Combination radiofrequency ablation with intratumoral liposomal doxorubicin: effect on drug accumulation and coagulation in multiple tissues and tumor types in animals.
OBJECTIVE
To determine whether use of radiofrequency (RF) ablation combined with intravenously (IV) administered liposomal doxorubicin, as compared with use of RF ablation or doxorubicin alone, facilitates increased tissue coagulation and interstitial drug accumulation in animal models.


METHODS
The institutional animal care and use committee approved this study. In experiment 1, multiple canine sarcomas were implanted in seven mildly immunosuppressed dogs and grown to a mean diameter of 4.8 cm. Tumors were assigned to three treatment groups: internally cooled RF ablation (12 minutes, 2000-mA pulsed technique) followed by IV liposomal doxorubicin (10 mg per animal) (n = 6), RF ablation alone (n = 6), and liposomal doxorubicin alone (n = 4). In experiment 2, the livers and kidneys of 10 rabbits and the thigh muscles of 10 rats were randomly assigned to one of two treatment groups: conventional RF ablation (90 degrees C +/- 2, 5 minutes) followed by IV liposomal doxorubicin (5 mg per rabbit, 1 mg per rat) or RF ablation alone (n = 5, each). Coagulation diameter and interstitial doxorubicin concentration (tissues were homogenized in acid alcohol, with doxorubicin extracted for 24 hours at 5 degrees C and quantified with fluorimetry) were measured 48 hours after treatment and compared. Multivariate analysis of variance and subsequent pairwise t tests (alpha = .05, two-tailed test) were performed.


RESULTS
Data are means +/- standard errors of the mean. A larger diameter of tumor destruction was observed in canine sarcomas treated with RF ablation-liposomal doxorubicin (3.7 cm +/- 0.6) compared with that in tumors treated with RF ablation (2.3 cm +/- 0.1) or liposomal doxorubicin (0.0 cm +/- 0.0) alone (P < .01). A new finding was a completely necrotic red zone (1.6 cm +/- 0.7) surrounding the central RF ablation-induced white coagulation zone. Greater but nonuniform drug uptake was observed particularly in this red zone (77.0 ng/g +/- 18.2) compared with uptake in the central zone (15.1 ng/g +/- 3.2), peripheral area of untreated tumor (38.9 ng/g +/- 8.0), and tumors treated with liposomal doxorubicin alone (43.9 ng/g +/- 6.7 for all regions) (P < .01 for all individual comparisons). In experiment 2, use of combined therapy led to increased coagulation in all tissues (liver: 17.6 mm +/- 3.1, P = .03; kidney: 11.0 mm +/- 3.1, P = .03; muscle: 13.1 mm +/- 1.3, P < .01) compared with use of RF ablation alone (liver, 13.4 mm +/- 1.5; kidney, 7.9 mm +/- 0.7; muscle, 8.6 mm +/- 0.5). Combined therapy, as compared with liposomal doxorubicin therapy alone, was also associated with increased doxorubicin accumulation in liver, kidney, and muscle (1.56 microg/g +/- 0.34, 4.36 microg/g +/- 1.78, and 3.63 microg/g +/- 1.43, respectively, vs 1.00 microg/g +/- 0.18, 1.23 microg/g +/- 0.32, and 0.87 microg/g +/- 0.53, respectively) (P < or = .01 for all individual comparisons).


CONCLUSIONS
Use of RF ablation combined with liposomal doxorubicin facilitates increased tissue coagulation and interstitial doxorubicin accumulation in multiple tissues and tumor types and may be useful for treatment of large tumors and achieving an ablative margin within the untreated tissue surrounding RF ablation-treated tumors.
Ahmed
Muneeb
M
Department of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA.
Liu
Zhengjun
Z
Lukyanov
Anatoly N
AN
Signoretti
Sabina
S
Horkan
Clare
C
Monsky
Wayne L
WL
Torchilin
Vladimir P
VP
Goldberg
S Nahum
SN
D000818:Animals; D017115:Catheter Ablation; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004357:Drug Synergism; D045604:Extracellular Fluid / Q000378:metabolism; D015552:Injections, Intralesional; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D009336:Necrosis; D009368:Neoplasm Transplantation; D009378:Neoplasms, Multiple Primary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D014018:Tissue Distribution
D004317:Doxorubicin