Ahmed ZeeneldinAssociate professor of Medical Oncology
• 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
• 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
Most common subtypes of STS• In children: • Rhabdomyosarcoma• in adults • Pleomorphic sarcoma (MFH), • GIST, • liposarcoma, • leiomyosarcoma, • synovial sarcoma, • malignant peripheral nerve sheath tumors
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)
• 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].
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
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
• 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
• 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
• 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
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.
• Ideally, the biopsy site should be excised en bloc with the definitive surgical specimen• Metalic clips can indicate suspiciuos margins to help RT
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
• Because the risk of failure in the surgical bed can be high, Many clinicians augment surgery with RT and chemotherapy, either preoperatively or postoperatively,
• 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
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
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
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
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
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
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.
• Abdominal wall of young pregnant females• Intra-abdominal mesenteric masses, and large extremity masses in older men and women.
• 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
Evaluation and Workup• H& P• Exclude Gardner’s syndrome• Imaging: • Local: CT or MRI • Chest• Biopsy
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
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
Rhabdomyosarcoma (RMS)• histologic subtypes: • Embryonal: children • Alveolar: adolescents • Pleomorphic: adults and aggressive • extremities (26%) • trunk (23%) • genitourinary tract (17%) and • head and neck (9%)
• Multidisciplinary• Surgery, RT, chemotherapy• Emberyonal and alvelar: May use pediatric protocols
• 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
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