Synovial Sarcoma

Transcription

Synovial Sarcoma

SAM: Soft Tissue Sarcoma
ASTRO
March 23rd 2013
Kaled M. Alektiar, M.D.
Dept. Of Radiation Oncology
Memorial Sloan-Kettering Cancer Center
Disclosure:
None
Randomized Trials in Extremity STS
• Amputation vs. surgery and radiotherapy
–
Rosenberg et al (NCI):
Ann Surg 1982
• Surgery alone vs. surgery and radiotherapy
–
–
Pisters et al (MSKCC) BRT:
Yang et al (NCI)
EBRT:
JCO, 1996
JCO, 1998
Amputation vs. WLE+RT
NCI Trial
43 pts
High grade STS
Extremity
27 pts
WLE+RT
16 pts
Amputation
Rosenberg et al Ann Surg, 1982
NCI Amputation Trial
Local Control
Overall Survival
WLE+BRT vs. WLE Alone Trial
164 PTS STS
EXTREMITY OR TRUNK
WLE
86 PTS
NO BRT
78 PTS
BRT
Pisters et al JCO, 1996
BRT Randomized Trial
Local Control
BRT
NO BRT
1.0
1.0
.8
Proportion Surviving
Proportion Free of Local Recurrence
.8
Overall Survival
.6
.4
p = 0.039
.2
.6
.4
p= 0.28
.2
0.0
0.0
0
20
40
60
80
100
120
Time (Months)
140
160
180
200
0
20
40
60
80
100
120
140
160
180
Time (Months)
200
WLE Alone vs. WLE+EBRT
NCI Trial
91 PTS STS
EXTREMITY
WLE + CT ♣
44 PTS
NO XRT
♣: CT for HG
47 PTS
POST-OP XRT
Yang et al JCO, 1998
NCI Trial
LC
OS
Patients on Two Ends of the Spectrum
Those with very poor local control
Those who are supposed to have
good local control
Influence Of Positive Margin
On Local Control
Negative Positive p-value
Preop EBRT1
91%
62%
0.005
BRT2
86%
74%
0.04
Postop EBRT3
79%
57%
0.07
1:Tanabe; Cancer 1994, 2:Alektiar; ASO 2002, 3: Suit, JCO 1988.
Predictors of Poor Survival
•
•
•
•
•
High grade (RR:4)
Deep location (RR: 2.8)
> 10 cm (RR: 2.1)
Leiomyosarcoma (RR:1.9)
MPNT (RR: 1.9)
• Positive margin (RR: 1.9)
• Lower extremity site (RR: 1.6)
• Local recurrence at presentation (RR: 1.5)
Pathologic Negative Re-excision:
200 pts with non-metastatic primary ext STS
S/P WLE and no RT
Median F/U: 82 mo
5-year LR:
9%
RR
p
Age ≥ 50
3.3
0.02
Stage III
3.4
0.01
5-y LR
None 4%
1 RF 12%
2 RF 31%
Cahlon O et al. Cancer 2008
Surgery Alone in STS of the Extremity:
Selected Series
Author (year)
# of pts
Selection
L Fail
D Fail
Karakousis (1986)
116
2 cm margin
10%
NR
Rydholm (1991)
56
“Contained”
7%
NR
Geer (1992)
117
T1, primary
8%
5%
Respondek (1997)
40
T1, primary
8%
NR
Baldini (1999)
74
Not specified
7%
12%
Small (< 5 cm) HG STS Of The Extremity
204 Pts
WLE
Negative margins
No RT
116/204 (57%)
pts
RT
88/204 (43%) pts
Alektiar et al JCO 2002
LC & RT
Proportion with Local Control (%)
100
RT
80
n = 88
n = 116
No RT
60
p = 0.3
40
20
0
0
5
10
Years
15
20
LC & RT
100
Proportion with Local Control (%)
Non-Central
80
n = 176
Central (axilla/groin)
60
n = 28
40
p = 0.007
20
0
0
5
10
Years
15
20
Cases
#1
40 yo s/p WLE of STS of the thigh:
• 20 cm
• Positive margin
• Low grade
• Well diff liposarcoma
#2
60 yo s/p WLE of STS of the forearm
• 2cm
• Negative but close margin
• High grade
• Leiomyosarcoma
Surgery Alone: Nomogram
• 684 pts
• Primary extremity STS
• Non-metastatic
• Treated with WLE
• No adjuvant RT or CT
0.4
• Median F/U: 58 mo
• 3-yr LR: 11%
• 5-yr LR: 13%
•10 yr LR: 19%
0.2
0
0
5
10
15
20
Cahlon O et al. Annl of Surg 2012.
Nomogram: 3 & 5 year Local Control:
Concordance Probability Estimate (CPE): 0.74
0
10
20
30
40
50
60
70
80
90
100
Points
>50
Age
<=50
>5cm
Size
<=5cm
Close or Positive
Margin
Negative
High
Grade
Low
Others
Histology
Atypical Lipoma or Well Diff
Total Points
0
50
100
150
200
250
300
350
400
450
Predicted LR rate at year 3
0.1
0.2
0.3 0.4 0.5 0.6 0.7
0.1
0.2
0.3 0.4 0.5 0.6 0.7 0.8
0
10
20
30
40
50
60
70
80
90
100
Points
>50
Age
<=50
>5cm
Size
<=5cm
Close or Positive
Margin
Negative
High
Grade
Low
Recommend: No RT
Histology
Others
Total Points
0
50
100
150
200
250
300
350
400
450
0.1
0.2
0.3
