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Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Educational Concepts Group, LLC. Additional terms and conditions may apply. FACULTY George D. Demetri, MD Dana-Farber Cancer Institute Kristen N. Ganjoo, MD Stanford University Medical Center Alexander Lazar, MD, PhD MD Anderson Cancer Center Richard F. Riedel, MD Duke Cancer Institute WELCOME AND INTRODUCTION George D. Demetri, MD – CHAIR Dana-Farber Cancer Institute HISTOPATHOLOGY, DIAGNOSTIC EVALUATION, AND STAGING OF NONGIST SOFT TISSUE SARCOMAS Alexander Lazar, MD, PhD MD Anderson Cancer Center Soft Tissue Sarcomas • Rare tumors • < 1% of adult solid tumors • US: 12,000 new cases • 4,700 deaths • Incidence appears to be increasing … NCI (2014) http://www.cancer.gov/researchandfunding/progress/snapshots/sarcoma. Siegel RL, et al. CA Cancer J Clin. 2015;65(1):5-29. Fletcher CDM. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon, France: IARC Press; 2013. NCI (2014) http://www.cancer.gov/researchandfunding/progress/snapshots/sarcoma. Sarcoma Classification • Can be challenging • Heterogeneous group of tumors with > 50 histological subtypes, each with varying clinical phenotypes and behavior • Some tumors are unclassifiable • Many benign entities (100:1), some of which can be confused for sarcomas Sarcoma Classification: Morphology • Round cell tumor, epithelioid, spindle cell sarcoma • Useful in unclassifiable tumors • Does not always provide information on behavior or nature of tumor • Important to determine malignant potential if possible Sarcoma Classification: Histogenesis/Line of Differentiation UPS/MFH Osteosarcoma Chondrosarcoma Leiomyosarcoma Rhabdomyosarcoma Angiosarcoma Liposarcoma Synovial Sarcoma - ?? MPNST ASPS - ?? Ewing Sarcoma/PNET - ?? UPS, undifferentiated pleomorphic sarcoma; MPNST, malignant peripheral nerve sheath tumors; ASPS, alveolar soft part sarcoma; PNET, primitive neurectodermal tumors. Courtesy of Dr Brian Rubin, Cleveland Clinic. 2013 WHO Classification • Classifies tumors based on: – Line of differentiation – Biological potential – (Molecular features) Fletcher CDM. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon, France: IARC Press; 2013. Question 1 Despite pathologists giving soft tissue sarcomas more than 50 different names, all sarcomas basically behave alike. 1. True 2. False 3. I don’t know Sarcoma Classification: Line of Differentiation • Morphologically or by immunohistochemical studies • Beware of mimics • Some tumors lack a normal counterpart (ie, synovial sarcoma) • Not all tumors with similar differentiation will behave the same ALT PLPS A-RMS Myogenin ALT, atypical lipomatous tumor; PLPS, pleomorphic liposarcoma; A-RMs, rhabdomyosarcoma. Soft Tissue Classification: Biological Potential Benign: Usually do not recur; recurrences usually nondestructive, almost never metastasizes Lipoma Intermediate Intermediate (locally (rarely aggressive): metastasizing): Often recur, Locally aggressive infiltrative and but can give rise to destructive metastasis (< 2%) Desmoid Angiomatoid FH Malignant: Recurs, destructive, high risk of metastasis Synovial Sarcoma • - • - Adipocytic tumors Intermediate Atypical lipomatous tumors/well differentiated liposarcomas Malignant Dedifferentied liposarcoma Myxoid/round cell liposarcoma Pleomorphic liposarcoma Liposarcoma, NOS Fibroblastic/Myofibroblastic Tumors Intermediate (locally aggressive) Superficial and desmoid fibromatoses Lipofibromatosis Intermediate (rarely metastasizing) Extrapleural solitary fibrous tumor/hemangiopericytoma Inflammatory myofibroblastic tumor Low grade myofibroblastic sarcoma Myxoinflammatory fibroblastic sarcoma Malignant Infantile fibrosarcoma Adult fibrosarcoma Myxofibrosarcoma Low-grade fibromyxoid sarcoma Sclerosing epithelioid fibrosarcoma • - Skeletal Muscle Tumors Malignant Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma • - Vascular Tumors Intermediate (locally aggressive) Kaposiform Hemangioendothelioma Intermediate (rarely metastasizing) Papillary intralymphatic angioendothelioma Retiform, and composite hemangioendothelioma Malignant Epithelioid hemangioendothelioma Angiosarcoma • • Chondro-Osseous Tumors Malignant Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Tumors of Peripheral Nerves - Malignant Malignant peripheral nerve sheath tumor Epithelioid malignant peripheral nerve sheath tumor • • So-Called Fibrohistiocytic Tumors Intermediate (rarely metastasizing) Giant cell tumor of tendon sheath and diffuse variant Plexiform fibrohistiocytic tumor Malignant Malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma • Smooth Muscle Tumors Malignant Leiomyosarcoma Rubin, et al. (2014) College of American Pathology guidelines. Fletcher CDM. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon, France: IARC Press; 2013. Tumors of Uncertain Differentiation Intermediate (rarely metastasizing) Angiomatoid fibrous histiocytoma Ossifying fibromyxoid tumor Soft Tissue Myoepithelioma/carcinoma Malignant Ewing Sarcoma Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Desmoplastic small round cell tumor Extrarenal rhabdoid tumor Intimal sarcoma UNCLASSIFIED – Malignant Potential uncertain 2002 2013 Benign Lipoma Lipomatosis Lipomatosis of nerve Lipoblastoma/lipoblastomatosis Angiolipoma Myolipoma Chondroid lipoma Extra-renal angiomyolipoma Extra-adrenal myelolipoma Spindle cell/pleomorphic lipoma Hibernoma Benign Lipoma Lipomatosis Lipomatosis of nerve Lipoblastoma/lipoblastomatosis Angiolipoma Myolipoma of soft tissue Chondroid lipoma Extra-renal angiomyolipoma Extra-adrenal myelolipoma Spindle cell/pleomorphic lipoma Hibernoma Intermediate (locally aggressive) Atypical lipomatous tumor / well differentiated liposarcoma Intermediate (locally aggressive) Atypical lipomatous tumor/well differentiated liposarcoma Malignant Dedifferentiated liposarcoma Myxoid liposarcoma Round cell liposarcoma Pleomorphic liposarcoma Mixed-type liposarcoma Liposarcoma, not otherwise specified Malignant Dedifferentiated liposarcoma Myxoid liposarcoma