Soft tissue sarcoma (sts)


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Comprehensive overview of soft tissue sarcoma: staging, diagnosis, risk stratification and treatment

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Soft tissue sarcoma (sts)

  1. 1. Ahmed ZeeneldinAssociate professor of Medical Oncology
  2. 2. • US: • In 2012: 11,280 new cases and 3,900 mortalities • adults: 1%, pediatrics: 15%• Egypt: • GPBCR: adults: 2.5%, pediatrics: 10% • NCI: adults: 2.8%, pediatrics: 10%• RT is a risk factor
  3. 3. • Most common primary sites • Extremities (60%), • Trunk (19%), • Retroperitoneum (15%) • Head and neck (9%)• Most common metastatic sites • Generally : lungs • With abdominal tumors: liver and peritoneum
  4. 4. • Mesenchymal cell origin • Fibrous: MFH, Fibrosarcoma, Myxofibrosarcoma, fibromyxoid sarcoma • Fat: liposarcoma • Muscle: SM: Leiomyosarcoma, Sk m: Rhabdomyosarcoma, • nerve and nerve sheath (Malignant peripheral nerve sheath tumor), • blood vessels (hemangioendothelioma, Angiosarcoma) • Chondro-osseous Tumors (Extraskeletal chondrosarcoma, Osteosarcoma) • Uncertain origin: • Synovial, Epithelioid, Alveolar, Clear cell , Desmoplastic small round cell • Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing • Extraskeletal myxoid chondrosarcoma • Extrarenal rhabdoid tumor • Undifferentiated sarcoma; • Sarcoma, not otherwise specified (NOS)
  5. 5. Most common subtypes of STS• In children: • Rhabdomyosarcoma• in adults • Pleomorphic sarcoma (MFH), • GIST, • liposarcoma, • leiomyosarcoma, • synovial sarcoma, • malignant peripheral nerve sheath tumors
  6. 6. Molecular Diagnosis of STS• (i) sarcomas with specific genetic alterations and usually simple karyotypes (eg, chromosomal translocations or point mutations); and• (ii) sarcomas with non-specific genetic alterations and complex unbalanced karyotypes.• Methods: • Conventional cytogenetic analysis, • Fluorescence in-situ hybridization (FISH) and • Polymerase chain reaction (PCR)
  7. 7. • EWSR1-ATF1 in clear cell sarcoma,• TLS-CHOP (also known as FUS-DDIT3) in myxoid or round cell liposarcoma,• SS18-SSX (SS18-SSX1 or SS18-SSX2) in synovial sarcoma, and• PAX-FOXO1 (PAX3-FOXO1 or PAX7-FOXO1) in alveolar rhabdomyosarcoma].
  8. 8. Evaluation and Workup• H&P: for DD• Lab: limited role• Bx: • core or open biopsies by experienced members. • FNA is generally inadequate• Radiology: • Local: • MRI: most important particularly in extremity STS • CT: most important particularly in retroperitoneal STS • Plain XR: optional • Possible metastatic sites: • CT Chest: in all cases • CT Abdomen and pelvis: myxoid round cell liposarcoma, angiosarcoma, leiomyosarcoma or epithelioid sarcoma • MRI spine: myxoid round cell liposarcomas • CT/MRI brain Alveolar soft part sarcoma (ASPS) • Local and Metastatic sites: • PET or PET/CT
  9. 9. PET or PET/CT in STS• Values: • Prognosis and grading: high SUVmax correlates with higher tumor grade and worse survival and disease progression • response to chemotherapy for firm, and deep >3 cm, high- grade extremity STS: decrease SUVmax (35-40% drop particularly after 1st cycle) correlates with response, RFS, DFS
  10. 10. • T1: <= 5 cm • A: superficial ( to and not invading superficial fascia) • Deep ( to or invading superficial fascia)• T2: > 5 cm • A: superficial ( to and not invading superficial fascia) • Deep ( to or invading superficial fascia)• No T3 or T4• NB: ovary has no T4 T1 T2 N1 M1• N1: regional LN (RARE) G1, GX IA IB III IV• M1: distant mets G2 IIA IIB III IV G3 IIA III III IV• Low grade: G1• High grade: G2,3• Grade cannot be assessed: GX
  11. 11. • Surgery: • Mainstay • Problems: recurrence, incomplete resection for difficult sites• RT: • May be used pre, intra, or postoperative • May be used as definitive Tx • External beam, brachytherapy or radiosurgery• Systemic therapy: • May be used ad neoadjuvant or adjuvant • May be combined with RT • May be used alone in disseminated disease • Includes: chemotherapy, targetd therapies
  12. 12. • Standard primary treatment for most sarcomas• Extremity STS • Limb sparing surgery (LSS) is recommended to preserve function • Amputation for non-functional limb or infeasible LSS or patient preference• If adequate initial surgery cannot be done: • Preoperative chemo or radio or chemoradio• To decrease local recurrence • Chemo or radio can be used (either pre or post)• Negative SM is always desirable and may need re-resection• Adjuvant RT in: • Close SM (<1 cm; R0) • Microscopic + SM (R1) on bone or major blood vessels
  13. 13. compartment resection isnot routinely necessary • Resect the tumor with appropriate negative margins (>1 cm) • Close margins (<1 cm) may be necessary to preserve uninvolved critical neurovascular structures, bones, joints.
