Santoro Foundation Golf Outing Raises Funds & Awareness for Prostate Cancer

September is Prostate Cancer Awareness Month. Not only does Prostate Cancer Awareness Month afford the opportunity to spread knowledge about prostate cancer to the public, but it also affords the opportunity to reflect on the many great people and families touched by this disease. In this blog, we would like to share the story of Alfred "Gus" Santoro III and The Santoro Foundation.

Shortly after his diagnosis in 2004, Gus Santoro underwent surgery at the Johns Hopkins Hospital to treat his prostate cancer. Gus and his son, Alfred "Fred" Santoro IV, played golf together every summer.  However, that summer – as Gus recovered from surgery – they could not play together. So Fred and his friends played a round of golf in Gus's honor. That round of golf turned into an annual event and the Santoro Foundation in 2006.

Fortunately, Gus remains cancer-free with an excellent quality of life ten years after his diagnosis. Gus credits the eradication of his cancer on annual check-ups and early detection of his disease. Therefore, The Santoro Foundation was started to raise public awareness regarding funding, research, treatment and breakthroughs in the fight against prostate cancer. Funds from the foundation are directed specifically to prostate cancer research and treatment facilities, to increase awareness of prostate cancer, and to recognize selfless people in the community. The Santoro Foundation offers academic scholarships to high school and college students who are active in their communities and giving of their time to help others.

The marquis event of the Santoro Foundation is the annual GUS OPEN charity golf tournament, played every year at The Club at Shannondell outside of Philadelphia. In addition to being an extremely fun event, the golf outing raises funds for prostate cancer research and raises awareness in the community to encourage men to see their doctors for regular check-ups. A full round of golf is followed by a family style dinner and charity auction that features golf and Philadelphia sports franchise memorabilia.

The majority of funds raised by the GUS OPEN are donated to the Brady Urological Institute and each year, the Brady sends a foursome to play in the tournament. Phillip M. Pierorazio, MD, has played in the tournament each of the last four years, "The Gus Open is one of my favorite Brady events of the year. The Santoro's are tremendous in their giving spirit and charitable efforts. It's an honor every year to play golf with them, to speak to their friends and family members about prostate cancer and to thank them for the funds that enable our research."

Adam Kern, Fred Santoro, Gus Santoro, Phillip Pierorazio and Debasish Sundi
at the Santoro Golf Outing, 2012.

Fred Santoro recently told The Alternative Press, "Ever year, doctors form John Hopkins come up, and my family and I have been invited to go down to John Hopkins to participate in their fundraisers, too. Though we are pretty small, our average donation is $5- to 6,000 to John Hopkins, and I'm sure they receive $10,000, $100,000 from other donors, but they treat us like any other donor. They send doctors up to play; they see what we need. They're very supportive."

"It's a good thing we're better at prostate cancer research and treatment than we are at golf," Pierorazio jokes.

The Gus Open is held every year at the end of the summer. You can read more about Fred's interview and the Santoro Foundation at: 
http://thealternativepress.com/towns/lower-providence/articles/santoro-foundation-to-host-saturday-golf-outing

You can support the Santoro Foundation on Facebook: https://www.facebook.com/SantoroFoundation





 

 

A New Test May Change the Meaning of a “Negative” Prostate Biopsy

Nearly one million men undergo prostate biopsy yearly in the US. 750,000 (3 in 4) of these biopsies are histologically found to be negative for evidence of prostate cancer by microscopic analysis. Other data suggest that of these 750,000 negative biopsies, 25% (187,000) actually have cancer in the prostate that the initial biopsy might have missed. A new tissue assay (made by ConfirmMDx) 

From MDxHealth.com

looks at the methylation (alteration of the DNA) of three genes to predict that cancer may have been missed and that a repeat biopsy should be recommended. The test relies on the concept that a "halo" of DNA-alterations (methylation) occurs around a foci of cancer within the prostate. With the ability to search for DNA-abnormalities in the "halo," this test effectively increases the size of each biopsy and decreases the likelihood of missing a prostate cancer.

