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FACULTY
George D. Demetri, MD
Dana-Farber Cancer Institute
Kristen N. Ganjoo, MD
Stanford University Medical Center
Alexander Lazar, MD, PhD
MD Anderson Cancer Center
Richard F. Riedel, MD
Duke Cancer Institute
WELCOME AND INTRODUCTION
George D. Demetri, MD – CHAIR
HISTOPATHOLOGY, DIAGNOSTIC
EVALUATION, AND STAGING OF NONGIST SOFT TISSUE SARCOMAS
Alexander Lazar, MD, PhD
MD Anderson Cancer Center
Soft Tissue Sarcomas
• Rare tumors
• < 1% of adult solid
tumors
• US: 12,000 new
cases
• 4,700 deaths
• Incidence appears
to be increasing …
NCI (2014)
http://www.cancer.gov/researchandfunding/progress/snapshots/sarcoma.
Siegel RL, et al. CA Cancer J Clin. 2015;65(1):5-29.
Fletcher CDM. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon, France: IARC Press; 2013.
NCI (2014) http://www.cancer.gov/researchandfunding/progress/snapshots/sarcoma.
Sarcoma Classification
• Can be challenging
• Heterogeneous group of tumors with > 50 histological
subtypes, each with varying clinical phenotypes and
behavior
• Some tumors are unclassifiable
• Many benign entities (100:1), some of which can be
confused for sarcomas
Sarcoma Classification:
Morphology
• Round cell tumor,
epithelioid, spindle cell
sarcoma
• Useful in unclassifiable
tumors
• Does not always
provide information on
behavior or nature of
tumor
• Important to determine
malignant potential if
possible
Histogenesis/Line of Differentiation
UPS/MFH
Osteosarcoma
Chondrosarcoma
Leiomyosarcoma
Rhabdomyosarcoma
Angiosarcoma
Liposarcoma
Synovial Sarcoma - ??
MPNST
ASPS - ??
Ewing Sarcoma/PNET - ??
UPS, undifferentiated pleomorphic sarcoma; MPNST, malignant peripheral nerve sheath tumors; ASPS, alveolar
soft part sarcoma; PNET, primitive neurectodermal tumors.
Courtesy of Dr Brian Rubin, Cleveland Clinic.
2013 WHO Classification
• Classifies tumors based
on:
– Line of differentiation
– Biological potential
– (Molecular features)
Fletcher CDM. WHO classification of tumours of soft tissue and bone. 4th ed. Lyon, France: IARC Press; 2013.
Question 1
Despite pathologists giving soft tissue sarcomas more than
50 different names, all sarcomas basically behave alike.
1. True
2. False
3. I don’t know
Line of Differentiation
• Morphologically or by
immunohistochemical
studies
• Beware of mimics
• Some tumors lack a
normal counterpart (ie,
synovial sarcoma)
• Not all tumors with similar
differentiation will behave
the same
ALT
PLPS
A-RMS
Myogenin
ALT, atypical lipomatous tumor; PLPS, pleomorphic liposarcoma; A-RMs, rhabdomyosarcoma.
Soft Tissue Classification:
Biological Potential
Benign:
Usually do not
recur;
recurrences
usually nondestructive,
almost never
metastasizes
Lipoma
Intermediate
Intermediate
(locally
(rarely
aggressive):
metastasizing):
Often recur,
Locally aggressive
infiltrative and but can give rise to
destructive
metastasis (< 2%)
Desmoid
Angiomatoid FH
Malignant:
Recurs,
destructive,
high risk of
metastasis
Synovial Sarcoma
•


-
•



-
Adipocytic tumors
Intermediate
Atypical lipomatous tumors/well differentiated
liposarcomas
Malignant
Dedifferentied liposarcoma
Myxoid/round cell liposarcoma
Pleomorphic liposarcoma
Liposarcoma, NOS
Fibroblastic/Myofibroblastic Tumors
Intermediate (locally aggressive)
Superficial and desmoid fibromatoses
Lipofibromatosis
Intermediate (rarely metastasizing)
Extrapleural solitary fibrous
tumor/hemangiopericytoma
Inflammatory myofibroblastic tumor
Low grade myofibroblastic sarcoma
Myxoinflammatory fibroblastic sarcoma
Malignant
Infantile fibrosarcoma
Adult fibrosarcoma
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma
Sclerosing epithelioid fibrosarcoma
•

-
Skeletal Muscle Tumors
Malignant
Embryonal rhabdomyosarcoma
Alveolar rhabdomyosarcoma
Pleomorphic rhabdomyosarcoma
•



-
Vascular Tumors
Kaposiform Hemangioendothelioma
Papillary intralymphatic angioendothelioma
Retiform, and composite hemangioendothelioma
Malignant
Epithelioid hemangioendothelioma
Angiosarcoma
•

•
Chondro-Osseous Tumors
Malignant
Mesenchymal chondrosarcoma
Extraskeletal osteosarcoma
Tumors of Peripheral Nerves

-
Malignant
Malignant peripheral nerve sheath tumor
Epithelioid malignant peripheral nerve sheath tumor
•

•
So-Called Fibrohistiocytic Tumors

Giant cell tumor of tendon sheath and diffuse variant
Plexiform fibrohistiocytic tumor


Malignant
Malignant fibrous histiocytoma/undifferentiated
pleomorphic sarcoma
•
Smooth Muscle Tumors

Malignant
Leiomyosarcoma
Rubin, et al. (2014) College of American Pathology guidelines.
Fletcher CDM. WHO classification of tumours of soft tissue and bone. 
4th ed. Lyon, France: IARC Press; 2013.
Tumors of Uncertain Differentiation
Angiomatoid fibrous histiocytoma
Ossifying fibromyxoid tumor
Soft Tissue Myoepithelioma/carcinoma
Malignant
Ewing Sarcoma
Synovial sarcoma
Epithelioid sarcoma
Alveolar soft part sarcoma
Clear cell sarcoma of soft tissue
Extraskeletal myxoid chondrosarcoma
Desmoplastic small round cell tumor
Extrarenal rhabdoid tumor
Intimal sarcoma
UNCLASSIFIED – Malignant Potential uncertain
2002
2013
Benign
Lipoma
Lipomatosis
Lipomatosis of nerve
Lipoblastoma/lipoblastomatosis
Angiolipoma
Myolipoma
Chondroid lipoma
Extra-renal angiomyolipoma
Extra-adrenal myelolipoma
Spindle cell/pleomorphic lipoma
Hibernoma
Benign
Lipoma
Lipomatosis
Lipomatosis of nerve
Lipoblastoma/lipoblastomatosis
Angiolipoma
Myolipoma of soft tissue
Chondroid lipoma
Extra-renal angiomyolipoma
Extra-adrenal myelolipoma
Spindle cell/pleomorphic lipoma
Hibernoma
Atypical lipomatous tumor / well differentiated
liposarcoma
Atypical lipomatous tumor/well differentiated
liposarcoma
Malignant
Dedifferentiated liposarcoma
Myxoid liposarcoma
Round cell liposarcoma
Mixed-type liposarcoma
Liposarcoma, not otherwise specified
Malignant
Dedifferentiated liposarcoma
Myxoid liposarcoma
Liposarcoma, not otherwise specified
Adapted from: Fletcher CDM. WHO classification of tumours of soft tissue and
bone. 3rd & 4th eds. Lyon, France: IARC Press; 2002 & 2013.
