Combined tumor therapy by using radiofrequency ablation and 5-FU-laden polymer implants: evaluation in rats and rabbits.
OBJECTIVE
To evaluate the use of 5-fluorouracil (5-FU)-laden polymer implants as an adjunct to radiofrequency (RF) ablation for tumor treatment.


METHODS
All animal studies were performed in compliance with the Case Western Reserve University Institutional Animal Care and Use Committee guidelines. Three studies were performed to investigate (a) in vitro dissolution of 5-FU-laden polymer implants in saline and bovine serum, (b) tissue distribution of 5-FU and its metabolite, 5-fluorouridine (5-FUrd), in the ablated liver tissue of rats (n = 4), and (c) efficacy of combined approach (n = 4) compared with that of ablation alone (n = 6) for VX2 liver tumor model in rabbits. Characterization of 5-FU release in vitro and distribution of 5-FU in rat liver tissue were analyzed by using high performance liquid chromatography; in vivo efficacy was assessed by using computed tomography and pathologic examination.


RESULTS
Results of the in vitro dissolution study showed that a 75% release of 5-FU occurred in 2 days when exposed to bovine serum and in 9 days when exposed to phosphate-buffered saline. In the ablated rat liver, the 5-FU level was higher at the center and lower at the periphery of the tissue both at 24 hours (41.0 mg per kilogram tissue vs 15.0 mg per kilogram tissue, respectively) and at 48 hours (8.0 mg per kilogram tissue vs 2.0 mg per kilogram tissue, respectively). The 5-FUrd concentration was twofold higher peripherally than centrally and was higher at 48 hours than at 24 hours. In rabbits, local delivery of 5-FU immediately after RF ablation provided a significant (P < .05) reduction in tumor size compared with ablation alone (1.80 cm3 +/- 0.28 [standard error] vs 3.53 cm3 +/- 0.52, respectively; P = .034) and a more than 20-fold reduction in tumor size compared with the control (1.80 cm3 +/- 0.28 vs 41.95 cm3 +/- 11.58, respectively; P = .018).


CONCLUSIONS
Combined treatment by using 5-FU polymer implants and RF ablation shows uniform sustained release of 5-FU for 48 hours at least 8 mm from the edge of the ablation zone and appears to be successful at controlling the growth of an experimental tumor in rabbits appreciably better than does ablation alone.
Haaga
John R
JR
Department of Radiology, University Hospitals of Cleveland and Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106-5056, USA.
Exner
Agata A
AA
Wang
Yadong
Y
Stowe
Nicholas T
NT
Tarcha
Peter J
PJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017115:Catheter Ablation; D002851:Chromatography, High Pressure Liquid; D003131:Combined Modality Therapy; D004343:Drug Implants; D005472:Fluorouracil / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000601:surgery*; D011108:Polymers; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014057:Tomography, X-Ray Computed
D000964:Antimetabolites, Antineoplastic; D004343:Drug Implants; D011108:Polymers; D005472:Fluorouracil