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)
NO radiotherapy: low grade liposarcoma
Low-grade sarcoma
Standard treatment at diagnosis (II)
+/- +
High-grade sarcoma
First question:
do we need chemotherapy?
Yes, we do !
40% of the patients die
of their sarcoma
RFS OS
Adjuvant therapy did not improve survival
-60% smaller than 8 cm -13% low-grade tumors
-52% compliance to chemotherapy
RFS OS
Adjuvant therapy did improve survival
-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
Patient related:
- dimension - grading - histotype - age
- performance - site
- …..
Standard chemotherapy approach may exist only within definite clinical settings
Chemotherapy related:
- drugs - dose
- intensity
- ……
Nomograms 2.0
Prognostic stratification on EORTC data
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
Overall Survival
High
Intermediate
Low
10-yr OS pr
66%
51%
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
Relapse-free survival
High
Intermediate
Low
10-yr OS pr
66%
51%
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
Tumor type Cytogenetic aberration Molecular genetics Well-
differentiated
adipocytic
Ring chromosomes and giant markers (12q 13-15)
Amplification (mdm2, CDK4) HMGA2)
sclerosing inflammator y
One histology with several different entities
Pleomorphic Complex karyotype P53 mutated in 60%;
NF1 in 5%
Spindle cell Monosomy 7 rearrangement 13q
Loss Rb Dedifferentiated Ring chromosomes and
giant markers (12q 13-15)
Amplification (mdm2, CDK4) HMGA2)
Myxoid t(12;16)(q13;p11)
t(12;22)(q13;q22)
DDIT3/FUS
DDIT3/EWSR1
Sarcoma several layers of heterogeneity
heterogeneity Uterus
Retroperitoneum Head &Neck
Limb
leiomyosarcoma
Clinical details ………
• 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, …..
Who: some hints
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
• 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), ….
The Italian way:
“weak” but consistent evidences
… 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
SURGEON ONCOLOGIST
RADIO THERAP IS T
WHO GOES FIRST?
If you make the step, do it right!
Aggressive chemotherapy more effective
Which therapy matters
13% were amputated
Adjuvant/neo-adjuvant therapy: CT + RT
-70% of pts affected by large, G3, STS are cured by CT+RT
- After, “more” chemo is useless
-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
Doxorubicin and its friends
Adjuvant/neo-adjuvant therapy: what’s next?
Study design
Relapse Free Survival is superior with anthracycline + ifosfamide
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
P=0.004
Median FU: 12.34 months (IQ range: 25.45)
0.62
0.38
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
P=0.033
Overall Survival is superior with anthracycline + ifosfamide
Median FU: 12.34 months (IQ range: 25.45)
0.89
0.64
RFS by histology subtype
Abs#10517 Hendifar et al, ASCO 2013
RANDOMIZED PHASE III TRIAL OF TRABECTEDIN VERSUS DOXORUBICIN- BASED CHEMOTHERAPY AS FIRST-LINE THERAPY IN
TRANSLOCATION-RELATED SARCOMAS
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
UPS, DDLPS, pleoLPS
>5 cm G2-3
>50% DM @2 yrs
R A N D O M I Z A T I O N
RT (50 Gy)
Pembro 200 mg x 3
Phase 2 randomized trial
1:1
S U R G E R Y RT (50 Gy)
Pembro 200 mg x 14
SARC 032 / NCT03092323
matched population total population
0,0%
5,0%
10,0%
15,0%
20,0%
25,0%
30,0%
35,0%
40,0%
Doxorubicin alone Doxorubicin + ifosfamide
Doxorubicin + Dacarbazine
25,6%
19,5%
30,9%
25,9%
21,5%
36,8%