Pleomorphic liposarcoma Liposarcoma, not otherwise specified Adapted from: Fletcher CDM. WHO classification of tumours of soft tissue and bone. 3rd & 4th eds. Lyon, France: IARC Press; 2002 & 2013. Adipocytic Tumors Liposarcoma Classification • Well differentiated liposarcoma • (Dedifferentiated) • Genetic amplification: 12q13~15 • Myxoid liposarcoma • (Round cell) • Translocation: t(12;16)(q13p11) • DDIT3 & FUS (EWSR1) • Pleomorphic liposarcoma • Complex karyotype • TP53 mutations Tumors of Uncertain Differentiation 2002 Benign Intramuscular myxoma (including cellular variant) Juxta-articular myxoma Deep (“aggressive”) angiomyxoma Pleomorphic hyalinizing angiectatic tumour Ectopic hamartomatous thymoma Intermediate (rarely metastasizing) Angiomatoid fibrous histiocytoma Ossifying fibromyxoid tumour (incl. atypical, malignant) Mixed tumour/myoepithelioma/ Parachordoma Malignant Synovial sarcoma Epithelioid sarcoma Alveolar soft-part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Extraskeletal Ewing sarcoma Desmoplastic small round cell tumour Extra-renal rhabdoid tumour Malignant mesenchymoma Neoplasms with perivascular epithelioid cell differentiation (PEComa) Clear cell myomelanocytic tumor Intimal sarcoma 2013 Benign Acral fibromyxoma Intramuscular myxoma (including cellular variant) Juxta-articular myxoma Deep (“aggressive”) angiomyxoma Pleomorphic hyalinizing angiectatic tumour Ectopic hamartomatous thymoma Intermediate (locally aggressive) Haemosiderotic fibrolipomatous tumor Malignant Synovial sarcoma (NOS, spindle cell, biphasic) Epithelioid sarcoma Alveolar soft-part sarcoma Clear cell sarcoma of soft tissue Extraskeletal myxoid chondrosarcoma Extraskeletal Ewing sarcoma Desmoplastic small round cell tumor Extra-renal rhabdoid tumour Neoplasms with perivascular epithelioid cell differentiation (PEComa) PEComa NOS, benign PEComa NOS, malignant Intimal sarcoma Intermediate (rarely metastasizing) Atypical fibroxanthoma Angiomatoid fibrous histiocytoma Ossifying fibromyxoid tumour (benign, malignant) Myoepithelioma Myoepithelial carcinoma Mixed tumor NOS (and malignant) Phosphaturic mesenchymal tumor (benign, malignant) Adapted from: Fletcher CDM. WHO classification of tumours of soft tissue and bone. 3rd & 4th eds. Lyon, France: IARC Press; 2002 & 2013. * Question 2 Sarcoma grading is basically pathology bunk; it provides little to guide treatment. 1. True 2. False 3. I don’t know Grading of Sarcomas • Attempt to assess the degree of malignancy (ie, metastatic potential and death) • Traditionally recognized as the most important prognostic factor (other than stage) Deyrup AT, Weiss SW. Histopathology. 2006;48(1):42-50. Grading Systems French Federation of Cancer Centers Sarcoma Group General Grade 1: Grade 2: Grade 3: total score of 2-3 points total score of 4-5 points total score of 6-8 points Tumor differentiation: 1 point: resembles normal adult mesenchymal tissue, may be confused with a benign lesion, such as well differentiated liposarcoma 2 points: histologic typing is certain, such as myxoid liposarcoma 3 points: synovial sarcoma, osteosarcoma, Ewing’s sarcoma/PNET, sarcomas of doubtful tumor type, embryonal and undifferentiated sarcomas Mitotic count: (count 10 successive high power fields [area of 0.17 mm squared] in most mitotically active areas) 1 point: 0-9 mitoses 2 points: 10-19 mitoses 3 points: 20 or more mitoses Tumor necrosis: 0 points: no necrosis on any slides 1 point: less than 50% necrosis for all examined tumor surface 2 points: tumor necrosis of 50% or more of examined tumor surface Rubin, et al. (2014) College of American Pathology guidelines; Neuville, et al. Pathology. 2014 ;46(2):113-120. Liposarcoma: Tumor Differentiation Score 1 2 ALT/WD LPS 3 De-Diff LPS Cellular Myxoid LPS Myxoid LPS Pleomorphic LPS Leiomyosarcoma: Tumor Differentiation Score 1 Well-Diff 2 Conventional 3 Epithelioid French Federation of Cancer Centers Sarcoma Group Grades of “Common” Sarcoma Types ● Fibrosarcoma-well differentiated - 1 ● Leiomyosarcoma-well differentiated - 1 ● Liposarcoma-well differentiated - 1 ● Angiosarcoma-well differentiated/conventional - 2 ● UPS/MFH-pleomorphic with storiform pattern - 2 ● Fibrosarcoma-conventional - 2 ● Leiomyosarcoma-conventional - 2 ● Liposarcoma-myxoid - 2 ● Liposarcoma-pleomorphic - 3 ● Liposarcoma-round cell - 3 ● Malignant triton tumor - 3 ● MFH-giant cell – 3 ● MFH-pleomorphic without storiform pattern - 3 ● Myxofibrosarcoma - 2 ● Osteosarcoma - 3 ● Leiomyosarcoma-epithelioid/poorly differentiated/pleomorphic - 3 ● PNET - 3 ● Rhabdomyosarcomaalveolar/embryonal/pleomorphic - 3 ● Angiosarcoma-poorly differentiated/epithelioid - 3 ● Chondrosarcoma-mesenchymal - 3 ● Clear cell sarcoma - 3 ● Epithelioid sarcoma - 3 ● Fibrosarcoma-poorly differentiated - 3 ● Synovial sarcoma - 3 Rubin, et al. (2014) College of American Pathology guidelines. Neuville, et al. Pathology. 2014 ;46(2):113-120. FNCLCC Grading • All 3 numbers are summed to determine degree of differentiation Grade 1 : Grade 2 : Grade 3 : 2-3 4-5 6-8 • Proven to correlate well with survival • 1 2 3 • Mitotic Count. In the most mitotically active area, 10 successive high-power fields (at 400x magnification = 0.1734 mm2) using a 40x objective. 0-9 mitoses per 10 HPFs 10-19 mitoses per 10 HPFs > 20 mitoses per 10 HPFs 0 1 2 Tumor Necrosis. Evaluated on gross examination and validated with histological sections No tumor necrosis < 50% tumor necrosis > 50% tumor necrosis • Degree of Differentiation. 1-3 Rubin, et al. (2014) College of American Pathology guidelines. Neuville, et al. Pathology. 2014 ;46(2):113-120. FNCLCC Grading Coindre JM, et al. Cancer. 2001;91(10):1914-1926. Sarcoma Grading: Challenges • Behavior determined by histotype (ie, Ewing’s, ALT) • Some not considered gradable (ES, SSC, AS) – provides no additional information • Some tumors graded but not predictive (ex. “low-grade” MPNST) • Some sarcomas are not classifiable thus behavior is unknown • Often done semi-objectively • What does intermediate really mean? Question 3 Molecular diagnostics can play an important and practical role in contemporary sarcoma diagnosis. 