1. Systemic Capecitabine and Oxaliplatin Administered with Hepatic Arterial Infusion (HAI) of Floxuridine (FUDR) Following Complete Resection of Colorectal Metastases (M-CRC) Confined to the Liver: Final Results of a North Central Cancer Treatment Group (NCCTG) Phase II Intergroup Trial SR Alberts, MR Mahoney, J Donohue, MS Roh, EM Green, DJ Sargent, LD Wagman, J Bolton. Rochester, MN, Pittsburg, PA, Duarte, CA, New Orleans, LA

2. Background Approximately 25% of patients with metastatic colorectal cancer will have liver-only metastases (1-3) Resection of liver metastases can result in long-term survival in a portion of patients. A 5-year survival rate of 25 ‑ 37% has been reported in a number of studies, with a median survival of 24 ‑ 42 months (4) The pattern of recurrence after first liver resection shows that 41% of recurrences involve only the liver (5). Recent studies of patients receiving hepatic artery infusion (HAI) therapy after resection have reported an improved survival as well as a decrease in hepatic recurrence compared to patients receiving systemic therapy.

3. Background In a study from Memorial Sloan-Kettering Cancer Center, patients were randomized to systemic chemotherapy alone with 5-fluorouracil (5-FU) and leucovorin (CF) versus systemic chemotherapy combined with HAI with FUDR (6). Seventy-four patients were randomized to combined therapy and 82 to systemic therapy. A significant benefit was seen in patients receiving combined therapy. The median survival in the group receiving combined therapy was 72.2 months compared to 59.3 months for those receiving systemic therapy alone. At two years the rate of survival free of hepatic recurrence was 90 percent in the combined therapy group compared to 60 percent in the systemic therapy only group (p<0.001). However, recurrence outside the liver appeared similar in both groups.

4. Background The combination of oxaliplatin, 5-FU, and CF has been shown to have superior activity compared to 5-FU and CF when used for metastatic disease or in the adjuvant setting. The combination of capecitabine and oxaliplatin appears to have comparable activity and does not require a central line. The NCCTG recently completed accrual to a trial assessing the potential benefits of capecitabine and oxaliplatin alternating with HAI FUDR for resected liver- only metastases to evaluate its benefit and tolerability.

5. Goals and Study Design Goals Primary: To assess the safety (i.e., toxicity) of capecitabine and oxaliplatin in combination with HAI FUDR. To assess the two-year survival rate Secondary: To assess two-year recurrence rate, time-to- recurrence, and toxicity.

6. Goals and Study Design Study Design Patients are considered evaluable if they have initiated post-resection HAI therapy. Treatment “success” in evaluable patients measured as a patient living at least 2 years from the date of resection. A 2-year survival of 85% considered clinically beneficial, while a 2-year survival rate is 70% or less considered of no clinical benefit (87% power; 0.09 significance level). Considered promising if at least 36 of 45 evaluable patients lived a minimum of 2 years post- metastasectomy.

7. Methods and Eligibility TimepointRequiredContraindications Prior to Metastasectomy  ECOG PS of 0 or 1.  One prior 5-FU based surgical adjuvant therapy (CPT11, CF, and LEV allowed).  Prior resection of hepatic metsastases allowed, if ultrasound not used in resection.  Prior history of completed resected CRC.  Pre-existing chronic hepatic disease (chronic active hepatitis, cirrhosis).  Prior HAI therapy with 5-FU or FUDR or any systemic chemotherapy for metastatic disease.  Extrahepatic metastases evident on preoperative work-up.

8. Methods and Eligibility Prior to HAI/SYS Therapy  Completely resected or cryoablated hepatic metastases.  Radiofrequency ablation may have been used on remaining metastases following surgical resection of the dominant mass.  In the case where synchronous resection was performed at the time of metastasectomy, the colon or rectal cancer must have been completely resected.  Histologic confirmation of metastatic colorectal adenocarcinoma.  Extrahepatic disease at time of metastasectomy.  ANC < 1200  PLT < 100,000  Creatinine > UNL or if creatinine is elevated, creatinine clearance < 60 mL/min/1.73 m 2  Direct bilirubin > 1.5 x UNL  AST > 2.5 x UNL  Alk Phos < 2.5 x UNL