  14. 14. • Ideally, the biopsy site should be excised en bloc with the definitive surgical specimen• Metalic clips can indicate suspiciuos margins to help RT
  15. 15. Surgical margin (SM) and residual (R)• Negative SM = R0 • Adequate: >1cm • Close: < 1cm • Close margins may be necessary to preserve uninvolved critical neurovascular structures, bones, joints • Adj RT is given in close margins• Positive SM = R1 or R2 • R1 resection - Microscopic residual disease • R2 resection - Gross residual disease • surgical re-resection to obtain negative margins should strongly be considered if it will not have a significant impact upon functionality • Adj RT is given in microscopically positive margin (R1) on bone, major blood vessels or a nerve• Uncertain margin: • Consult radiotherapist
  16. 16. • Because the risk of failure in the surgical bed can be high, Many clinicians augment surgery with RT and chemotherapy, either preoperatively or postoperatively,
  17. 17. • Source: • EBRT: conventional or IMRT • Brachytherapy• Timing • Preoperative: 50 Gy • Easier surgery • Poor wound healing • Boost if close or positive SM • Postoperative • Improve local control in high-grade extremity STS with positive SM or higher stage (III), old age • May be partly given immediately (Intraoperative) and completed later
  18. 18. Chemotherapy or chemoradiation• Preop chemoradiation: • Value: increase local control, DFS and OS • CTàRT±CTàSurgery à±CT • Regimens: • Doxorubicin (30 mg/m2/d x 3) concurrent with RT (300 cGy x 10) • IMAP x 2àRT±MAP on rest days (0, 21, 42) àIORT • MAID+RT (44 GY split)àsurgery àMAID x 3 if SM+• Preop chemotherapy: • Value: inconsistent • CTà surgery à±CT • Regimens: • MAID
  19. 19. Chemotherapy• Postop (adjuvant) chemotherapy: • Value: improve RFS and OS of extremity STS • EORTC trials lack OS benefit?? • surgery àCT • Regimens: • Doxorubicin based (doxo-ifos) • Epirubicin based (epi-ifo)• Definitive chemotherapy: • In advanced, unresectable or metastatic disease • Single agents: dacarbazine, doxorubicin, epirubicin or ifosfamide, gemcitabine, docetaxel, vinorelbine, pegylated liposomal doxorubicin and temozolomide • Anthracycline-based combination regimens: doxorubicin or epirubicin with ifosfamide and/or dacarbazine
  20. 20. Definitive Chemotherapy/targetedTherapy• In: • advanced, irrresectable or metastatic disease• Approaches: • Single agents CT: • dacarbazine, doxorubicin, epirubicin or ifosfamide, • gemcitabine, docetaxel, vinorelbine, pegylated liposomal doxorubicin and temozolomide • Trabectedin: good RR • Combinations CT: • Anthracycline-based combination regimens: first-line • doxorubicin or epirubicin with ifosfamide and/or dacarbazine • Non-antracycline combination regimens: after failure of anthracycline • gemcitabine and docetaxel particulalry in LMS • Targeted Tx: • Pazopanib: after failure of doxo-based regimens, Prolongs PFS, No in liposarcoma • Ohers: sunitinib, imatinib, crizotinib, sirolimus, avastin
  21. 21. Treatment of STS of extremities and trunk G Obs Preop Preo Preop Surg Posto Posto Posto erve RT pCT CRT p RT p CT p CRTI T1 (small, <5) 1 √ may T2 (large, >5) 1 √ √II T1 (small, <5) 2,3 May May √ √ May T2 (large, >5) 3 May May √ √ √ MayIII T2 (large, >5) 3 May May √ √ √ May N1 May May √+ √ May Radical LNDIV Limited M1 Dissemin’d May if May MAY May M1 Sym- Post op RT if : SM <1cm, non-intact fascial plane