1. True 2. False 3. I don’t know Adapted from: Demicco & Lazar. Semin Oncol 2011;38(s3):S3-18. Lazar: in Hornick Practical Soft Tissue Pathology: A Diagnostic Approach (2013) Elsevier Health Sciences. Lazar: in Hornick Practical Soft Tissue Pathology: A Diagnostic Approach (2013) Elsevier Health Sciences. Question 4 The current 7th Edition of AJCC sarcoma staging system is useful in my clinical practice. 1. Always 2. Almost always 3. Sometimes 4. Almost never 5. AJCC what? Staging • Determine extent of disease to predict prognosis and used to guide adjuvant treatment • Can also be used to compare patients with both same and different tumors • 7th AJCC Edition is applicable to most sarcomas • 8th Edition underway…. Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. AJCC Staging: pT • Pathologic Staging • pT – Depends on SIZE (≤ 5 or > 5 cm) and DEPTH (superficial – subcutis, deep – muscle) • May need to correlate radiologically • • • • Tx primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 5 cm or less (a, superficial; b, deep) T2 Tumor more than 5 cm (a, superficial; b, deep) Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. AJCC Staging: pN • • • • pN – Regional lymph nodes Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Regional lymph node metastases (no longer M1) • Lymph node metastases rare in most sarcomas • Does not appear to alter prognosis significantly • In assigning stage, and nodal status is unknown, they should be assumed as N0 Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. AJCC Staging: M and Grade • M – Distant metastases: Typically determined by site of primary – There is no pathological pMx or pM0 – clinically determined • M0 No distant metastases • M1 Distant metastases • Histological Grade (FNCLCC grading) • Gx (cannot assess), G1 – G3 Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. AJCC Stage Groups Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. 0.8 0.6 0.4 0.2 0.0 Cumulative Incidence of Local Recurrence 1.0 Atypical Lipomatous Tumor GIST Leiomyosarcoma Liposarcoma, dedifferentiated Liposarcoma, myxoid MFH Others Synovial Sarcoma Unclassified 0 12 24 36 48 60 72 84 96 108 120 Months from dates of surgery of Primary Tumor MDACC prospective soft tissue sarcoma database. 132 144 156 168 1.0 0.8 0.6 0.4 0.2 0.0 Cumulative Incidence of Local Recurrence Margin negative Margin positive 0 12 24 36 48 60 72 84 96 108 120 Months from dates of surgery of Primary Tumor MDACC prospective soft tissue sarcoma database. 132 144 156 168 Nomograms • Uses other factors to predict probability of survival • Points given for each variable and generated score gives predicted survival probability • May better direct care and counsel individual patients • Lumps several tumors of the same histotype together • Now: site-specific and histology-specific nomograms Kattan MW, et al. J Clin Oncol. 2002;20(3):791-796. Nomograms “Histology Specific” (LPS) Site Specific (RP) SS – Ad/If Dalal KM, et al. Ann Surg. 2006;244(3):381-391. Canter RJ, et al. Clin Cancer Res. 2008;14(24):8191-8197. Anaya DA, et al. Ann Oncol. 2010;21(2):397-402. Question 5 Soft tissue sarcoma pathology reports that I receive provide the relevant information needed to manage my patients in a structured format. 1. 2. 3. 4. 5. Always Almost always Sometimes Almost never Why would I ever read a pathology report? Rubin, et al. (2014) CAP guidelines. www.cap.org Conclusions • AJCC, CAP, & WHO are now aligned • Global staging is helpful, but limited – Easier to apply – ASPS is different than WD liposarcoma • Better therapies encourage better staging systems – GIST • Molecular prognostics are coming – Need to be simple/applicable to FFPE samples – Markers predicting response to therapy are key • Multidisciplinary approaches are critical – Surgery, Med-Onc, Radiology, Pathology, Research, etc – Glean insights from one another, work together AJCC, American Joint Committee on Cancer; ASPS, alveolar soft part sarcoma; WD, well-differentiated; GIST, gastrointestinal stromal tumor; FFPE, formalin-fixed paraffin embedded. THE PAST, PRESENT, AND FUTURE OF CYTOTOXIC CHEMOTHERAPY FOR ADVANCED, NON-GIST SOFT TISSUE SARCOMAS George D. Demetri, MD - CHAIR Dana-Farber Cancer Institute Sarcomas Were Viewed as a Poorly Understood “Black Box” Before the 21st Century The knowledge gained from studying this 1% of human cancer has been critical to advance the diagnosis and treatment of other far more common forms of cancer 1% = Sarcomas Evolution of Cancer Medicine: From Empiricism to Mechanism The Old Classic Approach Diagnose cancer based on where the tumor started or what the tissue looks like Try to kill the tumor with “acceptable” toxicity Cytotoxic Therapy (Empiric) Question 1 Conventional approved cytotoxic chemotherapy for advanced metastatic soft tissue sarcoma often (choose best answer): 1. Results in delay of tumor progression 2. Cures patients as well as in localized osteosarcoma 3. Is associated with proven benefits in overall survival 4. 1 and 2 5. 2 and 3 Sarcomas Played a Pivotal Historical Role in the Early Development of Chemotherapy • 1960’s and 1970’s – the era of “One Size Fits All” clinical trials for “Cancer” Cytotoxic Chemotherapy for Sarcomas: Evolution Over the Past 40 Years 1972 Doxorubicin and DTIC Activity Noted in Sarcomas Curative Impact of Chemotherapy in Osteosarcoma: 1982 Randomized Trial testing Adjuvant Chemotherapy vs Observation Practice-changing results with only 36 patients who accepted randomization (out of 113) Link MP, et al. N Engl J Med. 1986;314(25):1600-1606. 1980’s: Continued Incremental Development of Chemotherapy for Soft Tissue Sarcomas Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas 1982 Time to Treatment Failure (weeks) Schoenfeld DA, et al. Cancer. 