sam: soft tissue sarcoma astro march 23 2013 · sam: soft tissue sarcoma astro march 23rd 2013...

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: JCO, 1996 – Yang et al (NCI) EBRT: JCO, 1998

Amputation vs. WLE+RT NCI Trial

27 ptsWLE+RT

16 ptsAmputation

43 ptsHigh grade STS

Extremity

Rosenberg et al Ann Surg, 1982

Local Control Overall Survival

NCI Amputation Trial

WLE+BRT vs. WLE Alone Trial

86 PTSNO BRT

78 PTSBRT

164 PTS STSEXTREMITY OR TRUNK

WLE

Pisters et al JCO, 1996

Local Control

Time (Months)

200180160140120100806040200

Pro

port

ion

Fre

e of

Loc

al R

ecur

renc

e

1.0

.8

.6

.4

.2

0.0

p = 0.039


Overall Survival

Time (Months)

200180160140120100806040200

Pro

porti

on S

urvi

ving

1.0

.8

.6

.4

.2

0.0

p= 0.28

BRT Randomized Trial

BRT NO BRT

WLE Alone vs. WLE+EBRT NCI Trial

44 PTSNO XRT

47 PTSPOST-OP XRT

91 PTS STSEXTREMITYWLE + CT

Yang et al JCO, 1998 ♣: CT for HG

♣

NCI Trial LC OS

Yang et al JCO, 1998

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

Cahlon O et al. Cancer 2008

RR p

Age ≥ 50 3.3 0.02

Stage III 3.4 0.01

Median F/U: 82 mo 5-year LR: 9% 5-y LR

None 4% 1 RF 12% 2 RF 31%

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

Alektiar et al JCO 2002

204 Pts WLE

Negative margins

No RT 116/204 (57%)

pts

RT 88/204 (43%) pts

RT

No RT

n = 88 n = 116

p = 0.3

Small (< 5 cm) HG STS Of The Extremity LC & RT

0

20

40

60

80

100

0 5 10 15 20

Pro

po

rtio

n w

ith

Lo

ca

l Co

ntr

ol (

%)

Years

Central (axilla/groin)

Non-Central

n = 176

n = 28

p = 0.007

Small (< 5 cm) HG STS Of The Extremity LC & RT

0

20

40

60

80

100

0 5 10 15 20

Years

Pro

po

rtio

n w

ith

Lo

ca

l Co

ntr

ol (

%)

Cases 40 yo s/p WLE of STS of the thigh:

• 20 cm • Positive margin • Low grade • Well diff liposarcoma

#1 # 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

Cahlon O et al. Annl of Surg 2012.

0

0.2

0.4

0 5 10 15 20

• Median F/U: 58 mo • 3-yr LR: 11% • 5-yr LR: 13% •10 yr LR: 19%

Nomogram: 3 & 5 year Local Control: Concordance Probability Estimate (CPE): 0.74

Points 0 10 20 30 40 50 60 70 80 90 100

Age<=50

>50

Size<=5cm

>5cm

MarginNegative

Close or Positive

GradeLow

High

HistologyAtypical Lipoma or Well Diff

Others

Total Points 0 50 100 150 200 250 300 350 400 450

Predicted LR rate at year 30.1 0.2 0.3 0.4 0.5 0.6 0.7

Predicted LR rate at year 50.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Points 0 10 20 30 40 50 60 70 80 90 100

Age<=50

>50

Size<=5cm

>5cm

MarginNegative

Close or Positive

GradeLow

High


Others

Total Points 0 50 100 150 200 250 300 350 400 450



Recommend: No RT

60 yo s/p WLE of STS of the forearm • 2cm • Negative but close margin • High grade • Leiomyosarcoma

Case 2

Points 0 10 20 30 40 50 60 70 80 90 100

Age<=50

>50

Size<=5cm

>5cm

MarginNegative

Close or Positive

GradeLow

High


Others

Total Points 0 50 100 150 200 250 300 350 400 450



Recommend: RT

Wound Complications♣ NCIC TRIAL

• Reoperation • Hospital admission for IV antibiotics • Deep wound packing ≥ 120 days

O’Sullivan et al Lancet 2002

♣: Prospective data with criteria evaluated weekly to 4 months.

