Long-term follow-up of a prospective trial of pre-

operativeexternal-beam radiation

and post-operative brachytherapy

for retroperitoneal sarcomaLA Mikula, PF Ridgway, CN Catton, LA Mikula, PF Ridgway, CN Catton, JJ Jones, B O’Sullivan, MA Ko,JJ Jones, B O’Sullivan, MA Ko,

CJ SwallowCJ Swallow

University of TorontoUniversity of TorontoMount Sinai Hospital & Princess Margaret HospitalMount Sinai Hospital & Princess Margaret Hospital

Toronto, CanadaToronto, Canada

Retroperitoneal Sarcoma:Retroperitoneal Sarcoma:the Challengethe Challenge

Retroperitoneal SarcomaRetroperitoneal SarcomaPrincess Margaret HospitalPrincess Margaret Hospitaln=45 resected patients, 1975-n=45 resected patients, 1975-

19881988

0

20

40

60

80

100

perc

enta

ge o

f patie

nts 5 yr

10 yr

OS Local Relapse-

Free Survival

Distant relapse-Free

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

Adjuvant RadiationAdjuvant Radiation

Treatment SchemaTreatment Schema Patients with RPS referred to Princess Margaret Patients with RPS referred to Princess Margaret

Hospital, Toronto, June 1996-April 2003Hospital, Toronto, June 1996-April 2003 Inclusion criteria: resectable disease & no Inclusion criteria: resectable disease & no

mestastases; signed informed consentmestastases; signed informed consent

Pre-operative XRT: 45 Gy/5 weeks

4-6 weeks

Surgery

Post-operative brachytherapy (BT):

25 Gy (0.5Gy/hr, depth 0.5cm)

RPSn=83

n=55trial

resectionn=46

metsn=5

pre-op deathn=4

pre-op XRTn=40

BTn=2

BT and post-op XRT n=2

no RTn=2

+ BTn=19

- BTn=21

recent resection

n=14

incurablen=12

refusedtherapy n=2

XRT = external beam radiation therapyBT = post-operative brachytherapy

Jones et al, Ann Surg Onc 2002,9,346

Pre-operative External Pre-operative External Beam RadiationBeam Radiation

Conformal planning using 3D Conformal planning using 3D techniquestechniques

Shielding of contralateral kidney; Shielding of contralateral kidney; liverliver

Post-operative Post-operative BrachytherapyBrachytherapy

Single plane of 3-8 afterloading BT catheters Single plane of 3-8 afterloading BT catheters placed on the surgical bed with 1cm spacingplaced on the surgical bed with 1cm spacing

Planar implant dose of 0.5 Gy/hr, depth Planar implant dose of 0.5 Gy/hr, depth 0.5cm0.5cm

Afterloading iridium-192 pulsed dose rate Afterloading iridium-192 pulsed dose rate BT unitBT unit

BT initiated once GI function returned (7-14 BT initiated once GI function returned (7-14 days post-op)days post-op)

Outcomes & Follow-upOutcomes & Follow-up

Follow-up: clinic visit + CT scan every 6 Follow-up: clinic visit + CT scan every 6 months x5 years, then anuallymonths x5 years, then anually Minimum follow-up 48 monthsMinimum follow-up 48 months

Outcomes:Outcomes: SurvivalSurvival Disease recurrenceDisease recurrence Toxicity: Radiation Therapy Oncology Group Toxicity: Radiation Therapy Oncology Group

scoresscores Pre-operative toxicityPre-operative toxicity Acute post-operative toxicity (within 3 months)Acute post-operative toxicity (within 3 months) Late toxicity (3 months to 1 year post-op)Late toxicity (3 months to 1 year post-op)Jones et al, Ann Surg Onc

2002,9,346

Results: ToxicityResults: Toxicity

Pre-Operative Toxicity:Pre-Operative Toxicity:40 patients treated with 40 patients treated with

pre-op XRTpre-op XRT All patients had a maximum RTOG All patients had a maximum RTOG

score of ≤ 2score of ≤ 2

Acute toxicity scores related to Acute toxicity scores related to upper and lower GI symptoms …upper and lower GI symptoms … … … except for one patient who developed except for one patient who developed

cystitiscystitis

Jones et al, Ann Surg Onc 2002,9,346

Acute Post-operative Acute Post-operative Toxicity:Toxicity:

46 resected patients46 resected patients1

mild 3

hospital admission

4life-

threatening

5death

15 8 5 11 6 1

0none

2medicaltherapy

n=

Hepatic failure

4/6 had BT

Jones et al, Ann Surg Onc 2002,9,346

Modified Late ToxicityModified Late Toxicity(3-12 months post-op)(3-12 months post-op)

1mild

3hospital

admission

4life-

threatening

5death

36 1 1 1 1 2

0none

2medicaltherapy

n=

2 late complicationsof duodenal perforation 6/6 had BT

Jones et al, Ann Surg Onc 2002,9,346

Results:Results:Long-term Long-term Follow-upFollow-up

Clinicopathologic Features:Clinicopathologic Features:Pre-op XRT + SurgeryPre-op XRT + Surgery

N=40N=40 Male 15, female 25Male 15, female 25 Median age 58 yrs (range 41-75)Median age 58 yrs (range 41-75)

Primary presentation of RPS = 29 (72%)Primary presentation of RPS = 29 (72%) Referred with recurrent disease = 11 (28%)Referred with recurrent disease = 11 (28%)

