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

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.

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).

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%).

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.

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.

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.

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.

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.

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.

Timepoint Required Contraindications

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.

ANCa < 1200 PLT < 100,000 Creatinine > UNL or if creatinine

is elevated, creatinine clearance < 60 mL/min/1.73 m2

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

Surgical Outcome123 patients underwent surgery

47 patients (38%) not candidates 76 patients (62%) completed resectedfor 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 plannednon treatment related death, 21-56 days of refusal, and other reasons. metastasectomy

Protocol-directed Therapy

Cycle 1-4 SchemaFUDR (weeks 1-2, days 1-14)Capecitabine and Oxaliplatin (weeks 4-5, days 22-36)

Cycles 1-4

Type Agent Dose Route Week(s) of Cycle

Day(s) of Week of

Cycle

Rest Week

ReRx

Hepatic Artery

Infusion

FUDR 0.2 mg/kg/d HAI - continuous 1-2 1-14 3 q 6 weeksDXM 1 mg/24 hours Added to FUDR

2-week infusion

HEPARIN

1000 Units/24 hours

Added to FUDR 2-week infusion

Systemic Therapy

OXAL 130 mg/m2 IV over 2 hours 4-5 1 6

CAPCIT 1700 mg/m2/day

PO BID, given in the morning and

evening

1-14

Protocol-directed Therapy

Cycle 5-6 SchemaCapecitabine and Oxaliplatin alone

Cycles 5-6

Type Agent Dose Route Week(s) of Cycle

Day(s) of Week of

Cycle

Rest Week

ReRx

Systemic Therapy

OXAL 130 mg/m2 IV over 2 hours 1-2 1 3 Q3

CAPCIT 1700 mg/m2/day

PO BID, given in the morning and

evening

1-14

Patient Characteristics

Characteristic Frequency (%)

GenderFemaleMaleNot Reported

20 (37%)33 (61%)

1(2%)

Age (years)MedianRange

5634-79

ECOG Performance Status0-12Missing

35 (65%)18 (34%)

1(2%)

Number of Metastases> 2 UnilobarBilobarSingle

13 (24%)13 (24%)28 (52%)

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).

Outcome

Adverse EventsAdverse Event Grade 3

(%)Grade 4

(%)

Hematologic Neutropenia Thrombocytopenia

10

00

HepaticASTBilirubinAlkaline Phosphatase

411

000

NeurologicParesthesiaLaryngeal dysesthesiaNeuro/Sensory

911

000

Pulmonary Dyspnea

1 0

ConstitutionalFatigue

6 0

Dermatology/Skin Hand/Foot

1 0

*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.

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

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.

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).

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.

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.