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Soft tissues sarcoma_surgery_dr.potentiano


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Soft tissues sarcoma_surgery_dr.potentiano

  1. 1. Soft Tissue Sarcomas
  2. 4. INTRODUCTION: Incidence Sarcomas are a heterogeneous group of tumors that arise predominantly from the embryonic mesoderm, but also can originate, as does the peripheral nervous system, from the ectoderm.
  3. 5. <ul><li>Some cases of soft tissue sarcoma </li></ul><ul><li>These rare tumors account for less than 1% of cancers in adults and represent 7% of cancers in children. </li></ul><ul><li>Several distinct groups of sarcomas are recognized. </li></ul>
  4. 6. <ul><li>Soft tissue sarcomas can occur throughout the body and encompass more than 50 histiotypes. </li></ul><ul><li>Most primary soft tissue sarcomas originate in an extremity (59%); </li></ul><ul><li>The next most common sites are the trunk (19%) </li></ul><ul><li>Retroperitoneum (13%), </li></ul><ul><li>head and neck (9%). </li></ul>
  5. 7. <ul><li>The most common histologic types of soft tissue </li></ul><ul><li>sarcoma in adults (excluding Kaposi's sarcoma) are: </li></ul><ul><li>malignant fibrous histiocytoma (28%) </li></ul><ul><li>leiomyosarcoma (12%) </li></ul><ul><li>liposarcoma (15%) </li></ul><ul><li>synovial sarcoma (10%) </li></ul><ul><li>malignant peripheral nerve sheath tumors (6%) </li></ul><ul><li>Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. </li></ul>
  6. 9. Relative Frequency of Histologic Subtypes of Soft Tissue Sarcoma Histologic Subtypes n % Malignant fibrous histiocytomaxs 349 28 Liposarcoma 188 15 Leiomyosarcoma 148 12 Unclassified sarcoma 140 11 Synovial sarcoma 125 10 Malignant peripheral nerve sheath tumor 72 6 Rhabdomyosarcoma 60 5 Fibrosarcoma 38 3 Ewing's sarcoma 25 2 Angiosarcoma 25 2 Osteosarcoma 14 1 Epithelioid sarcoma 14 1 Chondrosarcoma 13 1 Clear cell sarcoma 12 1 Alveolar soft part sarcoma 7 1 Malignant hemangiopericytoma 5 0.4
  7. 10. <ul><li>Epidemiology </li></ul><ul><li>Except for malignant peripheral nerve sheath tumors in patients with neurofibromatosis, sarcomas do not seem to result from the progression or dedifferentiation of benign soft tissue tumors. </li></ul><ul><li>Sarcomas have many common clinical and pathologic features. </li></ul>
  8. 12. <ul><li>Overall the clinical behavior of most soft tissue sarcomas is similar and is determined by anatomic location (depth), grade, and size. </li></ul><ul><li>The dominant pattern of metastasis is hematogenous. </li></ul>
  9. 14. <ul><li>Lymph node metastases are rare (<5%) except for a few histologic subtypes such as: </li></ul><ul><li>epithelioid sarcoma </li></ul><ul><li>rhabdomyosarcoma </li></ul><ul><li>clear-cell sarcoma </li></ul><ul><li>angiosarcoma </li></ul>
  10. 15. <ul><li>Radiation Exposure </li></ul><ul><li>External radiation therapy is a well-established risk factor for soft tissue sarcoma. </li></ul><ul><li>An eight- to 50-fold increase in the incidence of sarcomas has been reported among patients treated for cancer of the breast, cervix, ovary, testes, and lymphatic system. </li></ul><ul><li>Post irradiation sarcomas are usually diagnosed at advanced stages and generally have a poor prognosis. </li></ul>
  11. 16. <ul><li>Occupational Chemicals </li></ul><ul><li>Exposure to some herbicides such as phenoxyacetic acids and wood preservatives containing chlorophenols has been linked to an increased risk of soft tissue sarcoma. </li></ul><ul><li>Several chemical carcinogens, including thorium oxide (Thoratrast), vinyl chloride, and arsenic, have been associated with hepatic angiosarcomas. </li></ul>
