Combined M anagement of Retroperiton Retroperiton neal Sarcoma - - PowerPoint PPT Presentation

Combined M Retroperiton Retroperiton

Carol J. Department of S Princess Margaret and Princess Margaret and University

Charles Catton, Brian O’Sullivan, Pete Abha Gupta, Korosh Khalili, Sangeet Gha Lynn Mikula Julia Jones Michael Ko Rya Princess Margaret Hospital Toronto, Canada Lynn Mikula, Julia Jones, Michael Ko, Rya

anagement of neal Sarcoma neal Sarcoma

Swallow Surgical Oncology d Mount Sinai Hospitals d Mount Sinai Hospitals y of Toronto

er Chung, Martin Blackstein, David Hogg, ai, Rita Kandel, David Howarth, Ilan Weinreb an Heisler Paul Ridgway Rebecca Gladdy l 50th Anniversary Conference a October 17, 2008 an Heisler, Paul Ridgway, Rebecca Gladdy

Presentation Freque PMH Sarcoma D (n=

10% 10% 15% 15%

ency by Primary Site atabase 1989-1997 1282) Site of Soft Tissue Sarcoma

Extremity and Trunk Viscera

Site of Soft Tissue Sarcoma

Viscera Head and Neck Retroperitoneum

65%

p

Overall Sur Overall Sur by Primary Site

Catton, O’Sullivan et al., Int J Ra

rvival after Resection rvival after Resection e of Soft Tissue Sarcoma PMH PMH

PMH ’75-’90 d Oncol Biol Phys 1994; 29:1005.

Combined Mana

• Scope of pro
• Scope of pro
• Work-up
• Resection tec
• Adjuvant rad
• Adjuvant rad

– rationale bidit – morbidity

• Long term on

agement of RPS g

blem blem chnique iation iation ncologic outcomes

R t it l S Retroperitoneal Sarc Th Ch ll ! coma: The Challenge!

Retroperitoneal Sarcoma: The Challenge

When I was a fellow*… “If it’s resectable, take it out!” *circa 1993-95, MSKCC

There is a better ma

• lymphoma
• asymptomatic be
• metastatic carcin

Think first, cut late

• paraganglioma

paraganglioma

• PNET etc.
• Soft Tissue Tum
• Soft Tissue Tum

anagement strategy

enign PNST noma

er

mour mour

Approach to the Re

• often asymptomatic
• e

asy p o a c

• increasingly incidental
• usually non urgent
• usually non-urgent
• broad differential
• avoid diagnostic laparot

etroperitoneal Mass

tomy

Approach to the Re Approach to the Re Reasons to Biops

• diagnosis unclear from

clinical presentation and clinical presentation and imaging AND treatment will be altered will be altered

• neoadjuvant treatment

planned planned

etroperitoneal Mass etroperitoneal Mass sy Percutaneously

Resection: Cornerstone of RPS Treatment

Retroperitoneal Retroperitoneal Resect 5 yr

80 100 patients

5 yr 10 yr

40 60 80 ntage of p 20 40 percen 0 Survival LR

* l t ti t 43% Catton, O’Sullivan et al., *complete gross resection rate was 43%

l Sarcoma: Outcome in l Sarcoma: Outcome in ted Patients

n = 45

1975 - 1990

n 45

Relapse Distant Relapse Free Free

Int J Rad Oncol Biol Phys 1994; 29:1005.

Catton, O’Sullivan et al., Int J Rad Oncol Biol Phys 1994; 29:1005.

*+

+#

4 = Lewis, 1998 MSKCC, n=231 10 = Stoeckle, 2001 FSG, n=94 30 = Heslin, 1997 MSKCC, n=198 , ,

*Chiappa et al., JSO 2006; 93:456.

+Yin Lu et al., CMJ 2007; 120:1047.

8 = Gronchi, 2004 Milano, n=167 9 = Singer 1995 DFCI n=83

+#

#van Dalen et al., EJSO 2006; 33:234.

