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Title: Chemotherapy in Soft Tissue Sarcoma: Evidences and New agents


1
Chemotherapy in Soft Tissue SarcomaEvidences
and New agents
  • Dr. Hernan Cortes-Funes
  • Servicio de Oncologia Medica

5th International Conference of the International
Society of Intraoperative Radiation
Therapy ISIORT 2008 , Madrid
2
Sarcomas
  • More than 50 histopathological subtypes
  • After initial therapy, local control is achieved
    in 80 patients
  • OS_at_5y 50 (death from metastases)
  • Selected patients with metastases (operable lung
    mets) OS_at_5y 25
  • For the remaining, the only available therapy is
    chemotherapy
  • Median survival 12 months
  • In round cell sarcomas (Rhabdo, Ewing) and bone
    sarcoma, chemotherapy is an essential part of
    initial therapy

3
Chemotherapy (CT) in Soft-Tissue Sarcomas (STS) -
Evidences
  • In advanced disease
  • In adjuvant setting of therapy
  • In Neoadjuvant setting
  • Towards a histology-driven CT
  • New agents for the treatment of STS

4
Chemotherapy for advanced disease evidences
5
Chemotherapy in STS
  • Classic Agents RR()
  • Doxorubicin 15-25
  • Ifosfamide 25
  • DTIC 18
  • New approaches
  • Liposomal Doxorubicin 10
  • High-dose Ifosfamide 14-38
  • Recently incorporated drugs
  • Gemcitabine - Docetaxel 6-18
  • Temozolomide 15
  • Trabectedin 4-8

6
Chemotherapy in STS single vs multiagent
  • Meta-analisis from eight randomized studies with
    CT on 2281 patients comparing
  • DOX (single agents) vs Combo (DOX based)
  • fixed effect model
  • Combo better than single agent in response
  • (OR 1.29 95 CI, 1.03 to 1.60 p 0.03)
  • random effects model
  • OR in not better (pooled analysis)
  • (OR 1.26 95 CI, 0.96 to 1.67 p 0.10)

Bramwell VHC, Anderson D, Charette ML, Sarcoma
Disease Site Group (see Acknowledgements).
Doxorubicin-based chemotherapy for the palliative
treatment of adult patients with locally advanced
or metastatic soft tissue sarcoma. Cochrane
Database of Systematic Reviews 2001, Issue 4.
Art. No. CD003293. DOI 10.1002/14651858.CD003293
.
7
Chemotherapy in STS single vs multiagent (cont.)
  • No significant difference between the two
    regimens was detected in the pooled data on
  • - one-year mortality rate (OR 0.87 95 CI,
    0.73 to 1.05 p0.14) and
  • - two-year mortality rate (OR 0.84 95 CI,
    0.67 to 1.06 p0.13)
  • Although reporting of adverse effects was limited
    and inconsistent among trials, adverse effects
    (nausea/vomiting and hematologic toxic effects)
    were consistently worse with combination
    chemotherapy.

Bramwell VHC, Anderson D, Charette ML, Sarcoma
Disease Site Group (see Acknowledgements).
Doxorubicin-based chemotherapy for the palliative
treatment of adult patients with locally advanced
or metastatic soft tissue sarcoma. Cochrane
Database of Systematic Reviews 2001, Issue 4.
Art. No. CD003293. DOI 10.1002/14651858.CD003293
.
8
Chemotherapy in STS adding Ifosfamide to a
Doxo-based regimenTumor response (complete or
partial)
Verma. Cancer Treat Rev. 2008 Jun34(4)339-347.
Epub 2008 Mar 3
9
Chemotherapy in STS adding Ifosfamide to a
Doxo-based regimenTumor response (complete or
partial)
Verma. Cancer Treat Rev. 2008 Jun34(4)339-347.
Epub 2008 Mar 3
10
Chemotherapy in STS Adding Ifosfamide to a
Doxo-based regimenOne year mortality
Verma. Cancer Treat Rev. 2008 Jun34(4)339-347.
Epub 2008 Mar 3
11
Chemotherapy in STS Adding Ifosfamide to a
Doxo-based regimenOne year mortality
Verma. Cancer Treat Rev. 2008 Jun34(4)339-347.
Epub 2008 Mar 3
12
Palliative chemotherapy for STS? The Royal
Marsden Hospital's sarcoma database (1991-2005)
  • 488 patients, median age 49 years, the majority
    (83) received chemotherapy for metastatic
    disease.
  • The most common histologic subtypes were
  • leiomyosarcoma (35)
  • synovial sarcoma (13),
  • liposarcoma (10), and
  • malignant fibrous histiocytoma (10).
  • 61 received single-agent chemotherapy, usually
    doxorubicin.
  • Response evaluation
  • objective response was reported in 33 of
    patients (53 in those with synovial sarcoma)
  • 22 had stable disease
  • 45 derived clinical benefit (objective responses
    stable disease for 6 months).
  • median duration of response was 9 months
  • median post-treatment overall survival (OS) was
    12 months


