Systemic chemotherapy in the setting of unresectable appendiceal epithelial neoplasms

1. Systemic chemotherapy in the setting of unresectableappendiceal epithelial neoplasms Eng C1, Blackham AU2, Overman M1, Fournier K3, Royal R3, Phillips JK1, Gajula P1, Levine EA2, Wolff RA1, Mansfield P3 The Department of Gastrointestinal Medical Oncology1, Surgical Oncology3, 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 histology1-3. • Typically patients present with advanced disease with mucinousascites 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 hyperthermicintraperitoneal chemotherapy (HIPEC) to help eradicate microscopic disease. But the procedure carries significant risk4-5, 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 benefit1,6-7 but were not conducted in the era of modern chemotherapy. • We previously conducted a single institution analysis (N=54) noting reasonable PFS and OS8, 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 unresectableappendiceal 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)

8. Chemotherapy Regimens(Table 2)

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. 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)

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.

15. References • Baratti D, et al: Pseudomyxomaperitonei: clinical pathological and biological prognostic factors in patients treated with cytoreductive surgery and hyperthermicintraperitoneal chemotherapy (HIPEC). Ann SurgOncol. 2008;15(2):526–534. • Yan H, et al: Histopathologic analysis in 46 patients with pseudomyxomaperitonei syndrome: failure versus success with a second-look operation. Mod Pathol. 2001;14(3):164–171. • Sugarbaker PH: Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxomaperitonei syndrome. Tumori. 2001;87(4):53–55. • Kusamura S, et al: Cytoreductive surgery followed by intraperitonealhyperthermic perfusion: analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique. Cancer. 2006;106:1144–1153. • Deraco M et al: Morbidity and quality of life following cytoreduction and HIPEC [review]. Cancer Treat Res. 2007;134:403–418. • Smith JW, et al. Pseudomyxomaperitonei of appendiceal origin. The Memorial Sloan-Kettering Cancer Center experience. Cancer. 1992; 70: 396-401. • Gough DB, et al. Pseudomyxomaperitonei. Long-term patient survival with an aggressive regional approach. Ann Surg. 1994; 219: 112-119. • Shapiro JF, et al: Modern systemic chemotherapy in surgically unresectableneoplasmsofappendiceal origin: a single-institution experience. Cancer. 2010 Jan 15;116(2):316-22.