9 = Singer, 1995 DFCI, n=83

#

Strategies to imp

I Surgical Technique

• I. Surgical Technique
• pre-surgical plannin
• intraoperative/ posto
• en bloc resection of
• II. Radiation delivery

Protect normal struc Protect normal struc

• removable implant
• pre-operative RT
• IORT boost
• brachytherapy boo

prove local control

ng

• perative care

adherent viscera y ctures; escalate dose ctures; escalate dose ts

• st

RPS Combined Treatm Technique – PM ec que

Structures resected en bloc with tumou en bloc with tumou Psoas/iliacus Large bowel Large bowel Kidney/adrenal Chest wall/diaphrag Chest wall/diaphrag Liver Pancreas Pancreas Stomach S l Spleen Small bowel

ment Protocol Surgical MH series ’96-’00 se es 96 00

d Percent ur (n= 46) ur (n 46) 63% 63% 63% 63% gm 31% gm 31% 31% 19% 19% 19% 19% 19% 12%

Technical Optimization of Resection

Technical Optimization of Resection

Randomized trials of local ma Randomized trials of local ma

Author Institute Tri Rosenberg (1982) NCI Am Rosenberg (1982) NCI Am Sx Pisters (1996) MSKCC Sx Pisters (1996) MSKCC Sx Sx Yang (1998) NCI Sx Sx O’Sullivan (2000) NCIC-CTG Pre Po Eilber (1990) UCLA Pre pre pre

anagement of extremity STS anagement of extremity STS

al Local Control mp vs 100% mp vs 100% x + EBRT 85% x vs 71% x vs 71% x +BRT 84% x vs 75% x + EBRT 99% e-op EBRT 93%

• st-op EBRT

93% e-op RT+ IV dox 92% e op RT +IA dox 93% e-op RT +IA dox 93%

* Catton, O’Sullivan et al., Int J Rad Oncol Biol Phys 1994; 29:1005.

Strategies to imp

I Surgical Technique

• I. Surgical Technique
• pre-surgical plannin
• intraoperative/ posto
• en bloc resection of
• II. Radiation delivery

Protect normal struc Protect normal struc

• removable implant
• pre-operative RT
• IORT boost
• brachytherapy boo

prove local control

ng

• perative care

adherent viscera y ctures; escalate dose ctures; escalate dose ts

• st

Rationale for PreOperat

preop

tive Radiotherapy for RPS

postop

Preoperative Radiation fo Complex Complex r Retroperitoneal Sarcoma: x Planning x Planning

Management of E

Stage II & III: Pre

Extremity Sarcoma

e- vs Post- Op RT

NCIC SR-2 Trial NCIC SR 2 Trial

O’Sullivan et al, Lancet 2002: 359:2235

Initial R esults of a Trial of Pr Initial R esults of a Trial of Pr R adiation Therapy and Post-o R etroperitone

Julia J. Jones, C harles N . Jean C outure, R yan L. H eisler, R U niversity of Toronto Sarcom a G rou M t Si i H it l T M ount Sinai H ospital, T Jone

re-operative External B eam re-operative External B eam

• perative B rachytherapy for

eal Sarcom a

C atton, Brian O ’Sullivan, R ita A. Kandel, C arol J. Sw allow p, Princess M argaret H ospital and T t O N C d Toronto, O N , C anada es et al, Ann Surg Oncol 2002: 9:346

PMH Protocol of Combin (XRT + SR + BRT) for Re

Pretreatment

• pathological and

diff ti l l

• differential renal
• CT Abdomen/Pe
• CT Chest

ned Modality Treatment etroperitoneal Sarcoma

t Assessment

imaging review (if i di t d) scan (if indicated) lvis

Combined Modality ( Retroperiton

Treatmen

• pre-op XRT 45- 50 Gy

Treatmen

pre-op XRT 45- 50 Gy

• 4 - 6 week wait
• total gross resection +

total gross resection

• > 5 day wait
• +/- pulsed dose rate B

/ pu sed dose a e

(XRT + SR + BRT) for neal Sarcoma

nt Schema

y/25 (5 weeks)

nt Schema

y/25 (5 weeks) + catheter placement catheter placement BRT to max 70 Gy

• a

0 Gy

Management of patients w

R

at Princess Marga between June 199

R n trial n=55 trial resection n=46 mets n=5 XRT BT pre-op XRT n=40 BT n=2 BT an XR no RT n=2 + BT

• BT

+ BT n=19

• BT

n=21 XRT = BT =

with retroperitoneal sarcoma

RPS

aret Hospital, Toronto 96 and October 2000.