Cancer 2008 112 1585-1591
13
Palliative chemotherapy for STS?
Cancer 2008 112 1585-1591
14
Palliative chemotherapy for STS?Multivariate
Analysis of Factors Predictive of Overall Survival
Cancer 2008 112 1585-1591
15
Palliative chemotherapy for STS?
Cancer 2008 112 1585-1591
16
Palliative chemotherapy for STSConclusions
  • Palliative chemotherapy in advanced STS should be
    regarded as a standard treatment option, with
    approximately half of patients deriving clinical
    benefit.
  • Doxorubicin-based combination regimens may be
    associated with superior survival to that
    achieved with doxorubicin alone, although this
    has yet to be confirmed in prospective randomized
    trials.
  • Other factors predictive of superior survival
    included younger age, absence of bone
    metastases, and synovial or liposarcoma
    histology.
  • Despite the short-term benefits of chemotherapy
    for certain patient subgroups, continuing
    research into new therapeutic agents for STS is
    required to improve the treatment of patients
    with locally advanced and metastatic disease,
    whose long-term outlook remains bleak.

Cancer 2008 112 1585-1591
17
Adjuvant Chemotherapy for Soft Tissue Sarcomas
evidences
18
Pervaiz et al. Cancer 2008 (online). DOI
10.1002/cncr.23592
19
2008 meta-analysis of Adjuvant CT in STSLocal
Recurrence
Pervaiz et al. Cancer 2008 (online). DOI
10.1002/cncr.23592
20
2008 meta-analysis of adjuvant CT in STS Distant
Recurrence
Pervaiz et al. Cancer 2008 (online). DOI
10.1002/cncr.23592
21
2008 meta-analysis of adjuvant CT in STSOverall
Survival
Pervaiz et al. Cancer 2008 (online). DOI
10.1002/cncr.23592
22
2008 meta-analysis of adjuvant CT in STS
Pervaiz et al. Cancer 2008 (online). DOI
10.1002/cncr.23592
23
Neoadjuvant Chemotherapy for Soft Tissue
Sarcomas evidences
24
Strategies for neoadjuvant CT
  • Radiochemotherapy
  • Still to be explored adequately
  • Only comparison respect to historical controls
  • Systemic chemotherapy
  • Not proven to be effective yet
  • Systemic chemotherapy plus hypertermia
  • EORTC 62961 sole prospective phase III (positive
    in PFS and OS) - feasibility?
  • Isolated limb perfusion
  • Consistent large phase II data.
  • No randomized comparisons. Feasibility?

