Regional Therapy for Management of Peritoneal Carcinomatosis from Gastrointestinal Malignancies Byrne Lee, MD FACS Chief, Mixed Tumor Surgery Service City of Hope Division of Surgical Oncology September 22, 2018
Nothing to disclose DISCLOSURE
Peritoneal Carcinomatosis: Incidence 10-15% of GI cancers have peritoneal implants at diagnosis Serosal Involvement Bowel Perforation Adnexal Metastases 25-35% - Peritoneum is the primary site of failure
Colorectal Cancer Carcinomatosis Poor prognosis Median survival 6 months - Chua et al, Cancer 1989 N=100 7 months - Jayne et al, Br J Surg 2002 N=349 5.2 months EVOCAPE, Cancer 2000 N=1100 12.7 Franko et al, JCO 2012 N=2095
Survival with Modern Chemotherapy - FOLFOX Franko, et al., JCO 2012
Survival with Modern Chemotherapy - FOLFIRI Franko, et al., JCO 2012
Peritoneal Surface Malignancies Pseudomyxoma peritonei Mesothelioma Primary peritoneal carcinoma Carcinomatosis Colorectal Gastric Appendiceal Ovarian/GYN Pancreatico-Biliary NETs Sarcomatosis
History Cancer Treat Rep, 1978
History Cancer Research, 1980
The 1 st HIPEC Cancer Research, 1980
The Sugarbaker Ann Surg 1995
The Sugarbaker 181 consecutive patients 51 CRC 130 Appendiceal cancer 24 month mean F/U
The Sugarbaker
The Sugarbaker
The Sugarbaker 3 deaths Fistula rate of 26% (19/72) in high risk patients Previous obstruction, chemotherapy, radiation Fistula rate of 1.8% (2/109) in low risk patients Anastomotic leak in 5.5%
Patient Selection Patients must be medically fit to undergo the rigors of cytoreductive surgery and HIPEC There must be no: extra-abdominal disease parenchymal hepatic metastases gross nodal metastases bulky retroperitoneal disease Peritoneal disease must be resectable to minimal surface disease
Peritoneal Carcinomatosis Index (PCI) Sugarbaker. The Cancer Journal 2009
Completeness of Cytoreduction Completeness of cytoreduction score CC-0 or CC-1 considered complete or optimal cytoreduction CC-2 or CC-3 considered incomplete cytoreduction Sugarbaker. The Cancer Journal 2009
Stripping of the Parietal Peritoneum All involved parietal peritoneum is removed Visceral peritoneum: Electro-evaporation of small tumors Bowel resection for large tumors Liver: Resection of Glisson capsule
Reconstruction Anastomoses: After HIPEC Ostomies Chest tubes
HIPEC Closed vs. Colisseum
Evidence?
Phase III Trial for CRC (5 withdrew) (2 progressed) (1 withdrew) (4 progressed) (5FU + Leucovorin) (Irinotecan) Mitomycin C for 120 minutes Verwaal, et al., J Clin Ocol, 2003
Phase III Trial for CRC 8% mortality 19% bone marrow toxicity 15% fistula rate Survival affected by extent of debulking Median survival HIPEC 22.4 mos Standard 12.6 mos Predicted 5 yr OS for treatment arm - 20% Verwaal, et al., J Clin Ocol, 2003
Verwaal, et al., J Clin Ocol, 2003 Median Survival HIPEC 22.4 mos Standard 12.6 mos
Verwaal, et al., Ann Surg Oncol, 2008
Verwaal, et al., Ann Surg Oncol, 2008
Is it possible to obtain definitive cure with CRS + HIPEC? Prospective study of patients with CRC and peritoneal carcinomatosis treated between January 1995 and December 2005 (n=93). Learning curve = includes some poor outcomes Cure = no recurrence at 5 years Median follow-up: 99 months Median Survival : 34 months Overall 5-year survival : 32% Goéré, et al. Ann Surg 2013
Is it possible to obtain definitive cure with CRS + HIPEC? At risk 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 Overall Survival Disease-free Survival 0 12 24 36 48 60 72 84 96 108 120 Months NED at 5 years = 16% 93 93 89 49 64 24 41 16 33 16 27 14 15 10 8 7 5 4 2 3 1 2
At 10 years: 102/612 pts =16.7% JCO, 2007
Is it possible to obtain definitive cure with CRS + HIPEC? Hepatectomy for LM or CRS + HIPEC for PC overall survival and definitive cure rates are similar Peritoneum should be considered as an organ Metastastectomy works
Is it the CRS or the HIPEC?
