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

• 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)

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

• N1: regional LN (RARE)• M1: distant mets

• Low grade: G1• High grade: G2,3• Grade cannot be assessed: GX

T1 T2 N1 M1

G1, GX IA IB III IV

G2 IIA IIB III IV

G3 IIA III III IV

• 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

• Resect the tumor with appropriate negative margins (>1 cm)• Close margins (<1 cm) may be necessary to preserve uninvolved

critical neurovascular structures, bones, joints.

compartment resection is not routinely necessary

• Ideally, the biopsy site should be excised en bloc with the definitive surgical specimen

• Metalic clips can indicate suspiciuosmargins 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±CTàSurgeryà±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/targeted Therapy• 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 Observe

PreopRT

PreopCT

PreopCRT

Surg Postop RT

Postop CT

Postop CRT

I T1 (small, <5) 1 √ may

T2 (large, >5) 1 √ √

II T1 (small, <5) 2,3 May May √ √ May

T2 (large, >5) 3 May May √ √ √ May

III T2 (large, >5) 3 May May √ √ √ May

N1 May May √ +Radical LND

√ May

IV Limited M1

Dissemin’dM1

May ifSym-

May MAY May

Post op RT if : SM <1cm, non-intact fascial plane

Treatment of STS of retroperitoneum or intra-abdominal

Observe

PreopRT

PreopCT

Surg Postop RT

Postop CT

Resectable May May √ ± IORT May in R1

or Boost

May

Unresectable √ √ √ if becomes resectableOtherwise as M!

IV Limited M1

Dissemin’dM1

May ifSym-

May MAY May

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• Observation:

• small size, asymptomatic, favorable sites

• Surgery:• Mainstay• Large size, symptomatic,

unfavorable sites• Preop RT or systemic therapy

may be given• Postop RT if large tumors or

SM+ (R1)

Irresectable Tumors• Observation• Definitive RT (54-58 Gy)

• No prior RT only • In extremity, head and neck or

superficial trunk• Not in retroperitoneal/intra-

abdominal• very slow response (~2ys)

• Systemic therapies:• NSAIDS• Hormonal therapies• Biologic therapies

• 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 p

Number 16 27 2:1 randomization

Local Recs % 0 4 0.06

DFS% 78 71 0.75

OS% 88% 83% 0.99

Chemotherapy No chemotherapy p

3-y DFS% 92 60 0.0008

3y- OS% 95 75 0.04

Highest recurrence was for SM+65 patients received postop: Adriamycin, cyclophosphamide, MTX