide local excision entails a radical or complete anatomic compartment resection. Surgical clips should be placed to delineate the extent of the resection bed for patients likely to require postoperative radiation therapy.Recent reports demonstrate encouraging results follow-ing radical en bloc resection with vascular reconstruction in the lower extremities.82,83 While en bloc resection with vascular reconstruction has been associated with increased rates of post-operative complications, reported local recurrence and 5-year survival rates are similar to those for patients not requiring ves-sel resection.84,85 Similarly, studies have shown acceptable func-tional outcomes with resection of the sciatic, tibial, and peroneal nerves with appropriate reconstruction and rehabilitation.86Bone invasion from extremity soft tissue sarcoma, which can generally be identified using high-quality cross-sectional imaging such as MRI, has been estimated to occur in


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Surgery_Schwartz. and rehabilitation.86Bone invasion from extremity soft tissue sarcoma, which can generally be identified using high-quality cross-sectional imaging such as MRI, has been estimated to occur in about 5% of patients and is associated with reduced overall survival.87 In cases of bone invasion, bone resection is required to obtain an adequate surgical margin and to achieve local control. Although tumor resection and repair of skeletal defects are possible, the likelihood of postoperative complications may be increased, and functional outcomes may be less favorable. Lin and colleagues88 recently analyzed 55 patients with soft tissue sarcomas abutting bone and reported that in the absence of frank cortical bone pen-etration, periosteum was an adequate surgical margin in patients treated with wide local excision and radiation.Soft tissue sarcomas arising in the distal extremities, particularly the hands and feet, present unique technical chal-lenges. While distal-extremity tumors are often


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Surgery_Schwartz. local excision and radiation.Soft tissue sarcomas arising in the distal extremities, particularly the hands and feet, present unique technical chal-lenges. While distal-extremity tumors are often detected at a smaller size (<5 cm) than proximal-extremity tumors, resec-tion and reconstruction techniques are often more complex for distal-extremity tumors, and preoperative planning is criti-cal to obtain favorable functional outcomes. Identifying the proximity of the tumor to underlying critical structures (e.g., bone, tendon, or neurovascular structures) using MRI is essen-tial for surgical planning. In a reported series of patients with sarcomas of the hands or feet treated with limited surgery only, 32% of patients had local recurrences.89 Preservation of function and acceptable recurrence rates with limited surgery and adjuvant radiation therapy for soft tissue sarcomas of the distal extremities have been reported.90 For locally advanced tumors, repair of bone defects, vascular


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Surgery_Schwartz. rates with limited surgery and adjuvant radiation therapy for soft tissue sarcomas of the distal extremities have been reported.90 For locally advanced tumors, repair of bone defects, vascular reconstruction, tendon transfers, and soft tissue reconstruction using regional or free flaps have resulted in good functional outcomes.91 Amputation remains a reasonable option for patients with soft tissue sar-comas of the distal extremities when acceptable oncologic or functional outcomes cannot be achieved using available limb salvage techniques.In an interesting study conducted in Ontario and Quebec, investigators found patients expecting a difficult recovery and patients with uncertain expectations had worse functional out-comes than patients anticipating an easy recovery, indicating that preoperative education including consultation with reha-bilitation services may optimize outcomes.92 Furthermore, all patients undergoing resection of extremity sarcomas should undergo physical therapy


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Surgery_Schwartz. education including consultation with reha-bilitation services may optimize outcomes.92 Furthermore, all patients undergoing resection of extremity sarcomas should undergo physical therapy beginning immediately after surgery and continuing until maximum function is achieved.1Brunicardi_Ch36_p1567-p1598.indd 157501/03/19 6:38 PM 1576SPECIFIC CONSIDERATIONSPART IILocoregional Lymphadenectomy. Several studies have reported improved survival for patients with isolated regional lymph node metastases treated with radical lymphadenectomy.28,63-65 Patients with clinically or radiologically suspicious regional nodes should have metastases confirmed by biopsy before radi-cal lymphadenectomy. An ultrasound-guided fine-needle aspi-ration or core biopsy of lymph nodes in selected patients with suspicious clinical or radiologic findings. The utility of sentinel lymph node biopsy has remained controversial despite the rec-ognition that several histologic subtypes of high-grade sarcoma are known


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Surgery_Schwartz. clinical or radiologic findings. The utility of sentinel lymph node biopsy has remained controversial despite the rec-ognition that several histologic subtypes of high-grade sarcoma are known to have a propensity for lymph node metastasis. However, there have been no prospective studies of the sen-sitivity and specificity of sentinel lymph node biopsy for such tumors, and as such, sentinel node biopsy for sarcoma should be performed in either highly selected patients or in the setting of a clinical trial.Amputation. Amputation is the treatment of choice for the 5% of patients with primary or recurrent extremity tumors whose tumors cannot be grossly resected with limb-sparing proce-dures and preservation of function. Historically, local excision of large, high-grade soft tissue sarcomas resulted in local fail-ure rates of 50% to 70%, even when a margin of normal tissue around the tumor was excised; consequently, radical resection or amputation was recommended. Today, however, the


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Surgery_Schwartz. resulted in local fail-ure rates of 50% to 70%, even when a margin of normal tissue around the tumor was excised; consequently, radical resection or amputation was recommended. Today, however, the addition of radiation therapy to less radical surgical resection has made limb salvage possible in most cases.A comparison of amputation versus limb-sparing sur-gery followed by adjuvant radiation therapy performed by the National Cancer Institute between 1975 and 1981 demonstrated no significant difference between the two groups in local recur-rence or overall survival rate.93 Potter and colleagues50 later reviewed the entire National Cancer Institute experience with 123 patients treated with conservative surgery plus radiation therapy and 83 treated with amputation. The local recurrence rate was significantly higher in the surgery and adjuvant radia-tion therapy group: 8% versus 0% in the amputation group. However, survival rates did not differ between the groups. Several large