Adipocytic Tumors
Liposarcoma Classification
• Well differentiated liposarcoma
• (Dedifferentiated)
• Genetic amplification: 12q13~15
• Myxoid liposarcoma
• (Round cell)
• Translocation: t(12;16)(q13p11)
• DDIT3 & FUS (EWSR1)
• Pleomorphic liposarcoma
• Complex karyotype
• TP53 mutations
Tumors of Uncertain Differentiation
2002
Benign
Intramuscular myxoma
(including cellular variant)
Juxta-articular myxoma
Deep (“aggressive”)
angiomyxoma
Pleomorphic hyalinizing
angiectatic tumour
Ectopic hamartomatous
thymoma
Intermediate (rarely
metastasizing)
Ossifying fibromyxoid tumour
(incl. atypical, malignant)
Mixed tumour/myoepithelioma/
Parachordoma
Malignant
Synovial sarcoma
Epithelioid sarcoma
Alveolar soft-part sarcoma
Extraskeletal myxoid
chondrosarcoma
Extraskeletal Ewing sarcoma
Desmoplastic small round cell
tumour
Extra-renal rhabdoid tumour
Malignant mesenchymoma
Neoplasms with perivascular
epithelioid cell differentiation
(PEComa)
Clear cell myomelanocytic
tumor
Intimal sarcoma
2013
Benign
Acral fibromyxoma
Intramuscular myxoma (including
cellular variant)
Juxta-articular myxoma
Deep (“aggressive”)
angiomyxoma
Pleomorphic hyalinizing
angiectatic tumour
Ectopic hamartomatous
thymoma
Intermediate (locally
aggressive)
Haemosiderotic fibrolipomatous
tumor
Malignant
Synovial sarcoma (NOS, spindle
cell, biphasic)
Epithelioid sarcoma
Alveolar soft-part sarcoma
Extraskeletal myxoid
chondrosarcoma
Extraskeletal Ewing sarcoma
Desmoplastic small round cell
tumor
Extra-renal rhabdoid tumour
Neoplasms with perivascular
epithelioid cell differentiation
(PEComa)
PEComa NOS, benign
PEComa NOS, malignant
Intimal sarcoma
Intermediate (rarely
metastasizing)
Atypical fibroxanthoma
Ossifying fibromyxoid tumour
(benign, malignant)
Myoepithelioma
Myoepithelial carcinoma
Mixed tumor NOS (and
malignant)
Phosphaturic mesenchymal
tumor (benign, malignant)
Adapted from: Fletcher CDM. WHO classification of tumours of soft tissue and bone. 3rd & 4th eds. Lyon,
France: IARC Press; 2002 & 2013.
*
Question 2
Sarcoma grading is basically pathology bunk; it
provides little to guide treatment.
1. True
2. False
3. I don’t know
Grading of Sarcomas
• Attempt to assess the degree of malignancy (ie,
metastatic potential and death)
• Traditionally recognized as the most important
prognostic factor (other than stage)
Deyrup AT, Weiss SW. Histopathology. 2006;48(1):42-50.
Grading Systems
French Federation of Cancer Centers
Sarcoma Group
General
Grade 1:
Grade 2:
Grade 3:
total score of 2-3 points
Tumor differentiation:
1 point:
resembles normal adult mesenchymal tissue, may be confused with a benign lesion,
such as well differentiated liposarcoma
2 points: histologic typing is certain, such as myxoid liposarcoma
3 points: synovial sarcoma, osteosarcoma, Ewing’s sarcoma/PNET, sarcomas of doubtful tumor
type, embryonal and undifferentiated sarcomas
Mitotic count: (count 10 successive high power fields [area of 0.17 mm squared] in most
mitotically active areas)
1 point:
0-9 mitoses
2 points: 10-19 mitoses
3 points: 20 or more mitoses
Tumor necrosis:
0 points: no necrosis on any slides
1 point:
less than 50% necrosis for all examined tumor surface
2 points: tumor necrosis of 50% or more of examined tumor surface
Rubin, et al. (2014) College of American Pathology guidelines; Neuville, et al. Pathology. 2014 ;46(2):113-120.
Liposarcoma: Tumor Differentiation Score
1
2
ALT/WD LPS
3
De-Diff LPS
Cellular Myxoid LPS
Myxoid LPS
Pleomorphic LPS
Leiomyosarcoma: Tumor Differentiation
Score
1
Well-Diff
2
Conventional
3
Epithelioid
French Federation of Cancer Centers
Sarcoma Group
Grades of “Common” Sarcoma Types
● Fibrosarcoma-well differentiated - 1
● Leiomyosarcoma-well differentiated - 1
● Liposarcoma-well differentiated - 1
● Angiosarcoma-well
differentiated/conventional - 2
● UPS/MFH-pleomorphic with storiform
pattern - 2
● Fibrosarcoma-conventional - 2
● Leiomyosarcoma-conventional - 2
● Liposarcoma-myxoid - 2
● Liposarcoma-pleomorphic - 3
● Liposarcoma-round cell - 3
● Malignant triton tumor - 3
● MFH-giant cell – 3
● MFH-pleomorphic without storiform
pattern - 3
● Myxofibrosarcoma - 2
● Osteosarcoma - 3
● Leiomyosarcoma-epithelioid/poorly
differentiated/pleomorphic - 3
● PNET - 3
● Rhabdomyosarcomaalveolar/embryonal/pleomorphic - 3
● Angiosarcoma-poorly
differentiated/epithelioid - 3
● Chondrosarcoma-mesenchymal - 3
● Clear cell sarcoma - 3
● Epithelioid sarcoma - 3
● Fibrosarcoma-poorly differentiated - 3
● Synovial sarcoma - 3
Neuville, et al. Pathology. 2014 ;46(2):113-120.
FNCLCC Grading
• All 3 numbers are
summed to determine
degree of differentiation
Grade 1 :
Grade 2 :
Grade 3 :
2-3
4-5
6-8
• Proven to correlate well
with survival
•
1
2
3
•
Mitotic Count. In the most
mitotically active area, 10
successive high-power fields (at
400x magnification = 0.1734 mm2)
using a 40x objective.
0-9 mitoses per 10 HPFs
10-19 mitoses per 10 HPFs
> 20 mitoses per 10 HPFs
0
1
2
Tumor Necrosis. Evaluated on
gross examination and validated
with histological sections
No tumor necrosis
< 50% tumor necrosis
> 50% tumor necrosis
•
Degree of Differentiation. 1-3
Neuville, et al. Pathology. 2014 ;46(2):113-120.
FNCLCC Grading
Coindre JM, et al. Cancer. 2001;91(10):1914-1926.
Sarcoma Grading: Challenges
• Behavior determined by histotype (ie, Ewing’s, ALT)
• Some not considered gradable (ES, SSC, AS) – provides
no additional information
• Some tumors graded but not predictive (ex. “low-grade”
MPNST)
• Some sarcomas are not classifiable thus behavior is
unknown
• Often done semi-objectively
• What does intermediate really mean?
Question 3
Molecular diagnostics can play an important and
practical role in contemporary sarcoma diagnosis.
1. True
2. False
3. I don’t know
Adapted from: Demicco & Lazar. Semin Oncol 2011;38(s3):S3-18.
Lazar: in Hornick Practical Soft Tissue Pathology: A Diagnostic Approach (2013) Elsevier Health Sciences.
