Isolated lung perfusion with FUDR in the rat: pharmacokinetics and survival

Although surgical resection remains the mainstay of treatment for metastatic pulmonary colorectal cancer, 5-year survival approaches only 30% to 40%. We have developed a model of isolated left lung perfusion (ILP) with FUDR (2'-deoxy-5-fluorouridine) for the treatment of pulmonary colorectal metastases. FUDR ILP toxicity and pharmacokinetics were evaluated and compared with continuous intravenous infusion in the rat.

Toxicity was first evaluated in F344 rats (n = 17) after left ILP (20-minute perfusion at 0.5 mL/min) with 21 mg/mL (n = 11), 28 mg/mL (n = 2), 35 mg/mL (n = 2), and 70 mg/mL (n = 2) of FUDR. Animals were followed up and weights recorded for 14 days postoperatively before a right pneumonectomy was performed to evaluate the effect of FUDR perfusion on left lung function. In the second study, 32 rats (n = 8/group) underwent: systemic FUDR (intravenous), or ILP with 7, 14, and 21 mg/mL respectively (ILP 7, ILP 14, and ILP 21 groups). Left lungs and serum were analyzed for FUDR and 5-fluorouracil by high-performance liquid chromatography.

Rats perfused with doses of FUDR greater than 21 mg/mL died perioperatively. All animals perfused at 21 mg/mL survived until day 14, and 8/11 survived a right pneumonectomy. Rats that survived ILP resumed normal weight gain and grooming habits within 1 week. Pharmacokinetic evaluation demonstrated that ILP at 21 mg/mL maximally elevated total lung FUDR and 5-fluorouracil levels (508.5 +/- 96.4 micrograms/g lung) in comparison with the ILP 14, ILP 7, and intravenous groups (299.1 +/- 44.8, 116.0 +/- 21.1, and 7.5 +/- 4.1 micrograms/g lung, respectively) (p < 0.05). Serum FUDR levels were 10.5 +/- 6.8, 1.3 +/- 0.5, 2.31 +/- 1.1, and 1.2 +/- 0.4 microgram/g lung (p = not significant) for intravenous, ILP 7, ILP 14, and ILP 21 groups, respectively.

Isolated left lung perfusion with FUDR is well tolerated to a maximum dose of 21 mg/mL and results in significantly higher FUDR and 5-fluorouracil lung levels with low serum levels compared with intravenous treatment. These higher pulmonary levels may offer advantages in the treatment of pulmonary colorectal metastases.