Jonathan I. Epstein, MD

The multicenter DOCUMENT (Detection of Cancer Using Methylated Events in Negative Tissue) study was conducted with 350 PSA-screened men from five major urologic centers, including Johns Hopkins University, Cleveland Clinic Foundation, Lahey Clinic, University of California Los Angeles and East Virginia Medical School. The study involved patients with an initial negative index prostate biopsy who had high-risk variables (e.g. High Grade PIN, Atypia high PSA, etc…) and compared this tissue methylation assay results to cancer detection in subsequent repeat biopsy within 24 months. Index and repeat biopsy tissues were subjected to blinded, centralized pathology review by Jonathan Epstein, MD, Reinhard Professor of Urologic Pathology and Director of Surgical Pathology at Johns Hopkins. The ConfirmMDx for Prostate Cancer test, was used to analyze the DNA from 3,687 negative tissue cores from the index prostate biopsy for epigenetic abnormalities. The study confirmed the previously published results using the same ConfirmMDx for Prostate Cancer test as a significant, independent predictor (odds ratio = 2.85) for the risk of prostate cancer in a repeat biopsy, outperforming standard clinical risk factors such as age, prostate specific antigen (PSA), digital rectal exam (DRE), and pathology in multivariate logistic regression analysis. In addition, the high negative predictive value of the epigenetic assay was confirmed (88%).[1]

Alan W. Partin, MD, PhD

Dr. Alan Partin, MD, PhD, Chairman of the Brady Urological Institute and Urologist-in-Chief at Johns Hopkins Hospital comments, 

"The DOCUMENT study validates the three-gene epigenetic assay as a better predictor of risk for the presence of occult cancer than any other factor in the clinic today. Results from this study provide further clinical evidence that the epigenetic test delivers actionable information to help guide urologists on the decision for repeat prostate biopsy."

"DOCUMENT was a pivotal validation study, demonstrating that the test's high negative predictive value and odds ratio are robust and reproducible in different cohorts of patients," stated Dr. Epstein. "The importance of this blinded, multicentered study is that it validated the performance of the test using predetermined analytical cutoff values in a population of U.S. patients undergoing routine PSA screening for prostate cancer."

The entire manuscript appears in the April 18, 2014 Edition of the Journal of Urology. Click here of follow the link below to read the entire manuscript.

Partin AW, Van Neste L, Klein EA, Marks LS, Gee JR, Troyer DA, Rieger-Christ K, Jones JS, Magi-Galluzzi C, Mangold LA, Trock BJ, Lance RS, Bigley JW, Van Criekinge W, Epstein JI. Clinical Validation of an Epigenetic Assay to Predict Negative Histopathological Results in Repeat Prostate Biopsies. J Urol. 2014 Apr 18. pii: S0022-5347(14)03341-2. doi: 10.1016/j.juro.2014.04.013.


 
[1] Stewart GD, Van Neste L, Delvenne P, Delrée P, Delga A, McNeill SA, O'Donnell M, Clark J, Van Criekinge W, Bigley J, Harrison DJ. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. J Urol. 2013 Mar;189(3):1110-6. doi: 10.1016/j.juro.2012.08.219. Epub 2012 Oct 8.

Historical Contribution: 1950, Further Investigations into Hormonal Relationship of Prostate Cancer

1950

H. Brendler, W. E. Chase and W. W. Scott. Prostatic Cancer - Further Investigation of Hormonal Relationships Archives of Surgery. 1950 61: 433-440

William Wallace Scott, MD

Huggins and Hodges seminal work that defined the hormonal nature of prostate cancer was published in 1941.[1] The following decade saw a surge in the enthusiastic investigation of the relationship between androgens (i.e. testosterone) and prostate cancer. Based on the work by Huggins and Hodges, it was believed that prostate cancer was dependent on androgens to grow and spread. Cases of progressive metastatic disease after castration (by orchiectomy or medications) were, therefore, believed to occur as a result of extradonadal androgens – namely from the adrenal. This was refuted in a study by Huggins and William Wallace Scott (2^nd Director of Urology at the Brady Urological Institute), where a patient who was previously castrated for prostate cancer, also underwent bilateral adrenalectomy and experienced continued progression of disease despite removal of all endogenous androgen.

