La chemioterapia neoadiuvante nei sarcomi: novità e attuali indicazioni Lorenzo D Ambrosio, MD PhD Divisione di Oncologia Medica Istituto di Candiolo

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1 La chemioterapia neoadiuvante nei sarcomi: novità e attuali indicazioni Lorenzo D Ambrosio, MD PhD Divisione di Oncologia Medica Istituto di Candiolo Fondazione del Piemonte per l Oncologia. IRCCS 12 CONGRESSO NAZIONALE AIOM GIOVANI PERUGIA 6-7 LUGLIO 2018

2 Standard treatment at diagnosis (I) Low-grade sarcoma NO radiotherapy: low grade liposarcoma

3 Standard treatment at diagnosis (II) High-grade sarcoma +/- +

4 First question: do we need chemotherapy? 40% of the patients die of their sarcoma Yes, we do!

5 Adjuvant therapy did not improve survival RFS OS -60% smaller than 8 cm -13% low-grade tumors -52% compliance to chemotherapy

6 Adjuvant therapy did improve survival RFS OS -60% larger than 10 cm -0% low-grade tumors -83% compliance to chemotherapy

7 EORTC data

8 EORTC data 25% 40%

9 Let s meta-analyze! The updated meta-analysis confirms an overall advantage with a reduction of the risk of death in the range of 14%

10 Europe as of today on chemo in STS Roman empire 31 BC 14 AD

11 The need for a definite setting Standard chemotherapy approach may exist only within definite clinical settings Patient related: - dimension - grading - histotype - age - performance - site -.. Chemotherapy related: - drugs - dose - intensity -

12 Nomograms 2.0

13 Prognostic stratification on EORTC data

14 Overall Survival 10-yr OS pr High 66% Intermediate 51% Low VARIABLES HR lhr hhr P-VALUE Low pr-os Intermediate pr-os High pr-os

15 Relapse-free survival 10-yr OS pr High 66% Intermediate 51% Low VARIABLES HR lhr hhr P-VALUE Low pr-os Intermediate pr-os High pr-os

16 Sarcoma heterogeneity Adipocytic tumours Well differentiated / dedifferentiated liposarcoma Myxoid / round cell liposarcoma Pleomorphic liposarcoma Fibroblastic /myofibroblastic tumours Fibromatosis (desmoid) Solitary fibrous tumour / haemangiopericytoma Low grade myofibroblastic tumour Infantile fibrosarcoma Adult fibrosarcoma Mixofibrosarcoma So-called fibrohistiocytic tumours Pleomorphic MFH / Undifferentiated pleomorphic sarcoma Smooth muscle tumours Leiomyosarcoma Skeletal muscle tumours Embryonal rhabdomyosarcoma Alveolar rhabdomyosarcoma Pleomorphic rhabdomyosarcoma Vascular tumours Epithelioid haemangioendothelioma Angiosarcoma of soft tissue Chondro-osseous tumours Mesenchymal chondrosarcoma Extraskeletal osteosarcoma Tumours of uncertain differentiation Synovial sarcoma Epithelioid sarcoma Alveolar soft part sarcoma Clear cell sarcoma of soft tissue...

17 Sarcoma histologic complexity

18 One histology with several different entities Tumor type Cytogenetic aberration Molecular genetics Welldifferentiated adipocytic sclerosing Spindle inflammator cell y Dedifferentiated Myxoid Ring chromosomes and giant markers (12q 13-15) Monosomy 7 rearrangement 13q Ring chromosomes and giant markers (12q 13-15) t(12;16)(q13;p11) t(12;22)(q13;q22) Amplification (mdm2, CDK4) HMGA2) Loss Rb Amplification (mdm2, CDK4) HMGA2) DDIT3/FUS DDIT3/EWSR1 Pleomorphic Complex karyotype P53 mutated in 60%; NF1 in 5%

19 Sarcoma several layers of heterogeneity Uterus heterogeneity Limb Retroperitoneum Head &Neck leiomyosarcoma

20 Clinical details

21 Who: some hints The disease: histology, grading, size, site The patient: performance status, organ function, willingness,. The logistic: institution, social status, residence,. The doctor/the team: experience, facilities,.. This is always a complex and personalized decision

22 chemotherapy in soft tissue sarcomas

23 Chemotherapy: the struggle to become standard At diagnosis Before surgery : neo-adjuvant strategies After surgery : adjuvant strategies : lim