Lazar: in Hornick Practical Soft Tissue Pathology: A Diagnostic Approach (2013) Elsevier Health Sciences.
Question 4
The current 7th Edition of AJCC sarcoma staging
system is useful in my clinical practice.
1. Always
2. Almost always
3. Sometimes
4. Almost never
5. AJCC what?
Staging
• Determine extent of disease
to predict prognosis and
used to guide adjuvant
treatment
• Can also be used to
compare patients with both
same and different tumors
• 7th AJCC Edition is
applicable to most sarcomas
• 8th Edition underway….
Edge SB, et al. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010.
AJCC Staging: pT
• Pathologic Staging
• pT – Depends on SIZE (≤ 5 or > 5 cm) and DEPTH
(superficial – subcutis, deep – muscle)
• May need to correlate radiologically
•
•
•
•
Tx primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 5 cm or less (a, superficial; b, deep)
T2 Tumor more than 5 cm (a, superficial; b, deep)
AJCC Staging: pN
•
•
•
•
pN – Regional lymph nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases (no longer M1)
• Lymph node metastases rare in most sarcomas
• Does not appear to alter prognosis significantly
• In assigning stage, and nodal status is unknown, they
should be assumed as N0
AJCC Staging: M and Grade
• M – Distant metastases: Typically determined by site of
primary
– There is no pathological pMx or pM0 – clinically
determined
• M0 No distant metastases
• M1 Distant metastases
• Histological Grade (FNCLCC grading)
• Gx (cannot assess), G1 – G3
AJCC Stage Groups
0.8
0.6
0.4
0.2
0.0
Cumulative Incidence of Local Recurrence
1.0
Atypical Lipomatous Tumor
GIST
Leiomyosarcoma
Liposarcoma, dedifferentiated
Liposarcoma, myxoid
MFH
Others
Synovial Sarcoma
Unclassified
0
12
24
36
48
60
72
84
96
108
120
Months from dates of surgery of Primary Tumor
MDACC prospective soft tissue sarcoma database.
132
144
156
168
1.0
0.8
0.6
0.4
0.2
0.0
Cumulative Incidence of Local Recurrence
Margin negative
Margin positive
0
12
24
36
48
60
72
84
96
108
120
Months from dates of surgery of Primary Tumor
MDACC prospective soft tissue sarcoma database.
132
144
156
168
Nomograms
• Uses other factors to predict
probability of survival
• Points given for each variable
and generated score gives
predicted survival probability
• May better direct care and
counsel individual patients
• Lumps several tumors of the
same histotype together
• Now: site-specific and
histology-specific nomograms
Kattan MW, et al. J Clin Oncol. 2002;20(3):791-796.
Nomograms
“Histology Specific” (LPS)
Site Specific (RP)
SS – Ad/If
Dalal KM, et al. Ann Surg. 2006;244(3):381-391.
Canter RJ, et al. Clin Cancer Res. 2008;14(24):8191-8197.
Anaya DA, et al. Ann Oncol. 2010;21(2):397-402.
Question 5
Soft tissue sarcoma pathology reports that I
receive provide the relevant information needed to
manage my patients in a structured format.
1.
2.
3.
4.
5.
Always
Almost always
Sometimes
Almost never
Why would I ever read a pathology report?
Rubin, et al. (2014) CAP guidelines. www.cap.org
Conclusions
• AJCC, CAP, & WHO are now aligned
• Global staging is helpful, but limited
– Easier to apply
– ASPS is different than WD liposarcoma
• Better therapies encourage better staging systems
– GIST
• Molecular prognostics are coming
– Need to be simple/applicable to FFPE samples
– Markers predicting response to therapy are key
• Multidisciplinary approaches are critical
– Surgery, Med-Onc, Radiology, Pathology, Research, etc
– Glean insights from one another, work together
AJCC, American Joint Committee on Cancer; ASPS, alveolar soft part sarcoma; WD, well-differentiated;
GIST, gastrointestinal stromal tumor; FFPE, formalin-fixed paraffin embedded.
THE PAST, PRESENT, AND FUTURE OF
CYTOTOXIC CHEMOTHERAPY FOR
ADVANCED, NON-GIST SOFT TISSUE
SARCOMAS
George D. Demetri, MD - CHAIR
Sarcomas Were Viewed as a Poorly Understood
“Black Box” Before the 21st Century
The knowledge gained
from studying this
1% of human cancer
has been critical to
advance the diagnosis
and treatment of other
far more common
forms of cancer
1% = Sarcomas
Evolution of Cancer Medicine:
From Empiricism to Mechanism
The Old Classic Approach
Diagnose cancer
based on where the
tumor started or what
the tissue looks like
Try to kill the tumor
with “acceptable”
toxicity
Cytotoxic Therapy
(Empiric)
Question 1
Conventional approved cytotoxic chemotherapy for
advanced metastatic soft tissue sarcoma often
(choose best answer):
1. Results in delay of tumor progression
2. Cures patients as well as in localized osteosarcoma
3. Is associated with proven benefits in overall survival
4. 1 and 2
5. 2 and 3
Sarcomas Played a Pivotal Historical
Role in the Early Development of
Chemotherapy
• 1960’s and 1970’s – the era of “One Size Fits All”
clinical trials for “Cancer”
Cytotoxic Chemotherapy for Sarcomas:
Evolution Over the Past 40 Years
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
Curative Impact of Chemotherapy in
Osteosarcoma:
1982 Randomized Trial testing
Adjuvant Chemotherapy vs Observation
Practice-changing results
with only 36 patients
who accepted
randomization (out of 113)
Link MP, et al. N Engl J Med. 1986;314(25):1600-1606.
1980’s: Continued Incremental Development
of Chemotherapy for Soft Tissue Sarcomas
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
1982
Time to
Treatment
Failure
(weeks)
Schoenfeld DA, et al. Cancer. 1982;50(12):2757-2762.
Overall
Survival
(weeks)
Continued Development of
Chemotherapy for Soft Tissue Sarcomas
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
1982
1987
Ifosfamide
Activity
Noted in
Sarcomas
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
1982
1987
Ifosfamide
Activity
Noted in
Sarcomas
(1987)
Combinations
of Doxorubicin
plus
Ifosfamide
+/- CSFs
1992
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
1982
Combinations
of Doxorubicin
plus
Ifosfamide
+/- CSFs
1995
Ifosfamide
Activity
Noted in
Sarcomas
(1987)
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
Combinations
of Doxorubicin
plus
Ifosfamide
+/- CSFs
1982
1995
PFS
(years)
Ifosfamide
Activity
Noted in
Sarcomas
(1987)
Overall
Survival
(years)
Chemotherapy for Soft-Tissue Sarcomas
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
1982
Combinations
of Doxorubicin
plus
Ifosfamide
1992
Ifosfamide
Activity
Noted in
Sarcomas
(1987)
1999
HIGH DOSE
Ifosfamide
explored in
Sarcomas with
CSF support
(1997)
21st Century Splitting to Focus
Trials in “Soft Tissue Sarcomas”
Combinations
of Doxorubicin
with DTIC and
Cyclophosphamide
1972
Doxorubicin
and DTIC
Activity
Noted in
Sarcomas
1982
Combinations
of Doxorubicin
plus
Ifosfamide
+/- CSFs
1992
Ifosfamide
Activity
Noted in
Sarcomas
(1987)
GIST routinely removed
from studies of
“Soft Tissue Sarcomas”
2001
Progression-Free Survival as a Marker of
Clinical Activity in Soft Tissue Sarcomas
(eg, leiomyosarcomas and liposarcomas)
EORTC Soft Tissue and Bone Sarcoma Group database
P
F
S
“ACTIVE”
INACTIVE
Van Glabbeke M, et al. Eur J Cancer. 2002;38(4):543-549.