Without knowledge of the androgen receptor and castration-resistant mechanisms, researchers at the Brady Urological Institute sought to investigate the relationship between androgens and prostate cancer by treating three men with advanced cancer with testosterone proprionate and reported their results in this publication.

There are a number of interesting clinical findings from the cases:

• Two had bone metastases visible on x-ray (roentgenogram), both diffusely throughout the skeleton and involving the sternum.
• With testosterone injections, hemoglobin improved and acid phosphatase decreased.
• Interestingly, pain improved in the one patient with bone pain, bone lesions stabilized or improved in all patients – no patient had progression during follow-up.
• The two patients with bone metastases died within 100 days of starting treatment.
• The patient without bone metastases had no changed in acid or alkaline phosphatase, and had dramatic improvement of his voiding symptoms with diethylstilbestrol.

The clinical course and treatment of each patient is detailed in the figures.

 During this time period, the understanding of hormones and breast cancer was also expanding. In breast cancer, it was believed that androgens were related to osseous metastases while estrogens affected soft tissue disease. Through extension, Brendler, Chase and Scott hypothesize that androgens may play a role in the bone metastases so common in 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! 

[1] 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.

AR-V7 Identifies Patients Unlikely to Respond to Common Therapy for Advanced Prostate Cancer

Prostate cancer is driven by male hormones (otherwise known as androgens) like testosterone. In men with advanced prostate cancer, androgen deprivation therapy (ADT), or therapies that block androgens from acting on prostate cancer cells, can slow or stop the progression of the cancer. Unfortunately, prostate cancer cells will eventually survive and grow despite standard, first-line ADT – a state called castration-resistant prostate cancer (CRPC). For these men, treatments that further suppress the generation of androgens or block the androgen receptor are the next step. Abiraterone is a medication that inhibits important enzymes in the synthesis of androgens and enzalutamide blocks androgens from acting on the receptor on prostate cancer cells. These medications extend the lives of approximately 80% of the men who take them, however 20% will have little or no response.

Researchers at Johns Hopkins' Kimmel Cancer Center and Brady Urological Institute may have discovered why. These findings were published in the most recent version of the NEJM (New England Journal of Medicine) and demonstrate that prostate cancer patients whose tumors contain a shortened receptor called AR-V7 are less likely to respond to abiraterone or enzalutamide. AR-V7 is a shortened form of the androgen receptor that lacks a binding spot targeted by enzalutamide and abiraterone. With no binding spot for the two drugs, AR-V7 is free to manipulate prostate cancer cells' genetic material, which makes the cancer cells grow and spread. A total of 62 patients, 31 patients taking each medication, were studied by looking for AR-V7 in circulating tumor cells (CTCs) from blood samples.

Waterfall Plots of Best Prostate-Specific
Antigen (PSA) Responses According to
AR-V7 Status.  From NEJM.

Of the 31 patients taking enzalutamide:

• 39% were AR-V7-positive, and in these patients:
  • None (0%) had a PSA reduction, compared to 53% of patients who were AR-V7-negative (P=0.004)
  • PSA-progression-free survival was shorter (1.4 months vs. 6.0 months, P<0.001)
  • Survival was shorter (5.5 months vs. not reached, P=0.002)

Of the 31 patients taking abiraterone:

• 19% were AR-V7-positive, and in these patients:
  • None (0%) had a PSA reduction, compared to 68% of patients who were AR-V7-negative (P=0.004)
  • PSA-progression-free survival was shorter (1.3 months vs. not reached, P<0.001)
  • Survival was shorter (10.6 months vs. not reached, P=0.006)

Jun Luo, PhD

"In this study, we've connected AR-V7 detection with resistance to two popular drugs for prostate cancer, and we've done it in a non-invasive way," says Jun Luo, Ph.D., Associate Professor of Urology at the Brady Urological Institute at Johns Hopkins first identified AR-V7 in 2007. "We hope this study will motivate scientists and clinicians to conduct additional studies on AR-V7 and to develop effective therapies to overcome resistance."

