Regional therapies for low-volume appendiceal carcinomas and pseudomyxoma peritonei Garrett M Nash, MD, MPH, FACS Surgeon, Colorectal Service, Memorial Sloan Kettering Assistant Professor Surgery, Weill-Cornell Medical College

Regional therapies for Appendix Cancer Disclosures None

Overview History of intraperitoneal chemotherapy Regional therapies for Appendix Cancer History of intraperitoneal chemotherapy Very limited prospective data for any therapy for appendix cancer Cohort studies of appendix cancer Clinical trials Ovarian and colon cancer trials have been extrapolated to appendix cancer 4

Colorectal vs. Appendix Adenocarcinoma Regional therapies for Appendix Cancer Colorectal vs. Appendix Adenocarcinoma Colon Appendix Annual U.S. Incidence 140,000 <1,800 Mean age of onset (years) 68 48 Mucinous histologic type (%) 15 90 Well-differentiated (%) 10 80 Poorly differentiated (%) 10 10 PSM at onset of disease (%) 10 85 Minimally invasive (%) 1 75 Potential Surgical cases (n) 1,400 1,600 Connor SJ, et al. Dis Colon Rectum. 1998;41:75-80. Jayne DG, et al: Br J Surg 89:1545-50 Sugarbaker PH. E J Surg Oncol. 2006;32:644-7

Systemic Chemotherapy Regional therapies for Appendix Cancer Systemic Chemotherapy Pre-FOLFOX Post-FOLFOX

Systemic Chemotherapy Regional therapies for Appendix Cancer Systemic Chemotherapy Pre-FOLFOX Post-FOLFOX

Cytoreductive Surgery & Intraperitoneal Chemotherapy Regional therapies for Appendix Cancer Cytoreductive Surgery & Intraperitoneal Chemotherapy The goal of CRS is to leave no residual nodule larger than 2.5 mm (preferably 0mm) Since the early 1990s, in the absence of randomized trials, various protocols have utilized IPC for peritoneal metastasis for a variety of primary tumors 5-year survival in excess of 50% is associated with optimal CRS + IPC, compared to 20% for those with suboptimal CRS. Sugarbaker. Prog Clin Biol Res 1990;354B:141-70. Culliford, Paty. Ann Surg Oncol 2001;8:787-95. Sugarbaker. Eur J Surg Oncol 2001;27:239-43. Miner, Coit. Ann Surg 2005;241:300-8.

Heterogeneity of the disease Regional therapies for Appendix Cancer Heterogeneity of the disease

Regional therapies for Appendix Cancer Appendix Cancer Grade There are many grading systems for appendix cancer Low/well-diff/DPAM Intermediate/moderate-diff High/poor-diff/PMCA Panarelli NC, Yantiss RK. Arch Pathol Lab Med. 2011;135:1261-8.

Appendix Cancer Grade A DPAM (n=65) High grade PMCA-i (n=14) Low grade Regional therapies for Appendix Cancer Appendix Cancer Grade A DPAM (n=65) High grade (n=37) PMCA-i (n=14) Low grade (n=13) PMCA (n=29) Time to recurrence (years) Sugarbaker PH. E J Surg Oncol. 2006;32:644-7 Wagner. Dis Colon Rectum 2012;55:407-15

Regional therapies for Appendix Cancer Burden of Disease CT/MRI are inaccurate at measuring peritoneal disease Staging at laparotomy Single point in time Time to diagnosis Tumor biology

Regional therapies for Appendix Cancer

Peritoneal Carcinomatosis Index (PCI) Regional therapies for Appendix Cancer Peritoneal Carcinomatosis Index (PCI) High vol (n=24) Low vol (n = 26) Time to recurrence (years) Wagner. Dis Colon Rectum 2012;55:407-15

Cytoreductive Surgery Score Regional therapies for Appendix Cancer Cytoreductive Surgery Score 49 patients CRS & HIPEC2 50 patients CRS & EPIC1 0.1-2.5mm (n=24) CCR0 (n = 26) 0mm (n=26) Time to recurrence (years) Wagner, Nash. Dis Colon Rectum 2012;55:407-15 Verwaal. J Clin Oncol. 2003;21:3737-43.

