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Tumor Ablation Enhancement by Combining Radiofrequency Ablation and Irreversible Electroporation: An In Vitro 3D Tumor Study

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Abstract

We hypothesized and demonstrated for the first time that significant tumor ablation enhancement can be achieved by combining radiofrequency ablation (RFA) and irreversible electroporation (IRE) using a 3D cervical cancer cell model. Three RFA (43, 50, and 60 °C for 2 min) and IRE protocols (350, 700, and 1050 V/cm) were used to study the combining effect in the 3D tumor cell model. The in vitro experiment showed that both RFA enhanced IRE and IRE enhanced RFA can lead to a significant increase in the size of the ablation zone compared to IRE and RFA alone. It was also noted that the sequence of applying ablation energy (RFA → RE or IRE → RFA) affected the efficacy of tumor ablation enhancement. The electrical conductivity of 3D tumor was found to be increased after preliminary RFA or IRE treatment. This increase in tumor conductivity may explain the enhancement of tumor ablation. Another explanation might be that there is repeat injury to the transitional zone of the first treatment by the second one. The promising results achieved in the study can provide us useful clues about the treatment of large tumors abutting large vessels or bile ducts.

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References

  1. Ahmed, M., C. L. Brace, F. T. Lee, Jr, and S. N. Goldberg. Principles of and advances in percutaneous ablation. Radiology 258:351–369, 2011.

    Article  PubMed  Google Scholar 

  2. Alba-Martínez, J., M. Trujillo, R. Blasco-Giménez, and E. Berjano. Could it be advantageous to tune the temperature controller during radiofrequency ablation? A feasibility study using theoretical models. Int. J. Hyperth. 27:539–548, 2011.

    Article  Google Scholar 

  3. Appelbaum, L., E. Ben-David, M. Faroja, Y. Nissenbaum, J. Sosna, and S. N. Goldberg. Irreversible electroporation ablation: creation of large-volume ablation zones in in vivo porcine liver with four-electrode arrays. Radiology 270:416–424, 2014.

    Article  PubMed  Google Scholar 

  4. Arena, C. B., C. S. Szot, P. A. Garcia, M. N. Rylander, and R. V. Davalos. A three-dimensional in vitro tumor platform for modeling therapeutic irreversible electroporation. Biophys. J. 103:2033–2042, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chinn, S. B., F. T. Lee, Jr, G. D. Kennedy, et al. Effect of vascular occlusion on radiofrequency ablation of the liver: results in a porcine model. Am. J. Roentgenol. 176:789–795, 2001.

    Article  CAS  Google Scholar 

  6. Chu, K. F., and D. E. Dupuy. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat. Rev. Cancer 14:199–208, 2014.

    Article  CAS  PubMed  Google Scholar 

  7. Clasen, S., D. Schmidt, A. Boss, et al. Multipolar radiofrequency ablation with internally cooled electrodes: experimental study in ex vivo bovine liver with mathematic modeling. Radiology 238:881–890, 2006.

    Article  PubMed  Google Scholar 

  8. Davalos, R. V., L. Mir, and B. Rubinsky. Tissue ablation with irreversible electroporation. Ann. Biomed. Eng. 33:223–231, 2005.

    Article  CAS  PubMed  Google Scholar 

  9. Edelblute, C. M., J. Hornef, N. I. Burcus, et al. Controllable moderate heating enhances the therapeutic efficacy of irreversible electroporation for pancreatic cancer. Sci. Rep. 7:11767, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fang, Z., B. Zhang, M. Moser, E. Zhang, and W. Zhang. Design of a novel electrode of radiofrequency ablation for large tumors: a finite element study. J. Eng. Sci. Med. Diagn. Ther. 1:011001, 2018.

    Article  Google Scholar 

  11. Faroja, M., M. Ahmed, L. Appelbaum, et al. Irreversible electroporation ablation: is all the damage nonthermal? Radiology 266:462–470, 2013.

    Article  PubMed  Google Scholar 

  12. Goldberg, S. N., M. Ahmed, G. S. Gazelle, et al. Radio-frequency thermal ablation with NaCl solution injection: effect of electrical conductivity on tissue heating and coagulation—phantom and porcine liver study. Radiology 219:157–165, 2001.

    Article  CAS  PubMed  Google Scholar 

  13. Goldberg, S. N., M. C. Stein, G. S. Gazelle, R. G. Sheiman, J. B. Kruskal, and M. E. Clouse. Percutaneous radiofrequency tissue ablation: optimization of pulsed-radiofrequency technique to increase coagulation necrosis. J. Vasc. Interv. Radiol. 10:907–916, 1999.

    Article  CAS  PubMed  Google Scholar 

  14. Haemmerich, D., D. J. Schutt, A. S. Wright, J. G. Webster, and D. M. Mahvi. Electrical conductivity measurement of excised human metastatic liver tumours before and after thermal ablation. Physiol. Meas. 30:459, 2009.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hendy, M. P., M. H. Recht, and R. E. Welling. Radiofrequency ablation of the porcine liver with complete hepatic vascular occlusion. Ann. Surg. Oncol. 9:594–598, 2002.

