Tuesday, April 28, 2015

Historical Contribution: 1966: Gibbons, Transurethral Freezing of the Bladder


1966
Gibbons RP. Transurethral Freezing of the Bladder: An Experimental Study. J Urol. 1966. 95;33-44.

 

Presented at the Urological Research Forum at the annual American Urological Association in New Orleans, 1965, Dr. Robert Gibbons presented early experiments to treat non-invasive urothelial cancers of the bladder. The proposed hypothesis was that by circumferentially destroying the mucosa of the bladder, the risk of subsequent, recurrent non-invasive cancers could be eliminated. Therefore Gibbons set out to find an acceptable freezing material and device to deliver a treatment that could treat these non-invasive bladder cancers.

 

Using a specially designed transurethral cooling device, Gibbons was able to deliver coolant to the entire surface of the bladder – effectively destroying the urothelial layer. 



The experiments were carried out in 30 dogs, and anatomic and pathological evaluation was carried out of the bladders at varying time points following treatment. By carefully tuning the cooling apparatus, Gibbons was able to achieve greater than 75% mucosal slough in many of the experiments. Importantly, Gibbons was never able to achieve 100% mucosal destruction, nor could he create reproducible outcomes by standardizing the coolant and methods to cool the bladder. Anatomic examination demonstrated reduced bladder capacity, new onset hydronephrosis and abdominal adhesions in many animals. Pathological evaluation demonstrated involvement of the submucosa in most specimens and often noticed full-thickness necrosis of the bladder wall in a number of cases. Unfortunately, this corresponded to peritoneal infections and death in a number of the experiments.

 

While this experiment could be considered a failure, this was an outstanding attempt to treat non-invasive bladder cancers. In 1965, there was no BCG or other intravesical treatment for the management of non-invasive urothelial cancers. Thermal ablation, or "freezing" of cancers was en vogue and being attempted in gastric, esophageal, retinal, brain and kidney cancers.

 

Visit the Centennial Website or click here to see more about the first 100 years at the Brady.

 


HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years.  As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years.  In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field.  We hope you enjoy! 

Wednesday, April 22, 2015

Is Testosterone Replacement Therapy "Feeding the Fire" of Prostate Cancer?


Testosterone replacement therapy (TRT) is the administration of testosterone to men with abnormally low testosterone, termed hypogonadism, or "low T," Men with symptoms of low testosterone, can often benefit from TRT. Common symptoms of hypogonadism in post-pubertal men commonly include decreased muscle mass, decreased energy, depressed mood, decreased libido, decreased spontaneous erections, and erectile dysfunction [Wang et al., 2008, Basaria, 2014].

While TRT has been used for decades the last decade has seen a dramatic increase in the use of TRT. The percentage of men in the Unites States over 40 years of age prescribed TRT increased from less than 1% in 2001 to nearly 3% in 2011 [Baillargeon et al., 2013]. The increase in TRT and lack of data from large, long term randomized controlled trials (RCT) has raised concern for unrecognized adverse health risks, including potential increases in cardiovascular disease and prostate cancer (PC).

Changes in androgen use over time. From Baillargeon et al., 2013.

There is large body of both historic and modern data supporting a role for androgens in PC pathogenesis and progression.

In 1941, Huggins and Hodges proposed that PC growth was driven by androgens, after observing benefits of castration in PC patients [Huggins et al., 1941]. Current laboratory data demonstrate that many PC cell lines depend on testosterone for growth and spread.  [Kyprianou et al., 1990, Webber et al., 1996, Schwab et al., 2000]. In animal models, testosterone promotes PC tumor growth [Bladou et al., 1996, Ahmad et al., 2008].

The data supporting the androgen hypothesis has led to the dogma that TRT in PC patients is like "feeding the fire." Historically, there is data supporting this concept. In 1982 Fowler et al. reported on 52 men with metastatic PC patients who recieved testosterone. 38% of men had elevations in prostatic acid phosphatase (a blood test used to monitor PC), 2 men had measurable metastatic progression, and ther were 4 deaths [Fowler et al., 1982]. Importantly, these patients had advanced disease, and many had prior androgen deprivation [Fowler et al., 1982]. Thus, it would not be appropriate to apply these observations to men with clinically localized disease who receive early primary treatment and PSA monitoring.

 

There is currently no reliable data indicating an increase in PC in men without PC undergoing TRT.

