Avances en el Tratamiento de los
Sarcomas de Partes Blandas:
De la Quimioterapia a los fármacos antidiana
Xavier García del Muro Solans
Institut Català d’Oncologia. Barcelona
SOFT TISSUE SARCOMA: TREATMENT RESULTS
• Primary treatment of extremity STS with wide excision and
radiotherapy achieves more than 90% control success
• However, 5-year overall survival in the group of patients of
high-risk is 50%, because of development of metastases
• Some selected patients with
isolated pulmonary metastases could
benefit from surgery, achieving up to
20% of long-term survivors. For the
rest of pts, chemotherapy is the only available treatment
Van Glabbeke M. J Clin Oncol 1999
RESULTS OF CURRENT CHEMOTHERAPY IN ADVANCED STS:
Prognostic factors for the outcome of chemotherapy in 2185 pts
with STS treated with anthracycline-containing first-line regimens
• Retrospective analysis of 2185
pts with STS included in 7
EORTC clinical trials
• 1st-line Chemo including
anthracyclines: Doxorubicine,
Epirubicine, Doxo-IFX, Cyvadic
• RR (CR + PR): 26%
• Overall Survival: 51 weeks
Combination Chemotherapy in Soft Tissue Sarcoma
Study Drug N RR Survival
ECOG Doxorubicin 93 19% 8 mo
Doxorubicin + DTIC 95 13% 8 mo
SWOG Doxorubicin + DTIC 79 32% 9 mo
Doxo + DTIC + cytoxan 95 35% 10.5 mo
ECOG Doxorubicin 90 20% 9 mo
Doxorubicin + Ifosfamide 88 34% 12 mo
ISSG Doxorubicin + DTIC 170 17% 13 mo
MAID 166 32% 12 mo
EORTC Doxorubicin 212 24% 12 mo
Doxorubicin + Ifosfamide 202 27% 12 mo
Doxorubicin alone remains the standard treatment altough a combination
regimen seems justified when obtainig a response is important
Doxo continues being standard 1st-line treatment and HD regimens should only be used in clinical trials
132 pts from 23 centers from Spain and Portugal
Treatment Schedule:
ARM A: Doxorubicin 75 mg/m2
ARM B: DOX 90 mg/m2 + G-CSF q 2 wk x 3 cycles plus IFOS 12.5 gr/m2 + G-CSF q 3wk x 3 cycles
Study Design:Randomized phase II study. Endpoint: PFS. Premature closure if less than 25% RR differences
PICASSO 3: A phase 3 international, randomized, double-blind, placebo-
controlled study of doxorubicin plus palifosfamide vs. dox plus placebo for
patients in first-line for metastatic soft tissue sarcoma
C.W. Ryan, P. Schoffski, O. Merimsky, M. Agulnik, J.Y. Blay, S.M. Schuetze, J.Y. Buck,
X. Garcia del Muro, I.R. Judson, R.G. Maki
ESMO 2013 • 447 pts with mSTS randomized to
receive pali+dox (n=226) or
placebo+dox (n=221)
• Median PFS was 5.98 months for
pali+dox compared with 5.23
months for placebo+dox (HR=0.87,
95%CI 0.70–1.07; p=0.18)
• At interim analysis, median overall
survival was 15.91 months for
pali+dox vs 16.89 months for
placebo+dox (HR=1.05, 95%CI
0.79–1.39; p=0.74)
Incorporating new drugs in
the treatment of soft
tissue sarcoma:
- Chemotherapy
- Targeting agents
Stacchiotti S. Radiology 2009
RECIST RESPONSE CRITERIA ARE NOT ALWAYS USEFUL TO
IDENTIFY ACTIVITY
Correlation between Radiologic and Pathologic Response
by Using RECIST and Choi Criteria
New method for identifying active drugs in STS in clinical trials, based on the PFR at 3 m. found
in EORTC database. They establish a PFR at 3 m in pretreated pts for active and inactive agents
q3wk 24-h
n=136
qwk 3-h
n=134
Stats
n=270
206 events 104 102
Median, mo. 3.7 2.3 HR: 0.734 p=0.0302
Predictive impact of DNA repair functionality on clinical
outcome of advanced sarcoma treated with Trabectedin
Schöffski P. EJC 2011
16.8 m vs 8.2 m (HR, 0.56; 95% CI, 0.36 to 0.90; P .014) 4.2 m vs 2 m (HR, 0.58; 95% CI, 0.39 to 0.86; P .005)
Randomized phase II trial of Gemcitabine +/-
Docetaxel in advanced STS
Maki R. JCO 2007
Ensayo Fase I/II de Doxorubicina seguida
de Gemcitabina en SPB. Estudio GEIS
• Ptes con SPB avanzado sin Tto previo
• Esquema Tto:
Doxorubicina 60 mg/m2, d 1
Gemcitabina 800 mg/m2 en 80 m. d 1 y 8
• Fase II, 47 pts eval.:
Actividad: RR 19.5 % (CI 95%; 8-31)
