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
Standard treatment at diagnosis (I) Low-grade sarcoma NO radiotherapy: low grade liposarcoma
Standard treatment at diagnosis (II) High-grade sarcoma +/- +
First question: do we need chemotherapy? 40% of the patients die of their sarcoma Yes, we do!
Adjuvant therapy did not improve survival RFS OS -60% smaller than 8 cm -13% low-grade tumors -52% compliance to chemotherapy
Adjuvant therapy did improve survival RFS OS -60% larger than 10 cm -0% low-grade tumors -83% compliance to chemotherapy
EORTC data
EORTC data 25% 40%
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%
Europe as of today on chemo in STS Roman empire 31 BC 14 AD
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 -
Nomograms 2.0
Prognostic stratification on EORTC data
Overall Survival 10-yr OS pr High 66% Intermediate 51% Low VARIABLES HR lhr hhr P-VALUE Low pr-os 0.46 0.23 0.94 0.033 Intermediate pr-os 1.00 0.53 1.88 0.987 High pr-os 1.08 0.61 1.90 0.801
Relapse-free survival 10-yr OS pr High 66% Intermediate 51% Low VARIABLES HR lhr hhr P-VALUE Low pr-os 0.46 0.24 0.89 0.021 Intermediate pr-os 0.74 0.41 1.34 0.320 High pr-os 0.90 0.54 1.50 0.685
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...
Sarcoma histologic complexity
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%
Sarcoma several layers of heterogeneity Uterus heterogeneity Limb Retroperitoneum Head &Neck leiomyosarcoma
Clinical details
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
chemotherapy in soft tissue sarcomas
Chemotherapy: the struggle to become standard At diagnosis Before surgery : neo-adjuvant strategies After surgery : adjuvant strategies : lim
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
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
Why MTB is crucial
RADIOTHERAPIST WHO GOES FIRST? SURGEON ONCOLOGIST
If you make the step, do it right!
Which therapy matters Aggressive chemotherapy more effective
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
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
Adjuvant/neo-adjuvant therapy: what s next?
Study design
Relapse Free Survival is superior with anthracycline + ifosfamide Median FU: 12.34 months (IQ range: 25.45) 0.62 0.38 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.) - 0.007 Tailored 1.955 1.119-3.190
Overall Survival is superior with anthracycline + ifosfamide 0.89 P=0.033 Median FU: 12.34 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.) - 0.034 Tailored 2.687 1.104-6.937
RFS by histology subtype
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
RFS and quality of surgical resection
FUTURE DIRECTIONS
IMMUNOTHERAPY
T-VEC + pembrolizumab Kelly CM, et al. Abs #11516
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
SARC 032 / NCT03092323 Phase 2 randomized trial UPS, DDLPS, pleolps >5 cm G2-3 >50% DM @2 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
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
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.
Conclusions Localized High Risk STS of extremities/trunk wall Chirurgia unica strategia curativa R0 Chemioterapia dose-intense preoperatoria RFS / PFS OS
If you make the step, do it right!
THANKS FOR YOUR KIND ATTENTION! lorenzo.dambrosio@ircc.it