1. Padova, 30 maggio 2008 Carlo Riccardo Rossi Unità Melanoma e Sarcomi Clinica Chirurgica II - Università di Padova Ha uno spazio la chirurgia nella sarcomatosi retroperitoneale? Aggiornamento in tema di Sarcomi delle Parti Molli e GIST

2. SPREAD OF SOFT TISSUE SARCOMAS (STS) OR GISTs THROUGHTOUT THE ABDOMEN (WITHOUT DISTANT METASTASES) DEFINITION Peritoneal sarcomatosis

3. RETROPERITONEAL SARCOMAS LOCAL RECURRENCE AND SURVIVAL AuthorYearLocal Recurrence (%) 5 yrs Survival (%) Lewis JJ et al1998 2454 Stoeckle E et al2001 4846 Gilbeau L et al2002 5160 Gronchi A et al2004 4454 Ballo MT et al2006 4344 Peritoneal sarcomatosis

4. GISTs LOCAL RECURRENCE AND SURVIVAL AuthorYearLocal Recurrence (%) 5 yrs Survival Eilber FC et al2000 4831 De Matteo RP et al2000 4054 Crosby JA et al2001 4341 Pierie JP et al2001 6042 Before Imatinib advent Peritoneal sarcomatosis

5. TREATMENT: STATE OF THE ART Systemic Locoregional Peritoneal sarcomatosis

6. Antracyclin +/- ifosfamide Gemcitabine +/- docetaxel leiomyosarcoma Trabectedine (ET-743) liposarcoma leiomyosarcoma Imatinib STANDARD TREATMENT (SYSTEMIC CHEMOTHERAPY + SURGERY) Response rate: 20-40% Median survival 12-24 mos Response Rate: 50-85% Overall 2 yr survival: 71% Retroperitoneal Sarcomas GISTs Peritoneal sarcomatosis

7. SYSTEMIC CHEMOTHERAPY + PALLIATIVE SURGERY MD ANDERSON CANCER CENTER EXPERIENCE Bilimoria et al., Cancer 2001 N° of pts:51 Recurrence rate:72 % Median Survival:22 mos Peritoneal sarcomatosis

8. Aggressive Cytoreductive Surgery ± LOCOREGIONAL TREATMENT EPIC HIPEC Postoperative adhesions Low drug penetration 1-3mm Barriers to effective treatment (Early Post-operative IntraPeritoneal Chemiotherapy) (Hyperthermic IntraPeritoneal Chemotherapy) Peritoneal sarcomatosis

9. CYTORIDUCTIVE SURGERY Peritoneal sarcomatosis

10. Body V d, [drug] Peritoneal cavity V d, [drug] Clearance K Intercompartmental Transport (IT) K > IT = ADVANTAGE High MW High Syst Cl INTRAPERITONEAL CHEMOTHERAPY RATIONALE Peritoneal sarcomatosis

11. HIPEC TECHNIQUE Peritoneal sarcomatosis

12. LOCOREGIONAL TREATMENT:EPIC/HIPEC THE WASHINGTON CANCER INSTITUTE N° of pts:43 Recurrence rate:100% Median Survival:20 months Berthet B et al. Eur J Cancer, 1999 Peritoneal sarcomatosis

13. Eilber FC et al, Ann Surg Oncol, 1999 UCLA MEDICAL CENTER N° of pts:35 Recurrence rate:48% Median Survival:24 mos LOCOREGIONAL TREATMENT:EPIC Peritoneal sarcomatosis

14. INSTITUT GUSTAVE ROUSSY Bonvalot S et al, EJSO, 2005 N° of pts:38 Recurrence rate:100% Overall Survival:29 months LOCOREGIONAL TREATMENT:EPIC Peritoneal sarcomatosis

15. LOCOREGIONAL TREATMENT: HIPEC Rossi CR et al, Cancer 2002 DOXO:15.25 mg/l CDDP:43.00 mg/l RESULTS PADOVA UNIVERSITY Cytoreductive Surgery and Hyperthermic Intra-Peritoneal Chemotherapy (Phase I study) Peritoneal sarcomatosis

16. perfusate plasma Open symbols = DOXO Filled symbols = CDDP Rossi et al, Cancer 2002 LOCOREGIONAL TREATMENT (HIPEC): PHARMACOKINETICS OF DOXO Peritoneal sarcomatosis

17. LOCOREGIONAL TREATMENT (HIPEC): PHARMACOKINETICS OF DOXO Rossi et al., Cancer 2002 PERITONEUM MUSCLE FATTUMOR Peritoneal sarcomatosis

