HIPEC Controversies in the Indications and Application of Regional Chemotherapy for Peritoneal Surface Malignancies Crescent City Cancer Update: GI and HPB Saturday September 24, 2016 George M. Fuhrman, MD FACS Ochsner Clinic Foundation New Orleans, LA OVERVIEW Rationale for Combined (Surgery and Chemotherapy) to Treat Peritoneal Malignancy Indications Staging Operative Technique Morbidity 1
Rationale Surgical Oncology is focused on resection of primary tumor plus regional site for staging and control Distant disease unresectable/nonsurgical Exceptions for unique circumstances Hepatic Resection Colorectal metastasis Rationale Peritoneal Surface can be considered localized disease unique circumstance Combined modality treatment to eradicate disease that is limited to the abdominal cavity Balance oncologic benefit with risk of treatment 2
Rationale Cytoreduction resect all gross disease what you can see Chemotherapy treat what you can t see achieves 18-620 lower systemic drug exposure with penetration to 5 mm below the surface Hyperthermia enhance drug cytotoxicity Appendiceal Mesothelioma Colorectal Indications 3
Staging Prior Surgical Score (Sugarbaker) PSS 0 biopsy only PSS 1 one region dissected during prior ex lap PSS 2 2-5 regions previously dissected PSS 3 - > 5 regions dissected After completeness of resection and histology PSS most significant predictor of survival Sugarbacker et al Ann Surg Oncol 1999;6:727-31 Completeness of Resection RO no gross disease with negative margins RI no gross disease with positive microscopic margins R2 gross residual disease R2a - < 5 mm residual disease R2b 5-20 mm residual disease R2c - > 20 mm residual disease R0/1 survival advantage compared to R2 patients The most powerful predictor of outcome 2-4 fold improvement in survival 4
PSDSS Peritoneal Carcinomatosis Disease Severity Score 3 factors Clinical Symptoms 0 pts asymptomatic 1 pt mild symptoms 6 severe symptoms (weight loss, pain, obstruction, ascites) PCI Histology PSDSS Peritoneal Carcinomatosis Disease Severity Score 3 factors Clinical Symptoms PCI Divide abdomen into ninths and score disease in each area 0,1,2,3 based on amount of tumor 4 small bowel segments with same scores Maximum PCI 13X3 = 39 PCI<10= 1 pt, 10-20= 3 pts, > 20 7 pts Histology 5
PSDSS Peritoneal Carcinomatosis Disease Severity Score 3 factors Clinical Symptoms PCI Histology Well differentiated node negative 1 pt Moderately differentiated with nodal disease 3 pts Poorly differentiated or signet ring formation 9 pts PSDSS Peritoneal Carcinomatosis Disease Severity Score PSDSS 4 groups (< 4, 4-7, 8-10, > 10) PSDSS strongly correlates with completeness of resection and the administration of HIPEC and therefore survival Helpful in comparing experience across centers and for multi-institutional studies 6
CRS/HIPEC Appendiceal Cancer 481 patients 317 Low grade 93 high grade 28 % morbidity/2.7% Mortality Complete resection(44.4%) and node negative(75%) predicts best outcome Median Survival 30 months for node +/High grade 85 months for node +/Low Grade 153 months for node -/ High Grade NR (82% alive at 90 months) node -/Low Grade Votanopoulos et al Ann Surg Onc 2015 22:1274-9. CRS/HIPEC for Peritoneal Mesothelioma 405 patients 53 month overall median survival Predictors of survival Histology 79% epithelial tumors 63 mo mean survival 12% sarcomatoid/biphasic 16 mo mean survival 6% involved nodes (56 vs. 20 mo mean survival) 46% complete CRS (8 vs. 1 yr mean survival) 2 % mortality/22 day mean hospital stay Yan et al J Clin Oncol 27:6237-42 2009 7
CRS/HIPEC for Colorectal Cancer Using the Peritoneal Disease Severity Score (PSDSS) 884 patient evaluated in a multicenter study 275 not treated patients median survival (months) 45 for I, 19 for II, 8 for III, and 6 for IV 609 treated patients median survival (months) 86 for I, 43 for II, 29 for III, and 28 for IV Cytoreduction/HIPEC vs. Systemic Chemotherapy in Colorectal Carcinomatosis Randomized trial Netherlands 51 patients 5-FU/leucovorin 54 cytoreduction plus heated MMC 8-year follow up 7.7 month vs. 12.6 month progression free survival 12.6 month vs 22.2 month disease specific survival Ann Surg Oncol 15(9):2426-2432 2008 8
Wake Forest Experience 1991-2013, 53 years old, 53% female 1000 patients 1097 treatments Tumor types 472 Appendix 248 CRS 72 Mesothelioma 69 Ovary 46 Gastric 97 Other 4% mortality 8 day median hospital stay 32% overall five year survival Levine et al J Am Coll Surg 2014;218:573-87. Wake Forest Experience 50% transfusion requirement 19% stoma creation Mean PCI 12 Time in OR mean 10 hrs (183-1,531 minutes) 50% R0/R1 Organs Resected: Omentum(72%), Colon (50%), Spleen(41%), Small Bowel(32%), Ovaries(32%), Gallbladder (29%), Uterus(17%), Stomach(11%) 9
Wake Forest Experience Most powerful predictors of survival Performance status Tumor Type Resection status Experience Patient without symptoms, Low grade appendiceal tumors, completely resected, and treated in high volume centers do best Estimate that only 10 US centers have treated more than 100 patients Levine et al J Am Coll Surg 2014;218:573-87 Wake Forest Experience Lesson learned Heavily pre-treated systemic chemotherapy patients are often referred once they become ECOG 2 or 3 patients Cr < 3 Liver enzymes < 3X normal WBC > 4 Platelets > 100K Ureteral Stents Parenchymal liver disease must be resectable Don t currently treat hepatic, biliary, pancreatic, gastric, or sarcoma patients Levine et al J Am Coll Surg 2014;218:573-87 10
Operative Technique Omentectomy Anastomosis Ostomies Visceral Resections Hyperthermia Open vs Closed Selection of Drug Technical aspects As resection is nearing completion cool patient to 34-35 degrees C Use closed technique two 24 Fr inflow and two 32 Fr outflow tubes placed in the midline wound (not through fascia) with temp probes attached Maximum inflow temp 43 degrees Outflow temp 40 degrees 120 minute perfusion MMC > 5 micrograms/ml appendiceal Cisplatin 250 mg/sq meter - mesothelioma MMC or oxaliplatin (200 mg/sq meter) Colorectal Dose reduction in elderly or poorer performance status patients 11
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Morbidity/Mortality 27-56%/2.7-11% Abscess Fistula Prolonged ileus Pneumonia DVT/PE Hematologic toxicity Morbidity associated with PCI score, duration of surgery, # anatomoses 13
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PSDSS Peritoneal Carcinomatosis Disease Severity Score No symptoms 0 pt PCI 6 = 1 pt Favorable path = 1 pt PSDSS = 2 so in the most favorable group 16
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A 52 year old with free air has a perforated sigmoid cancer Resection in the middle of the night with colostomy Transmural tumor 1/18 nodes involved Posterior bladder biopsied demonstrating involvement No other visible disease at exploration Post op CEA 1.0 (unchanged) Adjuvant systemic therapy (FOLFOX) nearly completed HIPEC at the time of stoma takedown? 20
Conclusions Preferred treatment for patients with low grade node negative appendiceal carcinoma and mesothelioma Selective with treatment of high grade and node positive appendiceal and colorectal Rarely appropriate for other tumor types Complete cytoreduction is key 21