1. Role of biologic therapy in the treatment of unresectable appendiceal epithelial neoplasms Eng C 1, Overman M 1, Fournier K 2, Royal R 2, Ohinata A 1, Rafeeq S 2, Phillips JK 1,Gajula P 1, Wolff RA 1, Mansfield P 2 The Department of Gastrointestinal Medical Oncology 1, Surgical Oncology 2, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

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. Typical patients exhibit extensive accumulation of mucinous ascites and tumors within the peritoneal cavity, arising from the appendix. Since patients often present with advanced disease, treatment and management of this malignancy is difficult. 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 lowers the rate of surgical candidacy of this population even further.

4. Thus, for those patients (pts) who recur, or are otherwise sub-optimal candidates for CRS, systemic maintenance therapy is considered and has been associated with a reasonable PFS and OS 6, but to date there is a lack of consensus regarding an optimal chemotherapy regimen. Given the recent advances in biologic therapy, and the concurrent costs, it is important to evaluate whether the addition of these agents to chemotherapy is of therapeutic benefit to this population.

5. Aim To determine the benefit to overall survival, progression-free survival, and clinical or radiographic response following the use of biologic therapy in combination with chemotherapy in biologic-naïve, surgically unresectable appendiceal epithelial neoplasm patients.

6. Methods Study Design and Population Retrospective consecutive cohort study of biologic-naïve patients with surgically unresectable AEN, treated with systemic chemotherapy plus biologic therapy, from 2000-2010. Control cases not receiving biologic therapy were consecutively selected from the same timeframe. Eligible patients were required to obtain all radiographic imaging at MDACC. 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=130 (%) Age at diagnosis (Mean)52 Standard Deviation11 Sex: Male64 (49) Female66 (51) Ethnicity White109 (84) Black12 (9) Hispanic7 (5) Asian/Pacific Islander2 (2) Histologic Grade Well37 (28) Moderate43 (33) Poor50 (39) Poor+Signet Ring31 (24) Signet Ring Yes33 (25) No97 (75) Biologic Agent Yes65 (50) No65 (50) Prior CRS/HIPEC None62 (48) CRS42 (32) CRS+HIPEC26 (20)

8. Chemotherapy Regimens (Table 2) N=130 (%) 5-FU /Capecitabine28 (22) + Biologic3 (2) FOLFOX/CapeOx68 (52) + Biologic48 (37) FOLFIRI/CapeIri18 (14) + Biologic13 (10) Other16 (12) + Biologic1 (1) N=65 (%) Bevacizumab59 (45) Cetuximab5 (4) Panitumumab1 (1) Biologic Agents Used in First Line (Table 3)

9. Results 130 pts were evaluable for OS and PFS. Median follow up: 78 months. Survival outcomes (Figures 1 & 2): The addition of biologic therapy improved median PFS (8M vs. 4M, p-value = 0.08) and was statistically significant for OS (62M vs. 42M, p-value = 0.03). Multivariate analysis indicated improved PFS (HR: 0.72; 95% CI: 0.50-1.01; p-value: 0.06) and significantly improved OS (HR: 0.55; 95% CI: 0.34-0.88; p value = 0.01) in favor of biologic therapy. Median lines of subsequent therapy = 1 28 of 59 (47%) continued bevacizumab beyond progression of disease.

10. Determination of response: 117 pts (90%) were evaluable for response. Best response to the regimens were recorded. 33 (28%) pts had progressive disease. 20 (17%) pts had a partial response. 64 (55%) pts had stable disease. There was a significant difference in response between those patients who received biologics compared to those who did not (p=0.02) (Table 4). Treatment Response Bio vs. No Bio (Table 4) N=117 (%) Biologics Progressive Disease Stable Disease Response 59 (50) 9 (15) 38 (65) 12 (20) No Biologics Progressive Disease Stable Disease Response 58 (50) 24 (41) 26 (45) 8 (14)

11. Figure 1. OS – Biologic vs. No Biologic

12. Figure 2. PFS – Biologic vs. No Biologic

13. Conclusions The use of biologic therapy, primarily anti-VEGF therapy in our analysis, in combination with chemotherapy versus systemic chemotherapy alone appears to have a role in surgically unresectable appendiceal epithelial neoplasm (AEN) patients, with a trend for improvement in PFS and clear benefit in OS. Our analysis was underpowered to determine the role of anti-EGFR therapy as a single agent or in combination with chemotherapy but indicates further analysis should be pursued in this patient population. Given the cost of biologic therapy, cost-benefit analyses should be pursued. 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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