  12. 17. <ul><li>Trauma </li></ul><ul><li>Trauma is an injury calls attention to a preexisting tumor that may be accentuated by an edema or a hematoma. </li></ul><ul><li>Although patients with sarcomas often report a history of trauma, no causal relationship has been established. </li></ul>
  13. 19. <ul><li>Chronic Lymphedema </li></ul><ul><li>The association between chronic lymphedema after axillary dissection and subsequent lymphangiosarcoma. </li></ul><ul><li>Lymphangiosarcoma also has been described after filarial infections and in the lower extremities of patients with congenital or heritable lymphedema. </li></ul>
  14. 21. <ul><li>Genetics </li></ul><ul><li>Specific inherited genetic alterations are associated with an increased risk of bone and soft tissue sarcomas. </li></ul><ul><li>New developments in the field of molecular biology have led to better understanding of the basic cellular processes governed by oncogenes and tumor suppressor genes. </li></ul>
  15. 22. <ul><li>Oncogene Activation </li></ul><ul><li>Oncogenes are genes that can induce malignant transformation and tend to drive cells toward proliferation. </li></ul><ul><li>Several oncogenes have been identified in association with soft tissue sarcomas including: </li></ul><ul><li>MDM2 </li></ul><ul><li>N-myc </li></ul><ul><li>c-erbB2 </li></ul><ul><li>ras </li></ul>
  16. 23. <ul><li>These oncogenes produce specific oncoproteins that either play a role in nuclear function and cellular signal transduction or function as growth factors or growth factor receptors. </li></ul><ul><li>Amplification of these genes has been shown to correlate with adverse outcome in several soft tissue sarcomas. </li></ul>
  17. 24. <ul><li>Tumor Suppressor Genes </li></ul><ul><li>Tumor suppressor genes play a critical role in growth inhibition and can suppress growth in cancer cells. </li></ul><ul><li>Inactivation of tumor suppressor genes (also known as anti-oncogenes ) can occur through hereditary or sporadic mechanisms. </li></ul>
  18. 26. <ul><li>The two genes that are most relevant to soft tissue tumors are: the retinoblastoma ( Rb ) tumor suppressor gene and the p53 tumor suppressor gene. </li></ul><ul><li>Mutations or deletions in Rb can lead to development of retinoblastoma or sarcomas of soft tissue and bone. </li></ul><ul><li>Mutations in the p53 tumor suppressor gene are the most common mutations in human solid tumors. </li></ul>
  19. 28. Initial Assessment
  20. 29. <ul><li>Clinical Presentation </li></ul><ul><li>Soft tissue sarcoma most commonly presents as an asymptomatic mass. </li></ul><ul><li>The size at presentation is usually associated with the location of the tumor. </li></ul><ul><li>Smaller tumors are generally located in the distal extremities. </li></ul>
  21. 30. <ul><li>Soft tissue sarcomas often grow in a centrifugal fashion and compress surrounding normal structures. </li></ul><ul><li>Their impingement on bone or neurovascular bundles produces pain, edema, and swelling. </li></ul><ul><li>Retroperitoneal soft tissue sarcoma almost always presents as a large asymptomatic mass . </li></ul>
  22. 32. <ul><li>The differential diagnosis of a soft tissue mass includes benign lesions including: lipomas, lymphangiomas, leiomyomas, and neuromas. </li></ul><ul><li>Small lesions that have not changed for several years by clinical history may be closely observed. </li></ul><ul><li>All other tumors should be considered for biopsy to establish a definitive diagnosis. </li></ul>
  23. 33. <ul><li>Diagnostic Imaging </li></ul><ul><li>Pretreatment radiologic imaging serves several purposes </li></ul><ul><li>It defines the local extent of a tumor </li></ul><ul><li>Can be used to stage malignant disease </li></ul><ul><li>Assists in percutaneous biopsy procedures </li></ul><ul><li>Aids in the diagnosis of soft tissue tumors </li></ul>