    Article  PubMed  Google Scholar 

  16. Hung, H. H., Y. Y. Chiou, C. Y. Hsia, et al. Survival rates are comparable after radiofrequency ablation or surgery in patients with small hepatocellular carcinomas. Clin. Gastroenterol. Hepatol. 9:79–86, 2011.

    Article  PubMed  Google Scholar 

  17. Ivey, J. W., E. L. Latouche, M. L. Richards, et al. Enhancing irreversible electroporation by manipulating cellular biophysics with a molecular adjuvant. Biophys. J. 113:472–480, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ivorra, A., B. Al-Sakere, B. Rubinsky, and L. M. Mir. In vivo electrical conductivity measurements during and after tumor electroporation: conductivity changes reflect the treatment outcome. Phys. Med. Biol. 54:5949, 2009.

    Article  PubMed  Google Scholar 

  19. Jiang, C., R. V. Davalos, and J. C. Bischof. A review of basic to clinical studies of irreversible electroporation therapy. IEEE Trans. Biomed. Eng. 62:4–20, 2015.

    Article  PubMed  Google Scholar 

  20. Jiang, C., Q. Shao, and J. Bischof. Pulse timing during irreversible electroporation achieves enhanced destruction in a hindlimb model of cancer. Ann. Biomed. Eng. 43:887–895, 2015.

    Article  PubMed  Google Scholar 

  21. Kunjachan, S., A. Detappe, R. Kumar, et al. Nanoparticle mediated tumor vascular disruption: a novel strategy in radiation therapy. Nano Lett. 15:7488–7496, 2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Laufer, S., A. Ivorra, V. E. Reuter, B. Rubinsky, and S. B. Solomon. Electrical impedance characterization of normal and cancerous human hepatic tissue. Physiol. Meas. 31:995, 2010.

    Article  PubMed  Google Scholar 

  23. Lencioni, R., L. Crocetti, D. Cioni, et al. Single-session percutaneous ethanol ablation of early-stage hepatocellular carcinoma with a multipronged injection needle: results of a pilot clinical study. J. Vasc. Interv. Radiol. 21:1533–1538, 2010.

    Article  PubMed  Google Scholar 

  24. Lu, D. S., S. S. Raman, P. Limanond, et al. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J. Vasc. Interv. Radiol. 14:1267–1274, 2003.

    Article  PubMed  Google Scholar 

  25. Neal, II, R. E., P. A. Garcia, J. L. Robertson, and R. V. Davalos. Experimental characterization and numerical modeling of tissue electrical conductivity during pulsed electric fields for irreversible electroporation treatment planning. IEEE Trans. Biomed. Eng. 59:1076–1085, 2012.

    Article  PubMed  Google Scholar 

  26. Pech, M., A. Janitzky, J. J. Wendler, et al. Irreversible electroporation of renal cell carcinoma: a first-in-man phase I clinical study. Cardiovasc. Interv. Radiol. 34:132–138, 2011.

    Article  Google Scholar 

  27. Peng, Z.-W., Y.-J. Zhang, M.-S. Chen, et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J. Clin. Oncol. 31:426–432, 2013.

    Article  PubMed  Google Scholar 

  28. Pillai, K., J. Akhter, T. C. Chua, et al. Heat sink effect on tumor ablation characteristics as observed in monopolar radiofrequency, bipolar radiofrequency, and microwave, using ex vivo calf liver model. Medicine 94:9, 2015.

    Article  Google Scholar 

  29. Rossmann, C., M. McCrackin, K. E. Armeson, and D. Haemmerich. Temperature sensitive liposomes combined with thermal ablation: effects of duration and timing of heating in mathematical models and in vivo. PLoS ONE 12:e0179131, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sakr, A. A., A. A. Saleh, A. A. A. Moeaty, and A. A. Moeaty. The combined effect of radiofrequency and ethanol ablation in the management of large hepatocellular carcinoma. Eur. J. Radiol. 54:418–425, 2005.

    Article  PubMed  Google Scholar 

  31. Sano, M. B., R. E. Fan, and L. Xing. Asymmetric waveforms decrease lethal thresholds in high frequency irreversible electroporation therapies. Sci. Rep. 7:40747, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shao, Q., F. Liu, C. Chung, et al. Physical and chemical enhancement of and adaptive resistance to irreversible electroporation of pancreatic cancer. Ann. Biomed. Eng. 46:25–36, 2017.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Swenson, C. E., D. Haemmerich, D. H. Maul, B. Knox, N. Ehrhart, and R. A. Reed. Increased duration of heating boosts local drug deposition during radiofrequency ablation in combination with thermally sensitive liposomes (ThermoDox) in a porcine model. PLoS ONE 10:e0139752, 2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Takahashi, H., B. Kahramangil, E. Kose, and E. Berber. A comparison of microwave thermosphere versus radiofrequency thermal ablation in the treatment of colorectal liver metastases. HPB 20:1157–1162, 2018.

