Tuesday, September 2, 2014

Historical Contribution: 1947, Colston & Brendler, Endrocrine Therapy for Prostate Cancer


J. A. Colston and H. Brendler. Endocrine therapy in carcinoma of the prostate; preparation of patients for radical perineal prostatectomy. J Am Med Assoc 1947 134: 848-53

In the July, 1947 issue of JAMA (Journal of the American Medical Association), Drs. Colston and Brendler reviewed the use of androgen deprivation therapy in the treatment of prostate cancer. Their goal was to specifically address the role of neoadjuvant hormone ablation in preparation for radical prostatectomy.

Their conclusions drew on data from over 200 patients treated with DES (diethylstilbestrol) at the Brady Urological Institute, they found that approximately 75% had regression of their primary tumor and 45% had regression in distant metastases –for at least some time period. Huggins and Hodges had recently published their seminal work on Androgens and Prostate Cancer (1941), and the mode of action of androgens in prostate cancer was not yet well understood. DES was believed to neutralize the androgens needed by growing prostate cancer cells and create specific histologic and chemical changes leading to apoptosis, loss of cellular material and eventual replacement by normal, mesenchymal (fibrous tissue, smooth muscle) cells. This was matched by the clinical observation that most prostate glands and cancers softened and shrank after DES treatment. However, it was also well known that most prostate cancers would recur after a period of androgen deprivation, leading to the belief that cancer cells are not destroyed by ADT, by rendered "dormant." Additionally, no patient was ever cured by ADT alone.

Therefore, to investigate patients who may be cured by a combination of surgery and hormone therapy, they found it useful to classify patients into four categories that had both prognostic and therapeutic implications.
  1. Early, confined to the gland, what we would called clinically localized or organ-confined disease.
  2. Moderately advanced – involving only the bases of the seminal vesicles or apex of the gland.
  3. Advanced – (i.e. locally advanced) extensive local invasion into the SV, ligaments supporting the prostate, urethra or rectum.
  4. Metastatic – never cured by ADT or surgery
Patients with early disease were previously described in a number of papers (including one reviewed in the Historical Contribution, 1943). Important points in this population include:
  • A 22% overall operative rate – much higher than other institutions at the time
  • Selection criteria which included:
    • Clinically localized disease
    • No metastases
    • A good surgical candidate
    • A reasonable life expectancy
  • Operative mortality of 5-6%
In the 200 patients treated with DES who did not meet initial criteria for radical prostatectomy, seven patients with moderately advanced disease had adequate response to hormone ablation to allow surgical extirpation.
"The response of each of these patients to the administration of estrogen was so gratifying that it was deemed worthwhile to perform the radical operation in order to attempt a complete eradication of the disease."
The operation was uneventful in all seven cases and the clinical response is noted in the figures.  However, two patients developed urethrovesical strictures and one died of diffuse metastatic disease.

Therefore they concluded ADT (most commonly by DES) can facilitate surgical resection of moderately advanced prostate cancer. They temper their conclusions by stating that follow-up, albeit promising, is short and long-term follow-up will provide more answers. This is a fascinating look at the early experience with neoadjuvant hormone therapy for prostate cancer.

To read the entire manuscript: follow the link above, visit the Centennial Website or 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! 


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