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Surgery_Schwartz. rate was significantly higher in the surgery and adjuvant radia-tion therapy group: 8% versus 0% in the amputation group. However, survival rates did not differ between the groups. Several large single-institution studies have since also reported favorable local control rates with conservative resection plus radiation therapy.94-96Isolated Regional Perfusion. Isolated regional perfusion is a limb-sparing technique in which a soft tissue sarcoma is perfused with high concentrations of tumor necrosis factor-alpha (TNF-α) and melphalan under hyperthermic conditions. The use of TNF-α is not approved by the U.S. Food and Drug Administration (FDA) and is used only in European countries. The technique is generally used for locally advanced, multifo-cal, or locally recurrent disease; it has also served as a pallia-tive treatment to achieve local control for patients with distant metastases.Limb perfusion requires isolating the main artery and vein of the perfused limb from the systemic


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Surgery_Schwartz. also served as a pallia-tive treatment to achieve local control for patients with distant metastases.Limb perfusion requires isolating the main artery and vein of the perfused limb from the systemic circulation. The ana-tomic approach is determined by tumor site: external iliac ves-sels are used for thigh tumors, femoral or popliteal vessels for calf tumors, and axillary vessels for upper extremity tumors. The vessels are dissected, and all collateral vessels are ligated. The main artery and vein are then cannulated and connected to a pump oxygenator similar to that used in cardiopulmonary bypass. Either a tourniquet or an Esmarch band is applied to the limb to achieve complete vascular isolation. Chemotherapeutic agents are then added to the perfusion circuit and circulated for 90 minutes. Systemic leakage from the perfused limb is moni-tored continuously with 99Tc-radiolabeled human serum albumin injected into the perfusate, and radioactivity above the precor-dial area is recorded


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Surgery_Schwartz. Systemic leakage from the perfused limb is moni-tored continuously with 99Tc-radiolabeled human serum albumin injected into the perfusate, and radioactivity above the precor-dial area is recorded with a Geiger counter. During the entire procedure, hyperthermia of the perfused limb is maintained by external heating and by warming the perfusate to 40°C. At the end of the procedure, the limb is washed out, the cannulas are extracted, and the blood vessels are repaired.Despite the 40-year history of using isolated limb per-fusion to treat extremity sarcomas, many questions about this technique remain to be answered. The optimal chemotherapeu-tic agent in the perfusion circuit, the benefits of hyperthermia, and the effectiveness of hyperthermic perfusion as neoadjuvant or adjuvant treatment remain to be elucidated. Studies published to date have involved heterogeneous patient groups and various chemotherapeutic agents. Despite these limitations, response rates from 18% to 80% and overall


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Surgery_Schwartz. to be elucidated. Studies published to date have involved heterogeneous patient groups and various chemotherapeutic agents. Despite these limitations, response rates from 18% to 80% and overall 5-year survival rates from 50% to 70% have been reported.97-101 However, survival out-comes following isolated limb perfusion have not yet been directly compared with survival outcomes after more conven-tional treatment approaches.In the initial report of isolated regional perfusion for extremity sarcomas, published in 1974, McBride reported results in 79 patients with extremity sarcomas who had been treated with isolated limb perfusion during the previous 14 years.97 All patients received melphalan and dactinomycin. The overall 5-year survival rate was 57%, and only 13 patients had subsequent amputation for recurrent disease. Over the next 20 years, isolated perfusion for treatment of extremity sarcoma fell out of favor for several reasons. Most notably, improved survival and decreased local


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Surgery_Schwartz. for recurrent disease. Over the next 20 years, isolated perfusion for treatment of extremity sarcoma fell out of favor for several reasons. Most notably, improved survival and decreased local recurrence rates could be obtained with less radical therapy, including conservative surgical exci-sion combined with radiation to allow limb sparing in patients who were previously thought to require amputation.A 1992 report by Lienard and colleagues101 renewed interest in isolated limb perfusion for extremity tumors. Those investigators reported a 100% response rate among patients with extremity melanomas and sarcomas treated with high-dose recombinant TNF-α plus interferon-γ and melphalan in an iso-lated perfusion circuit. This report led to larger studies geared specifically to patients with sarcoma. The largest of these stud-ies, the European Multicenter Study, was reported by Egger-mont and colleagues in 1996.99 In that study of 186 patients, the overall tumor response rate was 82%, and the


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Surgery_Schwartz. The largest of these stud-ies, the European Multicenter Study, was reported by Egger-mont and colleagues in 1996.99 In that study of 186 patients, the overall tumor response rate was 82%, and the clinical and pathologic complete response rate was 29%. Although all of the study participants were reported to initially be candidates for amputation, the rate of limb salvage following isolated limb perfusion was 82%.99 Subsequent studies have shown high local response and limb salvage rates and acceptable local and sys-temic toxic effects.102However, results in the United States have been inferior to those reported in Europe. In a study by Fraker and colleagues, the complete response rate was 26%, and an additional 30% of patients had a partial response. Fourteen patients (32%) under-went amputation for progressive tumors, while the remaining 30 patients (68%) were able to undergo limb-sparing surgery after isolated limb perfusion.100 The inferior results in the U.S.-based studies are


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Surgery_Schwartz. amputation for progressive tumors, while the remaining 30 patients (68%) were able to undergo limb-sparing surgery after isolated limb perfusion.100 The inferior results in the U.S.-based studies are thought to be due to patient selection biases and the degree of treatment before limb perfusion.While isolated limb perfusion for extremity sarcoma has fallen out of favor, recent reports of isolated limb infusion from the H. Lee Moffitt Cancer Center have shown promising Brunicardi_Ch36_p1567-p1598.indd 157601/03/19 6:38 PM 1577SOFT TISSUE SARCOMASCHAPTER 36results.103 Patients with extremity sarcoma and who are con-sidered for amputation are offered the option of isolated limb infusion with high-dose melphalan and actinomycin-D on pro-tocol. Isolated limb infusion is a less invasive technique that can be repeated. Percutaneous cannulas are placed prior to infu-sion, the extremity is isolated similar to limb perfusion with an Esmarch band or tourniquet, and the perfusion is


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Surgery_Schwartz. technique that can be repeated. Percutaneous cannulas are placed prior to infu-sion, the extremity is isolated similar to limb perfusion with an Esmarch band or tourniquet, and the perfusion is normothermic and acidotic. Results from a multicenter retrospective study have demonstrated an overall response rate of 58%, and after a median follow-up of 21 months, there was an overall limb sal-vage rate of 78%. The benefits over limb perfusion remain the ability to repeat the technique in patients with disease response and less operative morbidity and risk of vascular injury from open surgery and cannulation of the iliac vessels. Although to date the technique has been well established for patients with locally advanced extremity disease for melanoma, its applica-tion for advanced, locally recurrent extremity sarcoma deserves further study.Radiation TherapyRadiation therapy is part of the standard treatment for high-grade extremity and trunk wall soft tissue sarcomas either in the preor


