Abstract

Case Presentation

A Novel Strategy to Improve Radiotherapy Effectiveness: First-in-Human MR-guided Focused Ultrasound-Stimulated Microbubbles (MRgFUS+MB) Radiation Enhancement Treatment

Daniel Moore-Palhares, Murtuza Saifuddin, Ling Ho, Lin Lu, Archya Dasgupta, Martin Smoragiewicz, Irene Karam, Andrew Bayley, Arjun Sahgal, Ian Poon and Gregory J Czarnota*

Published: 24 August, 2023 | Volume 7 - Issue 2 | Pages: 047-051

Background and aim: Preclinical in vitro and in vivo experiments suggest that radiation-induced tumour cell death can be enhanced 10- to 40-fold when combined with focused-ultrasound (FUS)-stimulated microbubbles (MB). The acoustic exposure of MB in the tumour volume causes vasculature perturbation, activation of the acid sphingomyelinase (ASMase) ceramide pathway, and resultant endothelial cell apoptosis. When the tumour is subsequently treated with radiation, there is increased endothelial cell death and anoxic tumour killing. Here we describe a first-in-human experience treating patients with magnetic resonance (MR)-guided FUS-stimulated MB (MRgFUS+MB) radiation enhancement.
Case presentation: A head and neck cancer patient with recurrent disease underwent radiotherapy for 5 separate sites of locoregional disease followed by systemic therapy. The first consisted of a course of 45 Gy in 5 fractions alone, the second of 30 Gy in 5 fractions with hyperthermia, and the three others of 20-30 Gy in 5 fractions along with MRgFUS+MB treatment. The treatment methodology used an MR-coupled FUS-device operating at 500 KHz and 540 kPa peak negative pressure with an insonification time of 750 ms spread over 5 minutes to stimulate intravenously administered MB within tumour target. All sites treated with stimulated MB had a complete radiological response, and subsequently, the patient’s other cutaneous metastatic disease disappeared. The patient has been under surveillance for over two years without active treatment or disease progression.
Discussion: MRgFUS+MB was well-tolerated with no reported treatment-related adverse events, which can be attributed to the capability of FUS to selectively stimulate MB within the tumour volume while sparing the surrounding normal tissue. Sustained local control at all target sites aligns with earlier preclinical findings suggesting the radiation enhancement potential of FUS+MB.
Conclusion: MRgFUS+MB represents a novel and promising therapy for enhancing radiation efficacy and improving therapeutic index with potential improvements in disease control.

Read Full Article HTML DOI: 10.29328/journal.jro.1001052 Cite this Article Read Full Article PDF

Keywords:

Microbubbles; Radiation-sensitizing agents; Magnetic resonance imaging; Focused ultrasound; Ultrasonography; Head and neck neoplasms