1982;50(12):2757-2762. Overall Survival (weeks) Continued Development of Chemotherapy for Soft Tissue Sarcomas Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas 1982 1987 Ifosfamide Activity Noted in Sarcomas Continued Development of Chemotherapy for Soft Tissue Sarcomas Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas 1982 1987 Ifosfamide Activity Noted in Sarcomas (1987) Combinations of Doxorubicin plus Ifosfamide +/- CSFs 1992 Continued Development of Chemotherapy for Soft Tissue Sarcomas Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas 1982 Combinations of Doxorubicin plus Ifosfamide +/- CSFs 1995 Ifosfamide Activity Noted in Sarcomas (1987) Continued Development of Chemotherapy for Soft Tissue Sarcomas Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas Combinations of Doxorubicin plus Ifosfamide +/- CSFs 1982 1995 PFS (years) Ifosfamide Activity Noted in Sarcomas (1987) Overall Survival (years) Continued Development of Chemotherapy for Soft-Tissue Sarcomas Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas 1982 Combinations of Doxorubicin plus Ifosfamide 1992 Ifosfamide Activity Noted in Sarcomas (1987) 1999 HIGH DOSE Ifosfamide explored in Sarcomas with CSF support (1997) 21st Century Splitting to Focus Trials in “Soft Tissue Sarcomas” Combinations of Doxorubicin with DTIC and Cyclophosphamide 1972 Doxorubicin and DTIC Activity Noted in Sarcomas 1982 Combinations of Doxorubicin plus Ifosfamide +/- CSFs 1992 Ifosfamide Activity Noted in Sarcomas (1987) GIST routinely removed from studies of “Soft Tissue Sarcomas” 2001 Progression-Free Survival as a Marker of Clinical Activity in Soft Tissue Sarcomas (eg, leiomyosarcomas and liposarcomas) EORTC Soft Tissue and Bone Sarcoma Group database P F S “ACTIVE” INACTIVE Van Glabbeke M, et al. Eur J Cancer. 2002;38(4):543-549. “Modern” Cytotoxic Chemotherapy Does NOT Significantly Improve Clinical Outcomes in Soft Tissue Sarcoma Patients Following Resection Minor Benefit in Relapse-Free Survival only in first 3 years Woll PJ, et al. Lancet Oncol. 2012;13(10):1045-1054. Randomized Trial of First-Line Chemotherapy in Metastatic Soft Tissue Sarcomas Doxorubicin R Doxorubicin + Ifosfamide Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423. Does Combination Chemotherapy Improve Outcomes for Metastatic Soft Tissue Sarcomas? (EORTC 62012) Eligibility: • High grade STS (2-3) • Age 18-60 • No previous chemo for advanced/metastatic disease • WHO PS < 2 Stratification: • Age (< 50 vs ≥ 50) • PS (0 vs 1) • Liver metastases (0 vs +) • Histological grade (2 vs 3) Single-agent Doxorubicin (75 mg/m2 bolus or as a 72-hour continuous i.v. infusion) R 2 d 1-3 Doxorubicin 25 mg/m New Treatment: B + Ifosfamide 2.5 g/m2 d 1-4 + PEG-Filgrastim 6 mg s.c. d5 Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423. Objective Response Rates Complete Response Partial Response Overall RESPONSE RATE No Change Progressive Disease Early Death – Progression Early Death – Other cause Not evaluable Treatment Doxo Doxo-Ifos (n = 228) (n = 227) n (%) n (%) Total (n = 455) n (%) 1 (0.4) 30 (13.2) 4 (1.8) 56 (24.7) 5 (1.1) 86 (18.9) 13.6 26.5 105 (46.1) 114 (50.2) 219 (48.1) 74 (32.5) 4 (1.8) 3 (1.3) 11 (4.8) 30 (13.2) 5 (2.2) 2 (0.9) 16 (7.0) 104 (22.9) 9 (2.0) 5 (1.1) 27 (5.9) Significant difference between the two arms: P < 0.001. Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423. Progression-Free Survival: Statistically Different (P = 0.003) Favoring Dox + Ifos Dox + Ifos Median PFS: 7.4 months (ORR 27%) Dox Median PFS 4.6 months (ORR 14%) (year) Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423. Overall survival Overall Survival 100 90 80 HR = 0.83 (95.5% CI 0.67-1.03) Stratified log rank test, P = 0.076 70 60 No difference statistically 50 40 30 20 10 0 (years) 0 O 188 184 N 228 227 1 2 3 Number of patients at risk : 113 54 29 130 64 30 4 19 20 5 14 13 6 9 7 Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423. 7 2 3 8 Treatment Doxo DxIf Reasons for Discontinuing Therapy on EORTC 62012: First-Line Single Agent vs Combination Chemotherapy for Metastatic Soft Tissue Sarcomas Treatment Doxo (n = 121) n (%) 95 (41.7) Doxo+Ifos (n = 109) n (%) 47 (20.7) Toxicity (including toxic death) 6 (2.6) 40 (17.6) Patient’s refusal (not related to toxicity) 4 (1.8) 10 (4.4) Progression of Disease/death due to PD Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423. Randomized Trial of a Newer First-Line Chemotherapy in Metastatic Soft Tissue Sarcomas Doxorubicin Negative Study: NO BENEFIT with combo Rx R Doxorubicin + Palifosfamide 2013 Data: International Phase III Trial of Palifosfamide + Doxo vs Doxo Alone as First-Line Therapy for Metastatic “Non-GIST Soft Tissue Sarcomas” Overall Survival MEDIAN OVERALL SURVIVAL 1.4 years Ryan C, et al. ECCO 2013. Question 2 Trials of ifosfamide and doxorubicin in soft tissue sarcomas demonstrate that (choose best one): 1. There is no need to develop any new chemotherapy for advanced sarcomas since the results are so good 2. No other chemotherapy will ever work in sarcomas 3. Progression-free survival can be improved 4. Patients will never participate in clinical trials Randomized Trial of an EVEN NEWER First-Line Chemotherapy in Metastatic Soft Tissue Sarcomas Doxorubicin FULLY ACCRUED: Analyses Pending R Doxorubicin + TH-302 New Drugs for Soft Tissue Sarcomas: Gemcitabine + Docetaxel Combination May Improve PFS and OS Compared to Gemcitabine Alone PFS OS PS 0 Maki RG, et al. J Clin Oncol. 2007;25(19):2755-2763. PS 1 Improved Outcomes With Combination Gemcitabine + Dacarbazine vs Dacarbazine Alone in Second-Line Metastatic Soft Tissue Sarcomas ORR DTIC: 4% Gem + DTIC: 12% OS PFS Median PFS DTIC: 2.0 mo Gem + DTIC: 4.2 mo Median OS Garcia-Del-Muro X, et al. J Clin Oncol. 