The majority of studies on TRT and PC are small, and to date, there have been no prospective studies on TRT with sufficient patient numbers to determine increased PC risk. By one estimate, 6,000 patients receiving 5 years of TRT would be needed to detect a 30% increase in PC incidence [Bhasin et al., 2003]. In a systematic review of 40 prospective studies, there was no study which demonstrated an association between TRT and PC risk in men without prior PC. In addition, a meta-analysis of 19 studies, there was no significant increase in PC or significant PSA increases necessitating prostate biopsy. [Calof et al., 2005].

 

TRT in patients with localized PC appears safe, based on limited data

Using Medicare data, Kaplan and colleagues reported on 149,354 men, including 1,181 men who received TRT after a diagnosis with PC. Overall, TRT was not associated with PC deaths [Kaplan et al., 2014]. Similarly, Pastuszak and colleagues reported on 103 men who after prostatectomy were treated with TRT. There was an overall increase serum PSA, but no evidence of increased cancer recurrence over 36 months [Pastuszak et al., 2013]. In a smaller study, Morgentaler et al. examined 13 patients with untreated PC, enrolled in an active surveillence program and receiving TRT. After a median follow-up of 2.5 years, 2 men had worse pathology on subsequent biopsy, but no cases of disease or PSA progression were seen [Morgentaler et al., 2011].

 

Summary

Overall, there remains no clear answer to the question "Does testosterone promote prostate cancer development in humans?" Thus, TRT in men with prostate cancer remains controversial. There is clear evidence that androgens can promote PC in animal models. It is clear that the influence of testosterone on PC disease progression is of paramount importance to both patients and providers as they weight the potential benefits of TRT. Currently, there is a growing amount of evidence that TRT is safe in well-selected men with clinically localized PC. However, these results are based on TRT in a small number of patients. Furthermore, the heterogeneity in PC progression and aggressiveness may give rise to heterogeneity in the responsiveness of tumors to TRT. Thus, until the results of future RCTs are available, TRT should only be offered to select patients who are carefully monitored and well-informed about the potential risks and benefits.

 

This blog was written by Jason E. Michaud M.D., Ph.D., urology resident at the Brady Urological Institute, currently in his laboratory research year.

 


 