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Surgery_Schwartz. extremity sarcoma deserves further study.Radiation TherapyRadiation therapy is part of the standard treatment for high-grade extremity and trunk wall soft tissue sarcomas either in the preor postoperative setting. Patients with low-grade tumors or small, superficial high-grade tumors that have been resected with adequate margins may safely avoid radiation therapy.The evidence supporting adjuvant radiation therapy for patients eligible for conservative surgical resection comes from two randomized trials104,105 and three large single-institution reports.106-108 In a randomized trial by the National Cancer Institute, 91 patients with high-grade extremity tumors were treated with limb-sparing surgery followed by chemotherapy alone or radiation therapy plus chemotherapy. The 10-year local control rate was 98% for patients receiving radiation therapy compared with 70% for those not receiving radiation therapy (P = .0001).104 Similarly, in a randomized trial from Memorial Sloan-Kettering


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Surgery_Schwartz. rate was 98% for patients receiving radiation therapy compared with 70% for those not receiving radiation therapy (P = .0001).104 Similarly, in a randomized trial from Memorial Sloan-Kettering Cancer Center, 164 patients underwent conservative surgery followed by observation or brachytherapy. For patients with high-grade tumors, the 5-year local control rate was 66% in the observation group and 89% in the brachytherapy group (P = .003).105 For patients with low-grade tumors, no significant difference was observed between treatment groups.109Until recently, the standard treatment guidelines required radiation therapy after surgery for all patients with intermediate or high-grade tumors of any size. However, small tumors (≤5 cm) have not generally been associated with local recurrence, and radiation therapy for such tumors may not be necessary.105 In a series of 174 patients reported by Geer and colleagues, post-operative radiation therapy did not improve 5-year local recur-rence or


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Surgery_Schwartz. radiation therapy for such tumors may not be necessary.105 In a series of 174 patients reported by Geer and colleagues, post-operative radiation therapy did not improve 5-year local recur-rence or overall survival rates for patients with small soft tissue sarcomas.110 Karakousis and colleagues reported a 5-year local recurrence rate of 6% for 80 patients with extremity sarcomas treated with wide local excision and observation, a rate similar to that for the 64 patients who underwent resection with nar-rower surgical margins and postoperative radiation therapy.111The optimal mode of radiation therapy (external-beam radiation therapy, brachytherapy, or intensity-modulated radia-tion therapy [IMRT]) and timing of radiation therapy (preopera-tive, intraoperative, or postoperative) have yet to be defined. External-beam radiation therapy can be delivered using pho-tons or particle beams (electrons, protons, pions, or neutrons). Conventional fractionation is usually 1.8 to 2 Gy per day. CT


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Surgery_Schwartz. be defined. External-beam radiation therapy can be delivered using pho-tons or particle beams (electrons, protons, pions, or neutrons). Conventional fractionation is usually 1.8 to 2 Gy per day. CT is an integral part of radiation therapy, used to define the gross tumor volume and to estimate the margin of tissue at risk for microscopic tumor involvement. The optimal radiation margin is not well defined: a margin of 5 to 7 cm is standard, but some centers advocate wider margins for tumors larger than 15 cm. At most institutions, the typical preoperative dose is 50 Gy given in 25 fractions, and resection is performed 4 to 8 weeks after completion of radiation therapy to allow acute radiation changes to subside. Postoperative radiation therapy planning is based on tumor site, tumor grade, surgical margins, and institutional preferences. The entire surgical scar and drain sites should be included in the field so that a near-full dose can be administered to the superficial skin. Metallic


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Surgery_Schwartz. margins, and institutional preferences. The entire surgical scar and drain sites should be included in the field so that a near-full dose can be administered to the superficial skin. Metallic clips placed in the tumor bed during surgery can help define the limits of the resection and aid in radiation therapy planning. Doses of 60 to 70 Gy are usually necessary for postoperative treatment.No consensus exists on the optimal sequence of radia-tion therapy and surgery. The available data come largely from single-institution, nonrandomized studies. Proponents of pre-operative radiation therapy note that multidisciplinary planning with radiation oncologists, medical oncologists, and surgeons is easier early in the course of therapy. In addition, for some radiosensitive histologic subtypes, such as myxoid liposarcoma, preoperative radiation therapy may shrink the tumor, facilitat-ing resection with negative margins. Furthermore, a tissue bed undisturbed by resection has better tissue


Surgery_Schwartz

Surgery_Schwartz. such as myxoid liposarcoma, preoperative radiation therapy may shrink the tumor, facilitat-ing resection with negative margins. Furthermore, a tissue bed undisturbed by resection has better tissue oxygenation and can be successfully treated with lower doses of radiation. In addi-tion, Nielsen and colleagues112 demonstrated that preoperative radiation fields are smaller than postoperative radiation fields and that the average number of joints included in the field is lower with preoperative than postoperative radiation therapy, which may result in improved functional outcome. Critics of preoperative radiation therapy cite the difficulty of pathologic assessment of margins and the increased rate of postoperative wound complications.113 However, reconstructive surgical tech-niques with advanced tissue transfer procedures are being used more often in these high-risk wounds and reportedly result in better outcomes. The higher doses generally required for post-operative radiation therapy


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Surgery_Schwartz. tissue transfer procedures are being used more often in these high-risk wounds and reportedly result in better outcomes. The higher doses generally required for post-operative radiation therapy have also been shown to be associ-ated with greater long-term functional impairment.The only randomized comparison of preoperative and postoperative radiation therapy to date was performed by the National Cancer Institute of Canada Clinical Trials–Canadian Sarcoma Group.114 This trial was designed to examine compli-cations and functional outcome. The 190 patients enrolled from October 1994 to December 1997 were randomized to preopera-tive radiation therapy (50 Gy) or postoperative radiation therapy (66 Gy). With a median follow-up time of 3.3 years, the recur-rence and progression-free survival rates were similar in the two groups. The incidence of wound complications was higher in the preoperative group versus the postoperative group (35% vs. 17%), and the incidence of wound complications was