2011;29(18):2528-2533. DTIC: 8.2 mo Gem + DTIC: 16.8 mo Other New and/or Promising Chemotherapy Agents for Soft Tissue Sarcomas • Trabectedin (formerly Ecteinascidin-743, ET743) – Approved in Summer 2007 by European FDA (EMA) for treatment of soft tissue sarcomas – Investigational still in USA • Eribulin – Approved for breast carcinoma, investigational for soft tissue sarcomas Not All Molecular Targeted Agents are Rationally Designed – But the Clinical Evaluation Can Be Rational and Targeted Sea Tunicate, Ecteinascidia Turbinata Ecteinascidin-743 (Trabectedin), a tetrahydroisoquinoline alkaloid, MW=762. Not All Molecular Targeted Agents are Rationally Designed – But the Clinical Evaluation Can Be Rational and Targeted Binds to DNA minor groove, bending the helix Interacts with transcription factors and other DNA binding proteins Major activity in myxoid/round cell liposarcoma with TLS/CHOP fusion oncoprotein (DNA binding protein) Historical Overview of Trabectedin Clinical Trials in Soft Tissue Sarcomas N Progression- ProgressionMedian Free Rate Free Rate PFS @ 3 months @ 6 months Max # Cycles Active 146 39% 14% NA Inactive 234 21% 8% NA Group A 44 46% 18% 2.6 M 15 Group B 55 50% 24% 2.9 M 18 Group 1 26 38% 23% 1.8 M 10 Group 2 28 39% 25% 1.9 M 20 Garcia-Carbonero R, et al.4 36 31% 14% 1.7 M 21 136 53% 37% 3.3 M 37 EORTC Historical Thresholds1 Le Cesne A, et al2 Yovine A, et al3 Demetri G, et al. 5 • Samuels B, et al.6: Expanded Access Plan (SAR 3002) (N = 1803) Clinical Benefit Rate = 54% in Leiomyosarcoma and Liposarcoma patients 1. Van Glabbeke M, et al. Eur J Cancer. 2002;28:543-549. 2. Le Cesne A, et al. J Clin Oncol. 2005 23(3):576-584. 3. Yovine A, et al. J Clin Oncol. 2004;22(5):890-899. 4. Garcia-Carbonero R, et al. J Clin Oncol. 2004;22(8):1480-1490. 5. Demetri G, et al. J Clin Oncol. 2009;27(25):4188-4196. 6. Samuels B, et al. Annals of Oncol. 2013;24(6):1703-1709. Trabectedin in Sarcomas: Pivotal Trial Primary Endpoint = Time to Tumor Progression TTP: All Randomized Time To Progression (TTP): (Investigator Assessment) All Randomized Patients Updated May 08 (Investigator Assessment) p=0.0042 P = 0.0028 HR: 0.668HR: 0.658 q3wk 24-h qwk 3-h qwk 3-h Demetri GD, et al. J Clin Oncol. 2009;27(25):4188-4196.. Progression-Free Survival as a Marker of Clinical Activity in Soft Tissue Sarcomas (eg, leiomyosarcomas and liposarcomas) EORTC database Trabectedin q3 wks P F S Trabectedin weekly “ACTIVE” INACTIVE Both trabectedin schedules show substantially longer PFS than older “active” drugs in similar setting Van Glabbeke M, et al. Eur J Cancer. 2002;38(4):543-549. ET743 (Trabectedin) is Particularly Active in Myxoid and Round Cell Liposarcomas • Retrospective Series – multiple institutions • 51 patients • Advanced disease, all pretreated • Median follow-up 14 months • Overall Response Rate by RECIST 51% ( 95% CI 36-65%) Grosso F, et al. Lancet Oncol. 2007;8(7):595-602. baseline After 1 cycle Trabectedin Induces Changes in Tumor Density After 5 cycles After 8 cycles Before Tumor Changes in Size Courtesy Grosso, Casali, et al. Istituto Tumori Milano. Grosso F, et al. Lancet Oncol. 2007;8(7):595-602. After 11 cycles Progression-Free Rates at 12 weeks Leiomyosarcoma Liposarcomas Synovial sarc Other sarcoma 32% 47% 21% 19% New Randomized Trial Data to be Reported at ASCO Tomorrow in Liposarcoma and Leiomyosarcoma Subsets of Advanced Soft Tissue Sarcomas Leiomyo Or Liposarc Leiomyo Or Liposarc Dacarbazine BOTH TRIALS TO BE DISCUSSED June 1, 2015 SARCOMA SESSION Trabectedin (ET-743) Dacarbazine Eribulin Mutation Frequencies Vary Across Cancer Types EWING SARCOMAS RHABDOID TUMORS Lawrence MS, et al. Nature. 2013;499(7457):214-218.. Combination of PARP Inhibitor Olaparib + DNA Damaging Chemotherapy Temozolomide in Preclinical Xenograft Model of Ewing Sarcoma Brenner JC, et al. Cancer Res. 2012;72(7):1608-1613. Conclusions • Cytotoxic chemotherapy definitely can have clinically meaningful activity in sarcomas of soft tissue as well as bone sarcomas • Personalization to patient-specific clinical scenarios is key to the optimal use of chemotherapy for soft tissue sarcomas • New chemotherapy options are showing a great deal of promise as potential additions to the therapeutic armamentarium targeting soft tissue sarcomas to help patients with these life-threatening diseases PROGRESS IN TARGETED THERAPIES FOR ADVANCED, NON-GIST SOFT TISSUE SARCOMAS Richard F. Riedel, MD Duke Cancer Institute Outline • Introduction • Targeted therapy in unselected patients – mTOR – Multi-targeted TKIs – PD-1/PD-L1 • Targeted therapy in selected patients – ASPS, CCS, DFSP, IMT, PEComa, Liposarcoma • Conclusions The Challenge • Cytotoxic chemotherapeutic – Limited number of agents – Limited efficacy • Toxicity remains an issue • QOL is important to patients • Desire to move towards “Precision Medicine” Cytotoxic Chemotherapy Outcomes Treatment Response Median OS Doxorubicin ~ 10-20% ~ 12 months ~ 20% ~ 12 months ~ 25-35% ~ 12 months ~ 30% ~ 13 months Gemcitabine 8% ~ 12 months Gemcitabine/Docetaxel 16% ~ 18 months Gemcitabine/Navelbine 13% NR Dacarbazine 18% NR Ifosfamide AIM MAID Largely based on phase II studies MAID, mesna+doxorubicin+ifosfamide+dacarbazine; AIM, doxorubicin, ifosfamide, mesna. Riedel RF. Cancer. 2012;118(6):1474-1485. 90 Novel Therapeutic Targets • • • • • • • • PI3K/AKT/mTOR VEGF/VEGFR MET ALK HDAC HSP90 CDK4 MDM2 • • • • • • • • Hedgehog IGF1R EGFR MAPK PDGFR KIT PD-1/PD-L1 Angiopoeitin-TIE2 Clinical Trials: Lumpers or Splitters? • “Lumpers” – Pros: Ease of accrual, therapy more widely available – Cons: Results difficult to interpret given broad range of histologies • “Splitters” – Pros: Recognize molecular heterogeneity – Cons: Limited number of patients/subtype 92 NOVEL TARGETED THERAPIES UNSELECTED PATIENT POPULATIONS mTOR Inhibition: Ridaforolimus • Multicenter, open-label, phase II study – 212 patients with bone and soft tissue sarcoma – 12.5 mg IV daily x 5 days every 2 weeks – Clinical Benefit Rate of 29% – Response rate 1.9% – Median PFS 15.3 weeks – Median OS 40 weeks – Benefit in subgroups explored PFS, progression-free survival; OS, overall survival. Chawla SP, et al. J Clin Oncol. 2012;30(1):78-84. Ridaforolimus: SUCCEED Study Sarcoma MUlti-Center Clinical Evaluation of the Efficacy of RiDaforolimus • • • • • Multicenter Randomized Phase III Blinded Placebo-controlled Advanced Sarcoma Stable/Responsive Disease > 4 Cycles 1st-, 2nd-, 3rd-line 1:1 Maintenance Ridaforolimus (Oral) 5 days on: 2 days off 40 mg daily Maintenance Placebo Sample Size: 711 randomized Demetri GD, et al. J Clin Oncol. 