References

  1. Lacas B, Carmel A, Landais C, Wong SJ, Licitra L, Tobias JS, Burtness B, Ghi MG, Cohen EEW, Grau C, Wolf G, Hitt R, Corvò R, Budach V, Kumar S, Laskar SG, Mazeron JJ, Zhong LP, Dobrowsky W, Ghadjar P, Fallai C, Zakotnik B, Sharma A, Bensadoun RJ, Ruo Redda MG, Racadot S, Fountzilas G, Brizel D, Rovea P, Argiris A, Nagy ZT, Lee JW, Fortpied C, Harris J, Bourhis J, Aupérin A, Blanchard P, Pignon JP; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiother Oncol. 2021 Mar;156:281-293. doi: 10.1016/j.radonc.2021.01.013. Epub 2021 Jan 27. PMID: 33515668; PMCID: PMC8386522.
  2. Machiels JP, René Leemans C, Golusinski W, Grau C, Licitra L, Gregoire V; EHNS Executive Board. Electronic address: secretariat@ehns.org; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org; ESTRO Executive Board. Electronic address: info@estro.org. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Nov;31(11):1462-1475. doi: 10.1016/j.annonc.2020.07.011. Epub 2020 Oct 23. PMID: 33239190.
  3. Bollen H, van der Veen J, Laenen A, Nuyts S. Recurrence Patterns After IMRT/VMAT in Head and Neck Cancer. Front Oncol. 2021 Sep 16;11:720052. doi: 10.3389/fonc.2021.720052. PMID: 34604056; PMCID: PMC8483718.
  4. Czarnota GJ. Ultrasound-stimulated microbubble enhancement of radiation response. Biol Chem. 2015 Jun;396(6-7):645-57. doi: 10.1515/hsz-2014-0297. PMID: 25741736.
  5. El Kaffas A, Al-Mahrouki A, Hashim A, Law N, Giles A, Czarnota GJ. Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses. J Natl Cancer Inst. 2018 Sep 1;110(9):1009-1018. doi: 10.1093/jnci/djy011. PMID: 29506145; PMCID: PMC6136928.
  6. Sharma D, Leong KX, Czarnota GJ. Application of Ultrasound Combined with Microbubbles for Cancer Therapy. Int J Mol Sci. 2022 Apr 15;23(8):4393. doi: 10.3390/ijms23084393. PMID: 35457210; PMCID: PMC9026557.
  7. Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C, Kolesnick R. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science. 2001 Jul 13;293(5528):293-7. doi: 10.1126/science.1060191. PMID: 11452123.
  8. Czarnota GJ, Karshafian R, Burns PN, Wong S, Al Mahrouki A, Lee JW, Caissie A, Tran W, Kim C, Furukawa M, Wong E, Giles A. Tumor radiation response enhancement by acoustical stimulation of the vasculature. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):E2033-41. doi: 10.1073/pnas.1200053109. Epub 2012 Jul 9. PMID: 22778441; PMCID: PMC3409730.
  9. Lai P, Tarapacki C, Tran WT, El Kaffas A, Lee J, Hupple C, Iradji S, Giles A, Al-Mahrouki A, Czarnota GJ. Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo. Oncoscience. 2016 Mar 24;3(3-4):98-108. doi: 10.18632/oncoscience.299. Erratum in: Oncoscience. 2017 Jan 30;4(1-2):14. PMID: 27226983; PMCID: PMC4872648.
  10. Tran WT, Iradji S, Sofroni E, Giles A, Eddy D, Czarnota GJ. Microbubble and ultrasound radioenhancement of bladder cancer. Br J Cancer. 2012 Jul 24;107(3):469-76. doi: 10.1038/bjc.2012.279. Epub 2012 Jul 12. PMID: 22790798; PMCID: PMC3405216.
  11. Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, Wilson S, Fane L, Herzog CA, Zoghbi WA, Taylor R, Farrar M, Chaudhry FA, Porter TR, Irani W, Lang RM. The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr. 2008 Nov;21(11):1202-6. doi: 10.1016/j.echo.2008.07.019. Epub 2008 Oct 10. PMID: 18848430.
  12. Weiss RJ, Ahmad M, Villanueva F, Schmitz S, Bhat G, Hibberd MG, Main ML; CaRES Investigators. CaRES (Contrast Echocardiography Registry for Safety Surveillance): a prospective multicenter study to evaluate the safety of the ultrasound contrast agent definity in clinical practice. J Am Soc Echocardiogr. 2012 Jul;25(7):790-5. doi: 10.1016/j.echo.2012.04.002. Epub 2012 May 3. PMID: 22560734.
  13. Arina A, Gutiontov SI, Weichselbaum RR. Radiotherapy and Immunotherapy for Cancer: From "Systemic" to "Multisite". Clin Cancer Res. 2020 Jun 15;26(12):2777-2782. doi: 10.1158/1078-0432.CCR-19-2034. Epub 2020 Feb 11. PMID: 32047000.
  14. Wu J, Waxman DJ. Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy. Cancer Lett. 2018 Apr 10;419:210-221. doi: 10.1016/j.canlet.2018.01.050. PMID: 29414305; PMCID: PMC5818299.
  15. Liu S, Zhang Y, Liu Y, Wang W, Gao S, Yuan W, Sun Z, Liu L, Wang C. Ultrasound-targeted microbubble destruction remodels tumour microenvironment to improve immunotherapeutic effect. Br J Cancer. 2023 Mar;128(5):715-725. doi: 10.1038/s41416-022-02076-y. Epub 2022 Dec 3. PMID: 36463323; PMCID: PMC9977958.

Figures:

Figure 1

Figure 1

Figure 1

Figure 2

Figure 1

Figure 3

Similar Articles

Recently Viewed

Read More

Most Viewed

Read More

Help ?