“Modern” Cytotoxic Chemotherapy
Does NOT Significantly Improve Clinical Outcomes in
Soft Tissue Sarcoma Patients Following Resection
Minor Benefit in Relapse-Free Survival
only in first 3 years
Woll PJ, et al. Lancet Oncol. 2012;13(10):1045-1054.
Randomized Trial of
First-Line Chemotherapy in
Metastatic Soft Tissue Sarcomas
Doxorubicin
R
Doxorubicin + Ifosfamide
Judson I, et al. ESMO 2012; Judson I, et al. Lancet Oncol. 2014;15(4):415-423.
Does Combination Chemotherapy Improve
Outcomes for Metastatic Soft Tissue
Sarcomas? (EORTC 62012)
Eligibility:
• High grade STS (2-3)
• Age 18-60
• No previous chemo for
advanced/metastatic disease
• WHO PS < 2
Stratification:
• Age (< 50 vs ≥ 50)
• PS (0 vs 1)
• Liver metastases (0 vs +)
• Histological grade (2 vs 3)
Single-agent Doxorubicin
(75 mg/m2 bolus or as a 72-hour continuous i.v. infusion)
R
2 d 1-3
Doxorubicin
25
mg/m
New Treatment: B
+ Ifosfamide 2.5 g/m2 d 1-4
+ PEG-Filgrastim 6 mg s.c. d5
Objective Response Rates
Complete Response
Partial Response
Overall RESPONSE RATE
No Change
Progressive Disease
Early Death – Progression
Early Death – Other cause
Not evaluable
Treatment
Doxo
Doxo-Ifos
(n = 228)
(n = 227)
n (%)
n (%)
Total
(n = 455)
n (%)
1 (0.4)
30 (13.2)
4 (1.8)
56 (24.7)
5 (1.1)
86 (18.9)
13.6
26.5
105 (46.1)
114 (50.2)
219 (48.1)
74 (32.5)
4 (1.8)
3 (1.3)
11 (4.8)
30 (13.2)
5 (2.2)
2 (0.9)
16 (7.0)
104 (22.9)
9 (2.0)
5 (1.1)
27 (5.9)
Significant difference between the two arms: P < 0.001.
Progression-Free Survival:
Statistically Different (P = 0.003) Favoring
Dox + Ifos
Dox + Ifos
Median PFS: 7.4 months
(ORR 27%)
Dox
Median PFS
4.6 months
(ORR 14%)
(year)
Overall survival
Overall
Survival
100
90
80
HR = 0.83 (95.5% CI 0.67-1.03)
Stratified log rank test, P = 0.076
70
60
No difference statistically
50
40
30
20
10
0
(years)
0
O
188
184
N
228
227
1
2
3
Number of patients at risk :
113
54
29
130
64
30
4
19
20
5
14
13
6
9
7
7
2
3
8
Treatment
Doxo
DxIf
Reasons for Discontinuing Therapy on
EORTC 62012: First-Line Single Agent vs
Combination Chemotherapy for
Treatment
Doxo
(n = 121)
n (%)
95 (41.7)
Doxo+Ifos
(n = 109)
n (%)
47 (20.7)
Toxicity (including toxic death)
6 (2.6)
40 (17.6)
Patient’s refusal (not related to toxicity)
4 (1.8)
10 (4.4)
Progression of Disease/death due to PD
Randomized Trial of a Newer First-Line
Chemotherapy in Metastatic Soft Tissue
Sarcomas
Doxorubicin
Negative Study:
NO BENEFIT
with combo Rx
R
Doxorubicin + Palifosfamide
2013 Data: International Phase III Trial of
Palifosfamide + Doxo vs Doxo Alone as First-Line Therapy
for Metastatic “Non-GIST Soft Tissue Sarcomas”
Overall Survival
MEDIAN
OVERALL SURVIVAL
1.4 years
Ryan C, et al. ECCO 2013.
Question 2
Trials of ifosfamide and doxorubicin in soft tissue
sarcomas demonstrate that (choose best one):
1. There is no need to develop any new chemotherapy for
advanced sarcomas since the results are so good
2. No other chemotherapy will ever work in sarcomas
3. Progression-free survival can be improved
4. Patients will never participate in clinical trials
Randomized Trial of an
EVEN NEWER First-Line Chemotherapy in
Doxorubicin
FULLY ACCRUED:
Analyses
Pending
R
Doxorubicin + TH-302
New Drugs for Soft Tissue Sarcomas:
Gemcitabine + Docetaxel Combination May Improve
PFS and OS Compared to Gemcitabine Alone
PFS
OS
PS 0
Maki RG, et al. J Clin Oncol. 2007;25(19):2755-2763.
PS 1
Improved Outcomes With Combination
Gemcitabine + Dacarbazine vs Dacarbazine
Alone in Second-Line Metastatic Soft Tissue
Sarcomas
ORR
DTIC: 4%
Gem + DTIC: 12%
OS
PFS
Median PFS
DTIC:
2.0 mo
Gem + DTIC: 4.2 mo
Median OS
Garcia-Del-Muro X, et al. J Clin Oncol. 2011;29(18):2528-2533.
DTIC:
8.2 mo
Gem + DTIC: 16.8 mo
Other New and/or Promising Chemotherapy
Agents for Soft Tissue Sarcomas
• Trabectedin (formerly Ecteinascidin-743, ET743)
– Approved in Summer 2007 by European FDA (EMA)
for treatment of soft tissue sarcomas
– Investigational still in USA
• Eribulin
– Approved for breast carcinoma, investigational for soft
tissue sarcomas
Not All Molecular Targeted Agents are
Rationally Designed – But the Clinical
Evaluation Can Be Rational and Targeted
Sea Tunicate,
Ecteinascidia Turbinata
Ecteinascidin-743
(Trabectedin),
a tetrahydroisoquinoline
alkaloid, MW=762.
Not All Molecular Targeted Agents are
Rationally Designed – But the Clinical
Evaluation Can Be Rational and Targeted
 Binds to DNA minor groove,
bending the helix
 Interacts with transcription factors
and other DNA binding proteins
 Major activity in myxoid/round cell
liposarcoma with TLS/CHOP fusion
oncoprotein (DNA binding protein)
Historical Overview of Trabectedin
Clinical Trials in Soft Tissue Sarcomas
N
Progression- ProgressionMedian
Free Rate
Free Rate
PFS
@ 3 months @ 6 months
Max #
Cycles
Active
146
39%
14%
NA
Inactive
234
21%
8%
NA
Group A
44
46%
18%
2.6 M
15
Group B
55
50%
24%
2.9 M
18
Group 1
26
38%
23%
1.8 M
10
Group 2
28
39%
25%
1.9 M
20
Garcia-Carbonero R, et al.4
36
31%
14%
1.7 M
21
136
53%
37%
3.3 M
37
EORTC Historical
Thresholds1
Le Cesne A, et al2
Yovine A, et al3
Demetri G, et al.