  24. 35. <ul><li>Ultrasonography </li></ul><ul><li>Ultrasonography may have a diagnostic role for patients who cannot undergo magnetic resonance imaging. </li></ul><ul><li>Ultrasonography can also be a useful adjunct to magnetic resonance imaging when findings are indeterminate and for delineating adjacent vascular structures. </li></ul>
  25. 37. <ul><li>Computed Tomography </li></ul><ul><li>Contrast-enhanced CT can assess the extent of soft tissue tumor burden and proximity of the tumor to vital structures. </li></ul><ul><li>Computed tomography is the preferred imaging technique for evaluating retroperitoneal sarcomas. </li></ul><ul><li>Current CT techniques can provide a detailed survey of the abdomen and pelvis and delineate adjacent organs and vascular structures. </li></ul>
  26. 39. <ul><li>Magnetic Resonance Imaging </li></ul><ul><li>MRI accurately delineates muscle groups and distinguishes among bone, vascular structures, and tumor. </li></ul><ul><li>Sagittal and coronal views allow evaluation of anatomic compartments in three dimensions. </li></ul><ul><li>Soft tissue sarcomas of the extremities usually present on MRI as heterogeneous masses. </li></ul>
  27. 41. <ul><li>Biopsy Techniques </li></ul><ul><li>Fine-Needle Aspiration </li></ul><ul><li>Fine-needle aspiration is an acceptable method of diagnosing most soft tissue sarcomas, particularly when the results correlate closely with clinical and imaging findings. </li></ul><ul><li>Fine-needle aspiration biopsy is indicated for primary diagnosis of soft tissue sarcomas only at centers where cytopathologists have experience with these types of tumors. </li></ul><ul><li>Fine-needle aspiration biopsy is also the procedure of choice to confirm or rule out the presence of a metastatic focus or local recurrence. </li></ul><ul><li>If tumor grading is essential for treatment planning, fine-needle aspiration biopsy is not the technique of choice. </li></ul>
  28. 44. <ul><li>Core-Needle Biopsy </li></ul><ul><li>Core-needle biopsy is a safe, accurate, and economical diagnostic procedure for diagnosing sarcomas. </li></ul><ul><li>The tissue sample obtained from a core-needle biopsy is usually sufficient for several diagnostic tests such as electron microscopy, cytogenetic analysis, and flow cytometry. </li></ul><ul><li>The reported complication rate for core-needle biopsy is less than 1%. </li></ul>
  29. 46. <ul><li>Incisional Biopsy </li></ul><ul><li>Open biopsy is a reliable diagnostic method that allows adequate tissue to be sampled for definitive and specific histologic identification of bone or soft tissue sarcomas. </li></ul><ul><li>Incisional biopsy is indicated for deep tumors or for superficial soft tissue tumors larger than 3 cm. </li></ul><ul><li>Incisional biopsies are usually performed as a last resort when fine-needle aspiration or core biopsy specimens are nondiagnostic. </li></ul>
  30. 48. <ul><li>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. </li></ul><ul><li>A poorly-oriented biopsy incision often mandates an excessively large surgical defect for a wide local excision, which in turn can result in a larger postoperative radiotherapy field to encompass all tissues at risk. </li></ul>
  31. 49. Excisional Biopsy Excisional biopsy can be performed for easily accessible (superficial) extremity or truncal lesions smaller than 3 cm. Excisional biopsy should not be done for lesions involving the hands and feet because definitive reexcision may not be possible after the biopsy. Excisional biopsy results have a 30 to 40% rate of recurrence when margins are positive or uncertain. Excisional biopsies rarely provide any benefit over other biopsy techniques and may cause postoperative complications that could ultimately delay definitive therapy.
