Wednesday, February 5, 2014

Dr. Patrick C. Walsh's "Confession?": Men with High-Risk Prostate Cancer May Benefit From Radical Prostatectomy

Patrick C. Walsh, MD, University Distinguished Service Professor of Urology and Chairman Emeritus at the Brady Urological Institute at Johns Hopkins Hospital is a world-renowned urologist and surgeon, best known for pioneering the anatomic approach to radical prostatectomy and his expertise regarding benign and malignant neoplasms of the prostate.
Patrick C. Walsh, MD

In the Brady's weekly Grand Rounds conference, Dr. Walsh presented his "Confession?," a current review of the literature regarding prostate cancer treatment that indicates that patients with high-risk prostate cancer may benefit most from localized treatment.  To give a little background, in the 1970's, when Dr. Walsh arrived at the Brady, the trend in oncologic surgery was to do "big operations for little cancers and little operations for big cancers." This was reinforced by Dr. Hugh Jewett and others who spent their lifetime trying to define disease states that were curable with surgery.  Before the PSA era, this was men who had a B1 nodule (palpable cancer in less than 1/2 of one lobe).[1]  The impetus for the Partin Tables, was to refine the prediction of curability to optimally select the ideal surgical candidate for radical prostatectomy (RP).  Given the morbidity of RP, it was reasonable only to operate on those patients where the chances of cure are high.

For the better part of the last few decades, the ideal patient to be cured by RP was the man with organ-confined, Gleason 6 prostate cancer.  However recent data, which we will review below, indicate there may be a benefit of RP for men who are not cured by that surgery - men with high-risk prostate cancer (HRPC).

  • First, we now know that not all men with HRPC are equal.  Men can be stratified into favorable or unfavorable pathology.  Men with favorable HRPC have all Gleason pattern 4 disease that is either confined to the prostate or with extraprostatic extension (pT2-pT3a) and, 15-years after RP, 60% will be free from metastatic disease and 70% will be alive.  On the other hand, for men with unfavorable disease [any Gleason pattern 5, seminal vesicle invasion of lymph node metastases (pT3b or N1)], at 15-years, only 20% will be free from metastases and be alive.[2]
  • In the randomized, Scandinavian trial of RP versus watchful waiting, the greatest benefit of surgery (in reducing metastases and mortality from prostate cancer) was in the men with high-Gleason disease.[3]
  • In men with locally advanced disease, treatment with androgen deprivation therapy (ADT) and radiation therapy (RT) provides a survival benefit over ADT alone.[4]
  • Contrary to standard practice, men with positive lymph nodes who undergo removal of the prostate had a survival benefit when compared to men who only underwent a staging pelvic lymphadenectomy.[5,6]
  • In a propensity score-matched analysis of men with HRPC who eventually developed metastases, men who underwent primary surgery had a better prostate cancer survival when compared to men who received primary RT.[7]

Why would treating the primary tumor radically benefit men with metastatic prostate cancer?  In 1889, Paget proposed the seed and soil theory: tumor (seeds) will selectively colonize in organs with a favorable environment (soil).  Recent evidence suggests that endocrine factors released by the primary tumor in prostate cancer may create a premetastatic niche in bone-marrow derived cells, making them more receptive to tumor colonization.[8]

In summary: Complete elimination of the primary lesion may improve survival in men with advanced disease even though it many not be curative.  For this reason, biochemical and metastasis-free survival may underestimate the ultimate value of any primary treatment to the prostate.

So, how should we treat men who present with HRPC?  The STAMPEDE Trial is currently underway, examining ADT and RT to men with newly diagnosed metastatic prostate cancer with the hypothesis that treating the primary tumor may retard distant metastatic progression and prolong survival.[9] However, we also know that radiation doses up to 81 grey may be insufficient to treat HRPC.[10]  

Therefore, on an individual basis, men with HRPC who have lesions that can be completely excised should be counseled on the possible benefits of RP, with a full understanding that they will likely need adjuvant or salvage therapy (and additional therapies will have cancer benefits with quality-of-life implications).  RP is more of an option for the treatment of HRPC than it has ever been, and prostate cancer outcomes may continue to improve as we better understand high-risk disease.  There is an exciting new frontier in the fight against prostate cancer where clinical trials and protocols may define neo-adjuvant and adjuvant therapies to maximize survival for men with HRPC.