0.4 0.5 0.6 0.7
0.1
0.2
0.3 0.4 0.5 0.6 0.7 0.8
Case 2
60 yo s/p WLE of STS of the forearm
• 2cm
• Negative but close margin
• High grade
• Leiomyosarcoma
0
10
20
30
40
50
60
70
80
90
100
Points
>50
Age
<=50
>5cm
Size
<=5cm
Close or Positive
Margin
Negative
High
Grade
Low
Recommend: RT
Others
Histology
Total Points
0
50
100
150
200
250
300
350
400
450
0.1
0.2
0.3
0.4 0.5 0.6 0.7
0.1
0.2
0.3 0.4 0.5 0.6 0.7 0.8
Wound Complications♣
NCIC TRIAL
• Reoperation
• Hospital admission for IV antibiotics
• Deep wound packing ≥ 120 days
♣: Prospective data with criteria evaluated weekly
to 4 months.
O’Sullivan et al Lancet 2002
Timing: Preoperative vs. Postoperative RT
NCIC
180 adult pts
Stratified according to size of 10 cm
Randomized
88/180 pts
Preoperative XRT
50 Gy
92/180 pts
Postoperative XRT
66 Gy
Wound Complications
NCIC Trial
180 adult pts
Wound complications
26% (47/180)
Preoperative XRT
35% (31/88)
Postoperative XRT
17% (16/92)
p = 0.01
Preoperative vs. Postoperative RT
NCIC
Overall survival
HR of post-op to
pre-op with 95% CI
1.2 (0.7-2.0)
Log-rank
p-value
0.48
Late Complications (> grade 2)
NCIC Trial
Pre-op RT
Post-op RT
p
Fibrosis
31.5%
48.2%
0.07
Stiffness
17.8%
23.2%
0.51
Edema
15.1%
23.2%
0.26
Davis AM et al. Radiother Oncol 2005.
Function by Treatment Arm
NCIC Trial
Pre-op RT
Post-op RT
p
MSTS
60
63
0.08
TESS
64
66
0.17
Musculoskeletal Tumor Society Rating Scale
Toronto Extremity Salvage Score
Davis AM et al. Radiother Oncol 2005.
Influence of Site on Complications
369 pts
Primary HG Extremity STS
WLE and RT at MSKCC
103 pts
Upper Extremity
Wound re-op 1%
Two groups were comparable
• Size: < vs. ≥ 5 cm
• Prior excision
• RT type: BRT vs. EBRT
• Depth: deep vs. superficial
• Margin status
266 pts
Lower Extremity
Wound re-op 11%
p = 0.002
Alektiar K M et al. IJROBP 2005
Influence of Subsite: Thigh Compartment
Femoral vessels
Femur
Sciatic nerve
Rimner A et al. Cancer 2008
Complications & Thigh Compartment
Wound re-op
Edema
Neuropathy
Rimner A et al. Cancer 2008
Why IMRT in Extremity STS?
Can IMRT Reduce The Morbidity in STS?
Bone Fracture in STS Of Extremity
n
RT Type
% Fracture
MSKCC1
369
BRT
4%
UF2
285
Preop
4%
NCI3
145
Postop
6%
PMH4
364
Preop & Postop
6%
1.
2.
3.
4.
Alektiar et al Ann Surg Oncol 2002
Helmsteder et al Clinc Ortho 2000
Stinson et al. IJROBP 1991
Holt et al. JBJS 2005
364 lower extremity EBRT and at PMH (1986-98); no chemo.
• Females (6% vs 2%, p = 0.02); > 55 yr (7% vs 1%, p = 0.004)
• Cox: age, gender, and RT independent
• Median fracture time: 44 mos (range, 12 to 153 months)
Fracture rates:
Crude rates 5-yr frequency
Overall
6.3 %
4%
High-dose (60-66 Gy)
10 %
7%
2%
0.6 %
Low-dose (50 Gy,
generally pre-op)
Holt et al. JBJS 2005
• 205 consecutive patients with thigh STS
over 15–years (1982–1997) at MSKCC
without bone invasion or bone resection
• 5-year actuarial fracture risk was 29% if
resection included periosteum (P = 0.0001)
• Cox regression, entire group:
 Periosteal excision was the only independent factor
• Separate Cox model, periosteal stripping subset (n = 54):
 Female gender: 47% risk (P = 0.022)
 Chemotherapy: 45% risk (P = 0.020) Lin et al. Cancer 1998
Nomogram For RT-associated
Femoral Fractures
Gortzak Y et al. Cancer 2010
Dosimetric Predictors of
Fracture in Lower Extremity STS
Fracture pts
Non fracture pts
p
Mean Dose
45 ± 8 Gy
37 ± 11 Gy
0.01
Max. Dose
64±7 Gy
59 ± 8 Gy
0.02
V40
76 ± 17 %
64 ± 22%
0.01
Dickie CI et al IJROBP 2009.
IMRT Dosimetric Advantages
PTV
3-D
PTV
GTV
GTV
IMRT
%
Hong et al Int J Rad Oncol Biol Phys, 2004
Dosimetric Plans for Thigh STS
2 cm
Target volume
Treatment volume
0.5 cm
IMRT Outcome Data:
Preliminary Results for Primary STS
of The Extremity