Timing: Preoperative vs. Postoperative RT NCIC

88/180 ptsPreoperative XRT

50 Gy

92/180 ptsPostoperative XRT

66 Gy

180 adult ptsStratified according to size of 10 cm

Randomized


Wound Complications NCIC Trial

Preoperative XRT35% (31/88)

Postoperative XRT17% (16/92)

180 adult ptsWound complications

26% (47/180)

p = 0.01 O’Sullivan et al Lancet 2002

Preoperative vs. Postoperative RT NCIC


HR of post-op to Log-rank pre-op with 95% CI p-value 1.2 (0.7-2.0) 0.48

Overall survival

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

Davis AM et al. Radiother Oncol 2005.

Musculoskeletal Tumor Society Rating Scale Toronto Extremity Salvage Score

Influence of Site on Complications

103 ptsUpper ExtremityWound re-op 1%

266 ptsLower Extremity

Wound re-op 11%

369 ptsPrimary HG Extremity STS

WLE and RT at MSKCC

p = 0.002 Alektiar K M et al. IJROBP 2005

Two groups were comparable • Size: < vs. ≥ 5 cm • Prior excision • RT type: BRT vs. EBRT • Depth: deep vs. superficial • Margin status

Influence of Subsite: Thigh Compartment

Femur

Sciatic nerve

Femoral vessels

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 UF2

NCI3

PMH4

369 BRT 4% 285 Preop 4% 145 Postop 6% 364 Preop & Postop 6%

1. Alektiar et al Ann Surg Oncol 2002 2. Helmsteder et al Clinc Ortho 2000 3. Stinson et al. IJROBP 1991 4. 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 %

Low-dose (50 Gy, 2 % 0.6 % 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 3-D

IMRT Dosimetric Advantages

%

GTV PTV

GTV PTV

Hong et al Int J Rad Oncol Biol Phys, 2004

Dosimetric Plans for Thigh STS

Target volume

Treatment volume

2 cm

0.5 cm

IMRT Outcome Data: Preliminary Results for Primary STS

of The Extremity

# pts: 31 Site: Extremity Presentation: Primary STS Time period: 02/02- 03/05 Mean age: 58 (range: 30-80) Sex: 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

Complete gross resection 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

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:

LC 94% 86-100

DMFS 62% 46-77

OS 65% 45-85 0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80Months

Prop

ortio

n Su

rviv

ing

LCDMOS

Alektiar KM et al. JCO 2008

Bone Fractures with IMRT

G1 G2

G3 G3

IMRT vs. BRT

BRT


Influence of Grade BRT Randomized Trial

Local Control

High Grade

Time (Months)

200180160140120100806040200

Pro

port

ion

Fre

e of

Loc

al R

ecur

renc

e

1.0

.8

.6

.4

.2

0.0

Local Control

Low Grade

Time (Months)

200180160140120100806040200

Pro

po

rtio

n F

ree

of

Lo

cal R

ecu

rre

nce

1.0

.8

.6

.4

.2

0.0

p = 0.43 p = 0.001

BRT NO BRT

NCI Trial

Yang et al JCO, 1998

LC in HG LC in LG

Type of RT and Time Period: Primary HG Extremity

0%

20%

40%

60%

80%

100%

1989-1994 1995-2000 2001-2006 2007-2011

IMRT3-DBRT

IMRT vs. BRT For Primary HG STS of the Extremity

63 IMRT2/02-12/06

50 Gy pre-op (10 pts)63 Gy post-op (53 pts)

71 BRT1/95-11/0345 Gy LDR

900-1000 cGy/day

All 134 ptsReceived RT at MSKCC

1/1/95-12/31/06

Alektiar KM et al. Cancer 2011

Size (cm) ≤ 10 >10

30 (48%) 33 (52%)

50(70%) 21 (30%)

0.005

Margin Negative Positive/close

32 (51%) 31 (49%)

57 (80%) 14 (20%)

0.006

Bone manipulation Yes No

19 (30%) 44 (70%)

9 (13%) 62 (87%)