25
Diagram of therapeutic regimen in RTOG 9514
Kraybill, W. G. et al. J Clin Oncol 24619-625
2006
26
Kaplan-Meier curves of overall survival (OS),
distant-disease-free survival (DDFS),
disease-free survival (DFS), distant metastases
(DM), and cumulative incidence curves of time to
local-regional failure (LRF)
Kraybill, W. G. et al. J Clin Oncol 24619-625
2006
27
Adverse events in RTOG 9514
Kraybill, W. G. et al. J Clin Oncol 24619-625
2006
28
  • Apart from this study, the literature evaluating
    clinically meaningful down staging
  • is limited, and the ambiguity in the eligibility
    criteria in the report from Kraybill et al does
    not allow us to shed further light on this
    important issue.
  • STS will require improved understanding of
    sarcoma biology, new drugs,
  • histology-specific trials, improved industry and
    government support, and novel forms
  • of collaboration

29
Soft tissue Sarcomaa heterogeneous group of
diseases
30
Histological diversity of STSWHO classification
  • Tumors of adipose tissue
  • So-called fibrohistiocytic tumors
  • Tumors of skeletal muscle
  • Tumors of smooth muscle
  • Tumors of blood and lymph vessels
  • Fibroblastic and myofibroblastic tumors
  • Tumors of cranial and peripheral nerves
  • Extraskeletal cartilaginous and osseous tumors
  • Tumors of uncertain histogenesis

Fletcher, CDM, Unni, KK, Mertens, F, Eds.
Pathology and Genetics of tumours of soft tissue
and bone. Lyon, IARC 2002
31
Histological diversity of STS
  • Perivascular tumors
  • Malignant
  • Malignant glomus tumor
  • Tumors of blood and lymph vessels
  • Intermediate (locally aggressive)
  • Kaposiform hemangioendothelioma
  • Intermediate (rarely metastasizing)
  • Hemangioendothelioma, retiform and composite
  • Papillary intralymphatic angioendothelioma
  • Kaposis sarcoma
  • Malignant
  • Angiosarcoma
  • Epithelioid hemangioendothelioma Tumors of
    cranial and peripheral nerves
  • Malignant
  • Malignant peripheral nerve sheath tumor (MPNST,
    neurofibrosarcoma)
  • Malignant Triton tumor (MPNST with
    rhabdomyosarcoma)
  • Malignant granular cell tumor
  • Gastrointestinal autonomic nerve tumor
    (plexosarcoma)
  • Primitive neuroectodermal tumor (PNET) (including
    extraskeletal Ewing sarcoma, neuroblastoma, and
    peripheral neuroectodermal tumor
    neuroepithelioma)
  • Tumors of adipose tissue
  • Intermediate (locally aggressive)
  • Atypical lipoma/well-differentiated liposarcoma
  • Malignant
  • Dedifferentiated liposarcoma
  • Myxoid liposarcoma
  • Pleomorphic liposarcoma
  • Round cell liposarcoma, Mixed-type liposarcoma
  • So-called fibrohistiocytic tumors
  • Intermediate (rarely metastasizing)
  • Plexiform fibrohistiocytic tumor
  • Giant cell tumor of soft tissues
  • Malignant
  • Pleomorphic malignant fibrous histiocytoma
    (MFH)/undifferentiated pleomorphic sarcoma
  • Giant cell MFH/undifferentiated pleomorphic
    sarcoma with giant cells
  • Inflammatory MFH/undifferentiated pleomorphic
    sarcoma with prominent inflammation
  • Tumors of skeletal muscle
  • Malignant
  • Rhabdomyosarcoma

Fletcher, CDM, Unni, KK, Mertens, F, Eds.
Pathology and Genetics of tumours of soft tissue
and bone. Lyon, IARC 2002
32
Molecular heterogeneity of soft tissue sarcomas
Baird, K. et al. Cancer Res 2005659226-9235
33
Molecular heterogeneity of liposarcomas
Baird, K. et al. Cancer Res 2005659226-9235
34
Connective Tissue Tumours Molecular Genetic
typing 5 types of sarcomas
  • Associated with specific translocations
    generating fusion genes
  • Ewing / PNET t (1122)
  • Synovial sarcoma t (X18)
  • Alveolar rhabdomyosarcoma t (113), t (213)
  • Desmoplastic small round cell tumor 1 (1122)
  • Etc
  • Kinase mutations (c-kit, PDGFR in GIST)
  • Gene inactivation (INI1 in rhabdoid tumours)
  • Simple genetic alterations (amplification mdm2
    cdk4 in liposarcoma)
  • Complex genetic alterations (leiomyosarcoma,
    malignant fibrohystiocytoma)