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Surgery_Schwartz. were similar in the two groups. The incidence of wound complications was higher in the preoperative group versus the postoperative group (35% vs. 17%), and the incidence of wound complications was signifi-cantly higher for tumors of the lower extremity (43%) than for those of the upper extremity (5%).114 Late radiation toxic effects (e.g., fibrosis, joint stiffness, and edema) were more common with postoperative than preoperative radiation therapy (48% vs. 32%) because of higher postoperative radiation doses and larger treatment field sizes.115Brachytherapy involves the placement of multiple radioactive seeds through catheters inserted in the tumor resection bed. The primary benefit of brachytherapy is the shorter overall treatment time of 4 to 6 days, compared to the 4 to 6 weeks generally required for preoperative or postoperative Brunicardi_Ch36_p1567-p1598.indd 157701/03/19 6:38 PM 1578SPECIFIC CONSIDERATIONSPART IIradiation therapy regimens. A cost-analysis comparison of


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Surgery_Schwartz. required for preoperative or postoperative Brunicardi_Ch36_p1567-p1598.indd 157701/03/19 6:38 PM 1578SPECIFIC CONSIDERATIONSPART IIradiation therapy regimens. A cost-analysis comparison of adjuvant brachytherapy versus adjuvant external-beam irradiation for soft tissue sarcomas showed that costs were lower with brachytherapy.116 The implications of cost have been studied after radical resections and immediate adjuvant brachytherapy with either staged or immediate reconstruction noting a lower cost with staged reconstruction and tissue transfer techniques.117 Brachytherapy can also be used for recurrent disease previously treated with external-beam radiation. Guidelines established at Memorial Sloan-Kettering Cancer Center recommend spacing the afterloading catheters in 1-cm increments while leaving a 2-cm margin around the surgical bed.105 After adequate wound healing is confirmed, usually after the fifth postoperative day, the catheters are loaded with seeds containing


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Surgery_Schwartz. increments while leaving a 2-cm margin around the surgical bed.105 After adequate wound healing is confirmed, usually after the fifth postoperative day, the catheters are loaded with seeds containing iridium-192 that deliver 42 to 45 Gy of radiation to the tumor bed over 4 to 6 days. Subsequent studies at the H. Lee Moffitt Cancer Center that sought to determine outcomes between staged immediate and delayed reconstruction noted advantages in improved local control, wound healing, and less radiation-associated toxicity with staged reconstruction.118 The primary disadvantage of brachytherapy is that it requires significant expertise, extended inpatient hospital stays, and bed rest.IMRT delivers radiation more precisely to the tumor than external-beam irradiation while minimizing the volume of sur-rounding tissues exposed to high radiation doses. The proposed benefits of preoperative IMRT include reduced risk of postop-erative wound infections because of minimization of the dose to the


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Surgery_Schwartz. of sur-rounding tissues exposed to high radiation doses. The proposed benefits of preoperative IMRT include reduced risk of postop-erative wound infections because of minimization of the dose to the skin119 and protection of underlying bone (e.g., femur) as a result of concave dose distributions.120 There have been no prospective randomized trials comparing the long-term out-comes following IMRT versus other types of radiation therapy. In a retrospective analysis of IMRT, patients with negative and positive/close (within 1 mm) margins were found to have 5-year local control rates of 94%.121 In addition, the rates of posttreat-ment edema and joint stiffness with IMRT were lower than the expected rates with conventional radiation therapy.Local toxic effects of radiation therapy vary according to radiation dose, field size, and timing (preoperative or postop-erative). With preoperative radiation therapy, the most frequent wound complications are wound dehiscence, wound necrosis,


Surgery_Schwartz

Surgery_Schwartz. according to radiation dose, field size, and timing (preoperative or postop-erative). With preoperative radiation therapy, the most frequent wound complications are wound dehiscence, wound necrosis, persistent drainage, infection, seroma formation, ulceration, and cellulitis.114 Postoperative irradiation of free flaps is often asso-ciated with wound complications, and patients should be advised that secondary surgical repair may be necessary; therefore, con-sideration for preoperative radiation rather than postoperative radiation for larger tumors requiring flap reconstruction is a logical and sound approach. Wound complication rates of 13% to 37% have been reported for preoperative radiation therapy, compared to 5% to 20% for postoperative radiation therapy.121 If catheters are loaded after the fifth postoperative day and/or if staged reconstruction is used, rates of wound complications after brachytherapy are improved if not similar to those after postoperative radiation


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Surgery_Schwartz. loaded after the fifth postoperative day and/or if staged reconstruction is used, rates of wound complications after brachytherapy are improved if not similar to those after postoperative radiation therapy.118Long-term (chronic) effects of radiation therapy (those occurring >1 year after completion of therapy) are generally related to fibrosis/contractures, lymphedema, neurologic injury, osteitis, and fractures, all of which can cause substantial func-tional impairment.122 Variables associated with poorer func-tional outcome after radiation therapy include larger tumors, higher doses of radiation (>63 Gy), longer radiation fields (>35 cm), poor radiation technique, neural sacrifice, postop-erative fractures, and wound complications.115,123 Additionally, complications of any kind are less likely after treatment for upper extremity sarcoma than after treatment for lower extremity sarcoma.113,114Definitive radiation therapy that delivers maximal-tissue-tolerance doses of radiation may


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Surgery_Schwartz. likely after treatment for upper extremity sarcoma than after treatment for lower extremity sarcoma.113,114Definitive radiation therapy that delivers maximal-tissue-tolerance doses of radiation may be appropriate for selected patients with unresectable soft tissue sarcomas. In a study of 112 patients with unresectable soft tissue sarcomas, tumor size and radiation dose were found to influence local control and survival.124 The local control rate was 51% for tumors smaller than 5 cm and 9% for tumors larger than 10 cm, and patients who received at least 64 Gy had better local control and survival.Systemic TherapyDespite improvements in local control rates, metastasis and death remain significant problems for patients with high-risk soft tissue sarcomas. Patients considered at high risk of death from sarcoma include those presenting with metastatic disease, localized sarcomas at nonextremity sites, or sarcomas of intermediateor high-grade histology larger than 5 cm.59,105Standard


