Combination of Radiofrequency Ablation with Antiangiogenic Therapy for Tumor Ablation Efficacy: Study in Mice

Purpose: To prospectively determine whether modulation of renal cell carcinoma (RCC) tumor microvasculature by using the antiangiogenic drug sorafenib could increase the extent of radiofrequency (RF)-induced coagulation in an RCC animal tumor model.

Materials and Methods: All investigations received animal care and utilization committee approval. RCC (human 786-0) was implanted subcutaneously into 27 nude mice. Sixteen mice were randomly assigned into one of three groups when tumors reached 12 mm in diameter: Six mice received 80 mg of sorafenib, a Raf kinase and vascular endothelial growth factor receptor inhibitor, per kilogram of body weight; five mice received 20 mg/kg sorafenib; and five mice received a control carrier vehicle alone. Antiangiogenic therapy was administered until a mean 1-mm reduction in tumor diameter was noted in one group. These 16 mice received a standard dose of RF ablation. Ablation size was visualized by using 2% triphenyltetrazolium chloride. An additional 11 tumors in mice treated with sorafenib alone were stained with CD31 to determine microvascular density (MVD). Resultant size of ablation was compared among groups; statistical significance was determined with analysis of variance. Differences in MVD were assessed with the Kruskal-Wallis test.

Results: Over the 9-day administration of sorafenib, mean tumor size in the control group reached 15.2 mm ± 0.8 (standard deviation). Tumors in mice receiving 20 mg/kg and 80 mg/kg sorafenib measured 12.2 mm ± 0.6 and 11.1 mm ± 0.5, respectively (P < .05). RF-induced coagulation diameter was 8.5 mm ± 0.4 and 11.1 mm ± 0.3 in the 20 mg/kg and 80 mg/kg sorafenib groups, respectively, but was only 6.7 mm ± 0.7 for animals that underwent RF ablation alone (P < .01). Likewise, significant decreases in MVD were noted in the sorafenib-treated animals (P < .01).

Conclusion: Treatment of RCC in nude mice with the antiangiogenic agent sorafenib resulted in markedly decreased MVD and significantly larger zones of RF-induced coagulation necrosis.