35
Selected agents for selected subtypes
  • Histotypes Drugs
  • GIST Imatinib, Sunitinib
  • Synovial sarcoma Ifosfamide
  • Angiosarcoma Taxanes, Vinorelbine
  • Leiomyosarcoma DTIC / TMZ, Trabectedin
  • Uterine LMS Gemcitabine /- Docetaxel
  • Endometrial Stromal sa Hormone therapy
  • Liposarcoma Doxorubicin

36
Kaplan-Meier curves for (A, B) progression-free
survival (PFS) and (C, D) overall survival (OS)
for patients with Eastern Cooperative Oncology
Group (ECOG) performance status (A, C) 0 and (B,
D) more than 0 in the gemcitabine and
gemcitabine-docetaxel arms
Maki, R. G. et al. J Clin Oncol 252755-2763 2007
37
100
80
60
40
20
0
1960
1970
1980
1990
2000
2010
2020
2030
2040
38
New Agents for STS
  • Biologic Small molecules (TKI) in clinic
  • Imatinib (Glivec)
  • AntiVEGFR
  • Sunitinib (Sutent)
  • Sorafenib (Nexavar)
  • Bevacizumab (Avastin
  • New Cytotoxic
  • Trabectidin (Yondelis)
  • Early clinical studies
  • IGF1RIs (GP, Mx)
  • mTOR I (Everolimus)
  • Nilotinib, Desitinib
  • IPI 504

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G. Demetri et al. NEJM 2002 347(7) 472-80
46
Outcome of Advanced Gastrointestinal Stromal
Tumor (GIST) Patients Treated With Imatinib
MesylateFour-Year Follow-Up of a Phase II
Randomized Trial.
47
KIT and PDGFRA mutations in GIST
Heinrich, M. C. et al. J Clin Oncol 214342-4349
2003
48
GIST Imatinib-associated OS and KIT genotype
(US experience)
Exon 11
Exon 11
Exon 9
Exon 9
No mutation
No mutation
Heinrich, M. C. et al. J Clin Oncol 214342-4349
2003
49
Imatinib-associates OS and KIT genotype
(European experience)
Exon 11
Exon 9
No mutation
Exon 11
No mutation
Exon 9
Debiec-Rychter et al. EJC 2006 1093-1102
50
Sunitinib (Sutent)
Demetri. Lancet 2006368 1329
51
GIST Beyond Imatinib/Sunitinib
(ASCO08)Nilotinib Sorafenib Everolimus
IPI 504 IGF1RI CT ??
52
Sorafenib in GIST resistant to Imatinib
Sunitinib
Wiebe. ASCO 2008
53
IPI-504Targeting HSP90 in GIST
54
Imatinib and Dermatofibrosarcoma Protuberans
DFSP)
DFSP cells characteristically contain the
translocation t(1722)(q22q13). This
translocation brings the platelet-derived growth
factor -chain gene (PDGFB) under control of the
collagen type 1 1 (COL1A1) promoter, which
appears to generate an autocrine loop involving
functional PDGF, causing stimulation of tumor
growth.
June 2001
Nov 2001
Maki RG. Int J Cancer 2002 100623
55
Imatinib and Chordoma
Casali P. Cancer 2004 1012086
56
Imatinib in Desmoid Tumours
Heinrich. JCO 2006 241195
57
Imatinib in Desmoid Tumours
18F (FDG)-PET-C. Imatinib treatment resulted in
a marked reduction in tumor-associated glucose
uptake even though there was no change in overall
tumor size. (A) Baseline (B) 12 months of
imatinib treatment.
Heinrich. JCO 2006 241195
58
Trabectidin ET 743 (Yondelis)
O
C
H
3
H
O
O
C
O
C
H
3
N
C
H
3
S
N
O
O
H
O
O
O
C
H
O
3
N
H
Class Tunicate Taxonomy Ecteinascidia
turbinata Original Source Caribbean
Mediterranean Sea
H
O
59
Trabectidin (ET 743) metastatic bone sarcoma
Partial Response after 4 cycles
Baseline
60
Trabectedin (Yondelis) in Myxoid Liposarcoma
radiological findings
Patient 26 MRI of left thigh showing progressive
decrease of contrast enhancement without tumour
shrinkage Baseline (A) after one course (B)
and after four courses of trabectedin (C).
Patient 21 Sequential CT scans of abdominal
tumour displaying a decrease in tumour density
followed by a decrease in tumour dimensions
Baseline (A) after one course (B) after five
courses (C) after eight courses (D) and after
11 courses of trabectedin (E).
Grosso F. Lancet Oncol 2007 8595
61
Trabectedin (Yondelis) in Myxoid Liposarcoma
pathological findings
Patient 26 Pretreatment (A) and post-treatment
(B) stained with haematoxylin and eosin
pretreatment (C) and post-treatment (D) with
immunostaining with CD31 highlighting the
vascular network.
Patient 21 (haematoxylin and eosin) before
treatment (A) and after treatment (BD) B,
deposition of sclerohyaline material and cellular
depletion C, mature lipoblast-featuring cells
D, necrosis.
Grosso F. Lancet Oncol 2007 8595
62
Anti-IGF1-R in STS
Olmos D. ASCO 2008 10501
63
Anti-VEGF therapy in sarcoma
  • Sarcomas are vascular neoplasms
  • VEGF plasma levels correlate with sarcoma grade
    and extent of disease
  • Sarcoma expression of HIF-1 alpha is an
    independent predictor of survival
  • Sarcoma VEGF expression correlates with tumor
    grade and risk of recurrence
  • VEGF receptors detected in sarcomas
  • Inhibition of HIF-1 a and VEGFR pathways
    associated with sarcoma response in preclinical
    models