5
• Samuels B, et al.6: Expanded Access Plan (SAR 3002) (N = 1803)
Clinical Benefit Rate = 54% in Leiomyosarcoma and Liposarcoma patients
1. Van Glabbeke M, et al. Eur J Cancer. 2002;28:543-549.
2. Le Cesne A, et al. J Clin Oncol. 2005 23(3):576-584.
3. Yovine A, et al. J Clin Oncol. 2004;22(5):890-899.
4. Garcia-Carbonero R, et al. J Clin Oncol. 2004;22(8):1480-1490.
5. Demetri G, et al. J Clin Oncol. 2009;27(25):4188-4196.
6. Samuels B, et al. Annals of Oncol. 2013;24(6):1703-1709.
Trabectedin in Sarcomas: Pivotal Trial Primary
Endpoint = Time to Tumor Progression
TTP: All Randomized
Time To Progression (TTP):
(Investigator Assessment)
All Randomized Patients
Updated May 08
(Investigator Assessment)
p=0.0042 P = 0.0028
HR: 0.668HR: 0.658
q3wk 24-h
qwk 3-h
qwk 3-h
Demetri GD, et al. J Clin Oncol. 2009;27(25):4188-4196..
Progression-Free Survival as a Marker of
Clinical Activity in Soft Tissue Sarcomas
(eg, leiomyosarcomas and liposarcomas)
EORTC database
Trabectedin
q3 wks
P
F
S
Trabectedin
weekly
“ACTIVE”
INACTIVE
Both trabectedin schedules show substantially longer PFS
than older “active” drugs in similar setting
Van Glabbeke M, et al. Eur J Cancer. 2002;38(4):543-549.
ET743 (Trabectedin) is Particularly Active
in Myxoid and Round Cell Liposarcomas
• Retrospective Series – multiple institutions
• 51 patients
• Advanced disease, all pretreated
• Median follow-up 14 months
• Overall Response Rate by RECIST
51% ( 95% CI 36-65%)
Grosso F, et al. Lancet Oncol. 2007;8(7):595-602.
baseline
After 1
cycle
Trabectedin
Induces Changes in
Tumor Density
After 5
cycles
After 8
cycles
Before Tumor
Changes in Size
Courtesy Grosso, Casali, et al. Istituto Tumori Milano.
Grosso F, et al. Lancet Oncol. 2007;8(7):595-602.
After 11
cycles
Progression-Free Rates at 12 weeks
Leiomyosarcoma
Liposarcomas
Synovial sarc
Other sarcoma
32%
47%
21%
19%
New Randomized Trial Data to be Reported at
ASCO Tomorrow in Liposarcoma and
Leiomyosarcoma Subsets of Advanced Soft
Tissue Sarcomas
Leiomyo
Or
Liposarc
Leiomyo
Or
Liposarc
Dacarbazine
BOTH TRIALS
TO BE DISCUSSED
June 1, 2015
SARCOMA SESSION
Trabectedin (ET-743)
Dacarbazine
Eribulin
Mutation Frequencies Vary Across
Cancer Types
EWING
SARCOMAS
RHABDOID
TUMORS
Lawrence MS, et al. Nature. 2013;499(7457):214-218..
Combination of PARP Inhibitor Olaparib +
DNA Damaging Chemotherapy Temozolomide in
Preclinical Xenograft Model of Ewing Sarcoma
Brenner JC, et al. Cancer Res. 2012;72(7):1608-1613.
Conclusions
• Cytotoxic chemotherapy definitely can have clinically
meaningful activity in sarcomas of soft tissue as well as
bone sarcomas
• Personalization to patient-specific clinical scenarios is
key to the optimal use of chemotherapy for soft tissue
sarcomas
• New chemotherapy options are showing a great deal of
promise as potential additions to the therapeutic
armamentarium targeting soft tissue sarcomas to help
patients with these life-threatening diseases
PROGRESS IN TARGETED THERAPIES
FOR ADVANCED, NON-GIST SOFT TISSUE
SARCOMAS
Richard F. Riedel, MD
Duke Cancer Institute
Outline
• Introduction
• Targeted therapy in unselected patients
– mTOR
– Multi-targeted TKIs
– PD-1/PD-L1
• Targeted therapy in selected patients
– ASPS, CCS, DFSP, IMT, PEComa, Liposarcoma
• Conclusions
The Challenge
• Cytotoxic chemotherapeutic
– Limited number of agents
– Limited efficacy
• Toxicity remains an issue
• QOL is important to patients
• Desire to move towards “Precision Medicine”
Cytotoxic Chemotherapy Outcomes
Treatment
Response
Median OS
Doxorubicin
~ 10-20%
~ 12 months
~ 20%
~ 12 months
~ 25-35%
~ 12 months
~ 30%
~ 13 months
Gemcitabine
8%
~ 12 months
Gemcitabine/Docetaxel
16%
~ 18 months
Gemcitabine/Navelbine
13%
NR
Dacarbazine
18%
NR
Ifosfamide
AIM
MAID
Largely based on phase II studies
MAID, mesna+doxorubicin+ifosfamide+dacarbazine; AIM, doxorubicin, ifosfamide, mesna.
Riedel RF. Cancer. 2012;118(6):1474-1485.
90
Novel Therapeutic Targets
•
•
•
•
•
•
•
•
PI3K/AKT/mTOR
VEGF/VEGFR
MET
ALK
HDAC
HSP90
CDK4
MDM2
•
•
•
•
•
•
•
•
Hedgehog
IGF1R
EGFR
MAPK
PDGFR
KIT
PD-1/PD-L1
Angiopoeitin-TIE2
Clinical Trials: Lumpers or Splitters?
• “Lumpers”
– Pros: Ease of accrual, therapy more widely available
– Cons: Results difficult to interpret given broad range
of histologies
• “Splitters”
– Pros: Recognize molecular heterogeneity
– Cons: Limited number of patients/subtype
92
NOVEL TARGETED THERAPIES
UNSELECTED PATIENT POPULATIONS
mTOR Inhibition: Ridaforolimus
• Multicenter, open-label, phase II study
– 212 patients with bone and soft tissue sarcoma
– 12.5 mg IV daily x 5 days every 2 weeks
– Clinical Benefit Rate of 29%
– Response rate 1.9%
– Median PFS 15.3 weeks
– Median OS 40 weeks
– Benefit in subgroups explored
PFS, progression-free survival; OS, overall survival.
Chawla SP, et al. J Clin Oncol. 2012;30(1):78-84.
Ridaforolimus: SUCCEED Study
Sarcoma MUlti-Center Clinical Evaluation of the Efficacy of RiDaforolimus
•
•
•
•
•
Multicenter
Randomized
Phase III
Blinded
Placebo-controlled
Advanced Sarcoma
Stable/Responsive
Disease
> 4 Cycles
1st-, 2nd-, 3rd-line
1:1
Maintenance
Ridaforolimus (Oral)
5 days on: 2 days off
40 mg daily
Maintenance
Placebo
Sample Size: 711 randomized
Demetri GD, et al. J Clin Oncol. 2013;31(19):2485-2492.
SUCCEED Study: PFS
96
SUCCEED Study: OS
97
Oncologic Drugs Advisory Committee:
March 20, 2012
Has a favorable risk-benefit profile for
ridaforolimus as a maintenance therapy for
patients with metastatic soft tissue or bone
sarcoma who have stable disease or better after
4 or more cycles of chemotherapy been
demonstrated?