Tumour characteristics:Tumour characteristics: Median size 19cm (range 4-40cm)Median size 19cm (range 4-40cm) 55% high grade55% high grade 70% liposarcoma70% liposarcoma

Liposarcoma

Leiomyosarcoma

MFH

Other

Treatment Treatment CharacteristicsCharacteristics

Patients who completed pre-op XRT & Patients who completed pre-op XRT & surgery:surgery: Median pre-op XRT dose = 45 Gy (range 45-Median pre-op XRT dose = 45 Gy (range 45-

57 Gy)57 Gy) Median BT dose = 23 Gy (range 7.5-25 Gy)Median BT dose = 23 Gy (range 7.5-25 Gy)

All resections were grossly completeAll resections were grossly complete 97% had resection of contiguous structures97% had resection of contiguous structures

No patients received adjunctive chemotherapyNo patients received adjunctive chemotherapy

Status at Last Follow-UpStatus at Last Follow-Up

Median follow-up 89 months (7.4 years)Median follow-up 89 months (7.4 years) No patients lost to follow-upNo patients lost to follow-up

4 patients recurred and were re-resected4 patients recurred and were re-resected

At last follow-up:At last follow-up: 25 alive and disease-free (62.5%)25 alive and disease-free (62.5%) 3 alive with recurrent disease (7.5%)3 alive with recurrent disease (7.5%) 9 dead of disease (22.5%)9 dead of disease (22.5%) 3 dead of other causes (7.5%)3 dead of other causes (7.5%)

Alive, disease-free

Alive, recurred

Dead of disease

Dead of other

5yr OS 10yr OS 75% 63%

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

(months)

Overall Survival (n=40)

5yr RFS 10yr RFS 69% 52%

median RFS ≈ 120 mos. median 89 mnths f/u

Recurrence-Free Survival (n=40)

Median not reached

5yr OS 10yr OS

80% 80%

Log Rank: p=0.27

median OS not reached

5yr OS 10yr OS

68% 54%

OS BT (n=19) vs no BT (n=21)

5yr RFS: 75% 10yr RFS:--

Log Rank: p=0.58

No BT: median RFS not reached

BT: median RFS ≈ 106 mnths

5yr RFS 10yr RFS 61% 47%

RFS BT (n=19) vs no BT (n=21)

5yr RFS 10yr RFS 68% ---

Log Rank: p=0.68

No BT, n=10

BT, n=12No BT: median OS not reached

BT: median OS ≈ 116 mnths

5yr RFS 10yr RFS 58% 47%

OS in High-Grade Tumours (n=22)

Prospective Trials of Combined Prospective Trials of Combined Radiation + Resection for RPSRadiation + Resection for RPS

Ttl Ttl N=N=

RxRx N=N= OS OS median/median/

5yr (%)5yr (%)

RFS RFS median/median/

5yr (%)5yr (%)

Sindelar Sindelar ’93, NIH ’93, NIH PhIII RCT PhIII RCT ’80-’85’80-’85

3535 PostOp XRT (50-55Gy)PostOp XRT (50-55Gy)

PostOp XRT (35-40Gy) PostOp XRT (35-40Gy) + IORT + misonidazole+ IORT + misonidazole

2020

151552 mos.52 mos.

45 mos.45 mos.

Robertson Robertson ’95, U ’95, U Mich PhIMich PhI

1616 PreOp XRT + IdUrdPreOp XRT + IdUrd

PreOp XRT + IdUrd + PreOp XRT + IdUrd + OROR

55

111118 mos.18 mos.

32 mos.32 mos.

Alektiar Alektiar ’00, ’00, MSKCC MSKCC PhI-II, PhI-II, ’92-’96’92-’96

49-49-17=17=3232

OR + IORT + PostOp OR + IORT + PostOp XRTXRT

OR + IORTOR + IORT

2525

7745%45% 55%55%

Pisters ’03, Pisters ’03, MDA PhI, MDA PhI, ’96-’01’96-’01

3535 Dox + PreOp XRTDox + PreOp XRT

Dox + PreOp XRT + ORDox + PreOp XRT + OR

… … + IORT+ IORT

88

55

2222

Phase I Phase I trialtrial

Mikula ’08, Mikula ’08, Toronto, Toronto, PhI-II, PhI-II, ’96-’00’96-’00

4040 PreOp XRTPreOp XRT

PreOp XRT + BTPreOp XRT + BT2121

191980%80%

68%68%75%75%

61%61%

Historical vs. Current Historical vs. Current DataData

0

20

40

60

80

100

perc

enta

ge o

f patie

nts 5 yr

10 yr

OS Local Relapse-

Free Survival

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

ConclusionsConclusions

Pre-operative XRT was well toleratedPre-operative XRT was well tolerated

Brachytherapy to the upper abdomen Brachytherapy to the upper abdomen was associated with significant toxicitywas associated with significant toxicity

Pre-operative XRT and aggressive Pre-operative XRT and aggressive surgical resection shows promise in surgical resection shows promise in improving local control and long-term improving local control and long-term survival in RPSsurvival in RPS

Intent-to-treat AnalysisIntent-to-treat Analysis

For all 55 patients entered into the trial: For all 55 patients entered into the trial: 2-year OS 73%2-year OS 73%

For 46 patients resected with curative For 46 patients resected with curative intent: 2-year OS 88%intent: 2-year OS 88%