Ahmad, I., Sansom, O.J., and Leung, H.Y. (2008) Advances in Mouse Models of Prostate Cancer. Expert Rev Mol Med 10: e16.
Al-Khazaali, A., Arora, R., and Muttar, S. (2015) Controversial Effects of Exogenous Testosterone on Cardiovascular Diseases. Am J Ther:
Andriole, G., Bruchovsky, N., Chung, L.W., Matsumoto, A.M., Rittmaster, R., Roehrborn, C. et al. (2004) Dihydrotestosterone and the Prostate: The Scientific Rationale for 5alpha-Reductase Inhibitors in the Treatment of Benign Prostatic Hyperplasia. J Urol 172: 1399-1403.
Andriole, G.L., Crawford, E.D., Grubb, R.L., Buys, S.S., Chia, D., Church, T.R. et al. (2009) Mortality Results from a Randomized Prostate-Cancer Screening Trial. New England Journal of Medicine 360: 1310-1319.
Araujo, A.B., O'donnell, A.B., Brambilla, D.J., Simpson, W.B., Longcope, C., Matsumoto, A.M. et al. (2004) Prevalence and Incidence of Androgen Deficiency in Middle-Aged and Older Men: Estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 89: 5920-5926.
Baillargeon, J., Urban, R.J., Ottenbacher, K.J., Pierson, K.S., and Goodwin, J.S. (2013) Trends in Androgen Prescribing in the United States, 2001 to 2011. JAMA Intern Med 173: 1465-1466.
Basaria, S. (2014) Male Hypogonadism. Lancet 383: 1250-1263.
Bhasin, S., Singh, A.B., Mac, R.P., Carter, B., Lee, M.I., and Cunningham, G.R. (2003) Managing the Risks of Prostate Disease During Testosterone Replacement Therapy in Older Men: Recommendations for a Standardized Monitoring Plan. J Androl 24: 299-311.
Bladou, F., Vessella, R.L., Buhler, K.R., Ellis, W.J., True, L.D., and Lange, P.H. (1996) Cell Proliferation and Apoptosis During Prostatic Tumor Xenograft Involution and Regrowth after Castration. Int J Cancer 67: 785-790.
Botelho, F., Pina, F., Figueiredo, L., Cruz, F., and Lunet, N. (2012) Does Baseline Total Testosterone Improve the Yielding of Prostate Cancer Screening? Eur J Cancer 48: 1657-1663.
Bremner, W.J., Vitiello, M.V., and Prinz, P.N. (1983) Loss of Circadian Rhythmicity in Blood Testosterone Levels with Aging in Normal Men. J Clin Endocrinol Metab 56: 1278-1281.
Calof, O.M., Singh, A.B., Lee, M.L., Kenny, A.M., Urban, R.J., Tenover, J.L. et al. (2005) Adverse Events Associated with Testosterone Replacement in Middle-Aged and Older Men: A Meta-Analysis of Randomized, Placebo-Controlled Trials. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 60: 1451-1457.
D'amico, A.V., Moul, J.W., Carroll, P.R., Sun, L., Lubeck, D., and Chen, M.H. (2003) Surrogate End Point for Prostate Cancer-Specific Mortality after Radical Prostatectomy or Radiation Therapy. J Natl Cancer Inst 95: 1376-1383.
Dai, B., Qu, Y., Kong, Y., Ye, D., Yao, X., Zhang, S. et al. (2012) Low Pretreatment Serum Total Testosterone Is Associated with a High Incidence of Gleason Score 8-10 Disease in Prostatectomy Specimens: Data from Ethnic Chinese Patients with Localized Prostate Cancer. BJU Int 110: E667-672.
Endogenous, H., Prostate Cancer Collaborative, G., Roddam, A.W., Allen, N.E., Appleby, P., and Key, T.J. (2008) Endogenous Sex Hormones and Prostate Cancer: A Collaborative Analysis of 18 Prospective Studies. J Natl Cancer Inst 100: 170-183.
Fowler, J.E. and Whitemore, W.F. (1982) Considerations for the Use of Testosterone with Systemic Chemotherapy in Prostate Cancer. Cancer 49: 1373-1377.
Gann, P.H., Hennekens, C.H., Ma, J., Longcope, C., and Stampfer, M.J. (1996) Prospective Study of Sex Hormone Levels and Risk of Prostate Cancer. J Natl Cancer Inst 88: 1118-1126.
Garcia-Cruz, E., Piqueras, M., Ribal, M.J., Huguet, J., Serapiao, R., Peri, L. et al. (2012) Low Testosterone Level Predicts Prostate Cancer in Re-Biopsy in Patients with High Grade Prostatic Intraepithelial Neoplasia. BJU Int 110: E199-202.
Haider, A., Zitzmann, M., Doros, G., Isbarn, H., Hammerer, P., and Yassin, A. (2014) Incidence of Prostate Cancer in Hypogonadal Men Receiving Testosterone Therapy: Observations from 5-Year Median Followup of 3 Registries. J Urol 193: 80-86.
Handelsman, D.J. (2013) Global Trends in Testosterone Prescribing, 2000-2011: Expanding the Spectrum of Prescription Drug Misuse. Med J Aust 199: 548-551.