9. Surgical Outcome 123 patients underwent surgery. 22 patients (18%) 54 patients (44%) unable to receive HAI/SYS due initiated HAI/SYS to inadequate LFT, progression, within the planned non treatment related death, 21-56 days of refusal, and other reasons.metastasectomy 47 patients (38%) not candidates for HAI/SYS due to: Extrahepatic disese (8) Unresectable disease (13) Positive margins (9) Other (17) 76 patients (62%) completed resected

10. Therapy FUDR (weeks 1-2, days 1-14) ↓ Capecitabine and Oxaliplatin (weeks 4-5, days 22-36) Cycles 1-4 TypeAgentDoseRouteWeek(s) of Cycle Day(s) of Week of Cycle Rest Week ReRx Hepatic Artery Infusion FUDR0.2 mg/kg/dHAI - continuous1-21-143q 6 weeks DXM1 mg/24 hoursAdded to FUDR 2-week infusion HEPARI N 1000 Units/ 24 hours Added to FUDR 2-week infusion Systemic Therapy OXAL130 mg/m 2 IV over 2 hours4-516 CAPCIT1700 mg/m 2 /day PO BID, given in the morning and evening 1-14

11. Therapy Capecitabine and Oxaliplatin alone Cycles 5-6 TypeAgentDoseRouteWeek(s) of Cycle Day(s) of Week of Cycle Rest Week ReRx Systemic Therapy OXAL130 mg/m 2 IV over 2 hours4-513 Q 3 weeks CAPCIT1700 mg/m 2 /day PO BID, given in the morning and evening 1-14

12. Patient Characteristics CharacteristicFrequency (%) Gender Female Male Not Reported 20 (37%) 33 (61%) 1(2%) Age (years) Median Range 56 34-79 ECOG Performance Status 0-1 2 Missing 35 (65%) 18 (34%) 1(2%) Number of Metastases > 2 Unilobar Bilobar Single 13 (24%) 28 (52%)

13. Treatment Summary 54 patients completed a total of 262 cycles of therapy (median 6; range 1-6). Treatment delays: 29 of 262 cycles of therapy most frequently on cycle 6 (8 delays out of 36 total cycles) lasted median of 14 days (range 1-42)

14. Outcome

15. Adverse Events Adverse EventGrade 3 Hematologic Neutropenia Thrombocytopenia 1010 Hepatic AST Bilirubin Alkaline Phosphatase 411411 Gastrointestinal Abdominal pain Nausea Vomiting Diarrhea 4 6 7 12 Neurologic Paresthesia Laryngeal dysesthesia Neuro/Sensory 911911 Pulmonary Dyspnea1 Constitutional Fatigue6 Dermatology/Skin Hand/Foot1 *CTC V2.0, Related to study drug only. One patient died of non- treatment related hypoxia 65% (35/54) of patients experienced at least one Grade 3 AE No Grade 4+ AEs occurred

16. Follow-up Median follow-up for living patients: 2.3 years (Range:0.6-4.2) Median survival: 3.8 years (95% CI: 3.4-UL not reached) 12 deaths, 6 within 2 years 26 patients with recurrences Median Time-to-Recurrence: 2.5 years (95% CI: 1.7- UL not reached) Liver-only: 4 Extra-hepatic only: 15 Liver and extrahepatic: 7

17. Discussion This trial met the preplanned level of success with 88% of patients living 2 or more years from date of surgery. Protocol treatment was well tolerated with no treatment-related deaths and no grade 4 toxicities. 48% of patients undergoing HAI/SYS developed recurrences a median 2.5 years after surgery.

18. Discussion Liver recurrences accounted for 42% of recurrences. Extrahepatic recurrences accounted for the majority of recurrences. The potential benefits of this approach are now being evaluated in a phase III trial comparing capecitabine and oxaliplatin alone or with HAI FUDR (NSABP C-09)

19. References 1. Steele GD Jr: The National Cancer Data Base Report on colorectal cancer. Cancer 74:1979-1989, 1994. 2. Moertel CG, Fleming TR, MacDonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon cancer. N Engl J Med 322:352-358, 1990. 3. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 150:195-203, 1986. 4. Fong Y: Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 49:231-255, 1999. 5. Fong Y, Cohen AM, Fortner JG, et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-946, 1997. 6. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039-48, 1999.