0.02

Nerve manipulation Yes No

34 (54%) 29 (46%)

10 (14%) 61 (86%)

0.002

IMRT BRT p

Distribution of Variables

No significant difference based on age, sex, depth, site, and CT

Significant Wound Complications: i.e. IV Antibiotics or Re-operation

IMRT: 12/63 (19%)1/12 re-operation

BRT: 8/71 (11%)4/8 re-operation

All: 20/134 pts (15%)5/20 re-operation

♠

♠: p = 0.6

Local Control and RT Type

IMRT retained its significance as the only independent predictor of improved LC on multivariate analysis, p = 0.04

Alektiar KM et al. Cancer 2011

0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150

Pro

port

ion

Loca

l Con

trol

Months

BRT = 71

p = 0.04

IMRT = 63

Updated IMRT Data

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)

LC DM OS

Alektiar KM et al ASTRO 2011

0102030405060708090

100

0 50 100 150

Prop

ortio

n Su

rviv

ing

Months

IMRT Data Compared to EBRT

88/180 ptsPreoperative XRT

50 Gy

92/180 ptsPostoperative XRT

66 Gy

180 adult ptsStratified according to size of 10 cm

Randomized

O’Sullivan B et al Lancet 2002 34% of all pts were > 10 cm In IMRT study 52% were > 10 cm

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

White et al Int J Radiat Oncol Biol Phys, 2005

Tumor cells present outside of tumor in 10/15 cases (67%) < 1 cm from tumor = 6/15 > 1 cm from tumor = 4/15

O'Sullivan, et al In: Clinical target volumes in conformal radiotherapy and intensity modulated radiotherapy. Springer: 205-227, 2003.

Does Targeted RT in STS = Less Volume?

GTV ?

CTV

Tumor bed or GTV

CTV

(Tum

or b

ed/G

TV –

CTV

= 4

cm

)

PTV (CTV - PTV = 1 cm)

CTV (tumor bed/GTV – CTV = 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

Scar

RT Field

Marginal LR

In-field LR

Distant LR

Relationship Between LR & RT Field

LR location

Surgical margin status RT scheduling

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)

Marginal 0 (0) 2 (1.2) 1 (0.2) 0 (0) 1 (1.8)

Out of field 6 (1.0) 3 (1.8) 4 (0.9) 4 (1.6) 1 (1.8)

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

1. 5-10% 2. 10-20% 3. 20-30% 4. > 30%

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 ?

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

Sarcoma Meta-analysis Collaboration, Lancet 1997

Adjuvant Chemotherapy Meta-Analysis: 1568 patients, 14 trials

p=0.12 p=0.0003

p=0.0001

p=0.016

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

Time (Months)

24020016012080400

Prop

ortio

n Su

rviv

ing

1.0

.8

.6

.4

.2

0.0

Soft Tissue Sarcoma Lymph Node vs Other Metastasis

Disease Specific Survival

MSKCC 7/1/82-12/31/00 n = 1051 p = 0.1

Lymph Node n = 160 Other n = 891

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

Tumor in adductor magnus displacing sciatic nerve

35 y/o m with posterior thigh

tumor with pelvic lymph node involvement

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

Powers MP et al Mod Path 2010

FISH: Split or break apart signals

Bridge J. Univ of Nebraska

Myxoid Liposarcoma vs. Other Histologies: 691 pts with extremity STS (88 myxoid lipo vs. 603 other)

Chung PW et al. Cancer 2009

5-y LC: 97.7% vs. 89.6%, respectively; p = 0.008

p = 0.0001 p = 0.0008

Spine IGRT

• Spinal mets: T12 • Preop IGRT: 24 Gy • Resection: 6 weeks • Tumor necrosis: 95% • Histology: myxoid lipo.

Schwab et al. Cancer 2007

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%

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

Prognostic Significance of Gene Profiling within Histology

Barretina J et al Nat Genet. 2010

Copy Number Alterations in STS

Future of STS Treatment

Single Gene Thousands of Genes Genome Wide

sam: soft tissue sarcoma astro march 23 2013 · sam: soft tissue sarcoma astro march 23rd 2013...

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