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

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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
.
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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
.
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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
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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
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Palliative chemotherapy for STS?
Cancer 2008 112 1585-1591
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Palliative chemotherapy for STS?Multivariate
Analysis of Factors Predictive of Overall Survival
Cancer 2008 112 1585-1591
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Palliative chemotherapy for STS?
Cancer 2008 112 1585-1591
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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
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Adjuvant Chemotherapy for Soft Tissue Sarcomas
evidences
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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
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2008 meta-analysis of adjuvant CT in STS Distant
Recurrence
Pervaiz et al. Cancer 2008 (online). DOI
10.1002/cncr.23592
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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
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Neoadjuvant Chemotherapy for Soft Tissue
Sarcomas evidences
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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?

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Diagram of therapeutic regimen in RTOG 9514
Kraybill, W. G. et al. J Clin Oncol 24619-625
2006
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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
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Adverse events in RTOG 9514
Kraybill, W. G. et al. J Clin Oncol 24619-625
2006
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• 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

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Soft tissue Sarcomaa heterogeneous group of
diseases
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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
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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
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Molecular heterogeneity of liposarcomas
Baird, K. et al. Cancer Res 2005659226-9235
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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)

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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

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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
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100
80
60
40
20
0
1960
1970
1980
1990
2000
2010
2020
2030
2040
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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
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Outcome of Advanced Gastrointestinal Stromal
Tumor (GIST) Patients Treated With Imatinib
MesylateFour-Year Follow-Up of a Phase II
Randomized Trial.
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KIT and PDGFRA mutations in GIST
Heinrich, M. C. et al. J Clin Oncol 214342-4349
2003
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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
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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
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Sunitinib (Sutent)
Demetri. Lancet 2006368 1329
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GIST Beyond Imatinib/Sunitinib
(ASCO08)Nilotinib Sorafenib Everolimus
IPI 504 IGF1RI CT ??
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Sorafenib in GIST resistant to Imatinib
Sunitinib
Wiebe. ASCO 2008
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IPI-504Targeting HSP90 in GIST
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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
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Imatinib and Chordoma
Casali P. Cancer 2004 1012086
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Imatinib in Desmoid Tumours
Heinrich. JCO 2006 241195
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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
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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
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Trabectidin (ET 743) metastatic bone sarcoma
Partial Response after 4 cycles
Baseline
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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
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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
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Anti-IGF1-R in STS
Olmos D. ASCO 2008 10501
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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

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Sorafenib in STS
Maki R. ASCO 2008
Ryan C / von Mehren M. ASCO 2008
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Sunitinib in STS
Keohan M. ASCO 2008
Vigil C. ASCO 2008
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Gemcitabinedocetaxelbevacizumabin STS
Verschraegen C. ASCO 2008
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Temozolomide bevacizumab in hemangiopericytome
Park MS. ASCO 2008
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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

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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.

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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

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Thank for your attention