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Surgery_Schwartz. of death from sarcoma include those presenting with metastatic disease, localized sarcomas at nonextremity sites, or sarcomas of intermediateor high-grade histology larger than 5 cm.59,105Standard Chemotherapy. For most patients with sarcoma, results of conventional chemotherapy regimens have been poor. The chemosensitivity of soft tissue sarcoma varies by histologic subtype.30 Synovial sarcoma, myxoid/round cell liposarcoma, and uterine leiomyosarcoma are sensitive to chemotherapy,125 whereas pleomorphic liposarcoma, myxofibrosarcoma, epithe-lioid sarcoma, leiomyosarcoma, MPNSTs, angiosarcoma, and desmoplastic round cell tumors have intermediate sensitivity to chemotherapy. Relatively chemoresistant histologic subtypes include clear cell sarcoma, endometrial stromal sarcoma, alveo-lar soft part sarcoma, and extraskeletal myxoid chondrosarcoma. Considering the variability of responses by histologic subtype, it is not surprising that clinical trials of standard chemotherapy, which


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Surgery_Schwartz. soft part sarcoma, and extraskeletal myxoid chondrosarcoma. Considering the variability of responses by histologic subtype, it is not surprising that clinical trials of standard chemotherapy, which often include heterogeneous populations with respect to tumor grade and histology, have demonstrated no overall sur-vival benefit.Doxorubicin and ifosfamide are the two most active agents against soft tissue sarcoma, with consistently reported response rates of 20% or greater and positive dose-response curves.126,127 The European guidelines recommend doxorubicin 75 mg/m2 every 3 weeks as first-line treatment for advanced disease.30 Treatment duration is based on response, but a maximum of six cycles is generally recommended because of the risk of cumula-tive cardiotoxicity. Ifosfamide is the recommended second-line treatment and is recommended for first-line treatment in patients with cardiac morbidity. The standard dose of ifosfamide is 9 to 10 g/m2; however, single-institution series


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Surgery_Schwartz. recommended second-line treatment and is recommended for first-line treatment in patients with cardiac morbidity. The standard dose of ifosfamide is 9 to 10 g/m2; however, single-institution series using higher-dose regimens (>10 g/m2) or standard-dose ifosfamide combined with doxorubicin have shown response rates of 20% to 60%.127 Synovial sarcomas have been shown to be particularly sensi-tive to ifosfamide. Ifosfamide-associated toxic effects include hemorrhagic cystitis, neurotoxicity, and renal tubular acidosis. Historically, combination therapy with doxorubicin plus ifos-famide, dacarbazine, or both has resulted in increased response rates but no improvement in overall survival.128 Dacarbazine as a single agent has also demonstrated activity in clinical trials.Over the past decade, several additional chemotherapeutic agents, including gemcitabine, taxanes, and trabectedin, have been noted to be active against soft tissue sarcomas. Gemcitabine as a single agent was reported to


Surgery_Schwartz

Surgery_Schwartz. several additional chemotherapeutic agents, including gemcitabine, taxanes, and trabectedin, have been noted to be active against soft tissue sarcomas. Gemcitabine as a single agent was reported to produce responses in 18% of patients with advanced sarcoma.129 Gemcitabine combined with docetaxel has been reported to produce response rates as high as 53% in patients with uterine leiomyosarcoma.129,130 Gemcitabine Brunicardi_Ch36_p1567-p1598.indd 157801/03/19 6:38 PM 1579SOFT TISSUE SARCOMASCHAPTER 36combined with vinorelbine has also been associated with clini-cal benefit in patients with advanced sarcomas.131 The taxanes (docetaxel and paclitaxel) have been found to be active against angiosarcomas, particularly of the face and scalp, likely because of their potent antiangiogenic effects.132,133Novel Chemotherapeutic Agents. Aldoxorubicin is a doxo-rubicin derivative that serves as a prodrug of doxorubicin that covalently binds to albumin in the blood until reaching the acidic


Surgery_Schwartz

Surgery_Schwartz. Chemotherapeutic Agents. Aldoxorubicin is a doxo-rubicin derivative that serves as a prodrug of doxorubicin that covalently binds to albumin in the blood until reaching the acidic tumor environment releasing doxorubicin into the tis-sue. A recent international, multicenter, phase 2b, open-label, randomized study enrolled 126 patients from 2012 to 2013. Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response, warranting further study.134Trabectedin, a marine-derived alkaloid that binds DNA, affecting transcription and inducing the formation of DNA double-strand breaks, has shown benefit in the treatment of advanced soft tissue sarcomas, particularly leiomyosarcoma, myxoid liposarcoma, and other translocation-related sarcomas.135 Trabectedin is generally well tolerated but can be associated with prolonged and severe neutropenia, thrombocytopenia, and


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Surgery_Schwartz. myxoid liposarcoma, and other translocation-related sarcomas.135 Trabectedin is generally well tolerated but can be associated with prolonged and severe neutropenia, thrombocytopenia, and hepatic toxic effects.Palifosfamide is a stabilized formulation of the active metabolite of ifosfamide that has been reported to be better tolerated than ifosfamide.136 Early trials have suggested anti-tumor activity comparable or superior to that of ifosfamide without nephrotoxicity; however, recent negative results of the PICASSO III Trial, a phase 3, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma, have neatly secured the fate of palifosfamide in the treatment of soft tissue sarcoma.137Targeted Therapies. Several targeted agents are being investigated for the treatment of soft tissue sarcomas. Among these are tyrosine kinase inhibitors (e.g., imatinib, suni-tinib, sorafenib, and dasatinib) that have been developed and approved


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Surgery_Schwartz. being investigated for the treatment of soft tissue sarcomas. Among these are tyrosine kinase inhibitors (e.g., imatinib, suni-tinib, sorafenib, and dasatinib) that have been developed and approved for treatment of GIST. Clinical data accumulated in phase 2 trials also support the use of tyrosine kinase inhibitors (e.g., imatinib, sorafenib, and sunitinib) in the management of other advanced sarcomas.128 Anti–vascular endothelial growth factor antibodies such as bevacizumab have demonstrated activity in patients with metastatic or unresectable angiosar-coma, solitary fibrous tumor, and epithelioid hemangioendo-thelioma.138 Pazopanib is an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor (PDGFR), and c-kit. In a recent phase 3 study, pazopanib showed efficacy against placebo in second or further line of therapy in patients with advanced soft tissue sarcoma.139 Inhibitors of the mammalian target of rapamycin