"Until now, we haven't been able to predict which patients will not respond to these therapies. If our results are confirmed by other researchers, a simple blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy," says Emmanuel Antonarakis, M.D., Assistant Professor of Oncology at Johns Hopkins and lead author on the study.

Emmanuel Antonarakis, MBBCh

"Patients whose blood samples contained AR-V7 got no benefit from either enzalutamide or abiraterone," says Antonarakis. He adds that AR-V7 could appear in patients' blood samples at the very start of therapy or acquired later, after therapy has begun. He says, "This test could be used before starting enzalutamide or abiraterone therapy, and if the test shows the presence of AR-V7, patients may opt for a different therapy. It could also be used to monitor patients during the course of therapy with enzalutamide or abiraterone for AR-V7, providing an indication these drugs may not work for much longer."

Take-home: If large-scale studies validate the findings, the investigators say men with detectable blood levels of AR-V7 should avoid these two drugs and instead take other medicines (such as chemotherapy, perhaps) to treat their prostate cancer.

To read the entire article follow this link to the New England Journal of Medicine (NEJM).

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J.  AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer.  N Engl J Med. 2014 Sep 3. DOI: 10.1056/NEJMoa1315815

The study was funded by the Prostate Cancer Foundation, the Department of Defense, and the National Institutes of Health's National Cancer Institute (CA058236, CA006973).

Source of Quotations: "Blood test for 'nicked' protein predicts prostate cancer treatment response" at http://www.eurekalert.org/pub_releases/2014-09/jhm-btf_1090214.php

Defining Very-High-Risk Localized Prostate Cancer

Approximately one out of every six men diagnosed with prostate cancer is classified as having high-risk disease. The current National Comprehensive Cancer Network (NCCN) defines high-risk disease as prostate cancer that meet one of the following features: clinical stage ≥T3 disease, Gleason sum of 8-10, or PSA >20 ng/ml [1]. Traditionally, high-risk prostate cancer was more commonly treated with androgen deprivation therapy (ADT) and radiotherapy (RT) rather than radical prostatectomy (RP) as it was thought that surgical management was less likely to improve long term survival [2]. More recently, Loeb et al. showed that surgery (RP) can provide improved long term survival in a subset of high-risk men: 10 year biochemical recurrence-free survival (BFS) of 68% and metastasis-free survival (MFS) of 84% [3]. Several additional studies further supported the favorable long term clinical outcomes following RP, thus providing high-risk patients with an attractive alternative to combination external beam RT and ADT [4, 5].

Although many high-risk patients who elect to undergo RP have excellent oncologic outcomes and do not require further adjuvant cancer-directed treatments, significant heterogeneity in clinical outcomes exists [6]. For example, patients with a Cancer of the Prostate Risk Assessment (CAPRA) score of 0-2 have less than a 25% chance of biochemical recurrence at 10 years following radical prostatectomy compared to greater than 75% chance in patients with a CAPRA score of 7-10. Similarly, Dr. Phillip Pierorazio lead a study at Johns Hopkins that showed a significant variation in cancer-specific survival at 15 years post radical prostatectomy between patients with seminal vesicle or lymph node involvement (37%-73%) compared to those without (76-96%) [7].The heterogeneity of clinical outcomes observed in these studies suggested potentially additional sub-groups within the high risk cohort of prostate cancer patients.