24 The Italian way: weak but consistent evidences Chemotherapy has never been shown detrimental: SMAC meta-analysis, Pervaiz update, EORTC 62931, Several studies showed tumor control: Issels study, Dutch study, Eilber s trial.. Combination chemotherapies are superior (response): EORTC 62012, Italiano s study (FSG on CBR),. of course, histology makes the difference

25 Guidelines: chemo isn t standard, but. -Surgery is the standard -RT: DFT 50 Gy neoadj; 66 Gy adj (boost) -CT adjuvant: 6% OS -CT neo-adj: local surgical benefit -Locally advanced: TNF-a + Mel Hyperthermia

26 Why MTB is crucial

27 RADIOTHERAPIST WHO GOES FIRST? SURGEON ONCOLOGIST

28 If you make the step, do it right!

29 Which therapy matters Aggressive chemotherapy more effective

30 Adjuvant/neo-adjuvant therapy: CT + RT -70% of pts affected by large, G3, STS are cured by CT+RT - After, more chemo is useless 13% were amputated

31 Doxorubicin and its friends -trabectedin: second-line all STS -high-dose ifosfamide: non-leiomyosarcoma -pazopanib: second-line non-adipocytic sarcoma -gemcitabine: leiomyosarcoma angiosarcoma -gemcitabine +/- docetaxel: soft tissue sarcomas uterine leiomyosarcoma -dacarbazine + gemcitabine: soft tissue sarcomas -paclitaxel: angiosarcoma -eribulin: liposarcoma

32 Adjuvant/neo-adjuvant therapy: what s next?

33 Study design

34 Relapse Free Survival is superior with anthracycline + ifosfamide Median FU: months (IQ range: 25.45) P=0.004 Table 2. EUROSARC: RFS - Cox s univariate HR and its 95% Confidence Intervals Treatment ARM HR 95% CI p Standard 1 (ref.) Tailored

35 Overall Survival is superior with anthracycline + ifosfamide 0.89 P=0.033 Median FU: months (IQ range: 25.45) 0.64 Table 4. EUROSARC: OS - Cox s univariate HR and its 95% Confidence Intervals Treatment ARM HR 95% CI p Standard 1 (ref.) Tailored

36 RFS by histology subtype

37 RANDOMIZED PHASE III TRIAL OF TRABECTEDIN VERSUS DOXORUBICIN- BASED CHEMOTHERAPY AS FIRST-LINE THERAPY IN TRANSLOCATION-RELATED SARCOMAS Abs#10517 Hendifar et al, ASCO 2013 IMPRESSIVE RESULTS IN MYXOID LIPOSARCOMAS

38 RFS and quality of surgical resection

39 FUTURE DIRECTIONS

40 IMMUNOTHERAPY

41 T-VEC + pembrolizumab Kelly CM, et al. Abs #11516

42 T-VEC + pembrolizumab - responses 7/20 responses (6/8 in loc adv) ORR 35% (75% in loc adv) DCR 70% Kelly CM, et al. Abs #11516

43 SARC 032 / NCT Phase 2 randomized trial UPS, DDLPS, pleolps >5 cm G2-3 >50% yrs R A N D O M I Z A T I O N 1:1 RT (50 Gy) RT (50 Gy) Pembro 200 mg x 3 S U R G E R Y Pembro 200 mg x 14

44 Doxo + DTIC for LMS? Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide or doxorubicin alone as first line treatment for advanced, metastatic or unresectable leiomyosarcoma (research project 1637): a retrospective study from the EORTC Soft Tissue and Bone Sarcoma Group Overall Response Rate 36,8% 40,0% 35,0% 30,0% 25,6% 25,9% 21,5% 30,9% 25,0% 20,0% 19,5% 15,0% 10,0% total population 5,0% matched population 0,0% Doxorubicin alone Doxorubicin + ifosfamide Doxorubicin + Dacarbazine D Ambrosio L, et al. Abs#11574 ASCO 2018

45 Doxo + DTIC for LMS STRASS2 Phase 3 Randomized trial Retroperitoneal LMS R A N D O M I Z A T I O N 1:1 SURGERY alone Doxorubicin + DTIC x 3 SURGERY DFS@5 years from 29% to 48% (HR= 0.6) 120 events. 230 randomized patients, accrued in 5years, study duration is expected to be 7.5 years.

46 Conclusions Localized High Risk STS of extremities/trunk wall Chirurgia unica strategia curativa R0 Chemioterapia dose-intense preoperatoria RFS / PFS OS

47 If you make the step, do it right!

48 THANKS FOR YOUR KIND ATTENTION!