Outcomes of Metastatic Appendix Cancer Regional therapies for Appendix Cancer Outcomes of Metastatic Appendix Cancer

Overall Survival, High Grade Appendix Cancer CRS + IPC Peritoneal Carcinomatosis From Colorectal Cancer Regional therapies for Appendix Cancer Overall Survival, High Grade Appendix Cancer CRS + IPC HIPEC HIPEC or EPIC EPIC Wash HC (2010) 1 Netherlands (2007) 2 France (2010) 3 Australia (2009) 4 MSKCC (2014) 5 n 58 36 59 11 37 5-year survival 40% <40% 63% Median follow up (years) n/a 4.3 7.3 2.0 5.0 1. Bijelic, et al. J Surg Oncol. 2010;102:576-81. 2. Smeenk, et al . Ann Surg. 2007;245:104-9. 3. Elias, et al. Eur J Surg Oncol. 2010;36:456-62. 4. Chua, et al. Ann Surg Oncol. 2009;16:1903-11. 5. Nash, unpublished.

Overall Survival, Low Grade Appendix Cancer CRS + IPC Peritoneal Carcinomatosis From Colorectal Cancer Regional therapies for Appendix Cancer Overall Survival, Low Grade Appendix Cancer CRS + IPC HIPEC EPIC Wash HC (2000) 1 WF-Creighton (2003) 2 Milan (2004) 3 Netherlands (2010) 4 MSKCC (2014) 6 n 168 73 28 84 13 5-year survival 81% 75% 96+% 64% 100% Median follow up (years) 3.9 2.9 2.4 1.9 6.0 Esquivel, et al. Br J Surg. 2000;87:1414-8. 2. Stewart, et al. Ann Surg Oncol. 2006 May;13(5):624-34. 3. Duraco, et al. Ann Surg Oncol. 2004;11:393-8. 4. Bruin, et al . Ann Surg Oncol. 2010;17:2330-40. 5. Nash, unpublished.

Regional therapies for Appendix Cancer Overall Survival, Low Grade Appendix Cancer CRS + HIPEC vs. Palliative/Selective Debulking Miner, Coit. Ann Surg 2005;241:300-8.

Trials of Intraperitoneal Chemotherapy Regional therapies for Appendix Cancer Trials of Intraperitoneal Chemotherapy

GOG RCTs of IP vs. IV chemo Regional therapies for Appendix Cancer GOG RCTs of IP vs. IV chemo Ovarian cancer with peritoneal only metastasis Optimal surgical cytoreduction IV only vs. IPC Overall Survival n = 546 P = 0.02 Overall Survival n = 462 P = 0.05 Overall Survival n = 415 P = 0.03 Alberts DS et al. N Engl J Med 1996;335:1950-1955 Markman. JCO 2001;19:1001-1007 Armstrong DK et al. N Engl J Med 2006;354:34-43. 21

Summary of Ovarian Cancer RCTs Regional therapies for Appendix Cancer Catheter based IPC has an OS advantage Toxicity depends of drug dosage more than method IPC not widely adopted for Ovarian CA Perceived technical complexity Lack of infrastructure Perceived toxicity 22

French Trial: RCT of EPIC Regional therapies for Appendix Cancer French Trial: RCT of EPIC Colorectal and high grade appendiceal CA 90 patients to find a 30% difference in 2-yr OS Primary resected, resectable liver metastasis 3 months best systemic chemotherapy Optimally surgical cytoreduction (liver rxn if necessary) randomization EPIC POD 1 MMC, POD2-5 5FU 6 mons systemic chemotherapy 6 mons systemic chemotherapy Elias, et al. Ann Surg Oncol. 2004;11(5):518-21.

French Trial: RCT of EPIC Regional therapies for Appendix Cancer French Trial: RCT of EPIC Colorectal and high grade appendiceal CA 90 patients to find a 30% difference in 2-yr OS Primary resected, resectable liver metastasis 3 months best systemic chemotherapy n = 35 (4 yrs) Optimally surgical cytoreduction (liver rxn if necessary) n = 16 n = 19 randomization EPIC POD 1 MMC, POD2-5 5FU 6 mons systemic chemotherapy n = 9 6 mons systemic chemotherapy Elias, et al. Ann Surg Oncol. 2004;11(5):518-21.