# pts:
Site:
Presentation:
Time period:
Mean age:
Sex:
31
Extremity
Primary STS
02/02- 03/05
58 (range: 30-80)
17F/14M
Alektiar KM et al. IJRPBP 2006
Tumors Characteristics
%
n
Grade
High
77
24
Depth
Deep
90
28
Tumor size
>10 cm
74
23
Site
Lower extremity
68
21
Surgery
%
n
100
31
Positive/close margin
55
17
Periosteal stripping/bone resection
32
10
Neurolysis/nerve resection
65
20
Tissue transfer for wound closure
23
7
Complete gross resection
Indications For IMRT
• Preoperative IMRT: 7/31
• Preserve normal soft tissue
Indications For IMRT
• Post-op IMRT: 24/31
• To reduce high RT dose
to the whole extremity
Complications of IMRT (%)
CTCAE
Grade
Dermatitis Wound (non-infectious)
Wound (infectious)
0
3
90
87
1
71
3
-
2
16
7
10
3
10
0
3
Complications of IMRT (%)
CTCAE
Grade
Edema
Stiffness
Neuropathy
0
68
62
67
1
19
19
28
2
13
19
5
3
0
0
0
Impact of IMRT on LC:
Patient Population (n = 41)
n
%
High grade
35
83%
> 10 cm
28
67%
Deep
38
90%
Positive/close
22
52%
Bone manipulated
11
26%
Nerve manipulated
25
60%
Alektiar KM et al. JCO 2008
Tumor Control
Median Follow-up: 35 months
5-year
95% CI:
100
90
LC
DMFS
94%
62%
86-100
46-77
80
70
60
LC
50
DM
OS
40
30
20
10
0
OS
65%
45-85
0
20
40
60
80
Months
Alektiar KM et al. JCO 2008
Bone Fractures with IMRT
G1
G3
G2
G3
IMRT vs. BRT
Influence of Grade
BRT Randomized Trial
Local Control
High Grade
Low Grade
1.0
1.0
Local Control
BRT
NO BRT
.8
.6
.4
p = 0.001
.2
.8
.6
.4
p = 0.43
.2
0.0
0.0
0
BRT
20
40
60
80
100
120
Time (Months)
140
160
180
200
0
20
40
60
80
100
120
140
160
180
Time (Months)
200
NCI Trial
LC in HG
LC in LG
Type of RT and Time Period:
Primary HG Extremity
100%
80%
60%
IMRT
3-D
BRT
40%
20%
0%
1989-1994
1995-2000
2001-2006
2007-2011
IMRT vs. BRT For Primary HG
STS of the Extremity
All 134 pts
Received RT at MSKCC
1/1/95-12/31/06
63 IMRT
2/02-12/06
50 Gy pre-op (10 pts)
63 Gy post-op (53 pts)
71 BRT
1/95-11/03
45 Gy LDR
900-1000 cGy/day
Alektiar KM et al. Cancer 2011
Distribution of Variables
Size (cm)
≤ 10
>10
Margin
Negative
Positive/close
Bone manipulation
Yes
No
Nerve manipulation
Yes
No
IMRT
BRT
p
30 (48%)
33 (52%)
50(70%)
21 (30%)
0.005
32 (51%)
31 (49%)
57 (80%)
14 (20%)
0.006
19 (30%)
44 (70%)
9 (13%)
62 (87%)
0.02
34 (54%)
29 (46%)
10 (14%)
61 (86%)
0.002
No significant difference based on age, sex, depth, site, and CT
Significant Wound Complications:
i.e. IV Antibiotics or Re-operation
All: 20/134 pts (15%)
5/20 re-operation
IMRT: 12/63 (19%)
1/12 re-operation
BRT: 8/71 (11%)
4/8 re-operation
♠: p = 0.6
♠
Local Control and RT Type
100
IMRT = 63
Proportion Local Control
90
BRT = 71
80
70
p = 0.04
60
50
40
IMRT retained its significance
as the only independent predictor of
improved LC on multivariate
analysis, p = 0.04
30
20
10
0
0
30
60
90
120
150
Months
Alektiar KM et al. Cancer 2011