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Surgery_Schwartz. recent phase 3 study, pazopanib showed efficacy against placebo in second or further line of therapy in patients with advanced soft tissue sarcoma.139 Inhibitors of the mammalian target of rapamycin pathway, including temsirolimus, everolimus, and ridaforolimus, have also shown activity against some soft tis-sue sarcomas (i.e., PEComas).140Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumor activity in human sarcoma xenografts. Recently, a phase 1b and random-ized phase 2 study of olaratumab and doxorubicin versus doxo-rubicin alone has demonstrated improvements in both objective response rates (18.2% vs. 11.9%, P = 0.34) and median over-all survival (26.5 vs. 14.7 months [stratified hazard ratio 0.46, 0.30–0.71, P = 0.0003]). Additional studies are warranted for this promising combination of agents.141Benefits of Systemic Therapy. The use of adjuvant and neoad-juvant chemotherapy for soft tissue sarcomas remains controver-sial.


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Surgery_Schwartz. studies are warranted for this promising combination of agents.141Benefits of Systemic Therapy. The use of adjuvant and neoad-juvant chemotherapy for soft tissue sarcomas remains controver-sial. More than a dozen individual randomized trials of adjuvant chemotherapy have failed to demonstrate improvement in disease-free or overall survival for patients with soft tissue sarcoma. How-ever, several limitations of these individual trials may explain the lack of observed improvement. First, the chemotherapy regimens used were suboptimal, consisting of single-agent therapy (most commonly with doxorubicin) and insufficiently intensive dosing schedules. Second, the patient groups were not large enough to reveal clinically significant differences in survival rates. Finally, most studies included patients at low risk of metastasis and death, namely those with small (<5 cm) and low-grade tumors.The Sarcoma Meta-Analysis Collaboration analyzed 1568 patients from 14 trials of doxorubicin-based


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Surgery_Schwartz. patients at low risk of metastasis and death, namely those with small (<5 cm) and low-grade tumors.The Sarcoma Meta-Analysis Collaboration analyzed 1568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy to evaluate the effect of adjuvant chemotherapy on localized, resectable soft tissue sarcomas.142 At a median follow-up time of 9.4 years, doxorubicin-based chemotherapy significantly improved the time to local and distant recurrence and recurrence-free survival rates. However, the absolute benefit in overall survival was only 4%, which was not significant (P = .12). In a subset analysis, patients with extremity tumors had a 7% benefit in terms of overall survival (P = .029).142After this meta-analysis, randomized controlled trials of more contemporary anthracycline/ifosfamide dosing combinations with relatively small numbers of patients have yielded conflicting results. In an Italian cooperative trial, adjuvant chemotherapy improved median disease-free and overall


Surgery_Schwartz

Surgery_Schwartz. dosing combinations with relatively small numbers of patients have yielded conflicting results. In an Italian cooperative trial, adjuvant chemotherapy improved median disease-free and overall survival times in patients with high-risk extremity soft tissue sarcomas.143 In that study, 104 patients with high-grade tumors 5 cm or larger were randomized to definitive surgery or surgery plus adjuvant chemotherapy consisting of epirubicin (60 mg/m2 per day on days 1 and 2) and ifosfamide (1.8 g/m2 per day on days 1 through 5) for five cycles. With a median follow-up time of almost 5 years, disease-free survival times were 16 months in the surgery-alone group and 48 months in the combined-treatment group (P = .04), and median overall survival times were 46 months in the surgery-alone group and 75 months in the combined-treatment group (P = .03).143 However, several years later, the surgery-alone and combined-treatment groups had equivalent relapse rates and deaths, which resulted in


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Surgery_Schwartz. and 75 months in the combined-treatment group (P = .03).143 However, several years later, the surgery-alone and combined-treatment groups had equivalent relapse rates and deaths, which resulted in statistically similar overall survival.144In an effort to further assess the role of chemotherapy in patients with stage III extremity sarcoma, a cohort analy-sis of the combined databases of The University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Can-cer Center was performed. Data on 674 patients with stage III extremity sarcoma who received either preoperative or postop-erative doxorubicin-based chemotherapy were reviewed. The 5-year disease-specific survival rate was 61%.145 Cox regres-sion analysis showed a time-varying effect of chemotherapy with an associated benefit during the first year while receiving chemotherapy. However, the clinical benefits of chemotherapy in patients with stage III sarcomas were not sustained beyond 1 year. Grobmyer and colleagues


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Surgery_Schwartz. during the first year while receiving chemotherapy. However, the clinical benefits of chemotherapy in patients with stage III sarcomas were not sustained beyond 1 year. Grobmyer and colleagues compared the outcomes of patients treated at two institutions (1990–2001) with surgery only or surgery plus preoperative chemotherapy containing doxorubicin and ifosfamide. In this analysis, chemotherapy was associated with an improvement in the 3-year disease-specific survival rate that was most pronounced in patients with tumors larger than 10 cm (62% for surgery alone vs. 83% for neoadju-vant chemotherapy and surgery).146Brunicardi_Ch36_p1567-p1598.indd 157901/03/19 6:38 PM 1580SPECIFIC CONSIDERATIONSPART IIMore recently, the European Organization for Research and Treatment of Cancer (EORTC) completed a phase 3 ran-domized study (trial EORTC-62931; conducted from 1995 through 2003) comparing surgery alone versus surgery plus adjuvant ifosfamide (5 g/m2) plus doxorubicin (75 mg/m2) with


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Surgery_Schwartz. completed a phase 3 ran-domized study (trial EORTC-62931; conducted from 1995 through 2003) comparing surgery alone versus surgery plus adjuvant ifosfamide (5 g/m2) plus doxorubicin (75 mg/m2) with growth factor support (lenograstim) every 21 days for five cycles in 351 patients with resected grade II or III soft tissue sarcoma at any site. The estimated relapse-free survival rate was 52% in both arms, and the overall survival rate was better in the control arm (69% vs. 64%).147 Although most individual studies are underpowered, data from all of these studies suggest that chemotherapy regimens that incorporate ifosfamide may provide some disease-free survival benefit but do not improve long-term overall survival for the majority of patients with soft tissue sarcoma.In 2008, two updates to the 1997 Sarcoma Meta-Anal-ysis Collaboration were published.148,149 O’Connor and col-leagues included all of the trials in the original meta-analysis and added data from four additional trials, for