2013;31(19):2485-2492. SUCCEED Study: PFS Demetri GD, et al. J Clin Oncol. 2013;31(19):2485-2492. 96 SUCCEED Study: OS Demetri GD, et al. J Clin Oncol. 2013;31(19):2485-2492. 97 Oncologic Drugs Advisory Committee: March 20, 2012 Has a favorable risk-benefit profile for ridaforolimus as a maintenance therapy for patients with metastatic soft tissue or bone sarcoma who have stable disease or better after 4 or more cycles of chemotherapy been demonstrated? For: 1 Against: 13 Abstain: 0 ODAC Committee • “For” – Desire for more treatment options – Preserve availability of the product for patients • “Against” – – – – Higher bar needed for maintenance therapy Statistical significance = Clinically meaningful Toxicities outweighed the benefits PFS improvement was marginal ODAC, Oncologic Drugs Advisory Committee; PFS, progression-free survival. Questions • • • • Does ridaforolimus have activity? Who is benefiting? Was the disease setting correct? Would the AE profile have been more acceptable in a relapsed/refractory setting? • Would adequate QOL data impact review? • Can we identify biomarkers of response and/or toxicity? • Combination approaches? AE, adverse events; QOL, quality of life. Multi-Targeted Tyrosine Kinase Inhibitors: Phase II Trials Primary Endpoint Sample Size Strata Statistical Design Result Imatinib1 CBR 185 10 Bayesian CBR 15% Pazopanib2 PFR12weeks 142 4 Simon 2-stage PFR12weeks > 40% LMS, SS, “Other” Sorafenib3 RECIST Response 145 (122 eval) 6 Simon 2-stage RR: 3% (14% angio) Sunitinib4 RECIST Response 53 (48 eval) 3 Simon 2-stage DCR: 22% (at least 16 weeks) CBR: Clinical benefit rate; LMS: Leiomyosarcoma; PFR: Progression-free rate; RECIST: Response Evaluation Criteria in Solid Tumors; DCR: Disease control rate; SS: Synovial sarcoma; RR: Response rate 1Chugh R, et al. J Clin Oncol. 2009;27(19):3148-3153. S, et al. J Clin Oncol. 2009;27(19):3126-3132. 3Maki R, et al. J Clin Oncol. 2009;27(19):3133-3140. 4George S, et al. J Clin Oncol. 2009;27(19):3154-3160. 2Sleijfer PALETTE Study PAzopanib ExpLorEd in SofT-TissuE Sarcoma • • • • • Multicenter Randomized Phase III Blinded Placebo-controlled Relapsed/Refractory Advanced Sarcoma* 2:1 Pazopanib 800 mg daily Placebo Sample Size: 369 patients enrolled and treated *Non-adipocytic, Non-GIST STS. van der Graaf WT, et al. Lancet. 2012;379(9829):1879-1886. PALETTE Trial: Pazopanib Progression-Free Survival van der Graaf WT, et al. Lancet. 2012;379(9829):1879-1886. 103 PALETTE Trial: Pazopanib Overall Survival van der Graaf WT, et al. Lancet. 2012;379(9829):1879-1886. 104 Oncologic Drugs Advisory Committee: March 20, 2012 Considering the observed improvement in PFS, the absence of an improvement in OS, and the adverse event profile of pazopanib, is the risk benefit assessment favorable for the use of pazopanib in the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy? For: 11 Against: 2 Abstain: 0 ODAC Committee • “For” – – – – Significant unmet need Well-designed trial Subset of patients (14%) > 1 year on therapy May benefit QOL but data limited • “Against” – Benefit was marginal – No improvement in QOL or OS FDA Approval: April 26, 2012 ODAC, Oncologic Drugs Advisory Committee; QOL, quality of life; OS, overall survival. Questions • • • • • What is the target? Is PFS an optimal outcome measure? Did additional therapies impact OS? What is unique about liposarcoma? Can we identify biomarkers? Checkpoint Inhibition: PD-1/PD-L1 • Developing story in sarcoma • Discordant data published to date – 2013 study • PD-L1 (58%) of soft tissue sarcoma • TILs (65%) with PD-1 expression noted – 2015 study • PD-1 (12%) and PD-L1 (22%) expression in sarcoma specimens • TILs (30%) and macrophage (58%) PD-L1 expression noted • Association between PD-1/PD-L1 expression and outcomes is inconsistent • Standardization needed TIL, tumor infiltrating lymphocytes. Kim JR, et al. PLoS One. 2013;8(12):e82870; D'Angelo SP, et al. Hum Pathol. 2015;46(3):357-365. SARC028: Pembrolizumab in Sarcoma • Study Design: – Open-label, phase II – Relapsed/refractory STS and bone sarcoma – Sample size: 80 (40 with STS, 40 with bone sarcomas) Relapsed/Refractory Disease Arm A: Soft Tissue Sarcoma Arm B: Bone Sarcoma Pembrolizumab 200 mg IV q21 days Pembrolizumab 200 mg IV q21 days Tumor biopsies: Screening, week 8 and week 34 (optional) www.clinicaltrials.gov NCT02301039. STS, soft tissue sarcoma. Relapsed/Refractory: SARC028 • Objectives – Primary: ORR (using RECIST 1.1) – Secondary: safety, tolerability, PFS, OS, RR (ir-RC) – Exploratory: PD-L1 expression as a biomarker, Tregs, MDSCs, immune monitoring Abstract #TPS10578 SARC 028: A phase II study of the anti-PD-1 antibody pembrolizumab (P) in patients (Pts) with advanced sarcomas. Melissa Amber Burgess Poster Board: #220b ASCO 2015 • Unselected histologies – Poster Discussion Abstract #10514 (Attia et al.): A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS). Abstract #10515 (Agulnik et al.): A phase II study of tivozanib in patients with metastatic and non-resectable soft tissue sarcomas. Abstract #10516 (Vitfell-Rasmussen et al.): A phase I/II clinical trial of belinostat (PXD101) in combination with doxorubicin in patients with soft tissue sarcomas (STS). 