RPS n=83

t

incurable refused

recent resection n=14

incurable n=12 refused therapy n=2 pre-op death n=4 nd post-op RT n=2 = external beam radiation therapy post-operative brachytherapy

Pre-opera RTOG acute to RTOG acute to

• All patients (n=40) ha

Acute toxicity scores

• Acute toxicity scores

GI symptoms excep

• One patient develope

ative XRT

• xicity scores
• xicity scores

ad a maximum score ≤ 2 s related to upper and lower s related to upper and lower pt for one patient ed cystitis

Intra-operative p b h th brachytherapy c placement of th t catheters

Brachytherapy cath Brachytherapy cath heter exit sites heter exit sites

• Iridium192 pulsed dose rate BT unit

p dose rate 0.5 Gy/hr, depth of 0.5 cm median dose 25 Gy, area 50 cm2

Acute post-ope

1 2

scale an

mild ho ad none medical therapy

15 8 5 n= 15 8 5 n=

erative toxicity

3 4 5

nd scores

• spital

mission life- threatening death

11 6 1 11 6 1

4/6 had BT H ti f il Hepatic failure

Modified la

1

scale an

2 1 mild h ad none 2 medical therapy

36 1 1 n=

2 late

• f duo

ate toxicity

3 4 5

nd scores

3 hospital dmission 4 life- threatening 5 death

1 1 2

complications

• denal perforation

6/6 had BT

• OS at 2 yrs (n=55) =

OS at 2 yrs (n 55) 73%

• OS at 2 yrs (n=46) =

88%

• RFS at 2 yrs (n=46) =

80% 80%

Phase II Trial of Com Overall Survival in pa Overall Survival in pa preoperative XRT a

5yr OS 75% 75%

Rx’d 06/96 to10/00 f/u to 08/07 no BT, n=21 BT, n=19 Versus historical PMH control in resected patie

mbined Management atients who completed atients who completed and resection, n=40

S 10yr OS 63% 63%

median OS not reached at median OS not reached at median 89 mos. f/u

(months)

ents: 5 yr OS 57%, 10 yr OS 20%

Mikula et al., 2008

Phase II Trial of Com Recurrence-Free Su completed preoperative

no BT, n=21 BT, n=19

5yr R 5y 69%

medi di medi Versus historical PMH control in resected patie

mbined Management urvival in patients who p XRT and resection, n=40

RFS 10yr RFS S 0y S % 52%

ian RFS ≈ 120 mos. i 89 f/ ian 89 mos. f/u ents: 5 yr RFS 45%, 10 yr RFS 17%

Mikula et al., 2008

Phase II Trial of Com Overall Survival in pat Overall Survival in pat preoperative XRT a

5yr OS 5yr OS 80% no BT, n=21 BT, n=19 Log Rank: p=0.27 5yr OS 5yr OS 68% med med

mbined Management tients who completed tients who completed and resection, n=40

10yr OS 10yr OS 80% S 10yr OS Median not reached S 10yr OS 54% ian OS not reached at ian 89 mos. f/u

Swallow et al., 2008

Phase II Trial of Com Recurrence-Free Sur Recurrence Free Sur completed preoperative X

5yr R 75 no BT, n=21 BT, n=19 Log Rank: p=0.58 5yr R 61% No BT: med median RF

mbined Management rvival in patients who rvival in patients who XRT and resection, n=40

RFS 10yr RFS 5%

• RFS

10yr RFS % 47% dian RFS not reached BT: FS ≈ 106 mos.

Swallow et al., 2008

Phase II Trial of Com Overall Survival in HIGH Overall Survival in HIGH completed preoperative X

no BT, n=10 BT, n=12 5yr RFS 68% Log Rank: p=0 68 Log Rank: p=0.68 5yr RF 58% No BT: median BT: median OS

Overall Sur

mbined Management H GRADE patients who H GRADE patients who XRT and resection, n=22

S 10yr RFS %

• FS

10yr RFS 47% OS not reached ≈ 116 mos. BT ≈ BT for: DFS high grade (n=22) OS recurrent (n=11)

Swallow et al., 2008 rvival (months)

OS recurrent (n 11) DFS recurrent (n=11)

Au, Yr, Institution Total N Rx

Prospective Trials of Combined

Design, Yrs. N Sindelar 1993, NIH. Ph III RCT ‘80 35 Postop XRT (50-55 Phase III RCT. ‘80- 85 Postop XRT (35-40 misonidazole Robertson 1995, U 16 Preop XRT + Iodod

• Mich. Phase I like.

Preop XRT + IdUrd Alektiar, 2000, 49 – Resection + IORT +

• MSKCC. Phase I/II

+ 9 off. ’92-96 17 = 32 Resection + IORT Pisters, 2003, MDA. Ph I (18 t 50 4 35 Dox + Preop XRT Phase I. (18 to 50.4 Gy XRT) ’96-01 Dox + Preop XRT + Dox + Preop XRT + IORT Mik la et al 2008 40 Preop XRT Mikula et al., 2008,

• Toronto. Phase I/II.