For: 1
Against: 13
Abstain: 0
ODAC Committee
• “For”
– Desire for more treatment options
– Preserve availability of the product for patients
• “Against”
–
–
–
–
Higher bar needed for maintenance therapy
Statistical significance = Clinically meaningful
Toxicities outweighed the benefits
PFS improvement was marginal
ODAC, Oncologic Drugs Advisory Committee; PFS, progression-free survival.
Questions
•
•
•
•
Does ridaforolimus have activity?
Who is benefiting?
Was the disease setting correct?
Would the AE profile have been more
acceptable in a relapsed/refractory setting?
• Would adequate QOL data impact review?
• Can we identify biomarkers of response and/or
toxicity?
• Combination approaches?
AE, adverse events; QOL, quality of life.
Multi-Targeted Tyrosine Kinase Inhibitors:
Phase II Trials
Primary
Endpoint
Sample
Size
Strata
Statistical
Design
Result
Imatinib1
CBR
185
10
Bayesian
CBR 15%
Pazopanib2
PFR12weeks
142
4
Simon
2-stage
PFR12weeks > 40%
LMS, SS, “Other”
Sorafenib3
RECIST
Response
145
(122 eval)
6
Simon
2-stage
RR: 3%
(14% angio)
Sunitinib4
RECIST
Response
53
(48 eval)
3
Simon
2-stage
DCR: 22%
(at least 16 weeks)
CBR: Clinical benefit rate; LMS: Leiomyosarcoma; PFR: Progression-free rate;
RECIST: Response Evaluation Criteria in Solid Tumors; DCR: Disease control rate;
SS: Synovial sarcoma; RR: Response rate
1Chugh
R, et al. J Clin Oncol. 2009;27(19):3148-3153.
S, et al. J Clin Oncol. 2009;27(19):3126-3132.
3Maki R, et al. J Clin Oncol. 2009;27(19):3133-3140.
4George S, et al. J Clin Oncol. 2009;27(19):3154-3160.
2Sleijfer
PALETTE Study
PAzopanib ExpLorEd in SofT-TissuE Sarcoma
•
•
•
•
•
Multicenter
Randomized
Phase III
Blinded
Placebo-controlled
Relapsed/Refractory
Advanced Sarcoma*
2:1
Pazopanib 800 mg
daily
Placebo
Sample Size: 369 patients enrolled and treated
*Non-adipocytic, Non-GIST STS.
van der Graaf WT, et al. Lancet. 2012;379(9829):1879-1886.
PALETTE Trial: Pazopanib
Progression-Free Survival
103
PALETTE Trial: Pazopanib
Overall Survival
104
Oncologic Drugs Advisory Committee:
March 20, 2012
Considering the observed improvement in PFS, the
absence of an improvement in OS, and the adverse event
profile of pazopanib, is the risk benefit assessment
favorable for the use of pazopanib in the treatment of
patients with advanced soft tissue sarcoma (STS) who
have received prior chemotherapy?
For: 11
Against: 2
Abstain: 0
ODAC Committee
• “For”
–
–
–
–
Significant unmet need
Well-designed trial
Subset of patients (14%) > 1 year on therapy
May benefit QOL but data limited
• “Against”
– Benefit was marginal
– No improvement in QOL or OS
FDA Approval: April 26, 2012
ODAC, Oncologic Drugs Advisory Committee; QOL, quality of life; OS, overall survival.
Questions
•
•
•
•
•
What is the target?
Is PFS an optimal outcome measure?
Did additional therapies impact OS?
What is unique about liposarcoma?
Can we identify biomarkers?
Checkpoint Inhibition: PD-1/PD-L1
• Developing story in sarcoma
• Discordant data published to date
– 2013 study
• PD-L1 (58%) of soft tissue sarcoma
• TILs (65%) with PD-1 expression noted
– 2015 study
• PD-1 (12%) and PD-L1 (22%) expression in sarcoma specimens
• TILs (30%) and macrophage (58%) PD-L1 expression noted
• Association between PD-1/PD-L1 expression and
outcomes is inconsistent
• Standardization needed
TIL, tumor infiltrating lymphocytes.
Kim JR, et al. PLoS One. 2013;8(12):e82870; D'Angelo SP, et al. Hum Pathol. 2015;46(3):357-365.
SARC028: Pembrolizumab in Sarcoma
• Study Design:
– Open-label, phase II
– Relapsed/refractory STS and bone sarcoma
– Sample size: 80 (40 with STS, 40 with bone
sarcomas)
Relapsed/Refractory Disease
Arm A: Soft Tissue Sarcoma
Arm B: Bone Sarcoma
Pembrolizumab 200 mg IV q21 days
Pembrolizumab 200 mg IV q21 days
Tumor biopsies: Screening, week 8 and week 34 (optional)
www.clinicaltrials.gov NCT02301039.
STS, soft tissue sarcoma.
Relapsed/Refractory: SARC028
• Objectives
– Primary: ORR (using RECIST 1.1)
– Secondary: safety, tolerability, PFS, OS, RR (ir-RC)
– Exploratory: PD-L1 expression as a biomarker, Tregs,
MDSCs, immune monitoring
Abstract #TPS10578
SARC 028: A phase II study of the anti-PD-1 antibody pembrolizumab
(P) in patients (Pts) with advanced sarcomas.
Melissa Amber Burgess
Poster Board: #220b
ASCO 2015
• Unselected histologies
– Poster Discussion
Abstract #10514 (Attia et al.): A phase Ib dose-escalation study of
TRC105 (anti-endoglin antibody) in combination with pazopanib in
patients with advanced soft tissue sarcoma (STS).
Abstract #10515 (Agulnik et al.): A phase II study of tivozanib in
patients with metastatic and non-resectable soft tissue sarcomas.
Abstract #10516 (Vitfell-Rasmussen et al.): A phase I/II clinical trial of
belinostat (PXD101) in combination with doxorubicin in patients with
soft tissue sarcomas (STS).
111
ASCO 2015
• Unselected histologies
– Oral Session (Monday, June 1, 3:00-6:00 PM)
Abstract #10501 (Tap et al.): A randomized phase Ib/II study
evaluating the safety and efficacy of olaratumab (IMC-3G3), a human
anti-platelet-derived growth factor α (PDGFRα) monoclonal antibody,
with or without doxorubicin (Dox), in advanced soft tissue sarcoma
(STS).
NOVEL TARGETED THERAPIES
SELECTED PATIENT POPULATIONS
Molecular Drivers in Select Histologies
Translocation/
Rearrangement
Fusion Transcript
Mechanism
ASPS
t(X;17)(p11;q25)
ASPL-TFE3
MET/VEGF
signaling activation
CCS
t(12;22)(q13;q12)
EWSR1-ATF1
MITF/MET
activation
DFSP
t(17;22)(q22;q13)
COL1A1-PDGFB
PDGFRB signaling
activation
IMT
ALK gene rearrangement
PEComa
TFE3 gene rearrangement
ASPS: alveolar soft part sarcoma
CCS: clear cell sarcoma
DFSP: dermatofibrosarcoma protuberans
IMT: inflammatory myofibroblastic tumor
PEComa: perivascular epithelioid cell tumor
MITF: microphthalmia-associated transcription factor
PDGFRB: platelet-derived growth factor receptor beta
Rutkowski P, et al. Int J Biochem Cell Biol. 2014;53:466-474.