Harman, S.M., Metter Ej Fau - Tobin, J.D., Tobin Jd Fau - Pearson, J., Pearson J Fau - Blackman, M.R., and Blackman, M.R. (2001) Longitudinal Effects of Aging on Serum Total and Free Testosterone Levels in Healthy Men. Baltimore Longitudinal Study of Aging.
Howden, L., Meyer, J. (2011) Age and Sex Composition: 2010, 2010 Census Briefs, Vol. 2015. United States Census Bureau.
Huggins, C. (1947) The Etiology of Benign Prostatic Hypertrophy. Bulletin of the New York Academy of Medicine 23: 696-704.
Huggins, C. and Hodges, C.V. (1941) Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate. 1941. Cancer Res 1: 293-297.
Imamoto, T., Suzuki, H., Fukasawa, S., Shimbo, M., Inahara, M., Komiya, A. et al. (2005) Pretreatment Serum Testosterone Level as a Predictive Factor of Pathological Stage in Localized Prostate Cancer Patients Treated with Radical Prostatectomy. Eur Urol 47: 308-312.
Kaplan, A.L., Trinh, Q.D., Sun, M., Carter, S.C., Nguyen, P.L., Shih, Y.C. et al. (2014) Testosterone Replacement Therapy Following the Diagnosis of Prostate Cancer: Outcomes and Utilization Trends. J Sex Med 11: 1063-1070.
Kyprianou, N., English, H.F., and Isaacs, J.T. (1990) Programmed Cell Death During Regression of Pc-82 Human Prostate Cancer Following Androgen Ablation. Cancer Res 50: 3748-3753.
Lane, B.R., Stephenson, A.J., Magi-Galluzzi, C., Lakin, M.M., and Klein, E.A. (2008) Low Testosterone and Risk of Biochemical Recurrence and Poorly Differentiated Prostate Cancer at Radical Prostatectomy. Urology 72: 1240-1245.
Leibowitz, R.L., Dorff, T.B., Tucker, S., Symanowski, J., and Vogelzang, N.J. (2010) Testosterone Replacement in Prostate Cancer Survivors with Hypogonadal Symptoms. BJU Int 105: 1397-1401.
Massengill, J.C., Sun, L., Moul, J.W., Wu, H., Mcleod, D.G., Amling, C. et al. (2003) Pretreatment Total Testosterone Level Predicts Pathological Stage in Patients with Localized Prostate Cancer Treated with Radical Prostatectomy. J Urol 169: 1670-1675.
Matsumoto, A.M. (2003) Fundamental Aspects of Hypogonadism in the Aging Male. Reviews in Urology 5: S3-S10.
Mearini, L., Zucchi, A., Nunzi, E., Villirillo, T., Bini, V., and Porena, M. (2013) Low Serum Testosterone Levels Are Predictive of Prostate Cancer. World J Urol 31: 247-252.
Miner, M., Barkin, J., and Rosenberg, M.T. (2014) Testosterone Deficiency: Myth, Facts, and Controversy. Can J Urol 21 Suppl 2: 39-54.
Morgentaler, A., Lipshultz, L.I., Bennett, R., Sweeney, M., Avila, D., Jr., and Khera, M. (2011) Testosterone Therapy in Men with Untreated Prostate Cancer. J Urol 185: 1256-1260.
Morgentaler, A. and Rhoden, E.L. (2006) Prevalence of Prostate Cancer among Hypogonadal Men with Prostate-Specific Antigen Levels of 4.0 Ng/Ml or Less. Urology 68: 1263-1267.
Morote, J., Ramirez, C., Gomez, E., Planas, J., Raventos, C.X., De Torres, I.M. et al. (2009) The Relationship between Total and Free Serum Testosterone and the Risk of Prostate Cancer and Tumour Aggressiveness. BJU Int 104: 486-489.
Muller, M., Den Tonkelaar, I., Thijssen, J.H., Grobbee, D.E., and Van Der Schouw, Y.T. (2003) Endogenous Sex Hormones in Men Aged 40-80 Years. Eur J Endocrinol 149: 583-589.
Muller, R.L., Gerber L Fau - Moreira, D.M., Moreira Dm Fau - Andriole, G., Andriole G Fau - Castro-Santamaria, R., Castro-Santamaria R Fau - Freedland, S.J., and Freedland, S.J. (2012) Serum Testosterone and Dihydrotestosterone and Prostate Cancer Risk in the Placebo Arm of the Reduction by Dutasteride of Prostate Cancer Events Trial.
Mulligan, T., Frick, M.F., Zuraw, Q.C., Stemhagen, A., and Mcwhirter, C. (2006) Prevalence of Hypogonadism in Males Aged at Least 45 Years: The Him Study. International Journal of Clinical Practice 60: 762-769.
Neaves Wb Fau - Johnson, L., Johnson L Fau - Porter, J.C., Porter Jc Fau - Parker, C.R., Jr., Parker Cr Jr Fau - Petty, C.S., and Petty, C.S. (1984) Leydig Cell Numbers, Daily Sperm Production, and Serum Gonadotropin Levels in Aging Men.
Pastuszak, A.W., Pearlman, A.M., Lai, W.S., Godoy, G., Sathyamoorthy, K., Liu, J.S. et al. (2013) Testosterone Replacement Therapy in Patients with Prostate Cancer after Radical Prostatectomy. J Urol 190: 639-644.