French Trial: RCT of EPIC Regional therapies for Appendix Cancer French Trial: RCT of EPIC Findings 60% 2-yr survival in both arms Elias, et al. Ann Surg Oncol. 2004;11(5):518-21.

Development of HIPEC Regional therapies for Appendix Cancer Theoretically, multiple cycles of EPIC may allow for greater cumulative tumor cell kill than a single cycle. However, GOG studies showed efficacy despite the lower number of cycles than planned Multi-cycle EPIC has proven to be difficult for many patients to tolerate due to post-operative pain, distension, and nausea. Multi-cycle EPIC is logistically challenging for many patients, who may have to travel far distances to specialty centers for treatment Thus, HIPEC….

Development of HIPEC Regional therapies for Appendix Cancer Intraoperative IPC was initially performed with a normothermic solution of chemotherapy. Subsequently, intraperitoneal hyperthermia was integrated into the treatment paradigm Cytotoxic to carcinoma cells inhibition of nuclear matrix-mediated functions essential to DNA replication, transcription and repair Increases sensitivity to mitomycin C Cavalieri. Cancer 1967;20:1351-81. González-Moreno. World J Gastrointest Oncol 2010;2:68-75. Carmignani. Eur J Surg Oncol 2004;30:864-8.

Dutch Trial: RCT of CRS + HIPEC Regional therapies for Appendix Cancer Dutch Trial: RCT of CRS + HIPEC Colorectal or high grade appendiceal CA Primary or recurrent disease No solid organ metastasis No induction chemotherapy randomization Surgical cytoreduction + HIPEC + 6 months 5FU/LV 6 months 5FU/LV +/- palliative surgery Verwaal. J Clin Oncol. 2003;21(20):3737-43.

Dutch Trial: RCT of CRS + HIPEC Regional therapies for Appendix Cancer Dutch Trial: RCT of CRS + HIPEC Verwaal. J Clin Oncol. 2003;21(20):3737-43.

Dutch Trial: RCT of CRS + HIPEC Regional therapies for Appendix Cancer Dutch Trial: RCT of CRS + HIPEC Verwaal, VJ. J Clin Oncol; 21:3737-3743 2003 Verwaal, VJ. Ann Surg Oncol; 15:2426–2432. 2008

Dutch Trial: RCT of CRS + HIPEC Regional therapies for Appendix Cancer Dutch Trial: RCT of CRS + HIPEC Grade V (death) 8% Grade III/IV surgical morbidity Hematologic 17% Gastrointestinal 17% (incl 7 fistulae) Hemorrhage 14% Cardiac 14% Infectious 12% Psychiatric 10% Renal 10% Pulmonary 8% Neuropathy 4% Verwaal. J Clin Oncol. 2003;21(20):3737-43.

Dutch Trial: RCT of CRS + HIPEC Regional therapies for Appendix Cancer Dutch Trial: RCT of CRS + HIPEC Benefit depended on success of CRS 18 CC0 patients – 48 month median survival 21 CC1 patients – 20 month median survival 10 CC2/3 patients – 5 month median survival Verwaal. J Clin Oncol. 2003;21(20):3737-43.

Dutch Trial: RCT of CRS + HIPEC Regional therapies for Appendix Cancer Dutch Trial: RCT of CRS + HIPEC Conclusion: Benefit of adding CRS + HIPEC to 5FU Major morbidity may be high Verwaal. J Clin Oncol. 2003;21(20):3737-43.

