1. Systemic chemotherapy in the setting of unresectable appendiceal epithelial neoplasms Eng C 1, Blackham AU 2, Overman M 1, Fournier K 3, Royal R 3, Phillips JK 1, Gajula P 1, Levine EA 2, Wolff RA 1, Mansfield P 3 The Department of Gastrointestinal Medical Oncology 1, Surgical Oncology 3, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Surgical Oncology Service, Wake Forest University, Winston-Salem, North Carolina. 2

2. Acknowledgements Philanthropic support was provided by the Ric Summers Appendiceal Cancer Research Fund.

3. Background Appendiceal epithelial neoplasms (AEN) are a rare tumor type comprising a spectrum from indolent, well-differentiated tumors to the highly aggressive signet-ring histology 1-3. Typically patients present with advanced disease with mucinous ascites and carcinomatosis, arising from the appendix. Furthermore, limited radiographic techniques may result in reduced visualization of the peritoneum for degree of tumor burden and origin of tumor.

4. The mainstay of treatment consists of surgical debulking, or cytoreductive surgery (CRS). Surgery is combined with hyperthermic intraperitoneal chemotherapy (HIPEC) to help eradicate microscopic disease. But the procedure carries significant risk 4-5, and may lower the rate of surgical candidacy of this population even further. Thus, for those patients (pts) who recur, or are otherwise sub-optimal candidates for CRS, systemic chemotherapy is considered. Prior case series suggested lack of benefit 1,6-7 but were not conducted in the era of modern chemotherapy. We previously conducted a single institution analysis (N=54) noting reasonable PFS and OS 8, but a definitive role for systemic chemotherapy has not been defined nor has an optimal chemotherapy regimen been identified. Hence, we have chosen to expand on this concept further.

5. Aim To compare the benefit of progression-free survival, and clinical or radiographic response of three different systemic chemotherapy regimens (5-FU, FOLFOX, and FOLFIRI) in chemotherapy-naïve, surgically unresectable appendiceal epithelial neoplasm patients.

6. Methods Study Design & Population Retrospective cohort study of chemotherapy-naïve patients with surgically unresectable AEN, treated with systemic chemotherapy (5-FU/capecitabine, FOLFOX/CapeOX, or FOLFIRI/CapeIRI) and registered at our institutions from 2000-2009. Patients were allowed to receive the addition of a biologic agent at the discretion of their treating physician. Patients were required to obtain all radiographic imaging at our respective institutions. An appropriate waiver of informed consent was obtained. Electronic medical records were reviewed for patient demographics, tumor characteristics, and clinical outcomes including: Prior CRS, with or without HIPEC, histology, systemic treatment received, tumor markers (CEA, CA-125, and CA 19-9), response (R), progression-free survival (PFS), and overall survival (OS). Best response to treatment was determined from radiographic imaging, tumor markers, and physician records. Statistical Analysis OS and PFS were determined using the Kaplan-Meier method. The log-rank test and Cox proportional hazard model were used for statistical comparisons.

7. Demographics (Table 1) N=136 (%) Histologic Grade Well + Moderate92(68) Poor44(32) Poor + Signet 26 (19) Signet Ring Yes30 (22) No106 (78) Prior CRS/HIPEC None62 (46) CRS33 (24) CRS+HIPEC41 (30) Biologics Yes59 (43) No77 (57)

8. Chemotherapy Regimens (Table 2) N=136 (%) 5-FU/Capecitabine43 (32) + Biologic5 (4) FOLFOX/CapeOX71 (52) + Biologic42 (31) FOLFIRI/CapeIRI22 (16) + Biologic12 (9)

9. Results 136 pts were evaluable for PFS and OS. Median follow up: 8.3 years. Survival outcomes (Figures 1 & 2): Median PFS by regimen is shown in Table 3. Combination chemotherapy (FOLFOX or FOLFIRI) increased median PFS vs. 5-FU alone to 8 months from 5 months (p=0.06). Multivariate analysis indicated combined chemotherapy increased PFS compared to 5-FU alone [HR: 0.6; 95% CI: 0.4- 0.9; p-value = 0.03]. Median OS was 42 months. Median subsequent lines of therapy = 1. N=136 (%) Median PFS (95% CI) p-value 5-FU43 (32)5 (3-7) 0.13 FOLFOX71 (52)8 (6-10) FOLFIRI22 (16)7 (3-11) Median PFS (Table 3)

10. Treatment response: 136 pts were evaluable for response. Best response to the regimens were recorded: 46 (34%) pts had progressive disease. 19 (14%) pts had a partial response. 71 (52%) pts had stable disease. The difference in responses between regimens was statistically significant (p=0.04) (Table 4).

11. Treatment Response by Regimen (Table 4) N=136 (%) Best Response to 5-FU-based regimen43(32) Progressive Disease Partial Response Stable Disease 23 (53) 3 (7) 17 (40) Best Response to FOLFOX-based regimen71 (52) Progressive Disease Partial Response Stable Disease 15 (21) 41 (58) Best Response to FOLFIRI-based regimen22 (16) Progressive Disease Partial Response Stable Disease 8 (36) 1 (5) 13 (59)

12. Figure 1. PFS – 5-FU vs. FOLFOX vs. FOLFIRI

13. Figure 2. Overall survival

14. Conclusions In the treatment of surgically unresectable AEN, multivariate analysis demonstrated that combination chemotherapy, notably oxaliplatin- based chemotherapy, resulted in significantly improved PFS vs. single agent 5-FU. Our analysis was underpowered to determine definitive benefit or lack of benefit for irinotecan-based combination therapy. Prospective analyses including cost-benefit should be considered. Tissue/blood correlatives and quality of life analysis are currently underway. We understand the limitations of a retrospective study with a small, select sample size. Nevertheless, we consider the results worthy of discussion for such a rare patient population.

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