ALK activation
-----------------
mTOR pathway
activation
Alveolar Soft Part Sarcoma (ASPS)
• Rare, mesenchymal neoplasm
• Presents as a painless, slow growing mass
• Lung metastases are common and often
indolent
• Chemotherapy and radiation therapy resistant
• Majority of cases express fusion protein
– ASPL-TFE3 translocation
– Results in aberrant MET signaling and overexpression of
genes associated with angiogenesis
ASPL , alveolar soft part locus; TFE3, transcription factor E3.
Tsuda M, et al. Cancer Res. 2007;67(3):919-929.
Alveolar Soft Part Sarcoma (ASPS)
• Multi-targeted TKIs
– Sunitinib
• Case reports/series
– Cediranib
• Phase II study (n = 46) of cediranib for metastatic ASPS
• ORR 35%; DCR at 24 weeks of 84%
• ARQ197 (MET inhibitor)
– Phase II study in MITF associated tumors (n = 13 ASPS)
– Disease stabilization of 81%
• Phase II studies of cediranib vs sunitinib; and crizotinib
– Ongoing
Stacchiotti S, et al. Clin Cancer Res. 2009;15(3):1096-1104. George S, et al. J Clin Oncol. 2009;27(19):3154-3160.
Hilbert M, et al. Pediatr Blood Cancer. 2012;58(3):475-476. Kummar S, et al. J Clin Oncol. 2013;31(18):2296-2302.
Goldberg J, et al. J Clin Oncol. 2009;15(suppl). Abstract 10502.
Clear Cell Sarcoma (CCS)
• Rare, mesenchymal neoplasm
– “Melanoma of soft parts”
•
•
•
•
Indolent growth
Potential for lymph node involvement
Chemotherapy resistant
Majority of cases express fusion protein
– EWSR1-ATF translocation
• Induces MITF expression
• Contributes to overexpression of MET
MITF, microphthalmia-associated transcription factor; EWSR1, Ewing sarcoma breakpoint region 1; ATF,
activating transcription factor.
Clear Cell Sarcoma (CCS)
• Multi-targeted TKIs
– Sunitinib and sorafenib
• Case reports
– Pazopanib
• Pre-clinical
• ARQ197 (MET inhibitor)
– Phase II study in MITF associated tumors (n = 7 CCS)
– Disease stabilization of 43%
– 1 PR, 2 SD
• Phase II study of crizotinib (ALK/MET inhibitor)
– Ongoing
Stacchiotti S, et al. Ann Oncol. 2010;21(5):1130-1131.
MITF, microphthalmia-associated transcription factor.
Mir O, et al. Ann Oncol. 2012;23(3):807-809.
Outani H, et al. BMC Cancer. 2014;14:455.
Goldberg J, et al. J Clin Oncol. 2009;15(suppl). Abstract 10502.
DFSP:
Dermatofibrosarcoma Protuberans
•
•
•
•
Rare, mesenchymal neoplasm
Cutaneous in origin
Locally aggressive
Characterized by reciprocal translocation
– t(17;22)(q11;q13.1)
– COL1A1-PDGFB fusion gene
– PDGFRB signaling via autocrine stimulation
PDGFB, platelet-derived growth factor beta; COL1A1, collagen type I alpha 1 gene.
DFSP:
Dermatofibrosarcoma Protuberans
• Multi-targeted TKI
– Imatinib
– Multiple small series/phase II studies
confirmed benefit
• ORR 46-90%
– FDA approved in 2006
• Unresectable, recurrent, and/or metastatic DFSP
McArthur GA, et al. J Clin Oncol. 2005;23(4):866-873. Rutkowski P, et al. J Clin Oncol. 2010;28(10):1772-1779.
Rutkowski P, et al. J Eur Acad Dermatol Venereol. 2011;25(3):264-270.
Inflammatory Myofibroblastic Tumor
(IMT)
•
•
•
•
•
Rare, mesenchymal tumor
Associated inflammatory infiltrate
Rearrangements in ALK – 50%
Aberrant ALK expression
Crizotinib is a multi-targeted TKI with activity
Butrynski JE, et al. N Engl J Med. 2010;363(18):1727-1733.
Perivascular Epithelioid Cell Tumors
(PEComa)
• Family of rare mesenchymal tumors
• Present as painless lesions within vessel wall
• Express melanocytic and smooth-muscle
differentiation
• Sporadic or associated with tuberous sclerosis
complex (TSC)
– mTOR inhibition supported by:
• Mutations in TSC1 or TSC2 genes
• Loss of heterozygosity at TSC2
• Sirolimus1, temsirolimus2, everolimus3
1Wagner AJ,
et al. J Clin Oncol. 2010;28(5):835-840.
et al. Ann Oncol. 2010;21(5):1135-1137.
3Gennatas C, et al. World J Surg Oncol. 2012;10:181.
2Italiano A,
Liposarcoma
• Well differentiated/Dedifferentiated (WD/DD) liposarcoma
– MDM2 inhibitors
• RG7112 (RO5045337) – Nutlin family member
• Phase II neoadjuvant study1: WD/DD liposarcoma
– 20 enrolled patients, 1 partial response
– CDK inhibitors
• Palbociclib (PD 0332991) – oral CDK4/6-specific inhibitor
• Phase II study2: WD/DD liposarcoma w/amplified CDK4
– 29 evaluable patients, 1 partial response
– PFS at 12 weeks: 66%
ASCO Educational Session
Tuesday, June 2, 11:30 AM
WD/DD Liposarcoma: New Challenges and New Directions
1Ray-Coquard
2Dickson
I, et al. Lancet Oncol. 2012;13(11):1133-1140.
MA, et al. J Clin Oncol. 2013;31(16):2024-2028.
ASCO 2015
• Selected histologies
Poster Session
Abstract #10542 (Schoffski et al.): Activity of crizotinib (C) in patients
(pts) with clear cell sarcoma (CCSA) in EORTC phase II trial 90101
"CREATE".
Oral Session
Abstract #10504 (Mir et al.): Activity of regorafenib (RE) in
leiomyosarcomas (LMS) and other types of soft-tissue sarcomas
(OTS): results of a double-blind, randomized placebo (PL) controlled
phase II trial.
124
Summary
• Systemic chemotherapeutic options are limited
– Number
– Effectiveness
• Novel therapies are needed
– Targeted therapies
• Unselected patient population
– FDA approval of pazopanib
• Selected patient population
– ASPS, CCS, DFSP, IMT, PEComa, Liposarcoma
• More trials in selected patient populations are needed
– Biomarker driven or studies enriched with biological correlatives
125
Question 1
Pazopanib was FDA approved 04/2012 for the treatment of
advanced soft tissue sarcoma. The efficacy of pazopanib
has been demonstrated in all of the following histologies
except:
1.
2.
3.
4.
Leiomyosarcoma
Liposarcoma
Synovial sarcoma
Undifferentiated pleomorphic sarcoma
Question 2
Well-differentiated/Dedifferentiated liposarcomas as
characterized by which of the following:
1.
2.
3.
4.
5.
6.
7.