Debasish Sundi, MD

Therefore, Dr. Debasish Sundi and colleagues performed a study to identify pre-operative characteristics that could better predict which patients would most benefit from radical prostatectomy and which patients may require multimodal therapy [8]. After univariate and multivariable analyses of extensive pre-operative characteristics in over 700 high-risk patients, the study determined that patients with primary Gleason pattern 5 on biopsy, ≥5 biopsy cores containing Gleason sum 8-10, or multiple NCCN high-risk features ("very high risk" criteria) carried threefold higher risks for prostate cancer metastasis (distant disease spread), and death due to prostate cancer.  For example, at 10 years after treatment, the rate of metastasis in high risk patients was 22%, compared to 63% in very high risk patients.

Figure 1. Kaplan–Meier curves showing significantly better biochemical free survival (BFS), metastasis free survival (MFS), cancer specific survival (CSS), and overall survival (OS). All analyses were performed exclusively on differences of clinical outcomes within the NCCN high risk cohort. JHU very-high-risk group were defined as patients with primary Gleason pattern 5 on biopsy, ≥5 biopsy cores containing Gleason sum 8-10, or multiple NCCN high-risk features. JHU high-risk group were the remaining NCCN high risk patients that did not meet the very-high risk criteria. [8]

Patients with very-high-risk prostate cancer may require more aggressive therapies in order to achieve optimal oncologic outcomes. Multimodal treatment approaches such as combination radiotherapy/hormonal therapy or surgery with early adjuvant therapy should be considered. Furthermore, patients with very high risk prostate cancer may also be ideal candidates for clinical trials that incorporate neoadjuvant and/or novel multimodal treatment approaches.

Summary:  

• Significant variations in clinical outcomes and cancer-specific survival exist within the NCCN high-risk group
• Patients with one of the following characteristics are thought to have very high risk prostate cancer and may benefit most from multimodal therapy and/or clinical trials:
• Primary Gleason primary pattern 5 on biopsy
• ≥5 cores containing Gleason sum 8-10 cancer on biopsy
• 2 or more of the following characteristics: 
• clinical stage ≥T3 stage
• Gleasonsum8-10
• PSA >20ng/ml

There are several exciting clinical trials currently ongoing at Johns Hopkins' Sidney Kimmel Comprehensive Cancer Center for patients with high-risk or advanced prostate cancer:

1. Neoadjuvant Study of Androgen Ablation Combined with Cyclophosphamide and GVAX Vaccine for Localized Prostate Cancer https://clinicaltrials.gov/ct2/show/NCT01696877?term=high+risk+prostate+cancer&state1=NA%3AUS%3AMD&rank=13
2. Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomyhttps://clinicaltrials.gov/ct2/show/NCT02203695?term=high+risk+prostate+cancer&state1=NA%3AUS%3AMD&rank=14
3. A Pre-surgical Study of LDE225 in Men With High-risk Localized Prostate Cancerhttps://clinicaltrials.gov/ct2/show/NCT02111187?term=high+risk+prostate+cancer&state1=NA%3AUS%3AMD&rank=6

This blog was written by Vinson Wang, Medical Student at the Johns Hopkins University School of Medicine.  Vinson recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Very High Risk Prostate Cancer" from which this blog is inspired. Vinson is looking forward to a career in urology.











References:

1. Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(5):686–718.
2. Gerber GS, Thisted RA, Chodak GW, Schroder FH, Frohmuller HG, Scardino PT, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. EurUrol 1997;32:385-90.
3. Loeb S, Schaeffer EM, Trock BJ, Epstein JI, Humphreys EB,Walsh PC. What are the outcomes of radical prostatectomy for high-risk prostate cancer? Urology 2010;76:710-4.
4. Zwergel U, Suttmann H, Schroeder T, Siemer S, Wullich B, Kamradt J, et al. Outcome of prostate cancer patients with initial PSA> or =20 ng/ml undergoing radical prostatectomy. EurUrol 2007;52:1058-65.
5. Spahn M, Joniau S, Gontero P, Fieuws S, Marchioro G, Tombal B, et al. Outcome predictors of radical prostatectomy in patients with prostate-specific antigen greater than 20 ng/ml: a European multi-institutional study of 712 patients. EurUrol 2010;58:1-7.
6. Cooperberg MR, Cowan J, Broering JM, Carroll PR. High-risk prostate cancer in the United States, 1990-2007. World J Urol. 2008;13:211–218. doi: 10.1007/s00345-008-0250-7. 
7. Pierorazio P.M., Guzzo T.J., Han M., Bivalacqua T.J., Epstein J.I., Schaeffer E.M., Schoenberg M., Walsh P.C., Partin A.W. Long-term survival after radical prostatectomy for men with high Gleason sum in pathologic specimen. Urology. 2010;76:715–721.
8. Sundi D, Wang VM, Pierorazio PM, Han M, Bivalacqua TJ, Ball MW, Antonarakis ES, Partin AW, Schaeffer EM, Ross AE. Very-high-risk localized prostate cancer: definition and outcomes.Prostate Cancer Prostatic Dis. 2014 Mar;17(1):57-63.

