1. Systemic Capecitabine and Oxaliplatin Administered with Hepatic Arterial Infusion (HAI) of Floxuridine (FUDR) Following Resection of Colorectal Metastases (M-CRC) Confined to the Liver: 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. Abstract BACKGROUND: The prognosis for patients with hepatic metastases from M-CRC can be poor. However, surgery followed by HAI FUDR plus systemic (SYS) 5-FU improves 5-yr survival rates. Oxaliplatin (OXAL) combined with capecitabine (CAPE) has demonstrated activity in advanced CRC. We report early results of an analysis of SYS OXAL plus CAPE, alternating with HAI FUDR. The primary endpoint is 2-yr survival (2YS), with 36 of 45 patients surviving 2 yrs as evidence of promising efficacy.

3. Abstract METHODS: Patients with M-CRC liver lesions amenable to resection +/- ablation were eligible. Prior adjuvant chemotherapy for completely resected primary was allowed. HAI + SYS therapy was initiated following metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m2/d FUDR and dexamethasone, d1-14 weeks 1 & 2. SYS therapy included 130 mg/m2 OXAL d1, with CAPE at 1000 mg/m2 p.o. BID, d1-14, weeks 4 & 5. Two additional 3-wk courses of SYS therapy were given. CAPE was reduced to 850 mg/m2/BID after interim review of toxicity (GI Cancer Symposium 2004).

4. Abstract PATIENT CHARACTERISTICS: 54 of 70 patients were able to initiate HAI FUDR + SYS. 52% had a solitary met and 24% presented with bilobar mets. RESULTS: Patients completed median of 6 cycles (range 1 - 6). Reasons for discontinuation included: refusal/toxicity (10), completed per protocol (32), recurrence (4), and medical/other (3). Toxicity appears below (n=54). No post-operative or treatment related deaths were reported. 69% (31/45) of evaluable patients are alive with a minimum 18 mos of follow-up. 6 deaths occurred in less than 2 yrs. 44% (20/45) have recurred, with 40% (8/20) having liver involvement. Median time-to- progression is 32 mos with an estimated 2YS rate of 86% (95% CI 76-97%).

5. Abstract CONCLUSIONS: The combination of HAI FUDR and SYS therapy appears to improve outcome following resection of hepatic CRC-M. Updated follow-up is necessary to solidify the primary endpoint of 2YS. Supported by NIH Grant CA25224-18, Sanofi-Synthelabo, and Roche Laboratories, Inc.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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. 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 a < 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 (a)Laboratory values required within 7 days of HAI/SYS treatment. Methods and Eligibility

12. Surgical Outcome 123 patients underwent surgery 47 patients (38%) not candidates 76 patients (62%) completed resected for HAI/SYS due to:  Extrahepatic Disease (8)  Unresectable Disease (13)  Positive Margins (9)  Other (17) 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

13. Protocol-directed Therapy Cycle 1-4 Schema 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

14. Protocol-directed Therapy Cycle 5-6 Schema 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 hours1-213 Q3 CAPCIT1700 mg/m 2 /day PO BID, given in the morning and evening 1-14

15. 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%)

16. Outcome 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).

17. Outcome

18. Adverse Events Adverse EventGrade 3 (%) Grade 4 (%) Hematologic Neutropenia Thrombocytopenia 1010 0000 Hepatic AST Bilirubin Alkaline Phosphatase 411411 000000 Neurologic Paresthesia Laryngeal dysesthesia Neuro/Sensory 911911 000000 Pulmonary Dyspnea 10 Constitutional Fatigue 60 Dermatology/Skin Hand/Foot 10 *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.  2% (1/54) of patients experienced Grade 4+ AEs.

19. Outcome Median follow-up for living patients: 27.5 months (Range:8-45) Median survival: 46 months (95% CI: 39.5-46.3) 11 deaths, 6 within 2 years 23 patients with recurrences –Median Time-to-Recurrence: 30.2 months (95% CI: 18.5-UL not reached) –Liver-only: 4 –Extra-hepatic only: 14 –Liver and extrahepatic: 5

20. Discussion This trial met the preplanned level of success with 87% of patients living 2 or more years from date of surgery. Protocol treatment was well tolerated with no treatment-related deaths and few grade 4 toxicities. 51% of patients undergoing HAI/SYS developed recurrences a median 30 months after surgery.

21. Discussion Liver recurrences accounted for 39% 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).

22. 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.

23. References 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.