104 pts
02/02- 05/08
Primary Extremity
Median F/U: 48 mo
Size > 10 cm: Only
predictor of poor LC
(RR: 2; p = 0.04)
Updated IMRT Data
100
90
80
70
60
50
40
30
20
10
0
LC
DM
OS
0
50
100
150
Months
Alektiar KM et al ASTRO 2011
IMRT Data Compared to EBRT
180 adult pts
Stratified according to size of 10 cm
Randomized
88/180 pts
Preoperative XRT
50 Gy
92/180 pts
Postoperative XRT
66 Gy
34% of all pts were > 10 cm
In IMRT study 52% were > 10 cm
O’Sullivan B et al Lancet 2002
Wound avoidance
with IMRT: Phase II





# of pts: 59
Med size: 9.5 cm
High grade: 93%
Deep: 98%
Wound comp: 30.5%
O’Sullivan B et al Cancer 2013
IMRT Results: PMH







# of pts: 59
Tumor size > 10 cm: 44%
High grade: 93%
Deep: 98%
Median F/U: 49 months
Local recurrence: 4/59 (6.8%)
5-year LR-free survival: 88.2%
O’Sullivan B et al Cancer 2013
Volume Delineation:
Extent of STS Cells Beyond Main Tumor Mass
MRI-Histological Correlation
Tissue sampled from tumor to margin
of resection in 6 planes
Presence of tumor cells (<1 cm or
>1cm) from nearest tumor edge by
light microscopy
Tumor cells present outside of
tumor in 10/15 cases (67%)
< 1 cm from tumor = 6/15
> 1 cm from tumor = 4/15
White et al Int J Radiat Oncol Biol Phys, 2005
Does Targeted RT in STS = Less Volume?
GTV ?
CTV
O'Sullivan, et al In: Clinical target volumes in conformal radiotherapy and
intensity modulated radiotherapy. Springer: 205-227, 2003.
CTV (Tumor bed/GTV – CTV = 4 cm)
CTV (tumor bed/GTV – CTV = 1 cm)
Tumor bed
or GTV
PTV (CTV - PTV = 1 cm)
Immobilization
Immobilization & Set-up Errors
31 LE STS treated with preop
IMRT
Interfractional & intrafractional
motion measured using CBCT &
optical localization system
A 5 mm margin of expansion from
CTV→PTV is adequate
Dickie C I et al IJROBP. 2010
Patterns of LR in Extremity STS
Marginal LR
Scar
In-field LR
RT Field
Distant LR
Relationship Between LR & RT Field
Surgical margin status
RT scheduling
LR location
R0 (%)
R1 + R2 ( %)
Preop (%)
Postop (%)
Preop + Boost (%)
Total LR
32 (5.3)
28 (17.0)
32 (6.9)
16 (6.4)
12 (22.1)
In field
26 (4.3)
23 (14.0)
27 (5.8)
12 (4.8)
10 (18.5)
0 (0)
2 (1.2)
1 (0.2)
0 (0)
1 (1.8)
6 (1.0)
3 (1.8)
4 (0.9)
4 (1.6)
1 (1.8)
Marginal
Out of field
Dickie C et al. IJROBP 2012
Patterns of LR (8/104) & Original RT Fields
Volume of LR Receiving 95% of
Prescription Dose*
n
%
In-field (completely inside D95%)
3
37.5
Marginal (crossed the D95%)
5
62.5
Distant (completely outside D95%)
0
0
* : Milano MT et al. IJROBP 2010
The Problem of Metastasis
What is the reported 3-year survival for a
65 y/o male with MFH of the thigh diagnosed
1 year ago and now with lung metastasis ?
1.
2.
3.
4.
5-10%
10-20%
20-30%
> 30%
RESECTION OF PULMONARY
METASTASIS
Complete
resection
3-year survival
MSKCC
83%
23%
MDACC
75%
23%
Gadd et al Ann Surg 1993
Lanza et al Ann Thorac Surg 1991
‘Correct’ answer Question 14 is “2” (11%)
Brennan et al JACS, 1996
Adjuvant Chemotherapy Meta-Analysis:
1568 patients, 14 trials
p=0.016
p=0.0001
p=0.0003
p=0.12
Sarcoma Meta-analysis Collaboration, Lancet 1997
Impact of CT on LC
Pervaiz N et al. Cancer 2009
Impact of CT on Distant Metastasis
Impact of CT on OS
CT vs. No CT:
Extremity Stage III STS
LC
DM
DSS
Cormier JN et al. JCO 2004
The Lack of Duration of CT Benefit
Cormier JN et al. JCO 2004
RT/CT for Extremity STS:
RTOG 9514
 64 pts HG STS ≥ 8 cm
 79% completed pre-op CT
 59% completed all CT
Kraybill W et al JCO 2006
RTOG 9514:
Update
Kraybill W et al Cancer 2010
Node Positive Presentation
Soft Tissue Sarcoma
Lymph Node vs Other Metastasis
Disease Specific Survival
1.0
Lymph Node n = 160
 Other n = 891

