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

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

RETROPERITONEAL SARCOMAS LOCAL RECURRENCE AND SURVIVAL AuthorYearLocal Recurrence (%) 5 yrs Survival (%) Lewis JJ et al Stoeckle E et al Gilbeau L et al Gronchi A et al Ballo MT et al Peritoneal sarcomatosis

GISTs LOCAL RECURRENCE AND SURVIVAL AuthorYearLocal Recurrence (%) 5 yrs Survival Eilber FC et al De Matteo RP et al Crosby JA et al Pierie JP et al Before Imatinib advent Peritoneal sarcomatosis

TREATMENT: STATE OF THE ART Systemic Locoregional Peritoneal sarcomatosis

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

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

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

CYTORIDUCTIVE SURGERY Peritoneal sarcomatosis

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

HIPEC TECHNIQUE Peritoneal sarcomatosis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chemotherapy +/- surgery +/- radiotherapy is the standard palliative treatment for sarcomatosis and locally advanced GISTs Median survival after standard treatment is 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