Systemic chemotherapy in the setting of unresectable appendiceal

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

AcknowledgementsPhilanthropic support was

provided by the Ric Summers Appendiceal Cancer Research Fund.

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 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.

• 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 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.

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.

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.

Demographics (Table 1)N=136 (%)

Histologic Grade

Well + Moderate 92(68)

Poor 44(32)

Poor + Signet 26 (19)

Signet Ring

Yes 30 (22)

No 106 (78)

Prior CRS/HIPEC

None 62 (46)

CRS 33 (24)

CRS+HIPEC 41 (30)

Biologics

Yes 59 (43)

No 77 (57)

Chemotherapy Regimens(Table 2)

N=136 (%)5-FU/Capecitabine 43 (32) + Biologic 5 (4)FOLFOX/CapeOX 71 (52) + Biologic 42 (31)FOLFIRI/CapeIRI 22 (16) + Biologic 12 (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-FU 43 (32) 5 (3-7)

0.13FOLFOX 71 (52) 8 (6-10)

FOLFIRI 22 (16) 7 (3-11)

Median PFS (Table 3)

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).

Treatment Response by Regimen (Table 4)

N=136 (%)

Best Response to 5-FU-based regimen 43(32)

Progressive Disease

Partial Response

Stable Disease

23 (53)

3 (7)

17 (40)

Best Response to FOLFOX-based regimen 71 (52)

Progressive Disease

Partial Response

Stable Disease

15 (21)

15 (21)

41 (58)

Best Response to FOLFIRI-based regimen 22 (16)

Progressive Disease

Partial Response

Stable Disease

8 (36)

1 (5)

13 (59)

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

Figure 2. Overall survival

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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