18. LOCOREGIONAL TREATMENT (HIPEC): SITILO* EXPERIENCE (Phase II study) CC0 CC1 68% 32% MORB MORT 33% 0% MEAN FU28 mo PTS:60 HISTOL:LIPO20 UTERUS 13 GIST14 OTHER13 GRADING:G123 G2-337 * ITALIAN SOCIETY FOR LOCOREGIONAL TREATMENT OF CANCER Peritoneal sarcomatosis

19. N° of pts:60 Recurrence rate:52% Overall Survival:34 months Rossi et al, Cancer 2004 LOCOREGIONAL TREATMENT (HIPEC): SITILO EXPERIENCE (Phase II study) Peritoneal sarcomatosis

20. PREOPERATIVE EVALUATION ELEGIBILITY METHODOLOGY FOLLOW – UP FUTURE INVESTIGATIONS RESULTS OF THE DISEASE CONSENSUS VOTING Peritoneal sarcomatosis 5th International Workshop on Peritoneal Surface Malignancy, Milano 2006

21. YES66,67% NO33,33% YES50,00% NO50,00% With regard to the non-GIST sarcomas, may we foresee a role for HIPEC in the era of molecularly targeted therapies? With regard to the GIST model, may we foresee a role for HIPEC in the era of molecularly targeted therapies? YES66,67% NO33,33% With regard to the GIST model, may we foresee a role for HIPEC in patient non responsive to targeted therapies? Results of the disease consensus voting ELIGIBILITY Peritoneal sarcomatosis 5th International Workshop on Peritoneal Surface Malignancy, Milano 2006

22. Investigational only58,33% Suitable for individual clinical use in selected patients 41,67% Only for palliation33,33% For Locoregional Control66,67% For Improvement on survival0,00% Results of the disease consensus voting ELIGIBILITY At the time of primary tumor treatment 9,09% At the time of recurrence72,73% Both18,18% Referring to retroperitoneal sarcomas, pelvic sarcomas, GIST, is there any clinical presentation in which abdominal sarcomatosis could be treated today with HIPEC outside a clinical study? In other words, as of today, should we consider HIPEC: As of today's knowledge, which is the selective contribution of cytoreductive surgery, antiblastic perfusion and hyperthermia to the potential efficacy of HIPEC, if any, in abdominal sarcomatosis? With regard to non-GIST sarcomas, which timing for HIPEC may we foresee within combined approaches incorporating pre/post-operative chemotherapy? Peritoneal sarcomatosis 5th International Workshop on Peritoneal Surface Malignancy, Milano 2006

23. cc-0: YesNo 100,00%0,00% cc-1: YesNo 62,50%37,50% YES25,00% NO75,00% Results of the disease consensus voting STATE OF THE ART OF METHODOLOGY YES91,67% NO8,33% YES25,00% NO75,00% YES27,27% NO72,73% 1-SURGERY: Definition of Complete Cytoreductive Surgery Is there a role for maximal palliative cytoreduction in not amenable to radical surgery? Is it sufficient a limited peritonectomy to the affected area? Is it indicated a complete parietal peritonectomy even in case of limited affected area? 2- HIPEC: Role of HIPEC in Palliative/inoperable Peritoneal sarcomatosis 5th International Workshop on Peritoneal Surface Malignancy, Milano 2006

24. Single0,00% Combination100,00% 1 cisplatin+mitomycin-C0,00% 2 cisplatin+doxorubicin100,00% 3 other0,00% Would you consider single agent or combination HIPEC best? What drugs would be best to use HIPEC combination agent Results of the disease consensus voting STATE OF THE ART OF METHODOLOGY Peritoneal sarcomatosis 5th International Workshop on Peritoneal Surface Malignancy, Milano 2006

25. YES91,67% NO8,33% Results of the disease consensus voting FUTURE INVESTIGATIONS SHOULD BE DIRECTED AT YES91,67% NO8,33% Do you think it is necessary to perform a large trial in order to identify the role of CRS + HIPEC in patients with Peritoneal Sarcomatosis? Should the patients be randomized to CRS+HIPEC vs. CRS alone 5th International Workshop on Peritoneal Surface Malignancy, Milano 2006 Peritoneal sarcomatosis

26. Chemotherapy +/- surgery +/- radiotherapy is the standard palliative treatment for sarcomatosis and locally advanced GISTs Median survival after standard treatment is 12-24 months for sarcomatosis before Imatinib (including GISTs) Imatinib improves median survival up to 58 months in GISTs (locoregional treatment excluded at present) There is no sufficient evidence supporting the locoregional treatment of sarcomatosis with surgery associated to EPIC/HIPEC Cytoreductive surgery and HIPEC should be further investigated in sarcomatosis confined to the peritoneum or imatinib resistant GISTs CONCLUSIONS Peritoneal sarcomatosis