Peritoneal metastases can be cured Peritoneal metastases can be cured. Select the right patients and you will get good results. Presented by Paul H. Sugarbaker, MD Director, Program in Peritoneal Surface Malignancy MedStar Washington Hospital Center Washington, DC Paul.Sugarbaker@medstar.net

Global Status of CRS/HIPEC for Peritoneal Metastases (PM) Appendiceal – Standard of care (caution with aggressive histologies) Peritoneal mesothelioma – Standard of care (consider use of NIPEC-LT) Colorectal – Standard of care (follow NCCN guidelines) Ovarian – Most common use of CRS/HIPEC (thousands of patients treated, >200 manuscripts, 7 RCTs in progress or published Gastric – Selective use for prevention or PCI <6 Unusual malignancies with isolated PM – Select patients by quantitative prognostic indicators

Peritoneal Metastases The panel currently believes that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for whom R0 resection can be achieved. The panel recognizes the need for (additional) randomized clinical trials that will address the risks and benefits associated with each of these modalities.

Standardized surgical technology to achieve a complete response: Peritonectomy procedures Anterior parietal Right subphrenic Left subphrenic Pelvic Omental bursa Mesenteric Visceral resections Greater omentum Spleen Uterus and ovaries Rectosigmoid colon Right colon Lesser omentum Stomach

Standardized HIPEC for pseudomyxoma peritonei, adenocarcinoma from appendiceal and colonic cancer: Dutch High Dose Mitomycin C Regimen: ‘Triple Dosing Regimen” Add mitomycin C to 3 L 1.5% dextrose peritoneal dialysis solution Add mitomycin C to the 1.5% peritoneal dialysis solution at a dose of 17.5 mg/m2 followed by 8.8 mg/m2 at 30 minutes and 8.8 mg/m2 at 60 minutes Total dose of mitomycin C 35 mg/m2 for 90-minute HIPEC treatment American Society of Peritoneal Surface Malignancy Low Dose Mitomycin C Regimen: ‘Concentration-Based Regimen” Add mitomycin C to 3 L 1.5% dextrose peritoneal dialysis solution Add mitomycin C to the 1.5% peritoneal dialysis solution at a dose of 30 mg/3 L followed by 10 mg at 60 minutes Dose of mitomycin C 40 mg/3 L for 90-minute HIPEC treatment

Elias High Dose Oxaliplatin Regimen for Open HIPEC Add oxaliplatin to 2 L/m2 5% dextrose solution Dose of oxaliplatin is 460 mg/m2 30-minute HIPEC treatment at 43°C Intravenous Component Add 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 to separate bags of 250 mL normal saline. Begin rapid intravenous infusion of both drugs one hour before intraperitoneal chemotherapy. Glehen Medium Dose Oxaliplatin Regimen for Closed HIPEC Add oxaliplatin to 2 L/m2 5% dextrose solution Dose of oxaliplatin is 400 mg/m2 30-minute HIPEC treatment at 43°C Intravenous Component Add 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 to separate bags of 250 mL normal saline. Begin rapid intravenous infusion of both drugs one hour before intraperitoneal chemotherapy .

Standardized HIPEC for sarcoma, gastric cancer, ovarian cancer, and peritoneal mesothelioma: Sugarbaker Regimen Add cisplatin to 2 L 1.5% dextrose peritoneal dialysis solution Add doxorubicin to the same 2 L 1.5% peritoneal dialysis solution Dose of cisplatin is 50 mg/m2 and doxorubicin is 15 mg/m2 for 90-minute HIPEC treatment Intravenous Chemotherapy Add ifosfamide 1300 mg/m2 to 1 L 0.9% sodium chloride. Begin continuous IV infusion over 90 minutes simultaneous with intraperitoneal chemotherapy Add mesna disulfide 260 mg/m2 in 100 mL 0.9% sodium chloride to be given IV as a bolus 15 minutes prior to ifosfamide infusion Add mesna disulfide 260 mg/m2 in 100 mL 0.9% sodium chloride to be given IV as a bolus 4 hours after ifosfamide infusion Add mesna disulfide 260 mg/m2 in 100 mL 0.9% sodium chloride to be given IV as a bolus 8 hours after ifosfamide infusion