© RSNA, 2007

References

  • 1 Nahum Goldberg S, Dupuy DE. Image-guided radiofrequency tumor ablation: challenges and opportunities—part I. J Vasc Interv Radiol 2001; 12: 1021–1032. Crossref, MedlineGoogle Scholar
  • 2 Dupuy DE, Goldberg SN. Image-guided radiofrequency tumor ablation: challenges and opportunities—part II. J Vasc Interv Radiol 2001;12:1135–1148. Crossref, MedlineGoogle Scholar
  • 3 Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999;230:1–8. Crossref, MedlineGoogle Scholar
  • 4 Solbiati L, Livraghi T, Goldberg SN, et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 2001;221(1):159–166. LinkGoogle Scholar
  • 5 Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005;234(3):961–967. LinkGoogle Scholar
  • 6 Tateishi R, Shiina S, Teratani T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma: an analysis of 1000 cases. Cancer 2005;103(6):1201–1209. Crossref, MedlineGoogle Scholar
  • 7 Livraghi T, Meloni F, Goldberg SN, Lazzaroni S, Solbiati L, Gazelle GS. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology 2000;214:761–768. LinkGoogle Scholar
  • 8 Hines-Peralta A, Goldberg SN. Review of radiofrequency ablation for renal cell carcinoma. Clin Cancer Res 2004;10(18 pt 2):6328S–6334S. Crossref, MedlineGoogle Scholar
  • 9 Jeffrey SS, Birdwell RL, Ikeda DM, et al. Radiofrequency ablation of breast cancer: first report of an emerging technology. Arch Surg 1999;134:1064–1068. Crossref, MedlineGoogle Scholar
  • 10 Dupuy DE, Safran H, Mayo-Smith WW, Goldberg SN. Radiofrequency ablation of painful osseous metastases [abstr]. Radiology 1998;209(P):389. Google Scholar
  • 11 Sewell PE, Vance RB, Wang YD. Assessing radiofrequency ablation of non-small cell lung cancer with positron emission tomography [abstr]. Radiology 2000;217(P):334. Google Scholar
  • 12 Lu DS, Yu NC, Raman SS, et al. Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology 2005;234(3):954–960. LinkGoogle Scholar
  • 13 Chang I, Mikityansky I, Wray-Cahen D, Pritchard WF, Karanian JW, Wood BJ. Effects of perfusion on radiofrequency ablation in swine kidneys. Radiology 2004;231(2):500–505. LinkGoogle Scholar
  • 14 Goldberg SN, Hahn PF, Tanabe KK, et al. Percutaneous radiofrequency tissue ablation: does perfusion-mediated tissue cooling limit coagulation necrosis? J Vasc Interv Radiol 1998;9(1):101–111. Crossref, MedlineGoogle Scholar
  • 15 Yamasaki T, Kurokawa F, Shirahashi H, Kusano N, Hironaka K, Okita K. Percutaneous radiofrequency ablation therapy for patients with hepatocellular carcinoma during occlusion of hepatic blood flow: comparison with standard percutaneous radiofrequency ablation therapy. Cancer 2002;95(11):2353–2360. Crossref, MedlineGoogle Scholar
  • 16 Shen P, Fleming S, Westcott C, Challa V. Laparoscopic radiofrequency ablation of the liver in proximity to major vasculature: effect of the Pringle maneuver. J Surg Oncol 2003;83(1):36–41. Crossref, MedlineGoogle Scholar
  • 17 Hines-Peralta A, Sukhatme V, Regan M, Signoretti S, Liu ZJ, Goldberg SN. Improved tumor destruction with arsenic trioxide and radiofrequency ablation in three animal models. Radiology 2006;240:82–89. LinkGoogle Scholar
  • 18 Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–1186. Crossref, MedlineGoogle Scholar
  • 19 Puglisi F, Scalone S, DiLauro V. Angiogenesis and tumor growth. N Engl J Med 1996;334(14):921. Google Scholar
  • 20 Ratain MJ, Eisen T, Stadler WM, et al. Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) [abstr]. J Clin Oncol 2005;23:388s. Google Scholar
  • 21 Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma [abstr]. J Clin Oncol 2005;23:380s. Google Scholar
  • 22 Horkan C, Ahmed M, Liu Z, et al. Radiofrequency ablation: effect of pharmacologic modulation of hepatic and renal blood flow on coagulation diameter in a VX2 tumor model. J Vasc Interv Radiol 2004;15(3):269–274. Crossref, MedlineGoogle Scholar
  • 23 Liszczak TM, Hedley-Whyte ET, Adams JF, et al. Limitations of tetrazolium salts in delineating infarcted brain. Acta Neuropathol (Berl) 1984;65:150–157. Crossref, MedlineGoogle Scholar
  • 24 Goldberg SN, Gazelle GS, Compton CC, Mueller PR, Tanabe KK. Treatment of intrahepatic malignancy with radiofrequency ablation: radiologic-pathologic correlation. Cancer 2000;88(11):2452–2463. Crossref, MedlineGoogle Scholar
  • 25 Walther MM, Alexander RB, Weiss GH, et al. Cytoreductive surgery prior to interleukin-2-based therapy in patients with metastatic renal cell carcinoma. Urology 1993;42:250–257. Crossref, MedlineGoogle Scholar
  • 26 Montie JE, Stewart BH, Straffon RA, Banowsky LH, Hewitt CB, Montague DK. The role of adjunctive nephrectomy in patients with metastatic renal cell carcinoma. J Urol 1977;117:272–275. Crossref, MedlineGoogle Scholar
  • 27 Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol 2000;174:323–331. Crossref, MedlineGoogle Scholar
  • 28 Lu DS, Raman SS, Vodopich DJ, Wang M, Sayre J, Lassman C. Effect of vessel size on creation of hepatic radiofrequency lesions in pigs: assessment of the “heat sink” effect. AJR Am J Roentgenol 2002;178(1):47–51. Crossref, MedlineGoogle Scholar
  • 29 De Bazelaire C, Rofsky NM, Duhamel G, Michaelson MD, George D, Alsop DC. Arterial spin labeling blood flow magnetic resonance imaging for the characterization of metastatic renal cell carcinoma. Acad Radiol 2005;12(3):347–357. Crossref, MedlineGoogle Scholar
  • 30 Hakimé A, Peddi H, Hines-Peralta AU, et al. CT perfusion for determination of pharmacologically mediated blood flow changes in an animal tumor model. Radiology 2007;243(3):712–719. LinkGoogle Scholar

Article History

Published in print: 2007