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Surgery_Schwartz. the 1997 Sarcoma Meta-Anal-ysis Collaboration were published.148,149 O’Connor and col-leagues included all of the trials in the original meta-analysis and added data from four additional trials, for a total of 18 trials with 2170 patients.148 The results showed a benefit of chemotherapy in terms of disease-free survival at 5 years and recurrence-free survival at 10 years but again failed to demon-strate a benefit in terms of long-term overall survival. The sec-ond update, by Pervaiz and colleagues, which did not include the EORTC-62931 trial, showed that adjuvant chemotherapy was associated with a significant decrease in the risk of death (hazard ratio, 0.77; P = .01).149Because the evidence regarding adjuvant systemic therapy for stage III soft tissue sarcoma is inconclusive, considerable variation still exists in treatment recommendations even though patients with large, stage II or stage III soft tissue sarcomas are at high risk for recurrence and metastasis. Chemotherapy may be


Surgery_Schwartz

Surgery_Schwartz. variation still exists in treatment recommendations even though patients with large, stage II or stage III soft tissue sarcomas are at high risk for recurrence and metastasis. Chemotherapy may be considered to downstage large tumors to enable limb-sparing procedures, particularly for tumors known to be chemosensi-tive. It is likely that subsets of high-risk patients with extremity soft tissue sarcoma defined on the basis of tumor size or histol-ogy derive significant benefit from systemic chemotherapy. For example, retrospective cohort analyses have noted a disease-specific survival benefit in patients with large, high-grade lipo-sarcomas and synovial sarcomas of the extremity treated with ifosfamide plus doxorubicin versus no chemotherapy.150Neoadjuvant (Preoperative) Chemotherapy. The use of neoadjuvant (preoperative) chemotherapy for soft tissue sarco-mas is based on the belief that only 30% to 50% of patients respond to standard adjuvant (postoperative) chemotherapy. The rationale


Surgery_Schwartz

Surgery_Schwartz. of neoadjuvant (preoperative) chemotherapy for soft tissue sarco-mas is based on the belief that only 30% to 50% of patients respond to standard adjuvant (postoperative) chemotherapy. The rationale for using neoadjuvant chemotherapy is that it enables oncologists to identify patients whose disease is sensi-tive to a particular chemotherapy regimen by assessing response while the primary tumor is in situ. Patients whose tumors do not respond to short courses of neoadjuvant chemotherapy can thus be spared the toxic effects of prolonged adjuvant chemotherapy. Another advantage of neoadjuvant chemotherapy is that it may shrink tumors, enabling less morbid operations. The theoreti-cal disadvantages of neoadjuvant chemotherapy are related to myelosuppression and potential postoperative wound healing complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the


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Surgery_Schwartz. complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the same regimen in high-risk extremity and trunk wall soft tissue sarcomas showed equivalence between the two approaches, sug-gesting the possibility of limiting chemotherapy administration to the three preoperative courses, improving the ratio between toxicity and expected benefit.151A subanalysis on response showed how tumor attenuation on CT scan and MRI obtained by the administration of such preoperative treatment was associated with a higher percentage of pathologic necrosis152 and better outcome.153Eilber and colleagues examined treatment-induced patho-logic necrosis in patients who received neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48%


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Surgery_Schwartz. neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48% compared to 13% with other combinations. The 5and 10-year local recur-rence rates were significantly lower for patients with 95% or greater pathologic necrosis (6% and 11%, respectively) than for patients with less than 95% pathologic necrosis (17% and 23%, respectively).Concurrent Chemoradiation TherapyTreatment approaches that combine systemic chemotherapy with radiosensitizers and concurrent external-beam radiation therapy may improve disease-free survival by treating micro-scopic disease and enhancing the treatment of macroscopic disease. Concurrent chemoradiation therapy with doxorubicin-based regimens reportedly produces favorable local control rates for patients with sarcoma.150 Since those findings were published, several groups have evaluated routes of administra-tion, alternative


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Surgery_Schwartz. regimens reportedly produces favorable local control rates for patients with sarcoma.150 Since those findings were published, several groups have evaluated routes of administra-tion, alternative chemotherapeutic agents, and the toxicity of combined therapies.Theoretical advantages notwithstanding, concurrent chemoradiation therapy decreases the total treatment time for patients with high-risk sarcoma. This decrease represents a sub-stantial advantage over current sequential combined-modality treatment approaches, for which the total duration of radiation therapy, chemotherapy, surgery, and rehabilitation frequently exceeds 6 to 9 months.Posttreatment SurveillanceCurrently, posttreatment surveillance is recommended for all patients with soft tissue sarcomas based on a few reports involving small numbers of patients, indicating that local recur-rence can be successfully treated with radical reexcision with or without radiation therapy.155,156 Similarly, several groups have reported that


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Surgery_Schwartz. small numbers of patients, indicating that local recur-rence can be successfully treated with radical reexcision with or without radiation therapy.155,156 Similarly, several groups have reported that survival can be prolonged by resection of pulmo-nary metastases.157-159The National Comprehensive Cancer Network (NCCN) recommends a history and physical and chest CT or radiog-raphy every 3 to 6 months for 2 to 3 years after completion of treatment. Because most cases of distant metastasis occur within 2 to 3 years of initial diagnosis, the NCCN guidelines indicate that follow-up intervals can be lengthened to every 6 months, and imaging can be done annually during years 2 through 5.1 Consideration should also be given to imaging the primary tumor site; most experts recommend that the tumor site be evaluated every 6 months with MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from


