Tuesday, September 30, 2014

Historical Contribution: 1957, Burt, Finney & Scott, Steroid Response to Prostate Cancer Treatment

Burt FB, Finney RP, Scott WW. Steroid Response to Therapy in Prostatic Cancer. Cancer. 1957. 10;4:825-30.


The discovery that prostate cancer was androgen-dependent by Huggins and Hodges in 1941, energized and dominated the field of urology for the next few decades.[1] By 1957, it was well-established that the only effective treatment for advanced prostate cancer was androgen-ablation. Dr. Scott and collaborators from Johns Hopkins hypothesized that to monitor the effectiveness of androgen-ablation, the response of endogenous steroids could be measured and catalogued. To that end, Burt, Finney and Scott, the Brady Urological Institute, summarize the understanding of steroid and steroid-responsiveness to androgen ablation therapy.

At the time of this manuscripts publication, it was established by a number of researchers that urinary excretion of 17-ketosteroids would decrease after orchiectomy or medical castration – only to rise again in patients after several months in patients with recurrent disease. However, it was unknown if there were any qualitative or quantitative differences in 17-ketosteroids among men with and without prostate cancer. Furthermore, the structure of these urinary steroids were unknown and differences, if they existed, between testicular and adrenal androgens were speculative.  Therefore, researchers from Johns Hopkins further developed and refined methods developed at Memorial Sloan-Kettering in New York City, using the enzyme glucuronidase, to separate urinary steroids into "androgen metabolites" and "corticoid metabolites" for each patient in the hopes of defining a "steroid-signature" for patients with prostate cancer.

Burt, Finney and Scott made a number of important clinical observations in this small study that confirmed and furthered the current understanding of androgens and prostate cancer.

  • As expected, six patients undergoing castration alone experienced reductions in androgen metabolites that corresponded to an immediate clinical response.
  • Estrogens (silbestrol) would decrease both androgen- and corticoid-metabolites in the urine – suggesting that silbestrol facilitates pituitary inhibition of androgens.

  • One patient experienced a prostate cancer recurrence within six weeks of orchiectomy and died 10 months later. His corticoid metabolites increased dramatically while his androgen metabolites increased only moderately indicating that the pituitary-adrenal axis played a role in recurrent disease.

  • To assess the role of the pituitary, they administered "test doses" of gonadotropin and ACTH (adrenocorticotropic hormone) before and after castration.
    • While androgen levels rose with gonadotropin, the corticoid levels remained stable.
    • ACTH had no impact on urinary steroid levels prior to orchiectomy, however dramatically increased steroid metabolites after orchiectomy.
"[T]he ratio of the androgen metabolites isolated during our investigation remained remarkably constant before and after castration, and before and after stimulation by adrenocorticotropic hormone (ACTH) or gonadotropin. Administered testosterone did not alter this ratio. This suggests a structural similarity between testicular and adrenal androgen and testosterone."
  • Two patients who failed castration and silbestrol therapy had a dramatic fall in androgen metabolites with the administration of cortisone. When cortisone levels were decreased, bone pain returned without a difference in androgen metabolite levels. It was theorized at the time, that a "cortisone-euphoria" improved symptoms of bone pain. However, Burt, Finney and Scott hypothesized that the cortisone acted on the androgen-axis and perhaps on the tumor, improving symptoms in a physiologic (and not psychiatric) manner.
  • Among ten patients with good and poor outcomes, those who did poorly had higher proportion of androgenic androsterone compared to etiocholanolone.
  • There was no lower limit of androgens, below which a clinical response could be guaranteed. Therefore, each cancer and patient had "different quantitative requirements for growth."
From these data, Burt, Finney and Scott were hoping to make objective recommendations for the management of patients with advanced prostate cancer - which they were able to partially achieve. They recommended that androgen-ablation start with estrogen (silbestrol) therapy – as estrogen would depress both gonadal and pituitary sources of androgens. If failed estrogen therapy, orchiectomy should be performed. Relapse after castration should be treated with cortisone. Scott and others previously wrote about and discussed adrenalectomy for patients refractory to all other treatments. The patient most likely to benefit from adrenalectomy would have high androgen metabolites while on cortisone therapy. Regretably, this study failed to demonstrate a single patient with only rising androgen metabolites while on systemic steroids – adding more evidence against adrenalectomy.

To read the entire manuscript: follow the link above, visit the Centennial Website or click here.

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! 

[1] Huggins, C., and Hodges, C. V.: Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate, Cancer Research 1:293, 1941.


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