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!

lorenzo.dambrosio@ircc.it