Objective: To obtain complete prostatic
cell death in the treatment of early stage prostate cancer by High Intensity
Focused Ultrasound (HIFU) therapy, we use Degarelix (GnRH antagonist) twice
simultaneously. Patients and Methods: The first Degarelix subcutaneous
injection was made two weeks before HIFU therapy, and second Degarelix was
applied two weeks after the HIFU therapy. No additional maintenance Degarelix
was used. To confirm the apoptosis induced by Degarelix, specimens obtained by
transurethral resection simultaneously on HIFU were stained with caspase 3 and
TUNEL. PSA was monitored every three months after this combination therapy as
long as two years. These PSA values were compared with those who previously
treated with HIFU without Degarelix. Results: Nine T1cN0M0 prostate cancer
patients were enrolled to “HIFU + Degarelix” therapy. Pre treatment mean PSA
level was 6.11 ± 1.83 ng/ml (SD), and PSA 3 months after the treatment was 0.02
± 0.02. These low PSA levels continued thereafter (0.16 ng/ml ± 0.19 at 24
months). The mean pretreatment PSA level of the 34 patients underwent HIFU
without Degarelix was 11.07 ± 13.9 ng/ml, 3 months post HIFU was 1.68 ± 3.04,
(2.80 ± 3.97 at 24 months). Caspase 3 and TUNEL were positive on the glandular
cells in TUR specimens of “HIFU + Degarelix” patients, suggesting Degarelix
induced apoptosis. Conclusion: Although the number of our patients was small,
the results of “Short course Degarelix + HIFU” would be promising for better
long-term outcome than HIFU mono-therapy.
References
[1]
Fitzmaurice, C., Dicker, D., Pain, A., Hamavid, H., Moradi-Lakeh, M., MacIntyre, M.F., et al. (2015) The Global Burden of Cancer 2013. JAMA Oncology, 1, 505-527. http://dx.doi.org/10.1001/jamaoncol.2015.0735
[2]
Schroder, F.H., Hugosson, J., Roobol, M.J., Tammela, T.L., Ciatto, S., Nelen, V., et al. (2009) Screening and Prostate-cancer Mortality in a Randomized European Study. The New England Journal of Medicine, 360, 1320-1328. http://dx.doi.org/10.1056/NEJMoa0810084
[3]
Loeb, S., Bjurlin, M.A., Nicholson, J., Tammela, T.L., Penson, D.F., Carter, H.B., et al. (2014) Overdiagnosis and Overtreatment of Prostate Cancer. European Urology, 65, 1046-1055. http://dx.doi.org/10.1016/j.eururo.2013.12.062
[4]
Eggener, S. (2010) Ablative Focal Therapy for Primary Treatment of Prostate Cancer. AUA Update Series, 29, 22-32.
[5]
Blana, S., Brown, S.C.W., Chaussy, C., Conti, G.N., Eastham, J.A., Ganzer, R., et al. (2009) High-Intensity Focused Ultrasound for Prostate Cancer: Comparative Definitions of Biochemical Failure. BJU International, 104, 1058-1062. http://dx.doi.org/10.1111/j.1464-410X.2009.08518.x
[6]
Crouzet, S., Chapelon, J.Y., Rouvière, O., Mege-Lechevallier, F., Colombel, M., Tonoli-Catez, H., et al. (2014) Whole-gland Ablation of Localized Prostate Cancer with High-Intensity Focused Ultrasound: Oncologic Outcomes and Morbidity in 1002 Patients. European Urology, 65, 907-914. http://dx.doi.org/10.1016/j.eururo.2013.04.039
[7]
Akakura, K., Bruchovsky, N., Goldenberg, S.J., Rennie, P.S., Buckley, A.R. and Sullivan, L.D. (1993) Effects of Intermittent Androgen Suppression on Androgen-Dependent Tumors. Cancer, 71, 2782-2790. http://dx.doi.org/10.1002/1097-0142(19930501)71:9<2782::AID-CNCR2820710916>3.0.CO;2-Z
[8]
Sun, Y., Wang, B.E., Leong, K.G., Yue, P., Li, L., Jhunjhunwala, S., et al. (2011) Androgen Deprivation Causes Epithelial-Mesenchymal Transition in the Prostate: Implication for Androgen-Deprivation Therapy. Cancer Research, 72, 527-536. http://dx.doi.org/10.1158/0008-5472.CAN-11-3004
[9]
Li, P., Yang, R. and Gao, W.Q. (2014) Contribution of Epithelial Mesenchymal Transition and Cancer Stem Cells to the Development of Castration Resistance of Prostate Cancer. Molecular Cancer, 13, 55. http://dx.doi.org/10.1186/1476-4598-13-55
[10]
Gavrieli, Y., Sherman, Y. and Ben-Sasson, S.A. (1992) Identification of Programmed Cell Death in Situ via Specific Labeling of Nuclear DNA Fragmentation. The Journal of Cell Biology, 119, 493-501. http://dx.doi.org/10.1083/jcb.119.3.493
[11]
Nicholson, D.W. and Thornberry, A. (1997) Caspases; Killer Proteases. Trends in Biochemical Sciences, 22, 299-306. http://dx.doi.org/10.1016/S0968-0004(97)01085-2
[12]
Cuello, A.C., Ed. (1993) Immunohistochemistry II. John Wiley & Sons, Ltd., New York.
[13]
Haar, G.T. and Coussios, C. (2007) High Intensity Focused Ultrasound: Physical Principles and Devices. International Journal of Hyperthermia, 23, 89-104. http://dx.doi.org/10.1080/02656730601186138
[14]
Cordeiro, E.R., Cathelineau, X., Thuroff, S., Marberger, M., Crouzet, S. and de la Rosette, J.J.M.C.H. (2012) High-Intensity Focused Ultrasound (HIFU) for Definitive Treatment of Prostate Cancer. BJU International, 110, 1228-1242. http://dx.doi.org/10.1111/j.1464-410X.2012.11262.x
[15]
Shoji, S., Uchida, T., Nakamoto, M., Kim, H., Abreu, A.D.C., Leslie, S., et al. (2013) Prostate Swelling and Shift During High Intensity Focused Ultrasound: Implication for Targeted Focal Therapy. The Journal of Urology, 190, 1224-1232. http://dx.doi.org/10.1016/j.juro.2013.03.116
[16]
Bruchovsky, N., Rennie, P.S., Coldman, A.J., Goldenberg, S.L., To, M. and Lawson, D. (1990) Effects of Androgen Withdrawal on the Stem Cell Composition of the Shionogi Carcinoma. Cancer Research, 50, 2275-2282.
[17]
Shore, N.D. (2013) Experience with Degarelix in the Treatment of Prostate Cancer. Therapeutic Advances in Urology, 5, 11-24. http://dx.doi.org/10.1177/1756287212461048