  32. 51. <ul><li>Pathologic Classification </li></ul><ul><li>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. </li></ul><ul><li>Tumors with limited metastatic potential include desmoids, atypical lipomatous tumors (also called well-differentiated liposarcoma ), dermatofibrosarcoma protuberans, and hemangiopericytomas. </li></ul>
  33. 52. <ul><li>Tumors with an intermediate risk of metastatic spread usually have a large myxoid component and include myxoid liposarcoma, myxoid malignant fibrous histiocytoma, and extraskeletal chondrosarcoma. </li></ul><ul><li>Among the highly aggressive tumors that have substantial metastatic potential are angiosarcomas, clear-cell sarcomas, pleomorphic and dedifferentiated liposarcomas, leiomyosarcomas, rhabdomyosarcomas, and synovial sarcomas. </li></ul>
  34. 53. <ul><li>Staging and Prognostic Factors </li></ul><ul><li>The current version of the American Joint Committee on Cancer staging criteria for soft tissue sarcomas relies on histologic grade, tumor size and depth, and the presence of distant or nodal metastases. </li></ul><ul><li>This system does not apply to visceral sarcomas, Kaposi's sarcomas, dermatofibrosarcomas, or desmoid tumors. </li></ul>
  35. 54. American Joint Committee on Cancer Primary Tumor (T) T1 Tumor 5 cm T1a Superficial tumor T1b Deep tumor T2 Tumor >5 cm T2a Superficial tumor T2b Deep tumor Regional Lymph Nodes (N ) N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distance Metastasis (M) M0 No distant metastasis M1 Distant metastasis Histologic Grade (G) G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Poorly differentiated or undifferentiated
  36. 55. Stage Grouping Stage I T1a, 1b, 2a, 2b N0 M0 G1–2 G1 Stage II T1a, 1b, 2a N0 M0 G3–4 G2–3 Stage III T2b N0 M0 G3–4 G2–3 Stage IV Any T N1 M0 Any G Any G Any T N0 M1 Any G Any G
  37. 56. <ul><li>Histologic Grade </li></ul><ul><li>Histologic grade remains the most important prognostic factor for patients with sarcomas. </li></ul><ul><li>For an accurate determination of tumor grade, an adequate tissue sample must be appropriately fixed, stained, and reviewed by an experienced sarcoma pathologist. </li></ul><ul><li>The features that define grade are cellularity, differentiation, pleomorphism, necrosis, and the number of mitoses. </li></ul>
  38. 57. <ul><li>Tumor Size </li></ul><ul><li>Tumor size has long been recognized to be an important prognostic variable in soft tissue sarcomas. </li></ul><ul><li>Sarcomas have classically been stratified into two groups on the basis of size; T1 lesions are 5 cm or smaller and T2 lesions are larger than 5 cm. </li></ul>
  39. 58. <ul><li>Nodal Metastasis </li></ul><ul><li>Lymph node metastasis of soft tissue sarcomas is rare; less than 5% manifest nodal spread </li></ul><ul><li>A few histologic subtypes, including rhabdomyosarcoma, epithelioid sarcoma, and malignant fibrous histiocytoma, have a higher incidence of nodal involvement. </li></ul><ul><li>Nodal disease is designated as stage IV disease. </li></ul>
  40. 59. <ul><li>Distant Metastasis </li></ul><ul><li>Distant metastases occur most often in the lungs. </li></ul><ul><li>Selected patients with pulmonary metastases may survive for long periods after surgical resection and chemotherapy. </li></ul><ul><li>Other potential sites of metastasis include bone, the brain, and the liver. Visceral and retroperitoneal sarcomas have a higher incidence of liver and peritoneal metastases. </li></ul>
  41. 60. <ul><li>Treatment </li></ul><ul><li>Accurate preoperative histologic diagnosis is critical in choosing a primary treatment strategy for soft tissue sarcomas. </li></ul><ul><li>Presentation with gross disease after incisional biopsy, core-needle biopsy, or fine-needle aspiration biopsy allows the treatment planning team the best opportunity to evaluate the tumor's proximity to vital structures and the likelihood of being able to perform surgical resection with negative histologic margins. </li></ul>
  42. 61. <ul><li>Surgery </li></ul><ul><li>Small (<5 cm) primary tumors with no evidence of distant metastatic disease are managed by local therapy consisting of surgery, alone or in combination with radiation therapy, when wide pathologic margins are limited because of anatomic constraints. </li></ul><ul><li>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 . </li></ul>
