La chemioterapia neoadiuvante nei sarcomi: novità...
Transcript of La chemioterapia neoadiuvante nei sarcomi: novità...
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
inflammatory
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
RA
DIO
THER
AP
IST
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%
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
D’Ambrosio L, et al. Abs#11574 ASCO 2018
Doxo + DTIC for LMS?
Overall Response Rate
Retroperitoneal LMS
SURGERY alone
Doxorubicin + DTIC x 3
R
A
N
D
O
M
I
Z
A
T
I
O
N
1:1
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.
Phase 3 Randomized trial
SURGERY
Doxo + DTIC for LMS – STRASS2
Localized High Risk STS of extremities/trunk wall
Conclusions
Chirurgia
unica strategia
curativa
R0
RFS / PFS
OS
Chemioterapia
dose-intense
preoperatoria
If you make the step, do it right!
THANKS FOR YOUR KIND ATTENTION!