Pierorazio, P.M., Ferrucci L Fau - Kettermann, A., Kettermann a Fau - Longo, D.L., Longo Dl Fau - Metter, E.J., Metter Ej Fau - Carter, H.B., and Carter, H.B. (2010) Serum Testosterone Is Associated with Aggressive Prostate Cancer in Older Men: Results from the Baltimore Longitudinal Study of Aging.
Rhoden, E.L. and Morgentaler, A. (2003) Testosterone Replacement Therapy in Hypogonadal Men at High Risk for Prostate Cancer: Results of 1 Year of Treatment in Men with Prostatic Intraepithelial Neoplasia. J Urol 170: 2348-2351.
Rove, K.O. and Crawford, E.D. (2014) Traditional Androgen Ablation Approaches to Advanced Prostate Cancer: New Insights. Can J Urol 21: 14-21.
Rubens R Fau - Dhont, M., Dhont M Fau - Vermeulen, A., and Vermeulen, A. (1974) Further Studies on Leydig Cell Function in Old Age.
Salonia, A., Gallina, A., Briganti, A., Abdollah, F., Suardi, N., Capitanio, U. et al. (2010) Preoperative Hypogonadism Is Not an Independent Predictor of High-Risk Disease in Patients Undergoing Radical Prostatectomy. Cancer 117: 3953-3962.
San Francisco, I.F., Rojas, P.A., Dewolf, W.C., and Morgentaler, A. (2014) Low Free Testosterone Levels Predict Disease Reclassification in Men with Prostate Cancer Undergoing Active Surveillance. BJU Int 114: 229-235.
Schroder, F.H., Hugosson, J., Roobol, M.J., Tammela, T.L.J., Ciatto, S., Nelen, V. et al. (2012) Prostate-Cancer Mortality at 11 Years of Follow-Up. New England Journal of Medicine 366: 981-990.
Schwab, T.S., Stewart, T., Lehr, J., Pienta, K.J., Rhim, J.S., and Macoska, J.A. (2000) Phenotypic Characterization of Immortalized Normal and Primary Tumor-Derived Human Prostate Epithelial Cell Cultures. Prostate 44: 164-171.
Shaneyfelt, T., Husein, R., Bubley, G., and Mantzoros, C.S. (2000) Hormonal Predictors of Prostate Cancer: A Meta-Analysis. Journal of Clinical Oncology 18: 847.
Shin, B.S., Hwang, E.C., Im, C.M., Kim, S.O., Jung, S.I., Kang, T.W. et al. (2010) Is a Decreased Serum Testosterone Level a Risk Factor for Prostate Cancer? A Cohort Study of Korean Men. Korean J Urol 51: 819-823.
Siiteri Pk Fau - Wilson, J.D. and Wilson, J.D. (1974) Testosterone Formation and Metabolism During Male Sexual Differentiation in the Human Embryo.
Spitzer, M., Huang, G., Basaria, S., Travison, T.G., and Bhasin, S. (2013) Risks and Benefits of Testosterone Therapy in Older Men. Nat Rev Endocrinol 9: 414-424.
Swerdloff, R. and Wang, C. (2011) Testosterone Treatment of Older Men: Why Are Controversies Created? The Journal of Clinical Endocrinology and Metabolism 96: 62-65.
Swyer, G.I.M. (1944) Post-Natal Growth Changes in the Human Prostate. Journal of Anatomy 78: 130-145.
Tenover, J.S., Matsumoto, A.M., Clifton, D.K., and Bremner, W.J. (1988) Age-Related Alterations in the Circadian Rhythms of Pulsatile Luteinizing Hormone and Testosterone Secretion in Healthy Men. J Gerontol 43: M163-169.
Vermeulen, A. and Kaufman, J.M. (1995) Ageing of the Hypothalamo-Pituitary-Testicular Axis in Men. Horm Res 43: 25-28.
Wang, C., Nieschlag, E., Swerdloff, R., Behre, H.M., Hellstrom, W.J., Gooren, L.J. et al. (2008) Investigation, Treatment and Monitoring of Late-Onset Hypogonadism in Males: Isa, Issam, Eau, Eaa and Asa Recommendations. Eur J Endocrinol 159: 507-514.
Webber, M.M., Bello, D., and Quader, S. (1996) Immortalized and Tumorigenic Adult Human Prostatic Epithelial Cell Lines: Characteristics and Applications. Part I. Cell Markers and Immortalized Nontumorigenic Cell Lines. Prostate 29: 386-394.
Wu, F.C., Tajar, A., Beynon, J.M., Pye, S.R., Silman, A.J., Finn, J.D. et al. (2010) Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. N Engl J Med 363: 123-135.
Xylinas, E., Ploussard, G., Durand, X., Fabre, A., Salomon, L., Allory, Y. et al. (2011) Low Pretreatment Total Testosterone (< 3 Ng/Ml) Predicts Extraprostatic Disease in Prostatectomy Specimens from Patients with Preoperative Localized Prostate Cancer. BJU Int 107: 1400-1403.
Yano, M., Imamoto, T., Suzuki, H., Fukasawa, S., Kojima, S., Komiya, A. et al. (2007) The Clinical Potential of Pretreatment Serum Testosterone Level to Improve the Efficiency of Prostate Cancer Screening. Eur Urol 51: 375-380.