This entry is extracted from a lecture given by Patrick C. Walsh, MD on January 30, 2014 at the Brady Urological Institute and Department of Urology Grand Rounds, Johns Hopkins Hospital, Baltimore, Maryland.  

[1] Jewett HJ. The present status of radical prostatectomy for stages A and B prostatic cancer.  Urol Clin North Am. 1975 Feb;2(1):105-24.
[2] Pierorazio PM, Ross AE, Lin BM, Epstein JI, Han M, Walsh PC, Partin AW, Pavlovich CP, Schaeffer EM.Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy. BJU Int. 2012 Oct;110(8):1122-8. doi: 10.1111/j.1464-410X.2012.10986.x. Epub 2012 Feb 28.
[3] Vickers A, Bennette C, Steineck G, Adami HO, Johansson JE, Bill-Axelson A, Palmgren J, Garmo H, Holmberg L.Individualized estimation of the benefit of radical prostatectomy from the Scandinavian Prostate Cancer Group randomized trial. Eur Urol. 2012 Aug;62(2):204-9. doi: 10.1016/j.eururo.2012.04.024. Epub 2012 Apr 19.
[4] Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P, Lund JA, Tasdemir I, Hoyer M, Wiklund F, Fosså SD; Scandinavian Prostate Cancer Group Study 7; Swedish Association for Urological Oncology 3.Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.Lancet. 2009 Jan 24;373(9660):301-8. doi: 10.1016/S0140-6736(08)61815-2. Epub 2008 Dec 16. Erratum in: Lancet. 2009 Apr 4;373(9670):1174.
[5] Engel J, Bastian PJ, Baur H, Beer V, Chaussy C, Gschwend JE, Oberneder R, Rothenberger KH, Stief CG, Hölzel D.  Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer.  Eur Urol. 2010 May;57(5):754-61. doi: 10.1016/j.eururo.2009.12.034. Epub 2010 Jan 20.
[6] Cadeddu JA, Partin AW, Epstein JI, Walsh PC. Stage D1 (T1-3, N1-3, M0) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. Urology. 1997 Aug;50(2):251-5.
[7] Shao YH, Kim S, Moore DF, Shih W, Lin Y, Stein M, Kim IY, Lu-Yao GL.Cancer-specific Survival After Metastasis Following Primary Radical Prostatectomy Compared with Radiation Therapy in Prostate Cancer Patients: Results of a Population-based, Propensity Score-Matched Analysis.  Eur Urol. 2013 May 21. pii: S0302-2838(13)00489-2. doi: 10.1016/j.eururo.2013.05.023. [Epub ahead of print]
[8] Kaplan RN, Psaila B, Lyden D.  Bone marrow cells in the 'pre-metastatic niche': within bone and beyond.  Cancer Metastasis Rev. 2006 Dec;25(4):521-9.
Parker CC, Sydes MR, Mason MD, Clarke NW, Aebersold D, de Bono JS, Dearnaley DP, Ritchie AW, Russell JM, Thalmann G, Parmar MK, James ND.Prostate radiotherapy for men with metastatic disease: a new comparison in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial.BJU Int. 2013 May;111(5):697-9. doi: 10.1111/bju.12087.
[10]Zelefsky MJ, Eastham JA, Cronin AM, Fuks Z, Zhang Z, Yamada Y, Vickers A, Scardino PT.  Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix.  J Clin Oncol. 2010 Mar 20;28(9):1508-13. doi: 10.1200/JCO.2009.22.2265. Epub 2010 Feb 16.


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