111 ASCO 2015 • Unselected histologies – Oral Session (Monday, June 1, 3:00-6:00 PM) Abstract #10501 (Tap et al.): A randomized phase Ib/II study evaluating the safety and efficacy of olaratumab (IMC-3G3), a human anti-platelet-derived growth factor α (PDGFRα) monoclonal antibody, with or without doxorubicin (Dox), in advanced soft tissue sarcoma (STS). NOVEL TARGETED THERAPIES SELECTED PATIENT POPULATIONS Molecular Drivers in Select Histologies Translocation/ Rearrangement Fusion Transcript Mechanism ASPS t(X;17)(p11;q25) ASPL-TFE3 MET/VEGF signaling activation CCS t(12;22)(q13;q12) EWSR1-ATF1 MITF/MET activation DFSP t(17;22)(q22;q13) COL1A1-PDGFB PDGFRB signaling activation IMT ALK gene rearrangement PEComa TFE3 gene rearrangement ASPS: alveolar soft part sarcoma CCS: clear cell sarcoma DFSP: dermatofibrosarcoma protuberans IMT: inflammatory myofibroblastic tumor PEComa: perivascular epithelioid cell tumor MITF: microphthalmia-associated transcription factor PDGFRB: platelet-derived growth factor receptor beta Rutkowski P, et al. Int J Biochem Cell Biol. 2014;53:466-474. ALK activation ----------------- mTOR pathway activation Alveolar Soft Part Sarcoma (ASPS) • Rare, mesenchymal neoplasm • Presents as a painless, slow growing mass • Lung metastases are common and often indolent • Chemotherapy and radiation therapy resistant • Majority of cases express fusion protein – ASPL-TFE3 translocation – Results in aberrant MET signaling and overexpression of genes associated with angiogenesis ASPL , alveolar soft part locus; TFE3, transcription factor E3. Tsuda M, et al. Cancer Res. 2007;67(3):919-929. Alveolar Soft Part Sarcoma (ASPS) • Multi-targeted TKIs – Sunitinib • Case reports/series – Cediranib • Phase II study (n = 46) of cediranib for metastatic ASPS • ORR 35%; DCR at 24 weeks of 84% • ARQ197 (MET inhibitor) – Phase II study in MITF associated tumors (n = 13 ASPS) – Disease stabilization of 81% • Phase II studies of cediranib vs sunitinib; and crizotinib – Ongoing Stacchiotti S, et al. Clin Cancer Res. 2009;15(3):1096-1104. George S, et al. J Clin Oncol. 2009;27(19):3154-3160. Hilbert M, et al. Pediatr Blood Cancer. 2012;58(3):475-476. Kummar S, et al. J Clin Oncol. 2013;31(18):2296-2302. Goldberg J, et al. J Clin Oncol. 2009;15(suppl). Abstract 10502. Clear Cell Sarcoma (CCS) • Rare, mesenchymal neoplasm – “Melanoma of soft parts” • • • • Indolent growth Potential for lymph node involvement Chemotherapy resistant Majority of cases express fusion protein – EWSR1-ATF translocation • Induces MITF expression • Contributes to overexpression of MET MITF, microphthalmia-associated transcription factor; EWSR1, Ewing sarcoma breakpoint region 1; ATF, activating transcription factor. Clear Cell Sarcoma (CCS) • Multi-targeted TKIs – Sunitinib and sorafenib • Case reports – Pazopanib • Pre-clinical • ARQ197 (MET inhibitor) – Phase II study in MITF associated tumors (n = 7 CCS) – Disease stabilization of 43% – 1 PR, 2 SD • Phase II study of crizotinib (ALK/MET inhibitor) – Ongoing Stacchiotti S, et al. Ann Oncol. 2010;21(5):1130-1131. MITF, microphthalmia-associated transcription factor. Mir O, et al. Ann Oncol. 2012;23(3):807-809. Outani H, et al. BMC Cancer. 2014;14:455. Goldberg J, et al. J Clin Oncol. 2009;15(suppl). Abstract 10502. DFSP: Dermatofibrosarcoma Protuberans • • • • Rare, mesenchymal neoplasm Cutaneous in origin Locally aggressive Characterized by reciprocal translocation – t(17;22)(q11;q13.1) – COL1A1-PDGFB fusion gene – PDGFRB signaling via autocrine stimulation PDGFB, platelet-derived growth factor beta; COL1A1, collagen type I alpha 1 gene. DFSP: Dermatofibrosarcoma Protuberans • Multi-targeted TKI – Imatinib – Multiple small series/phase II studies confirmed benefit • ORR 46-90% – FDA approved in 2006 • Unresectable, recurrent, and/or metastatic DFSP McArthur GA, et al. J Clin Oncol. 2005;23(4):866-873. Rutkowski P, et al. J Clin Oncol. 2010;28(10):1772-1779. Rutkowski P, et al. J Eur Acad Dermatol Venereol. 2011;25(3):264-270. Inflammatory Myofibroblastic Tumor (IMT) • • • • • Rare, mesenchymal tumor Associated inflammatory infiltrate Rearrangements in ALK – 50% Aberrant ALK expression Crizotinib is a multi-targeted TKI with activity Butrynski JE, et al. N Engl J Med. 2010;363(18):1727-1733. Perivascular Epithelioid Cell Tumors (PEComa) • Family of rare mesenchymal tumors • Present as painless lesions within vessel wall • Express melanocytic and smooth-muscle differentiation • Sporadic or associated with tuberous sclerosis complex (TSC) – mTOR inhibition supported by: • Mutations in TSC1 or TSC2 genes • Loss of heterozygosity at TSC2 • Sirolimus1, temsirolimus2, everolimus3 1Wagner AJ, et al. J Clin Oncol. 2010;28(5):835-840. et al. Ann Oncol. 2010;21(5):1135-1137. 3Gennatas C, et al. World J Surg Oncol. 2012;10:181. 2Italiano A, Liposarcoma • Well differentiated/Dedifferentiated (WD/DD) liposarcoma – MDM2 inhibitors • RG7112 (RO5045337) – Nutlin family member • Phase II neoadjuvant study1: WD/DD liposarcoma – 20 enrolled patients, 1 partial response – CDK inhibitors • Palbociclib (PD 0332991) – oral CDK4/6-specific inhibitor • Phase II study2: WD/DD liposarcoma w/amplified CDK4 – 29 evaluable patients, 1 partial response – PFS at 12 weeks: 66% ASCO Educational Session Tuesday, June 2, 11:30 AM WD/DD Liposarcoma: New Challenges and New Directions 1Ray-Coquard 2Dickson I, et al. Lancet Oncol. 2012;13(11):1133-1140. MA, et al. J Clin Oncol. 2013;31(16):2024-2028. ASCO 2015 • Selected histologies Poster Session Abstract #10542 (Schoffski et al.): Activity of crizotinib (C) in patients (pts) with clear cell sarcoma (CCSA) in EORTC phase II trial 90101 "CREATE". Oral Session Abstract #10504 (Mir et al.): Activity of regorafenib (RE) in leiomyosarcomas (LMS) and other types of soft-tissue sarcomas (OTS): results of a double-blind, randomized placebo (PL) controlled phase II trial. 124 Summary • Systemic chemotherapeutic options are limited – Number – Effectiveness • Novel therapies are needed – Targeted therapies • Unselected patient population – FDA approval of pazopanib • Selected patient population – ASPS, CCS, DFSP, IMT, PEComa, Liposarcoma • More trials in selected patient populations are needed – Biomarker driven or studies enriched with biological correlatives 125 Question 1 Pazopanib was FDA approved 04/2012 for the treatment of advanced soft tissue sarcoma. The efficacy of pazopanib has been demonstrated in all of the following histologies except: 1. 2. 3. 4. Leiomyosarcoma Liposarcoma Synovial sarcoma Undifferentiated pleomorphic sarcoma Question 2 Well-differentiated/Dedifferentiated liposarcomas as characterized by which of the following: 1. 2. 3. 4. 5. 6. 