‘96-00 40 Preop XRT Preop XRT + BT N OS RFS

Radiation and Resection for RPS

median/ 5 yr (%) median/ 5 yr (%) 5 Gy) 20 52 mos. 0 Gy) + IORT + 15 45 mos. deoxyuridine 5 18 mos. + Resection 11 32 mos. + Postop XRT 25 45% 7 8 + Resection + Resection 5 22 21 80% 75% 21 19 80% 68% 75% 61%

Au, Yr, Institution Total N Rx

Prospective Trials of Combi

Design, Yrs. N Sindelar 1993, NCI. Phase III RCT. ‘80- 35 Postop XRT (50-55 Postop XRT (35-40 85 p ( misonidazole Robertson 1995, U

• Mich. Phase I like.

16 Preop XRT + Iodod Preop XRT + IdUrd p Alektiar, 2000,

• MSKCC. Phase I/II

49 – 17 = Resection + IORT + Resection + IORT +. ’92-96 32 Pisters, 2003, MDA. Phase I. (18 to 50.4 Gy XRT) 35 Dox + Preop XRT Dox + Preop XRT + Gy XRT) Dox + Preop XRT + IORT Mikula et al., 2008, T t Ph I/II 40 Preop XRT

• Toronto. Phase I/II.

‘96-00 Preop XRT + BT N Local relapse Toxicity

ned Radiation and Resection

relapse 5 Gy) 0 Gy) + IORT + 20 15 n=16 n=6 GI in 10 neuropathy in y) p y 9 deoxyuridine + Resection 5 11 n=3 grd 4 GI + Postop XRT 25 7 34% 50% n=2 grd 2 neuropathy, n=1 grd 3 uro + Resection 8 5 n=6 grd 3-4 nausea; 1 uro with iort + Resection 22 with iort 21 late in 0 19 late in 6

Retroperiton “Time fo

• ACOSOG Z9031

ACOSOG Z9031

• eligible: biopsy prov

primary RPS p y

• opened Sept, 2004
• poor accrual due to

neal Sarcoma

• r a RCT”

ven, nonmetastatic, ; closed Feb, 2006

• a variety of factors

Overall Survival in p preoperative XRT a preoperative XRT a

Rx’d 06/96 to 03/05

5

N=50, Events=6 Rx d 06/96 to 03/05 f/u to 08/07 Me me min Versus historical PMH control in resected patient

patients treated with and resection n=50 and resection, n=50

5yr OS 87%

edian not reached at edian f/u 62 mos., nimum f/u 29 mos. ts: 5 yr OS 57%, 10 yr OS 20%

(months) Ridgway et al., 2008

Recurrence-Free Surv with preoperative XRT with preoperative XRT

Rx’d 06/96 to 03/05 N=50, Events=13 Rx d 06/96 to 03/05 f/u to 08/07

5y

Me me min Versus historical PMH control in resected patients:

vival in patients treated T and resection n=50 T and resection, n=50

yr RFS 74%

edian not reached at edian f/u 62 mos., nimum f/u 29 mos.

(months)

: 5 yr RFS 45%, 10 yr RFS 17%

Ridgway et al., 2008

Overall Survival in p preop XRT and resect preop XRT and resect

5yr

Rx’d 06/96 to 03/05

5yr 96

Low grade N=27 f/u to 08/07

5

High grade N=23

5yr 75

Log Rank Me g P=0.06 Me me min

patients treated with tion by GRADE n=50 tion, by GRADE, n=50

OS OS 6% OS r OS 5%

edian not reached at edian not reached at edian f/u 62 mos., nimum f/u 29 mos.

(months) Ridgway et al., 2008

Recurrence-Free Su preop XRT and resect preop XRT and resect

5

Rx’d 06/96 to 03/05 Low grade N=27 f/u to 08/07 High grade N=23 Log Rank Me g P=0.006 Me me min

rvival in patients with tion by GRADE n=50 tion, by GRADE, n=50

5yr RFS 91% 91% 5yr RFS 5yr RFS 59%

edian not reached at edian not reached at edian f/u 62 mos., nimum f/u 29 mos.

Ridgway et al., 2008 (months)

Combined Rx of

PMH + MDACC preop XRT trials

5yr OS

PMH MDACC preop XRT trials

5yr OS 61% 5yr LC 60%

Pawlik et al., Ann Surg Oncol 2006; 13: 508.

High Grade RPS

resected patients resected patients Zlotecki et al., Am J Clin Oncol 2005; 28: 310.

Au, Yr, Institution Total N Rx

Reports of Combined External

• Type. Yrs.