ALK rearrangements
MDM2 amplification
CDK4 amplification
1 and 2
1 and 3
2 and 3
1, 2, and 3
HOW I TREAT ADVANCED, NON-GIST
SOFT TISSUE SARCOMAS TODAY AND
WHAT THE NEAR FUTURE HOLDS
Kristen N. Ganjoo, MD
Stanford University Medical Center
Case 1
• 60-year-old male
• 3 months h/o left thigh swelling
• EXAM: Large mass in the lateral aspect of the left thigh
• When to get an MRI
– Mass larger than 3 cm, smaller if on hand or foot
– Mass that has rapidly increased in size
– Deep mass (deep to fascia)
Radiologic Evaluation
• Plain X-ray of affected extremity
• MRI of the extremity
• Chest CT for metastasis
• Special circumstance:
– CT abdomen/pelvis, MRI of spine (myxoid liposarcoma)
– Brain MRI (alveolar soft part sarcoma)
– Bone scan (clear cell sarcoma, alveolar soft part sarcoma)
Soft Tissue Mass in the Left Vastus
Lateralis
T1
T2 post contrast
Question 1
What is the next step towards diagnosis?
1. Fine Needle Aspirate
2. Core Needle Biopsy
3. Incisional Biopsy
4. Excisional Biopsy
5. Radical Resection
Biopsy Techniques
1. Fine Needle Aspiration
–
Allows cytological evaluation (appearance of individual cells).
Reports of 80-90% reliability
2. Core Needle Biopsy
–
Core of tissue allows for histological evaluation and other tests
(immunohistochemistry and cytogenetics) if there is enough tissue
Approx 90% accurate at determining benign vs malignant. Bx must
be placed where it can be removed at time of final surgery
3. Incisional Biopsy
–
Make an incision in the tumor and remove tissue. Incision must be
placed where it can be removed at time of final surgery
4. Excisional Biopsy
–
Remove entire tumor around its pseudocapsule. Good for small
superficial tumors. Allows you to sample entire tumor. However,
contamination is an issue
BIOPSY RISKS: Inaccurate sampling, contamination of
uninvolved tissues, hematoma, infection, wound issues
Pathology
Pathology
Undifferentiated Pleomorphic Sarcoma
Question 2
What treatment would you offer this patient at this
time?
1. Radical resection followed by post-operative
radiotherapy
2. Systemic chemotherapy followed by radical resection
3. Pre-operative radiotherapy followed by radical resection
4. Pre-operative chemotherapy/radiotherapy followed by
radical resection
5. Amputation
Pre- vs Post-Operative Radiotherapy
O'Sullivan B, et al. Lancet. 2002;359(9325):2235-2241.
Pre-Op vs Post-Op Radiation
O'Sullivan B, et al. Lancet. 2002;359(9325):2235-2241.
Concurrent Pre-Op Ifosfamide With Radiation
Pre Tx
Post Tx
Pathology
• Pre-Treatment Biopsy
• Post-Treatment Resection
Site: left thigh
Specimen type: radical resection
Depth: deep
Size: 13.0 cm
Tumor type: pleomorphic sarcoma
< 10% viable tumor
Question 3
What adjuvant chemotherapy do you recommend?
1. Ifosfamide/anthracycline
2. Gemcitabine/docetaxel
3. Anthracycline alone
4. Trabectedin
5. None
Adjuvant Chemotherapy for Sarcomas
1997
• SMAC meta-analysis
• 1568 adults with localized resectable STS (< 5% had
regimen that included ifosfamide)
– Longer local RF interval – HR for local recurrence 0.73 (95% CI
0.56-0.94)
– Longer distant RF interval – HR 0.70 (95% CI 0.57-0.85)
– Higher overall RF survival – HR for any recurrence 0.75 (95% CI
0.64-0.87)
• Absolute 6 to 10% improvement in RF survival at 10 years
– Trend towards better OS – HR for death 0.89 (95% CI 0.76-1.03)
STS, soft tissue sarcoma, RF, recurrence-free interval; HR, hazard ratio; CI confidence interval; OS, overall survival.
Sarcoma Meta-Analysis Collaboration. Lancet. 1997;350(9092):1647-1654.
2008
• Updated meta-analyses – 2008
– 18 randomized trials – 1953 patients, 1973 -2002
– The RR for local recurrence – 0.73 (95% CI 0.56 to 0.94)
– RR for distant and overall recurrence = 0.67 (95% CI 0.56 to
0.82)
– Doxorubicin with ifosfamide – OS benefit (RR 0.56, 95% CI 0.36
to 0.85)
– The absolute risk reduction – doxorubicin/ifosfamide – 11% (30
vs 41% risk death)
– No benefit for doxorubicin alone (RR 0.84, 95% CI 0.68 to 1.03)
RR, relative risk; CI confidence interval; OS, overall survival.
Pervaiz N, et al. Cancer. 2008;113(3):573-581.
• EORTC pooled analysis
– 2 trials
– 819 patients
• No significant OS advantage to doxorubicin/ifosfamide
• Only patients with R1 resection with OS benefit
Le Cesne A, et al. Ann Oncol. 2014;25(12):2425-2432.
Case 2
• 78-year-old-female with uterine mass resected in 2009
• Ovary and fallopian tube, right salpingo-oophorectomy
– Multiloculated serous cystadenoma, 8 cm
– Fallopian tube with paratubal cyst, 1 cm
• Uterus, left ovary and fallopian tube, total abdominal
hysterectomy and salpingo-oophorectomy
– Leiomyosarcoma, 13.5 cm, with extension through the uterine
• Serosa
– Ovary and fallopian tube with no significant abnormality
Question 4
What adjuvant therapy do you recommend?
1. Radiation alone
2. Gemcitabine/docetaxel followed by adriamycin
3. Gemcitabine/docetaxel followed by radiation
4. Adriamycin with or without radiation
5. None
Adjuvant Therapy for Resected Uterine
Leiomyosarcoma (LMS)
Phase III
GOG study
Stage I (corpus),
II (corpus/cervix)
uterine sarcoma
Adriamycin
n = 75
31/75 (41%) recurred
Observation
n = 81
43/81 (53%) recurred
No difference in PFS or OS
Omura GA, et al. J Clin Oncol. 1985;3(9):1240-1245.
Adjuvant Therapy for Resected Uterine
LMS
Phase II
Stage I/II
N = 18
Gemcitabine
+ docetaxel
4 cycles
Outcomes
Hensley ML, et al. Gynecol Oncol. 2009;112(3):563-567.
3-year PFS
59%
Median PFS
39 months
Median follow-up
48 months
Median OS
NR
SARC 005 – Adjuvant Therapy for
Resected Uterine LMS
Phase II
Stage I/II
N = 46
Gemcitabine
+ docetaxel
4 cycles
PFS
Adriamycin
4 cycles
OS
Outcomes
Hensley ML, et al. Cancer. 2013;119(8):1555-1561.
3-year PFS
57%
Median PFS
> 36 months
EORTC 55874 – Adjuvant Radiation for
Resected Uterine LMS
Phase III
Stage I/II
N = 224
LMS, n = 103
51 GY
28
fractions
5 wks
Observation
No benefit in PFS or
OS in uterine LMS
Reed NS, et al. Eur J Cancer. 2008;44(6):808-818.
Question 5
Our 78-year-old female did not receive adjuvant therapy
and relapsed in the abdomen/pelvis 18 months later. What
systemic therapy do you recommend?
1. Gemcitabine/docetaxel
2. Adriamycin
3. Trabectedin
4. Cisplatin-based therapy
5. Dacarbazine
Pre-treatment
Post 4 cycles of trabectedin

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