National Cancer Institute Milan Regimen 15.25 mg/L of doxorubicin and 43 mg/L of cisplatin for 90-minute HIPEC treatment Chemotherapy solution 4-6 liters based on capacity of the peritoneal space Van der Speeten K et al. Pharmacokinetic study of perioperative intravenous ifosfamide. Int J Surg Oncol. 2011;2011:185092 Deraco M et al. Experience with peritoneal mesothelioma at the Milan National Cancer Institute. World J Gastrointest Oncol. 2010;2:76-84 RENAPE – French HIPEC for Ovarian Cancer Cisplatin 80 mg in 3 L 0.9% sodium chloride at 42°C for 60 minutes

Sugarbaker GEMCITABINE-BASED Regimen for resected pancreas cancer and cisplatin-resistant ovarian cancer Add gemcitabine to 2 L 1.5% dextrose peritoneal dialysis solution, total chemotherapy solution 1.5 L/m2 Dose of gemcitabine is 1000 mg/m2 for 60-minute HIPEC treatment Sugarbaker MELPHALAN-BASED Regimen for reoperative cytoreductive surgery and cisplatin-resistant ovarian cancer and rare diseases with isolated peritoneal metastases Add melphalan to 2 L 1.5% dextrose peritoneal dialysis solution, total chemotherapy solution 1.5 L/m2 Dose of melphalan is 50-70 mg/m2 for 60-minute HIPEC treatment

BIDIRECTIONAL ADJUVANT NORMOTHERMIC CHEMOTHERAPY (BANC) – Long-Term Cancer Chemotherapy for Peritoneal Metastases

Distribution of peritoneal metastases is dependent upon flow of peritoneal fluid Gray’s Anatomy 41st Edition, 2016

Strategy for Treatment of Peritoneal Metastases Goal for CRS – complete visible resection of all tumor from the abdomen and pelvis. Goal for perioperative chemotherapy – preserve the surgical complete response by eradication of minimal residual disease.

Surgical Technology to Achieve a Complete Response Peritonectomy Procedures Visceral Resections Anterior parietal Right subphrenic Left subphrenic Pelvic Omental bursa Mesenteric Greater omentum Spleen Uterus and ovaries Rectosigmoid colon Right colon Lesser omentum Stomach

Prognostic Indicators for Treatment of Peritoneal Metastases Histopathology Lymph node status Abdominal-Pelvic CT Peritoneal Cancer Index Completeness of cytoreduction score Prior surgical score

Survival by Histopathology – Appendiceal Mucinous Neoplasms

Product-Limit Survival Estimates – Appendiceal Cancer

Survival by Lymph Node Status – Colon Cancer

Influence of Tumor Volume on Sensitivity of CT Scan

Sugarbaker PH et al. Int J Hyperthermia, 2017

Predictive Value Score Multivariate model of radiologic criteria predictive of suboptimal cytoreduction Criteria OR 95% CI P Predictive Value Score Retroperitoneal lymph nodes above the renal hilum (including subdiaphragmatic) > 1 cm 1.59 1.58 – 1.6 <0.001 1 Diffuse small bowel adhesions/thickening 1.87 1.86 – 1.87 Perisplenic lesion > 1 cm 2.27 1.7 – 3.03 2 Small bowel mesentery lesion > 1 cm 2.28 1.08 – 4.8 0.03 Root of the superior mesenteric artery lesion > 1 cm 2.4 1.34 – 4.32 0.003 Lesser sac lesion > 1 cm 4.61 4.39 – 4.84 4 Suidan et al. Gynecol Oncol, 2014

Survival by PCI – Colon Cancer Survival by PCI – Colon Cancer (N=416) (Glehen et al. AFC monograph, 2008) Survival by PCI – Colon Cancer

Survival by Completeness of Cytoreduction – Colon Cancer (N=416) (Glehen et al. AFC monograph, 2008)

Survival by Prior Surgical Score – Ovarian Cancer

Survival by Prior Surgical Score – Colorectal Cancer

Recommendations for use of CRS and HIPEC Clinical features suggesting a favorable outcome for use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal metastases General medical condition compatible with survival and recovery from the procedure. Clinical information regarding the peritoneal metastases compatible with a complete or near complete cytoreduction from contrast-enhanced CT. Relative sparing of the small bowel and colon. Absence of disease outside the abdomen/pelvis. If hepatic metastases are present, they are limited, compatible with wedge resection. Absence of disease within the porta hepatis. With high-grade malignancy, a low or moderate peritoneal cancer index. Clinical features suggesting cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should not be recommended Poor performance status. Rapid progression of a high-grade disease process. Low likelihood of a response to perioperative chemotherapy (extensive prior systemic chemotherapy) One or more concerning radiologic features by CT. Prior abdominal or pelvic radiation therapy. Local control of the primary cancer is unlikely.