.8
.6
.4
.2
0.0
0
40
80
120
160
200
Time (Months)
MSKCC 7/1/82-12/31/00 n = 1051 p = 0.1
240
Prognosis of Isolated LN Metastases
Royal Marsden
Behranwala et al Ann Surg
Oncol 11, 2004
Princess Margaret Hospital
Riad et al Clin Ortho,426, 2004
35 y/o m with
posterior thigh
tumor with pelvic
lymph node
involvement
Tumor in adductor magnus
displacing sciatic nerve
From: O'Sullivan, B., et al in Gunderson and Tepper, 2nd edition,2006
Advances in the Molecular Biology of
STS is Coinciding with RT Technical
Advances
Before IMRT
50 Gy
6 wks post-IMRT
Translocations in Myxoid Liposarcoma
FISH: Split or break apart signals
Bridge J. Univ of Nebraska
Powers MP et al Mod Path 2010
Myxoid Liposarcoma vs. Other Histologies:
691 pts with extremity STS (88 myxoid lipo vs. 603 other)
5-y LC: 97.7% vs. 89.6%, respectively; p = 0.008
p = 0.0001
p = 0.0008
Chung PW et al. Cancer 2009
Spine IGRT
Schwab et al. Cancer 2007
• Spinal mets: T12
• Preop IGRT: 24 Gy
• Resection: 6 weeks
• Tumor necrosis: 95%
• Histology: myxoid lipo.
Genes Alterations in STS
Histology
Alteration
Involved gene(s)
%
Synovial
t(X;18) (p11;q11)
SYT-SSX1, SYT-SSX2
90%
DSRCT
t(11;22) (p13;q12)
EWS-WT1
90%
Alveolar RMS
t(2;13)
PAX3-FKHR
85%
Myxoid liposarcoma
t(12;16) (q13;p11)
TLS (FUS)-CHOP
75%
Myxoid chondrosarcoma
t(9;22) (q22;q12)
EWS-CHN (TEC)
75%
Clear cell sarcoma
t(12;22) (q13;q12)
EWS-ATF1
75%
Prognostic Significance of Gene
Profiling within Histology
Two groups of MFH:
One (red bar) has an
abundance of genes
associated with muscle
and less favorable
prognosis
The second group
(blue bar) carries an
inflammatory profile.
Baird D et al. Cancer Res 2005
Copy Number Alterations in STS
Barretina J et al Nat Genet. 2010
Future of STS Treatment
Single Gene
Thousands of Genes
Genome Wide

Synovial Sarcoma

Transcription

Similar documents

Folie 1