Zlotecki, 2005, USF R t 40 preoperative

• USF. Retrosp.

’74-03 postoperative Tzeng, 2006, U Al b P 16 preoperative with b

• Alabama. Prosp.

’99-03 (75% partial respon Feng, 2007, U Mich Retrosp 85 (80% preoperative t ti

• Mich. Retrosp.

’87-05 (80% RPS) postoperative pre- and post- oper definitive Ridgway, 2008,

• Toronto. Prosp.

‘96-05 50 preoperative N OS RFS

Beam Radiation and Resection

median/ 5 yr (%) median/ 5 yr (%) 25 timing RT t i if but tox t 15 not signif greater with postop

• ost to margin

14 R0/1 nse) R0/1 18 53 34% 30% (ti i RT rative 53 4 13 (timing RT signif on UVA) 50 >67 mos./ 87% >67 mos./ 74%

Combined Management for RPS: Summ

• pre-operative XRT caus
• complete gross resectio

those explored

• combined preop RT and

favorable oncologic outc

t (Surgery + RT) Protocol mary of Results

sed minimal toxicity

• n achieved in 100% of

d resection resulted in comes

Au, Yr, Institution Total N Rx

Reports of Combined

Design, Yrs. N Gieschen, 2001, MGH. R t ’80 96 37 Preop XRT + re

• Retrosp. ’80-96

Preop XRT + re Petersen, 2002, Mayo

• Clinic. Retrosp. ’81-95

87 Preop XRT + IO Postop XRT + IO Postop XRT IO Pre- and post- o IORT Dziewirski 2006 46 Postop XRT + IO Dziewirski, 2006,

• Warsaw. Prosp. ’98-04

46 Postop XRT + IO IORT Krempien, 2006, Heidel berg Retrosp 67 Postop XRT + IO IORT Heidel-berg. Retrosp. ’91-04 IORT Ballo, 2007, MDACC. Retrosp ‘60-03 83 Preop XRT/Pos XRT alone (63)

• Retrosp. 60 03

XRT alone (63), (18), XRT + BT N OS notes

d IORT and Resection

median/ 5 yr (%) esection 13 30% LC 61% esection+ IORT 16 74% LC 83% ORT ORT 53 12 47% GI fistula in n=7, gr 3 ORT

• p XRT + IORT

12 12 10 g neuropathy in n=9 ORT 24 55% LC better ORT 24 22 55% LC better with XRT ORT 45 22 64% Neuropathy 8% 22 8% stop XRT XRT + IORT 50/33 No DR or effect Comps with postop , XRT + IORT (1), BT (1) effect IORT with postop

Application of Adjuva RT for RPS RT for RPS nt

Soft Tissue M t t ti Sit A Metastatic Site Accor

100 80 100 60

percent of metastases

20 40 extremity

P i it :

Brennan MF, J Am Coll Surg 1996; 182:520.

extremity

Primary site:

e Sarcoma: di t P i Sit rding to Primary Site

lung liver

• ther

viscera retroperitoneum viscera retroperitoneum

The Quandry of Metastatic Disease

The Quandry of Metastatic Disease

The Quandries of Recurrent Disease

• f/u with imaging?

t d t ti ?

• resect upon detection?
• await symptoms?
• await progression?
• await progression?
• Law of Diminishing

Returns

The Quandries of R

Lewis et al., Ann Surg 1998; 228: 355.

Recurrent Disease

Gronchi et al., Cancer 2004; 100: 2448.

Overall survival for resecte

Grouped by Grouped by

1.0 .9 .8 .7 6

l

.6 .5 .4

L k

m Surviva

.3 .2 .1

Log rank = 0 PMH/MSH 06/96 – 03/03

TFU

20

Cum

0.0

Follow-up n=60 (58+RT) Mikula et al

5 yr survival: primary = 95% SE(4.87

TFU

p ASCO 2005

ed RPS, by presentation

y Presentation y Presentation PRI = 41 REC =19

PRESENT

REC

REC =19 0 0085*

REC-censored PRI

0.0085*

80 60 40 PRI-censored

p time (mos.)

7%), recurrent = 53.15% SE (16.91%)

p ( )

The Quandries of Recurrent Disease

The Quandries of R Value of R2 Value of R2

Shibata et al., JACS 2001; 193: 373.

Recurrent Disease: 2 Resection? 2 Resection?

Yeh et al., Ann Surg Oncol 2005; 12: 1084.

Soft Tissue Sarcoma Staging: Soft Tissue Sarcoma Staging:

Grade, Depth, Size