  43. 62. <ul><li>Wide Local Excision </li></ul><ul><li>Wide local excision is the primary treatment strategy for extremity sarcomas. </li></ul><ul><li>The goal of local therapy for extremity sarcomas is to resect the tumor with a 2-cm margin of surrounding normal soft tissue. </li></ul><ul><li>The tumors are generally surrounded by a zone of compressed reactive tissue that forms a pseudocapsule, which may mistakenly guide resection (enucleation) by an inexperienced surgeon. </li></ul><ul><li>Extensions of tumor that go beyond the pseudocapsule must be considered in planning surgery and radiotherapy </li></ul>
  44. 63. Amputation Amputation is the treatment of choice for patients with the rare 5% of tumors that cannot be grossly resected with a limb-sparing procedure and preservation of function
  45. 66. <ul><li>Isolated Regional Perfusion </li></ul><ul><li>Isolated regional perfusion is an investigational approach for treating extremity sarcomas. </li></ul><ul><li>It has been attempted mainly as a limb-sparing alternative for patients with locally advanced soft tissue sarcomas or as a palliative treatment to achieve local control for patients with distant metastatic disease. </li></ul><ul><li>Isolated limb perfusion involves isolating the main artery and vein of the perfused limb from the systemic circulation. </li></ul>
  46. 67. <ul><li>Radiation Therapy </li></ul><ul><li>Despite a local recurrence rate of less than 10% after radical surgery, large numbers of patients died of metastatic disease. </li></ul><ul><li>This realization prompted the development of local therapy involving conservative surgical excision combined with postoperative radiation therapy. </li></ul>
  47. 68. <ul><li>The evidence for adjunctive radiation therapy for patients eligible for conservative surgical resection comes from two randomized trials and three large single-institution reports. the standard treatment guidelines were to administer radiotherapy as an adjunct to surgery for all patients with intermediate or highly aggressive tumors of any size. </li></ul><ul><li>The optimal mode (external beam or brachytherapy) and timing (preoperative, intraoperative, or postoperative) have yet to be defined . </li></ul>
  48. 69. <ul><li>Postoperative radiation therapy planning is based on tumor grade, assessment of surgical margins, and institutional preferences. No consensus exists on the optimal sequence of radiation therapy and surgery. </li></ul><ul><li>Careful attention to the performance of radiation therapy rather than the choice of technique (preoperative versus postoperative versus brachytherapy) can substantially minimize long-term complications. </li></ul>
  49. 70. <ul><li>Systemic Therapy </li></ul><ul><li>Systemic therapy generally is limited to patients with metastatic disease, those with small-cell sarcomas of any size, or those with large ( 5 cm) high-grade tumors or intermediate-grade tumors larger than 10 cm. </li></ul><ul><li>Metastasis and death remain a significant problem for patients with high-risk soft tissue sarcomas. </li></ul>
  50. 71. <ul><li>The high risk of death from sarcoma include those presenting with metastatic disease and those presenting with localized sarcomas at nonextremity sites or sarcomas with intermediate- or high-grade histology larger than 5 cm (T2). </li></ul><ul><li>The treatment for patients with high-risk localized or metastatic disease often includes chemotherapy. </li></ul>
  51. 72. <ul><li>Integrating Multimodality Therapy </li></ul><ul><li>The primary objective of multimodality treatment is cure; when this endpoint is not possible, the goal is palliation of symptoms. </li></ul><ul><li>Patients with a deep soft tissue mass should be referred, even before a biopsy is performed, to a tertiary treatment center that offers care by a team of specialists. </li></ul><ul><li>Such multidisciplinary teams typically include oncologists from several disciplines (medicine, pediatrics [if applicable], surgery, and radiation therapy), as well as a pathologist, radiologist, and ancillary staff. </li></ul>
  52. 74. <ul><li>Adjuvant Chemotherapy </li></ul><ul><li>The use of adjuvant chemotherapy for soft tissue sarcomas remains controversial. </li></ul><ul><li>The average 5-year disease-free survival rate for patients initially presenting with localized disease is only about 50%. </li></ul><ul><li>More than a dozen individual randomized trials of adjuvant chemotherapy have failed to demonstrate improvement in disease-free patients and overall survival in patients with soft tissue sarcomas. </li></ul>