Toxicidad: Neutropenia G4:49%, Mucositis G3:46%
Reducción dosis >40% pts
Lopez Pousa. Br J Cancer 2006
RANDOMIZED PHASE II TRIAL OF
TRABECTEDIN PLUS DOXORUBICIN VS
DOXORUBICIN IN ADVANCED STS
Study Design
Arms
Random
Assigment
1:1
Doxorubicin75mg/m23wx6cycles Followup
Trabectedin1.1mg/m2+Doxorubicin/3w60mg/m23wx6cycles FollowUp
CONTROL ARM
EXPERIMENTAL ARM
Clinical and Radiological every 6
weeks
ASSOCIATED STUDIES Pathologic Independent Review (done)
Radiological Independent Review (in process) Translational Research (in process)
Stratification Factor:
M1 ≤12m vs >12m
Control Arm
Experim Arm
P= 0.20
Months
Efficacy Data Progression Free Survival
Efficacy Data Survival
ControlArm(59)
ExperimentalArm(55)
p
MedianPFS(months)PFSat6mPFSat12m
5.80(3.5-8)49%26%
5.7(2.9-8.5)48%15%
0.20
MedianOS(months)OSat6mOSat12m
15.1(7.2-23)81%53%
13.3(10.1-16.5)77%54%
0.51
HR(IC95%) P
PFS 1.31(0.86-1.98) 0.20
OS 1.18(0.72-1.96) 0.51
Risk Reduction in Experimental Arm Martín Broto et al. ESMO 2013
SOFT TISSUE
SARCOMA: 60 subtypes
Updated WHO 2012
classification reflecting
relationship among
lineages and
prognosis:
- Malignant
- Locally aggressive
- Rarely metastasizing
Are there differences in chemosensitivity between
histopathologic STS subtypes
Subtype Chemotherapy Uterine Leiomyosarcoma GEM+DOC Temozolomide Synovial Sarcoma HD-IFOS Scalp Angiosarcoma Paclitaxel Caelyx Mixoid Liposarcoma Trabectedin Doxorubicin
Should clinical trials be performed on specific subtypes instead of all STS?
Pathways for Targeted Therapy in Sarcoma
VEGFR inhibitors in Specific Sarcoma Types
• Cediranib for metastatic alveolar soft part sarcoma
Phase II study with 43 evaluable pts
RR 35% PR+SD at 24 wk: 84%
Kummar et al. J Clin Oncol 2013
• Sunintib in solitary fibrous tumor
Observational study with 35 pts
2 PR 16 SD 14 Choi R mPFS 6 months
Stacchiotti et al. Ann Oncol 2012
• Temozolomide plus bevacizumab in hemangioperic.-SFT
Observational study with 14 pts
79% Choi R mPFS 9.7 months
Park et al. Cancer 2011
• Sorafenib in advanced angiosarcoma
Phase II study in superficial (26) and visceral (15) angiosarc.
mPFS 1.8 and 3.8 m, respectively
Ray-Coquard et al. Oncologist 2012
La inactivación del gen supresor PTEN en líneas musculares en ratones se
asocia al desarrollo de leiomiosarcomas con activación constitutiva de mTOR
Hernando E. Nat Med 2007
Wagner A. JCO 2010
Dermatofibrosarcoma protuberans
• 10 pts con DFSP fueron tratados con Imatinib 400 mg/12h
• 8 pts con DFSP localmente avanzado t(17;22): 4 RC / 4 RP
• 2 pts con DFSP metastásico con APª de fibrosarcoma, cariotipos más complejos: 1 pts t(17;22): RP y 1 pte no: PRO
• Imatinib es activo frente a DFSP con t(17;22), y parece no serlo en las variantes fibrosarcomatosas que carecen de ella
McArtur. JCO 2005
IMATINIB in Aggressive Fibromatosis (Desmoid Tm)
• Clinical and molecular studies of imatinib on advanced aggressive
fibromatosis
19 pts included, 3 RP (15%) and 4 SD >1y; PFR at 1y: 37%
16 pts WNT pathway mutations (APC or CTNNB1).
High plasma levels of PDGF-A and PDGF-B
Heinrich MC et al J Clin Oncol 2006
• Efficacy of Imatinib in Aggressive Fibromatosis:Phase II SARCtrial
51 pts included; PR 6%; PFR at 1y: 66%
Chugh R et al. Clin Cancer Res 2010
• Imatinib for progressive and recurrent aggressive fibromatosis:
FNCLCC/FSG Phase II trial
40 pts included; PR 12%; PFR at 1y: 66%; at 2y: 55%
Penel N et al. Ann Oncol 2011
Barretina J. Nat Genet 2010
• The efficacy of the current available treatments for
advanced sarcomas is limited and research is needed in
this field
• Participation in cooperative groups and Intergroup
collaboration should be encouraged to investigate
several of the important questions concerning sarcomas
• Close collaboration between clinicians and basic
researchers is necessary to design studies that will
provide answers to outstanding questions
Final Comments