1. Long-term follow-up of a prospective trial of pre-operative external-beam radiation and post-operative brachytherapy for retroperitoneal sarcoma LA Mikula, PF Ridgway, CN Catton, JJ Jones, B O’Sullivan, MA Ko, CJ Swallow University of Toronto Mount Sinai Hospital & Princess Margaret Hospital Toronto, Canada

2. Retroperitoneal Sarcoma: the Challenge

3. Retroperitoneal Sarcoma Princess Margaret Hospital n=45 resected patients, 1975-1988 OSLocal Relapse- Free Survival Distant relapse- Free Survival Catton, O’Sullivan et al, Int J Rad Oncol Biol Phys 1994; 29:1005.

4. Adjuvant Radiation

5. Treatment Schema Patients with RPS referred to Princess Margaret Hospital, Toronto, June 1996-April 2003 Patients with RPS referred to Princess Margaret Hospital, Toronto, June 1996-April 2003 Inclusion criteria: resectable disease & no mestastases; signed informed consent Inclusion criteria: resectable disease & no mestastases; 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)

6. RPS n=83 n=55 trial resection n=46 mets n=5 pre-op death n=4 pre-op XRT n=40 BT n=2 BT and post-op XRT n=2 no RT n=2 + BT n=19 - BT n=21 recent resection n=14 incurable n=12 refused therapy n=2 XRT = external beam radiation therapy BT = post-operative brachytherapy Jones et al, Ann Surg Onc 2002,9,346

7. Pre-operative External Beam Radiation Conformal planning using 3D techniques Conformal planning using 3D techniques Shielding of contralateral kidney; liver Shielding of contralateral kidney; liver

8. Post-operative Brachytherapy Single plane of 3-8 afterloading BT catheters placed on the surgical bed with 1cm spacing Single plane of 3-8 afterloading BT catheters placed on the surgical bed with 1cm spacing Planar implant dose of 0.5 Gy/hr, depth 0.5cm Planar implant dose of 0.5 Gy/hr, depth 0.5cm Afterloading iridium-192 pulsed dose rate BT unit Afterloading iridium-192 pulsed dose rate BT unit BT initiated once GI function returned (7-14 days post- op) BT initiated once GI function returned (7-14 days post- op)

9. Outcomes & Follow-up Follow-up: clinic visit + CT scan every 6 months x5 years, then anually Follow-up: clinic visit + CT scan every 6 months x5 years, then anually Minimum follow-up 48 months Minimum follow-up 48 months Outcomes: Outcomes: Survival Survival Disease recurrence Disease recurrence Toxicity: Radiation Therapy Oncology Group scores Toxicity: Radiation Therapy Oncology Group scores Pre-operative toxicity Pre-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

10. Results: Toxicity

11. Pre-Operative Toxicity: 40 patients treated with pre-op XRT All patients had a maximum RTOG score of ≤ 2 All patients had a maximum RTOG score of ≤ 2 Acute toxicity scores related to upper and lower GI symptoms … Acute toxicity scores related to upper and lower GI symptoms … … except for one patient who developed cystitis … except for one patient who developed cystitis Jones et al, Ann Surg Onc 2002,9,346

12. Acute Post-operative Toxicity: 46 resected patients 1 mild 3 hospital admission 4 life- threatening 5 death 15 8 5 11 6 1 0 none 2 medical therapy n= Hepatic failure 4/6 had BT Jones et al, Ann Surg Onc 2002,9,346

13. Modified Late Toxicity (3-12 months post-op) 1 mild 3 hospital admission 4 life- threatening 5 death 36 1 1 1 1 2 0 none 2 medical therapy n= 2 late complications of duodenal perforation 6/6 had BT Jones et al, Ann Surg Onc 2002,9,346

14. Results: Long-term Follow-up

15. Clinicopathologic Features: Pre-op XRT + Surgery N=40 N=40 Male 15, female 25 Male 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 grade 55% high grade 70% liposarcoma 70% liposarcoma

16. Treatment Characteristics Patients who completed pre-op XRT & surgery: Patients who completed pre-op XRT & surgery: Median pre-op XRT dose = 45 Gy (range 45-57 Gy) Median pre-op XRT dose = 45 Gy (range 45-57 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 complete All resections were grossly complete 97% had resection of contiguous structures 97% had resection of contiguous structures No patients received adjunctive chemotherapy No patients received adjunctive chemotherapy

17. Status 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-up No patients lost to follow-up 4 patients recurred and were re-resected 4 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%)

18. 5yr OS 10yr OS 75%63% median OS not reached at median 89 mos. f/u (months) Overall Survival (n=40)

19. 5yr RFS 10yr RFS 69%52% median RFS ≈ 120 mos. median 89 mnths f/u Recurrence-Free Survival (n=40)

20. 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)

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)

22. 5yr RFS 10yr RFS 68% --- Log Rank: p=0.68 No BT, n=10 BT, n=12 No BT: median OS not reached BT: median OS ≈ 116 mnths 5yr RFS 10yr RFS 58%47% OS in High-Grade Tumours (n=22)

23. Prospective Trials of Combined Radiation + Resection for RPS Ttl N= RxN= OS median/ 5yr (%) RFS median/ 5yr (%) Sindelar ’93, NIH PhIII RCT ’80-’85 35 PostOp XRT (50-55Gy) PostOp XRT (35-40Gy) + IORT + misonidazole 2015 52 mos. 45 mos. Robertson ’95, U Mich PhI 16 PreOp XRT + IdUrd PreOp XRT + IdUrd + OR 511 18 mos. 32 mos. Alektiar ’00, MSKCC PhI- II, ’92-’96 49- 17=32 OR + IORT + PostOp XRT OR + IORT 25745%55% Pisters ’03, MDA PhI, ’96- ’01 35 Dox + PreOp XRT Dox + PreOp XRT + OR … + IORT 8522 Phase I trial Mikula ’08, Toronto, PhI- II, ’96-’00 40 PreOp XRT PreOp XRT + BT 211980%68%75%61%

24. Historical vs. Current Data OSLocal Relapse- Free Survival Catton, O’Sullivan et al, Int J Rad Oncol Biol Phys 1994; 29:1005.

25. Conclusions Pre-operative XRT was well tolerated Pre-operative XRT was well tolerated Brachytherapy to the upper abdomen was associated with significant toxicity Brachytherapy to the upper abdomen was associated with significant toxicity Pre-operative XRT and aggressive surgical resection shows promise in improving local control and long-term survival in RPS Pre-operative XRT and aggressive surgical resection shows promise in improving local control and long-term survival in RPS

27. Intent-to-treat Analysis For all 55 patients entered into the trial: 2-year OS 73% For all 55 patients entered into the trial: 2-year OS 73% For 46 patients resected with curative intent: 2-year OS 88% For 46 patients resected with curative intent: 2-year OS 88%