  53. 76. <ul><li>Neoadjuvant (Preoperative) Chemotherapy </li></ul><ul><li>The rationale for using neoadjuvant and preoperative chemotherapy for soft tissue sarcomas is the belief that only 30 to 50% of patients will respond to standard (postoperative) chemotherapy. </li></ul><ul><li>Neoadjuvant chemotherapy enables oncologists to identify patients whose disease responds to chemotherapy by assessing that response while the primary tumor is in situ. </li></ul>
  54. 77. Special Situations
  55. 78. <ul><li>Retroperitoneal Sarcomas </li></ul><ul><li>Fifteen percent of adult soft tissue sarcomas occur in the retroperitoneum. Most retroperitoneal tumors are malignant, and about one-third are soft tissue sarcomas. </li></ul><ul><li>The most common sarcomas occurring in the retroperitoneum are liposarcomas, malignant fibrous histiocytomas, and leiomyosarcomas. </li></ul>
  56. 79. <ul><li>Retroperitoneal sarcomas generally present as large masses; nearly 50% are larger than 20 cm at the time of diagnosis. </li></ul><ul><li>The overall prognosis for patients with retroperitoneal tumors is worse than that for patients with extremity sarcomas. </li></ul><ul><li>Chemotherapy has not been shown to be effective against retroperitoneal sarcomas </li></ul>
  57. 81. <ul><li>Gastrointestinal Sarcomas </li></ul><ul><li>Gastrointestinal sarcomas, which account for only 0.1 to 3% of all gastrointestinal cancers, have presented a diagnostic and therapeutic dilemma for decades. </li></ul><ul><li>The overall prognosis for patients with gastrointestinal sarcomas is poor. For sarcomas at other sites, high histologic grade and large tumor size (>5 cm) have been shown to adversely affect prognosist. </li></ul>
  58. 82. <ul><li>Regional recurrence in the peritoneum (sarcomatosis) is a common pattern of failure after surgical resection. </li></ul><ul><li>The median survival time for patients after such recurrences is reported to range from 18 months to 2 years. </li></ul><ul><li>Endoscopy (esophagoduodenoscopy or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal trac </li></ul>
  59. 83. <ul><li>Gastrointestinal Stromal Tumors </li></ul><ul><li>Gastrointestinal stromal tumors (GISTs), which constitute the majority of gastrointestinal sarcomas, have distinctive immunohistochemical and genetic features. </li></ul><ul><li>They are thought to arise from a pacemaker cell within the gastrointestinal tract known as the interstitial cell of Cajal. </li></ul>
  60. 84. <ul><li>The interstitial cells of Cajal and GIST cells express the hematopoietic progenitor cell marker and the growth factor receptor c-Kit . </li></ul><ul><li>c-Kit is a transmembrane glycoprotein receptor with an internal tyrosine kinase component which when activated triggers a cascade of intracellular signals regulating cell growth and survival. </li></ul><ul><li>Surgery remains the primary treatment modality for both localized and locally advanced GISTs. </li></ul>
  61. 85. <ul><li>Pediatric Sarcomas </li></ul><ul><li>Soft tissue sarcomas account for 7 to 8% of all pediatric cancers, totaling approximately 600 new cases per year. </li></ul><ul><li>Associated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years, and they can occur at any site that has striated muscle. </li></ul>
  62. 86. <ul><li>These tumors generally present as a painless enlarging mass; about 30% arise in the head and neck region, 25% in the genitourinary system, and 20% in the extremities. </li></ul><ul><li>About 15 to 20% of cases have metastasis at presentation, most commonly (40 to 50%) involving the lungs. </li></ul>
  63. 87. Surgical-Pathologic Grouping of Soft Tissue Sarcoma Clinical Group Definition I a. Localized, completely resected, confined to site of origin b. Localized, completely resected, beyond site of origin II a. Localized, grossly resected microscopic residual tumor b. Regional disease, involved lymph nodes, completely resected c. Regional disease, involved lymph nodes grossly resected with microscopic residual tumor III a. Local or regional grossly visible disease after biopsy only b. Grossly visible disease after <50% resection of primary tumor IV Distant metastases at diagnosis