Septembeard Kicks off National Prostate Health Month at Hopkins

September is National Prostate Health Month and designates a month to increase the awareness of prostate health, provide public health screenings, educate patients and loved ones about prostate issues, and offers a chance to advocate for research and improvements in the way we treat prostate issues.   A number of organizations rally throughout the month of September to meet these goals.  The SEPTEMBEARD (www.septembeard.org) organization was founded in 2011 with the goal to eradicate prostate cancer.  By growing a beard, men around the world can raise awareness, raise funds for research and participate in the fight against prostate cancer.  Check out the Official Septembeard music video below.

The organization was created by Art Wagner, a sales and marketing executive, who was diagnosed and treated for prostate cancer.  Mr. Wagner's father had been diagnosed and treated for the disease several years previously.  Therefore, Mr. Wagner set out to raise funds to eradicate prostate cancer before future generations would have to deal with what he and his father endured.  Septembeard generates funds for the best prostate cancer research programs in the United States.

The Johns Hopkins Prostate Cancer Team is fortunate to be one of seven, outstanding research institutions to be funded by Septembeard.  Johns Hopkins has a long history of leadership in diagnosing, treating, and conducting groundbreaking research for prostate cancer.  Notable contributions made by researchers at Johns Hopkins include:

• The radical retropubic prostatectomy was developed by Dr. Patrick C. Walsh at the Brady Institute.  
• The first prostate cancer gene was identified at John Hopkins.  
• The Partin Tables and Han Tables, widely used to predict prostate cancer’s stage and likelihood of recurrence, were developed by our team.  
• Hopkins houses the only urology robotics laboratory in the country. 

Last year's efforts funded a project titled, “Study of Clonal Heterogeneity Among Prostate Cancer Circulating Tumor Cells.” This study is led by Michael Gorin, MD and Research Year Resident at the Brady Urological Institute.  Dr. Gorin is currently sequencing the genome of circulating prostate cells to determine how these cells leave the prostate and develop metastases.

The concept of Septembeard is relatively simple.  Men form teams, grow beards and compete to raise money which is shared among the research institutions.  The team from Hopkins is named Team Hopkins Beards of The Brady and donations can be made at: http://septembeard.org/team/2015/.  In addition, a variety of merchandise is available at the Septembeard.org website (https://septembeard.org/store/) - all proceeds fund research at the elite prostate cancer research centers.

The Brady Residents and members of TEAM HOPKINS BEARDS OF THE BRADY on September 2nd, as Septembeard gets underway.  Support the Brady and Septembeard at: http://septembeard.org/team/2015/ 

There are a number of ways to get involved:

• Visit the SEPTEMBEARD website (www.septembeard.org)
• Or the Septembeard Facebook Site (https://www.facebook.com/Septembeard)
• Create a team and grow a beard
• Donate to an existing team (Team Hopkins Beards of The Brady)
• Check out the merchandise  (https://septembeard.org/store/)
• Spread the word!!!

We thank you for your support and look forward to another great year as we get closer to eradicating prostate cancer!!!

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

1947

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!