CRS e HIPEC: Efficacia e Limiti

CRS e HIPEC: Efficacia e Limiti Marcello Deraco M.D. Responsabile Tumori Peritoneali

The Concept of Cytoreductive Surgery Means a complete removal of all macroscopic tumor in the peritoneal cavity; It could require Peritonectomy Procedures eventually associated with intestinal and/or organ resection

Peritoneal Mesothelioma: Cytoreductive Surgery

Pseudomyxoma Peritonei: Cytoreductive Surgery

Cytoreductive Surgery in Colon Cancer

Heated Intra Peritoneal Chemotherapy (HIPEC) Is a treatment that allow to expose the abdominal cavity to high drug concentration in hyperthermic condition trought a perfusional procedure. John Spratt Professor of Surgery University of Louisville Cancer Research (1980) 40:253-260

HIPEC (Heated Intraperitoneal Chemotherapy) DRUGS? Temperature: 42.5 C Mean flow: 700 ml ration: 90 minutes

Drug Molecula r weight AUCpe/ AUCpl Tumour penetration Dose for HIPEC Mechanism of hyperthermic modulation Doxorubicin 580 87.9 4-6 cell layers 15.25mg/L of perfusate a Enhanced tissue absorption; increased Dx aglycon concentration Caelyx 100mg/m2 b Mitomycin C 334 23.5 NA 35mg/m2 Enhanced tissue absorption; cell membrane permeability alteration; increased activation and intracellular alkylation, inhibition of DNA damage repair Mitoxantrone 517 5.6-15.2 5-6 cell layers 28mg/m2 c yes Cisplatin 300 14 2-2.5 mm 300mg/m2 b Enhanced tissue absorption; increased DNA adduct formation; increased activity at low ph; Increased production of O2 radicals; reduction of cisplatin resistance Carboplatin 371 1.9-5.2 0.2-0.5 mm 1000mg/m2 b Enhanced tissue absorption; increased DNA adduct formation; Oxaliplatin 397 16 1-2 mm 200mg/m2 b Enhanced tissue absorption Paclitaxel 854 1000* NA 175mg/m2 c Increased disruption of microtubules system and apoptosis Gemcitabine 300 12.5-26.8 NA 120mg/m2 d Enhanced tissue absorption; activation to triphosphate metabolite; inhibition of DNA damage repair

PC from CRC: No Strict Selection

Overview of metastatic colorectal cancer studies: distribution of involved areas (N= 4392, Metastatic sites=6684) liver 14% 16% LN 10% Lungs 46% 5% 8% other primary unresected peritoneum Saltz 00, Douillard 00, Comella 02, Seymour, Giantonio 06,Tournigand 04, Bajetta 04, Chen 06, Hospers 06, Bennouna 06,

CONCLUSION: PC is a significant predictor of survival among patients with mcrc Survival is longer than in most historical retrospective studies Future studies may consider: stratification based on carcinomatosis status exploration of combined treatments, such as cytoreduction and intraperitoneal chemotherapy Median OS:12.7 (pccrc) vs17.6 months (non-pccrc), p<0.001 5-year overall survival is 6% for non-pccrc vs 4.1% for pccrc patients

Curative intent group Palliative intent group

523 Pt WITH PC from CRC

Pts: 146 Median follow-up, months (range) 19 (1e108)

Variables Associated with Indication and Feasibility of CRS ECOG Performance Status < 2 No evidence of biliary, ureteral or intestinal obstruction No evidence of extraabdominal disease Liver metastases: correlated with Primary (no more than 3 for CRC) Clear Zone II Small bowel Class 1, maybe some areas of Class 2 but no Class 3 PCI correlated with Primary Ascite Tumor Grading

PCI > 20 as an absolute exclusion criteria for CRS+HIPEC in CRC? Lesion size score LSS-0 cm No detectable LSS-1 <0.5 LSS-2 0-5-5 LSS-3 >5 66,7% 33,3% Yes No Sugarbaker, Ann Surg 1995

PCI as a Prognostic Indicators of Survival 523 Pt WITH PC from CRC

CC-Score as a Prognostic Indicators of Survival 523 Pt WITH PC from CRC

PC from CRC: Strict Case Selection

Median surv 23.9 mts Median surv 62.7 mts

PERITONEAL CARCINOMATOSIS FROM COLORECTAL CANCER: LITERATURE SUMMARY SCENARIOS sct old median/months sct new median/months CRS+HIPEC+sCT median/months PC: NOT SELECTED PATIENTS PC: SELECTED PATIENTS 6 12,7 30 (prev. Old sct) 12 23,7 63 (news sct)

Period January 1995 - February 2009 2 randomized (1 completed) 47 studies 2 controlled 43 observational (3 multicentric) Median survival 11.9-60.1 months 5-year survival 11-51% (median 19%) Operative morbidity 14.8-76% Operative death 0-12%

CLINICAL SCENARIOS CRC with High Risk Probabilityto develop a PC pt4 Obclusion Perforation Ovariam M+ Resectable Limited PC Resectable Ctm+ Metacronous PC-CRC: Favorable Prognostic Factors Unfavorable Prognostic Factors Unespected Syncronous PC-CRC Limited Disease Extensive

LINEE GUIDA (ROL) PER LA PRATICA CLINICA NELLA CARCINOSI PERITONEALE DA CA COLORETTALE