  64. 88. <ul><li>Recurrent Sarcomas </li></ul><ul><li>Up to 20% of patients with extremity sarcoma develop recurrent disease. The adequacy of surgical resection of sarcomas arising from any anatomic site is clearly related to local recurrence rates. </li></ul><ul><li>Patients with microscopically positive surgical margins are at increased risk of local recurrence. </li></ul><ul><li>The effect of local treatment failure on survival and distant disease-free survival is controversial. </li></ul><ul><li>Many believe that recurrence is a harbinger of distant metastatic disease. </li></ul>
  65. 89. <ul><li>Palliative Strategies </li></ul><ul><li>Most patients with soft tissue sarcomas present without evidence of distant metastases. </li></ul><ul><li>The known risk factors for distant metastasis include tumor grade, histiotype, primary site, and size. </li></ul><ul><li>Metastases are present at diagnosis in 40 to 50% of patients with intermediate- or high-grade extremity sarcomas, as compared with only 5% in patients with low-grade sarcomas. </li></ul><ul><li>Most metastases to distant sites occur within 2 to 3 years of initial diagnosis. </li></ul><ul><li>Recurrence after surgery for abdominal soft tissue sarcomas is common. </li></ul>
  66. 90. <ul><li>Surgical Excision of Metastatic Sarcoma </li></ul><ul><li>The most common initial site of metastasis of soft tissue sarcomas is the lung. </li></ul><ul><li>Selected patients with a limited number of pulmonary nodules (fewer than four), long disease-free intervals, and no endobronchial invasion may become long-term survivors after pulmonary resection; to 40% of patients with complete resection of metastatic disease confined to the lung are long-term survivors. </li></ul><ul><li>In a retrospective multi-institutional study of 255 patients, the 5-year overall survival rate after metastasectomy was reported to be 38%. </li></ul><ul><li>Favorable prognostic factors in that study included microscopically free margins, age younger than 40 years, and grade I or II tumors. </li></ul>
  67. 91. <ul><li>Chemotherapy for Metastatic Sarcoma </li></ul><ul><li>The only available treatment for most patients with metastatic disease is chemotherapy. </li></ul><ul><li>Response rates for patients with stage IV soft tissue sarcoma have been low. </li></ul><ul><li>Several prognostic factors have been defined for patients undergoing chemotherapy, including performance status, previous response to chemotherapy, younger age, absence of hepatic metastases, low-grade tumors, and long disease-free interval. </li></ul>
  68. 92. Research Perspectives
  69. 93. <ul><li>Experimental Therapeutics </li></ul><ul><li>In the emerging modern era of cancer treatment, it will become possible to design cancer therapies specifically targeted to the particular molecular mechanisms involved in a tumor's growth. </li></ul><ul><li>As molecular techniques become more advanced, many potential pathways for therapeutic development are being elucidated. </li></ul><ul><li>For example, fusion genes, which have been of interest in the molecular diagnosis and characterization of specific subtypes of soft tissue sarcomas, represent a potential target for treatment with antisense oligonucleotides. </li></ul><ul><li>In vitro studies have demonstrated that transfection with antisense expression plasmids can result in suppression of tumor cell growth. </li></ul>
  70. 94. <ul><li>Chemotherapeutic Agents </li></ul><ul><li>Tyrosine kinases are enzymes that bind adenosine triphosphate (ATP) and transfer phosphates from ATP to the tyrosine residues on substrate proteins. </li></ul><ul><li>These enzymes have long been considered attractive targets for selective pharmacologic inhibition because many human cancers display deregulated kinase pathways. </li></ul>
  71. 95. <ul><li>Clinical Trials </li></ul><ul><li>The rarity of soft tissue sarcomas creates a challenge for studying the effects of treatment. </li></ul><ul><li>Collaborative efforts are required to accrue adequate numbers of patients for such studies. </li></ul>