7. ALK rearrangements MDM2 amplification CDK4 amplification 1 and 2 1 and 3 2 and 3 1, 2, and 3 HOW I TREAT ADVANCED, NON-GIST SOFT TISSUE SARCOMAS TODAY AND WHAT THE NEAR FUTURE HOLDS Kristen N. Ganjoo, MD Stanford University Medical Center Case 1 • 60-year-old male • 3 months h/o left thigh swelling • EXAM: Large mass in the lateral aspect of the left thigh • When to get an MRI – Mass larger than 3 cm, smaller if on hand or foot – Mass that has rapidly increased in size – Deep mass (deep to fascia) Radiologic Evaluation • Plain X-ray of affected extremity • MRI of the extremity • Chest CT for metastasis • Special circumstance: – CT abdomen/pelvis, MRI of spine (myxoid liposarcoma) – Brain MRI (alveolar soft part sarcoma) – Bone scan (clear cell sarcoma, alveolar soft part sarcoma) Soft Tissue Mass in the Left Vastus Lateralis T1 T2 post contrast Question 1 What is the next step towards diagnosis? 1. Fine Needle Aspirate 2. Core Needle Biopsy 3. Incisional Biopsy 4. Excisional Biopsy 5. Radical Resection Biopsy Techniques 1. Fine Needle Aspiration – Allows cytological evaluation (appearance of individual cells). Reports of 80-90% reliability 2. Core Needle Biopsy – Core of tissue allows for histological evaluation and other tests (immunohistochemistry and cytogenetics) if there is enough tissue Approx 90% accurate at determining benign vs malignant. Bx must be placed where it can be removed at time of final surgery 3. Incisional Biopsy – Make an incision in the tumor and remove tissue. Incision must be placed where it can be removed at time of final surgery 4. Excisional Biopsy – Remove entire tumor around its pseudocapsule. Good for small superficial tumors. Allows you to sample entire tumor. However, contamination is an issue BIOPSY RISKS: Inaccurate sampling, contamination of uninvolved tissues, hematoma, infection, wound issues Pathology Pathology Undifferentiated Pleomorphic Sarcoma Question 2 What treatment would you offer this patient at this time? 1. Radical resection followed by post-operative radiotherapy 2. Systemic chemotherapy followed by radical resection 3. Pre-operative radiotherapy followed by radical resection 4. Pre-operative chemotherapy/radiotherapy followed by radical resection 5. Amputation Pre- vs Post-Operative Radiotherapy O'Sullivan B, et al. Lancet. 2002;359(9325):2235-2241. Pre-Op vs Post-Op Radiation O'Sullivan B, et al. Lancet. 2002;359(9325):2235-2241. Concurrent Pre-Op Ifosfamide With Radiation Pre Tx Post Tx Pathology • Pre-Treatment Biopsy • Post-Treatment Resection Site: left thigh Specimen type: radical resection Depth: deep Size: 13.0 cm Tumor type: pleomorphic sarcoma < 10% viable tumor Question 3 What adjuvant chemotherapy do you recommend? 1. Ifosfamide/anthracycline 2. Gemcitabine/docetaxel 3. Anthracycline alone 4. Trabectedin 5. None Adjuvant Chemotherapy for Sarcomas 1997 • SMAC meta-analysis • 1568 adults with localized resectable STS (< 5% had regimen that included ifosfamide) – Longer local RF interval – HR for local recurrence 0.73 (95% CI 0.56-0.94) – Longer distant RF interval – HR 0.70 (95% CI 0.57-0.85) – Higher overall RF survival – HR for any recurrence 0.75 (95% CI 0.64-0.87) • Absolute 6 to 10% improvement in RF survival at 10 years – Trend towards better OS – HR for death 0.89 (95% CI 0.76-1.03) STS, soft tissue sarcoma, RF, recurrence-free interval; HR, hazard ratio; CI confidence interval; OS, overall survival. Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350(9092):1647-1654. Adjuvant Chemotherapy for Sarcomas 2008 • Updated meta-analyses – 2008 – 18 randomized trials – 1953 patients, 1973 -2002 – The RR for local recurrence – 0.73 (95% CI 0.56 to 0.94) – RR for distant and overall recurrence = 0.67 (95% CI 0.56 to 0.82) – Doxorubicin with ifosfamide – OS benefit (RR 0.56, 95% CI 0.36 to 0.85) – The absolute risk reduction – doxorubicin/ifosfamide – 11% (30 vs 41% risk death) – No benefit for doxorubicin alone (RR 0.84, 95% CI 0.68 to 1.03) RR, relative risk; CI confidence interval; OS, overall survival. Pervaiz N, et al. Cancer. 2008;113(3):573-581. Adjuvant Chemotherapy for Sarcomas • EORTC pooled analysis – 2 trials – 819 patients • No significant OS advantage to doxorubicin/ifosfamide • Only patients with R1 resection with OS benefit Le Cesne A, et al. Ann Oncol. 2014;25(12):2425-2432. Case 2 • 78-year-old-female with uterine mass resected in 2009 • Ovary and fallopian tube, right salpingo-oophorectomy – Multiloculated serous cystadenoma, 8 cm – Fallopian tube with paratubal cyst, 1 cm • Uterus, left ovary and fallopian tube, total abdominal hysterectomy and salpingo-oophorectomy – Leiomyosarcoma, 13.5 cm, with extension through the uterine • Serosa – Ovary and fallopian tube with no significant abnormality Question 4 What adjuvant therapy do you recommend? 1. Radiation alone 2. Gemcitabine/docetaxel followed by adriamycin 3. Gemcitabine/docetaxel followed by radiation 4. Adriamycin with or without radiation 5. None Adjuvant Therapy for Resected Uterine Leiomyosarcoma (LMS) Phase III GOG study Stage I (corpus), II (corpus/cervix) uterine sarcoma Adriamycin n = 75 31/75 (41%) recurred Observation n = 81 43/81 (53%) recurred No difference in PFS or OS Omura GA, et al. J Clin Oncol. 1985;3(9):1240-1245. Adjuvant Therapy for Resected Uterine LMS Phase II Stage I/II N = 18 Gemcitabine + docetaxel 4 cycles Outcomes Hensley ML, et al. Gynecol Oncol. 2009;112(3):563-567. 3-year PFS 59% Median PFS 39 months Median follow-up 48 months Median OS NR SARC 005 – Adjuvant Therapy for Resected Uterine LMS Phase II Stage I/II N = 46 Gemcitabine + docetaxel 4 cycles PFS Adriamycin 4 cycles OS Outcomes Hensley ML, et al. Cancer. 2013;119(8):1555-1561. 3-year PFS 57% Median PFS > 36 months EORTC 55874 – Adjuvant Radiation for Resected Uterine LMS Phase III Stage I/II N = 224 LMS, n = 103 51 GY 28 fractions 5 wks Observation No benefit in PFS or OS in uterine LMS Reed NS, et al. Eur J Cancer. 2008;44(6):808-818. Question 5 Our 78-year-old female did not receive adjuvant therapy and relapsed in the abdomen/pelvis 18 months later. What systemic therapy do you recommend? 1. Gemcitabine/docetaxel 2. Adriamycin 3. Trabectedin 4. Cisplatin-based therapy 5. Dacarbazine Pre-treatment Post 4 cycles of trabectedin