2. 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

3. Regional therapies for Appendix Cancer
Disclosures
None

4. 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

5. 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) Mucinous histologic type (%) Well-differentiated (%) Poorly differentiated (%) PSM at onset of disease (%) 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:
Sugarbaker PH. E J Surg Oncol. 2006;32:644-7

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

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

8. 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:
Culliford, Paty. Ann Surg Oncol 2001;8:
Sugarbaker. Eur J Surg Oncol 2001;27:
Miner, Coit. Ann Surg 2005;241:300-8.

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

10. 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:

11. 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

12. 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

13. Regional therapies for Appendix Cancer

14. 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

15. Cytoreductive Surgery Score
Regional therapies for Appendix Cancer
Cytoreductive Surgery Score
49 patients CRS & HIPEC2
50 patients CRS & EPIC1 mm
(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:

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

17. 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:
2. Smeenk, et al . Ann Surg. 2007;245:104-9.
3. Elias, et al. Eur J Surg Oncol. 2010;36:
4. Chua, et al. Ann Surg Oncol. 2009;16:
5. Nash, unpublished.

18. 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:
2. Stewart, et al. Ann Surg Oncol May;13(5):
3. Duraco, et al. Ann Surg Oncol. 2004;11:393-8.
4. Bruin, et al . Ann Surg Oncol. 2010;17:
5. Nash, unpublished.

19. 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.

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

21. 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:
Markman. JCO 2001;19:
Armstrong DK et al. N Engl J Med 2006;354:34-43. 21

22. 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

23. 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):

24. 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):

25. 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):

26. 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….

27. 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:
González-Moreno. World J Gastrointest Oncol 2010;2:68-75.
Carmignani. Eur J Surg Oncol 2004;30:864-8.

28. 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):

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

30. Dutch Trial: RCT of CRS + HIPEC
Regional therapies for Appendix Cancer
Dutch Trial: RCT of CRS + HIPEC
Verwaal, VJ. J Clin Oncol; 21:
Verwaal, VJ. Ann Surg Oncol; 15:2426–

31. 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):

32. 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):

33. 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):

34. 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

35. 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

36. 2nd French Comparative Study
Regional therapies for Appendix Cancer
2nd French Comparative Study
n = 528, multicenter, retrospective,
Colorectal peritoneal dz (+ liver mets n=77)
CRS + IPC (84:16 HIPEC/EPIC)
Elias. J Clin Oncol 2010;28:63-9.

37. 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 [95% CI, ])
Hospital experience with CRS (>/< 7 years, P<0.001)
Elias. J Clin Oncol 2010;28:63-9.

38. 2nd French Comparative Study
Regional therapies for Appendix Cancer
*significant on multivariable analysis

39. 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

40. 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.

41. 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)

42. 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

43. 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

44. 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.

45. 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

46. Thanks