  72. 96. <ul><li>Trials for Extremity and Truncal Soft Tissue Sarcoma </li></ul><ul><li>Radiation Therapy Oncology Group S-0120 Trial </li></ul><ul><li>The Radiation Therapy Oncology Group S-0120 Trial is an ongoing phase I/II trial of preoperative radiotherapy given with or without an antiangiogenesis compound (Sugen-5416; SU5416) in the management of low- and intermediate-grade soft tissue sarcoma of the extremities and trunk. </li></ul><ul><li>The trial is designed to evaluate the possible synergistic mechanisms between the two types of therapy. </li></ul><ul><li>The objectives of the study are to define the maximum tolerated dose of SU5416 that can be given with preoperative radiation, to assess whether SU5416 has quantitative antiangiogenic effects in vivo, and to assess clinical endpoints including disease-free survival, local recurrence, distant metastases, and overall survival rates in patients treated with radiation or with radiation combined with SU5416. </li></ul>
  73. 97. <ul><li>Trials for Retroperitoneal Soft Tissue Sarcoma </li></ul><ul><li>Radiation Therapy Oncology Group S-0124 Trial </li></ul><ul><li>The Radiation Therapy Oncology Group S-0124 Trial is an ongoing multicenter phase II trial of an innovative preoperative chemotherapy and radiation therapy approach to soft tissue sarcomas of the retroperitoneum. </li></ul><ul><li>Patients with intermediate- or high-grade retroperitoneal sarcomas are given preoperative systemic therapy with doxorubicin and ifosfamide (up to four cycles), followed by preoperative external beam radiotherapy (45 to 50 Gy), and then surgical resection with an intraoperative or postoperative radiation boost. </li></ul><ul><li>The objective of the trial is to assess the feasibility, toxicity, and complications of this multimodality treatment regimen. </li></ul>
  74. 98. <ul><li>Adjuvant Therapy Trials for Gastrointestinal Stromal Tumors </li></ul><ul><li>Given the promising results of imatinib therapy for metastatic or locally advanced GISTs, the logical next step is to study the efficacy of imatinib as adjuvant and neoadjuvant therapy to determine whether it can lower recurrence rates and prolong disease-specific survival after complete resection. </li></ul><ul><li>The sections that follow discuss ongoing trials of adjuvant and neoadjuvant imatinib for patients with resectable GISTs. </li></ul>
  75. 99. <ul><li>Radiation Therapy Oncology Group S-01320 Trial </li></ul><ul><li>The Radiation Therapy Oncology Group S-01320 Trial is an ongoing phase II trial of neoadjuvant or adjuvant imatinib for patients with potentially resectable primary or recurrent GISTs. Patients with biopsy-proven, c-Kit–expressing GISTs are considered eligible if they have a potentially resectable primary tumor that is 5 cm or larger or a potentially resectable recurrent tumor that is 2 cm or larger. </li></ul><ul><li>The accrual goal is 63 patients over approximately 2 years to ensure 50 evaluable patients. </li></ul>
  76. 100. <ul><li>American College of Surgeons Oncology Group Z9000 Trial </li></ul><ul><li>The American College of Surgeons Oncology Group is sponsoring the Z9000 trial, a phase II study of adjuvant imatinib given after complete resection of high-risk primary GISTs. </li></ul><ul><li>High-risk disease is defined as tumor size of at least 10 cm in maximum dimension or the presence of tumor rupture before or during surgery; intraperitoneal hemorrhage; or multifocal intraperitoneal tumors smaller than 5 cm. </li></ul>
  77. 101. <ul><li>Phase III Trials </li></ul><ul><li>The American College of Surgeons Oncology Group also is sponsoring the Z9001 trial, a phase III randomized double-blind study of adjuvant imatinib versus placebo after complete resection of primary GISTs. Eligible patients will include those with a primary c-Kit–expressing GIST 3 cm or larger, tumor rupture before or during surgery, intraperitoneal hemorrhage, or 1 to 4 multifocal tumors. </li></ul>
  78. 102. <ul><li>Conclusion </li></ul><ul><li>Soft tissue sarcomas are a family of rare tumors, constituting approximately 1% of adult malignancies. </li></ul><ul><li>The etiology in the vast majority of patients is sporadic. </li></ul><ul><li>The management of such diverse tumors is complex. </li></ul><ul><li>Diagnosis by light microscopy is inexact. </li></ul><ul><li>Molecular diagnosis, although still in its infancy, holds great promise for the future. </li></ul><ul><li>In spite of these confounding issues, the natural history of soft tissue sarcomas is well established. </li></ul>