64
Sorafenib in STS
Maki R. ASCO 2008
Ryan C / von Mehren M. ASCO 2008
65
Sunitinib in STS
Keohan M. ASCO 2008
Vigil C. ASCO 2008
66
Gemcitabinedocetaxelbevacizumabin STS
Verschraegen C. ASCO 2008
67
Temozolomide bevacizumab in hemangiopericytome
Park MS. ASCO 2008
68
Chemotherapy for Soft-Tissue Sarcomas
Conclusions (1)
  • 1.- Standard Chemotherapy is a palliative
    procedure for advance disease
  • 2.- Combination chemotherapy in advanced patients
    produce a high response rate in young symptomatic
    patients with good clinical situation (PS), or
    locally advanced disease
  • 3.- After decades of treatments with
    anthracyclines, Ifosfamide and/or Dacarbacine
    several new agents have been demonstrate activity
    in some type of STS such as
  • Gemcitabine (alone or in combination with
    docetaxel)
  • Trabectidine
  • 4.- In the future we will design treatment guided
    by histologic type of sarcoma

69
Chemotherapy for Soft-Tissue Sarcomas
Conclusions (2)
  • 5.- Gastrointestinal Stroma Tumors (GIST) is a
    evident example of the evolution of knowledge of
    the molecular biology of tumor behavior and the
    specific design of agents against point mutation
    (c-kit, PDGFR..).
  • 6.- At the present time we have several
    therapeutic lines for sensitive, resistant and
    relapsing patients, producing survival benefit
  • 7. There are an important basic and clinical
    research programs for new drugs against new
    molecular targets for GIST related and other
    types of sarcomas.

70
Chemotherapy for Soft-Tissue Sarcomas
Conclusions (3)
  • 8.- The majority of clinical studies with
    biologic agents still in early phases and some of
    them such as antiangiogenic agents, mTOR
    inhibitors which have shown some preliminary
    positive data. Nevertheless we need more time to
    allocate it into the standard use for advanced or
    resistant patients.
  • 9.- Adjuvant treatment after surgical removal was
    no prove to the effective in STC and must no be
    considerer as standard
  • 10.- Preoperative chemotherapy combined with XRT
    still under investigation and could be effective
    in some selective cases

71
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