IV Chemo v. CRS/HIPEC/IV Chemo ACOSOG Randomized Trial Regional therapies for Appendix Cancer IV Chemo v. CRS/HIPEC/IV Chemo ACOSOG Randomized Trial IV CHEMO S T R A I F Y* R A N D O M I Z E Primary Outcome 1.Overall Survival Secondary Outcomes 1. PFS 2. Toxicity burden 3. QOL appraisal 4. CTC during Rx 5. EDR and miRNA array CLOSED Colon Cancer Limited Peritoneal Metastases n=310 Cross Over @ Progression CRS + HIPEC + IV Chemo *Stratification Synchronous v. Metachronous ECOG 0-1 v. 2 Measurable v. Non-measurable

Regional therapies for Appendix Cancer RCT in Progress: French Trial Prodige 7 of Fed Francophone de Canc Digestive HIPEC Complete CRS CCR-0 RESULTS PENDING no HIPEC

2nd French Comparative Study Regional therapies for Appendix Cancer 2nd French Comparative Study n = 528, multicenter, retrospective, 1990-2007 Colorectal peritoneal dz (+ liver mets n=77) CRS + IPC (84:16 HIPEC/EPIC) Elias. J Clin Oncol 2010;28:63-9.

2nd French Comparative Study Regional therapies for Appendix Cancer 2nd French Comparative Study 3.3% mortality 31% Grade 3/4 morbidity Median LOS 18 days (IQR 14-26) Morbidity associated with PCI (OR 1.067 [95% CI,1.035-1.099]) Hospital experience with CRS (>/< 7 years, P<0.001) Elias. J Clin Oncol 2010;28:63-9.

2nd French Comparative Study Regional therapies for Appendix Cancer *significant on multivariable analysis

Regional therapies for Appendix Cancer Conclusions CRS + IPC has good outcomes for low grade appendix cancer but is rarely curative for high grade appendix cancer 10+ yrs median survival for optimally debulked low grade appendix, 30% recurrence at 5 years 4+ yrs median survival for optimally debulked high grade appendix, 60% recurrence at 5 years Biology vs. treatment effect? Grade/Quantity/Completeness of Cytoreduction No data to support one type of IPC over another

ICARuS Trial Intraperitoneal Chemotherapy After cytoReductive Surgery Regional therapies for Appendix Cancer ICARuS Trial Intraperitoneal Chemotherapy After cytoReductive Surgery Jacob Peter Gowy's The Flight of Icarus.

Optimal Surgical Debulking, n = 212 Randomization during surgery ICARuS Trial: Intraperitoneal Chemotherapy After cytoReductive Surgery Optimal Surgical Debulking, n = 212 Randomization during surgery Stratification: 1) Appendix vs. Colorectal Primary 2) Chemo w/in the past 6 months vs. No recent chemo HIPEC (using MMC) EPIC (using FUDR x 1 cycle)

Objectives Primary endpoint: 3-year disease free survival (estimated) ICARuS Trial: Intraperitoneal Chemotherapy After cytoReductive Surgery Objectives Primary endpoint: 3-year disease free survival (estimated) Secondary endpoint: Treatment toxicity. Tertiary endpoints: Molecular analysis of tumors, quality of life, and nutrition

ICARuS Trial: Intraperitoneal Chemotherapy After cytoReductive Surgery Inclusion Criteria Appendiceal or colorectal cancer with peritoneal metastasis. Plan to undergo complete cytoreduction of all peritoneal disease Good candidate for extensive surgery ECOG performance status ≤ 1 Hematology: ANC ≥ 1.5X109/L; Platelets >100x109/L. Adequate Renal function Creatinine <1.5 x the upper limit of normal (ULN) or calculated creatinine clearance of ≥ 50cc/min. Adequate Hepatic function: Bilirubin less than 1.5 mg/dL

ICARuS Trial: Intraperitoneal Chemotherapy After cytoReductive Surgery Exclusion Criteria Previous complete cytoreduction and/or intraperitoneal chemotherapy. Classical carcinoid (goblet cell carcinoid is OK) Metastasis to sites other than lymph nodes or peritoneal surfaces.

Power Analysis 212 patients will be 1:1 randomized ICARuS Trial: Intraperitoneal Chemotherapy After cytoReductive Surgery Power Analysis 212 patients will be 1:1 randomized 110 events with a median follow-up of 3 years 90% power to detect a 20% difference in the proportion of patients (60% vs 40%, which corresponds to a hazard ratio of 1.75) with disease progression or death within 3 years of CRS/IPC

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