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Surgery_Schwartz. site be evaluated every 6 months with MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from typical postsurgical changes: a discrete nodule with low signal intensity on T1-weighted images and higher signal intensity on T2-weighted images that enhances after adminis-tration of intravenous contrast material is strongly suggestive of recurrence and should be biopsied. Ultrasonography may be an alternative to MRI or CT for assessing for recurrence in the extremities.Brunicardi_Ch36_p1567-p1598.indd 158001/03/19 6:38 PM 1581SOFT TISSUE SARCOMASCHAPTER 36Recurrence is common after surgery for abdominal soft tissue sarcomas. CT is useful for detecting recurrences at primary and distant anatomic sites in the abdomen and pelvis. After surgery, CT every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, today many experienced


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Surgery_Schwartz. sites in the abdomen and pelvis. After surgery, CT every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, today many experienced surgeons are advocating less aggressive imaging for asymptomatic patients, particularly after a second recurrence of retroperitoneal sarcoma, arguing that there is insufficient evidence to suggest that survival is improved by earlier detection.Whooley and colleagues reviewed the efficacy of the sur-veillance strategy used at Roswell Park Cancer Institute for 174 patients with soft tissue sarcomas of the extremities.160 Patients were evaluated every 3 months for the first 2 years, every 4 to 6 months during year 3, and every 6 months during years 4 and 5. Local recurrence occurred in 18% of patients at a median time after completion of treatment of 14 months, and all but one of the recurrences were detected with physical examination alone. Fifty-seven patients had distant recurrences (at a


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Surgery_Schwartz. at a median time after completion of treatment of 14 months, and all but one of the recurrences were detected with physical examination alone. Fifty-seven patients had distant recurrences (at a median of 18 months after treatment), of which 36 were asymptomatic and diagnosed by surveillance imaging. The investigators determined that the positive predictive value of chest radiography during follow-up was 92%.160 However, evaluation of the primary tumor site by CT or MRI was ineffective in detecting recurrences. The authors recommended that patient characteristics, location of the primary tumor, previous treatment, and physician familiarity with changes after surgery and radiation therapy should all be considered in determining the need for radiographic imaging.Management of Recurrent SarcomaUp to 20% of patients with extremity sarcoma develop locally recurrent disease, which is often accompanied by distant metastases; thus, all patients with recurrent extremity sarcoma should undergo


Surgery_Schwartz

Surgery_Schwartz. to 20% of patients with extremity sarcoma develop locally recurrent disease, which is often accompanied by distant metastases; thus, all patients with recurrent extremity sarcoma should undergo a full staging assessment. Patients with microscopically positive surgical margins are at increased risk of local recurrence. In a series of 179 patients with locally recurrent extremity soft tissue sarcoma at Memorial Sloan-Kettering Cancer Center, the median interval to local recurrence was 16 months; 65% of patients developed a local recurrence by 2 years, and 90% by 4 years.155 The majority of patients (89%) were treated with additional limb-sparing surgery, and 73% received additional adjuvant therapy; the disease-specific survival after treatment of first local recurrence was 55% at 4 years. Independent prognostic factors for disease-specific survival after local recurrence included tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that an


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Surgery_Schwartz. years. Independent prognostic factors for disease-specific survival after local recurrence included tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that an isolated local recurrence should be treated aggressively with resection with negative margins.For patients with extremity sarcomas, achieving negative margins on resection of recurrent disease frequently requires amputation. However, in some patients with recurrent extrem-ity sarcoma, function-preserving resection combined with addi-tional radiation therapy, with or without chemotherapy, can produce acceptable rates of local control.161-163 Nori and col-leagues reported a local control rate of 69% among 40 patients with recurrent tumors treated with reexcision and brachytherapy to a median dose of 45 Gy.163 In a similar series, Midis and col-leagues reported that limb-sparing surgery was possible in 66% of patients, and the 5-year local recurrence-free survival rate was 72% in those


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Surgery_Schwartz. dose of 45 Gy.163 In a similar series, Midis and col-leagues reported that limb-sparing surgery was possible in 66% of patients, and the 5-year local recurrence-free survival rate was 72% in those patients.161The primary determinant of survival in patients with soft tissue sarcoma is the development of distant metastases. Patients with extremity sarcomas generally develop pulmonary metastases.160 Less common sites of metastasis for soft tissue sarcomas include bone (7%), liver (4%),49 and lymph nodes (5–7%).28 Myxoid liposarcoma of the extremity is known to metastasize to the abdomen and pelvis; therefore, staging CT of these regions must be performed before definitive local therapy is administered.32Management of Recurrent and Distant Metastatic Sarcoma. In selected individuals with distant metastatic disease, surgical resection of a primary soft tissue sarcoma may be appropriate as a palliative procedure. The decision should be based on the patient’s symptoms, which often include


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Surgery_Schwartz. metastatic disease, surgical resection of a primary soft tissue sarcoma may be appropriate as a palliative procedure. The decision should be based on the patient’s symptoms, which often include pain; ability to achieve local tumor control; comorbidities; anticipated morbidity of the surgical procedure; and the extent of metastases.The most common initial site of distant metastasis of soft tissue sarcomas is the lung. Selected patients with a limited number of pulmonary nodules (less than four nodules), long disease-free intervals, and no endobronchial invasion may become long-term survivors after pulmonary resection (Fig. 36-8); 15% to 40% of patients with complete resection of metastatic disease confined to the lung are long-term survivors.159,160,164 In a retrospective multi-institutional study of 255 patients with lung metastases, the 5-year overall survival rate after metastasectomy was 38%.157 Favorable prognostic factors in that study included microscopically tumor-free


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Surgery_Schwartz. study of 255 patients with lung metastases, the 5-year overall survival rate after metastasectomy was 38%.157 Favorable prognostic factors in that study included microscopically tumor-free margins, age younger than 40 years, and grade 1 or 2 tumor.157 For patients who are surgical candidates, pulmonary resection alone can be more cost-effective than watchful waiting, chemotherapy, or chemotherapy plus surgery.158Chemotherapy for Distant Metastatic Sarcoma. Doxorubicin, either alone or combined with other agents, has been the primary treatment modality for patients with advanced or distant metastatic sarcomas for several decades.128 Although most patients with metastatic disease are not curable, some Figure 36-8. A 69-year-old patient with a history of a dedifferenti-ated liposarcoma of the retroperitoneum developed a solitary lung metastasis 6 years after surgical resection.Brunicardi_Ch36_p1567-p1598.indd 158101/03/19 6:38 PM 1582SPECIFIC CONSIDERATIONSPART IIpatients with