Surgery versus No Surgery Is there a trial comparing? Similar patients Surgery No Surgery
Complete resection alone of PC? N Selection Median OS 5-Y Survival Mulsow 2011 31 PCI<10 25 months 22% (Erlangen) Cashin 2012 57 + SPIC* 25 months 18% (Uppsala) Evrard 2012 30 PCI<10 30 months 25% (Bordeaux) *SPIC = Sequential postop. intraperitoneal chemo.
Unicancer Prodige 7 trial design Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Background Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Background Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Baseline Characteristics Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Peritoneal Carcinomatosis Characteristics Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Safety: Mortality Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Safety: Morbidity at 30 days Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Morbidity at 30 days: Intra-abdominal complications Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Morbidity at 60 days Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Overall survival (ITT) Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Relapse-free survival (ITT) Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Forest Plot for Overall Survival Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Overall survival and PCI Presented By Fran?Ois Quenet at 2018 ASCO Annual Meeting
Death of HIPEC for CRC? No improvement in OS or PFS Higher morbidity and LOS Higher PCI in the HIPEC arm We do not use Oxaliplatinum Length of perfusion only 30 minutes Cytoreductive Surgery works Steep Learning Curve High Morbidity and Mortality Should be referred to specialty center/group
Gastric Cancer Yang, et al, Ann Surg Oncol 2011
Gastric Cancer CYTO-CHIP: Cytoreductive surgery versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A propensityscore analysis from BIG RENAPE and FREGAT working groups
Cyto Chip 277 patients with gastric cancer and PC 180 CRS and HIPEC 97 CRS 19 French HIPEC centers from 1989-2014 Mean PCI 6 vs 2 CCR0 or 1
Cyto Chip Median OS 18.8 vs 12.1 mos 5 year survival 19.87% vs 6.43% Morbidity and Mortality similar Recommendation for CRS + HIPEC for gastric cancer and limited PC
Diffuse Malignant Peritoneal Mesothelioma Cystic Epithelioid Biphasic Sarcomatoid
Diffuse Malignant Peritoneal Mesothelioma Yan et al., J Clin Oncol, 2009
Diffuse Malignant Peritoneal Mesothelioma Helm, et al., Ann Surg Oncol, 2015
What s Next?
PIPAC Reymond, et al. Surg Endosc 2009
PIPAC Pressurized Intraperitoneal Aerosolized Chemotherapy Performed during laparoscopy CRS is not performed at the time of treatment Outpatient surgery Adjunct to systemic chemotherapy Can be repeated
PIPAC Laparoscopic access can be difficult Should not be performed in symptomatic patients Bowel obstruction? Escape of chemotherapy
PIPAC
PIPAC
Future Directions Non-chemotherapy based perfusion Imaging needs to get better Use of fluorescence in the OR to assess CRS Molecular profiling of peritoneal metastasis Immune environment of the peritoneal cavity
Conclusions The treatment of Peritoneal Surface malignancies has dramatically changed during the last 30 years. CURE is possible in some PSM Complete CRS is critical Incomplete cytoreduction provides NO benefit HIPEC with Oxaliplatinum does not improve survival
Conclusions Clinical trials needed PRODIGE 7 Better imaging will help with patient selection Research into new perfusion agents and techniques on the way
Questions? BYLEE@COH.ORG