    Article  PubMed  Google Scholar 

  35. Takaki, H., A. Nakatsuka, J. Uraki, et al. Renal cell carcinoma: radiofrequency ablation with a multiple-electrode switching system—a phase II clinical study. Radiology 267:285–292, 2013.

    Article  PubMed  Google Scholar 

  36. Trujillo, M., Q. Castellví, F. Burdío, et al. Can electroporation previous to radiofrequency hepatic ablation enlarge thermal lesion size? A feasibility study based on theoretical modelling and in vivo experiments. Int. J. Hyperth. 29:211–218, 2013.

    Article  Google Scholar 

  37. Watanabe, S., K. Kurokohchi, T. Masaki, et al. Enlargement of thermal ablation zone by the combination of ethanol injection and radiofrequency ablation in excised bovine liver. Int. J. Oncol. 24:279–284, 2004.

    PubMed  Google Scholar 

  38. Wendler, J., M. Porsch, S. Nitschke, et al. A prospective Phase 2a pilot study investigating focal percutaneous irreversible electroporation (IRE) ablation by NanoKnife in patients with localised renal cell carcinoma (RCC) with delayed interval tumour resection (IRENE trial). Contemp. Clin. Trials 43:10–19, 2015.

    Article  CAS  PubMed  Google Scholar 

  39. Wright, A. S., L. A. Sampson, T. F. Warner, D. M. Mahvi, J. Lee, and T. Fred. Radiofrequency versus microwave ablation in a hepatic porcine model. Radiology 236:132–139, 2005.

    Article  PubMed  Google Scholar 

  40. Yang, Y., M. A. Moser, E. Zhang, W. Zhang, and B. Zhang. Development of a statistical model for cervical cancer cell death with irreversible electroporation in vitro. PLoS ONE 13:e0195561, 2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yao, C., Y. Lv, Y. Zhao, S. Dong, H. Liu, and J. Ma. Synergistic combinations of short high-voltage pulses and long low-voltage pulses enhance irreversible electroporation efficacy. Sci. Rep. 7:15123, 2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang, B., M. A. Moser, E. M. Zhang, Y. Luo, C. Liu, and W. Zhang. A review of radiofrequency ablation: large target tissue necrosis and mathematical modelling. Phys. Med. 32:961–971, 2016.

    Article  PubMed  Google Scholar 

  43. Zhang, B., M. A. Moser, E. M. Zhang, Y. Luo, and W. Zhang. A new approach to feedback control of radiofrequency ablation systems for large coagulation zones. Int. J. Hyperth. 33:367–377, 2017.

    Article  CAS  Google Scholar 

  44. Zhao, Y., S. Bhonsle, S. Dong, et al. Characterization of conductivity changes during high-frequency irreversible electroporation for treatment planning. IEEE Trans. Biomed. Eng. 2017. https://doi.org/10.1109/TBME.2017.2787038.

    Article  PubMed  Google Scholar 

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Acknowledgments

This article was supported by 111 Project (D18003) of China. The first author (BZ) received financial support from National Natural Science Foundation of China (Grant No. 81801795), and the last author (WZ) was supported by National Sciences and Engineering Research Council of Canada through Discovery Grant (Grant No. 417649).

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Authors and Affiliations

  1. Tumor Ablation Group, Biomedical Science and Technology Research Center, School of Mechatronic Engineering and Automation, Shanghai University, 99 Shangda Road, Baoshan, Shanghai, 200444, China

    Bing Zhang & Wenjun Zhang

  2. School of Mechanical and Power Engineering, East China University of Science and Technology, Shanghai, 200237, China

    Yongji Yang & Lujia Ding

  3. Department of Surgery, University of Saskatchewan, Saskatoon, SK, S7N 0W8, Canada

    Michael A. J. Moser

  4. Division of Vascular & Interventional Radiology, Department of Medical Imaging, University of Toronto, Toronto, ON, M5T 1W7, Canada

    Edwin M. Zhang

  5. Department of Mechanical Engineering, University of Saskatchewan, Saskatoon, SK, S7N 5A9, Canada

    Wenjun Zhang

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  1. Bing Zhang
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  3. Lujia Ding
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  4. Michael A. J. Moser
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Correspondence to Bing Zhang.

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Associate Editor Michael Gower oversaw the review of this article.

Appendix

Appendix

See Fig. A1.

Figure A1
figure 8

Respective X–Y images of ablation zone along Z axis for (a) Protocol 12 and (b) Protocol 23.

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Zhang, B., Yang, Y., Ding, L. et al. Tumor Ablation Enhancement by Combining Radiofrequency Ablation and Irreversible Electroporation: An In Vitro 3D Tumor Study. Ann Biomed Eng 47, 694–705 (2019). https://doi.org/10.1007/s10439-018-02185-x

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  • DOI: https://doi.org/10.1007/s10439-018-02185-x

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