  22. 22. Treatment of STS of retroperitoneum or intra-abdominal Obs Preop Preo Surg Posto Posto erve RT pCT p RT p CT Resectable May May √ ± IORT May May in R1 or Boost Unresectable √ √ √ if becomes resectable Otherwise as M!IV Limited M1 Dissemin’d May if May MAY May M1 Sym- Post op RT if : SM <1cm, non-intact fascial plane
  23. 23. Desmoid Tumors(Aggressive Fibromatoses)• Mesenchymal neoplasms• Well-circumscribed, differentiated fibrous tissue with no histopathological features of malignancy.• However, they are often categorized as low-grade sarcomas • locally destructive and infiltrative but rarely metastasize • Need extensive surgery • Tend to recur locally after excision with long natural history • 10% of patients died of progressive disease.
  24. 24. • Abdominal wall of young pregnant females• Intra-abdominal mesenteric masses, and large extremity masses in older men and women.
  25. 25. • Component of the familial adenomatous polyposis (FAP)• may also arise through elective surgical intervention (eg, colectomy) in susceptible patients.• 85% have mutations in exon 3 of CTNNB1 gene encoding for β catenin AND this was associated with more recurrences
  26. 26. Evaluation and Workup• H& P• Exclude Gardner’s syndrome• Imaging: • Local: CT or MRI • Chest• Biopsy
  27. 27. Resectable Tumors Irresectable Tumors• Observation: • Observation • small size, asymptomatic, • Definitive RT (54-58 Gy) favorable sites • No prior RT only • In extremity, head and neck or• Surgery: superficial trunk • Mainstay • Not in retroperitoneal/intra- abdominal • Large size, symptomatic, • very slow response (~2ys) unfavorable sites • Systemic therapies: • Preop RT or systemic therapy • NSAIDS may be given • Hormonal therapies • Postop RT if large tumors or • Biologic therapies SM+ (R1) • Surgery • Radical surgery if the above fails
  28. 28. Systemic treatment of desmoids• Indications: • advanced or unresectable desmoids• Agents • NSAIDS: sulindac or celecoxib • Hormonal: tamoxifen, toremifene • Biological agents: low-dose interferon • Chemotherapy: methotrexate and vinblastine, doxorubicin-based regimens • tyrosine kinase inhibitors: imatinib and sorafenib
  29. 29. Rhabdomyosarcoma (RMS)• histologic subtypes: • Embryonal: children • Alveolar: adolescents • Pleomorphic: adults and aggressive • extremities (26%) • trunk (23%) • genitourinary tract (17%) and • head and neck (9%)
  30. 30. • Multidisciplinary• Surgery, RT, chemotherapy• Emberyonal and alvelar: May use pediatric protocols
  31. 31. • VD±C: vincristine and dactinomycin (with or without cyclophosphamide),• VAC: vincristine, doxorubicin and cyclophosphamide• VAC alternating with ifosfamide and etoposide• HD methotrexate with CNS and leptomeningeal invovlvment when RT is not feasible
  32. 32. Amputation LSS+RT pNumber 16 27 2:1 randomizationLocal Recs % 0 4 0.06DFS% 78 71 0.75OS% 88% 83% 0.99Highest recurrence was for SM+65 patients received postop: Adriamycin, cyclophosphamide, MTX Chemotherapy No chemotherapy p 3-y DFS% 92 60 0.0008 3y- OS% 95 75 0.04