Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

High-risk prostate cancer—classification and therapy

Key Points

  • Patients with high-risk prostate cancer have a significant chance of developing systemic or local recurrence, and are at higher risk for symptoms and/or death from the disease

  • Definitions vary for what constitutes high-risk disease in localized prostate cancer, but are historically based on clinicopathological findings including clinical stage, Gleason score, and PSA

  • The literature is limited as a consequence of variations in definition, lack of prospective randomized trials, limitations in statistical plan (underpowered studies), the need for long-term follow-up, and suboptimal end points

  • Several key principles for radiotherapy have been established, including the importance of dose, and the addition of androgen-deprivation therapy

  • Optimal surgical management requires completely removing the gland itself, confirming negative margins intraoperatively, and discussing the potential need for post-operative radiotherapy

  • Treatment of potential lymph-node involvement, either surgically or with extended pelvic radiation, is favoured in high-risk disease, but lacks level I evidence

Abstract

Approximately 15% of patients with prostate cancer are diagnosed with high-risk disease. However, the current definitions of high-risk prostate cancer include a heterogeneous group of patients with a range of prognoses. Some have the potential to progress to a lethal phenotype that can be fatal, while others can be cured with treatment of the primary tumour alone. The optimal management of this patient subgroup is evolving. A refined classification scheme is needed to enable the early and accurate identification of high-risk disease so that more-effective treatment paradigms can be developed. We discuss several principles established from clinical trials, and highlight other questions that remain unanswered. This Review critically evaluates the existing literature focused on defining the high-risk population, the management of patients with high-risk prostate cancer, and future directions to optimize care.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Clinical states of prostate cancer.

References

  1. Scher, H. I. & Heller, G. Clinical states in prostate cancer: toward a dynamic model of disease progression. Urology 55, 323–327 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 63, 11–30 (2013).

    PubMed  Google Scholar 

  3. Cooperberg, M. R., Broering, J. M. & Carroll, P. R. Time trends and local variation in primary treatment of localized prostate cancer. J. Clin. Oncol. 28, 1117–1123 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. D'Amico, A. V. et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 280, 969–974 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Thompson, I. et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J. Urol. 177, 2106–2131 (2007).

    Article  PubMed  Google Scholar 

  6. Roach, M. et al. Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int. J. Radiat. Oncol. Biol. Phys. 47, 609–615 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Roach, M. 3rd et al. Defining high risk prostate cancer with risk groups and nomograms: implications for designing clinical trials. J. Urol. 176, S16–S20 (2006).

    Article  PubMed  Google Scholar 

  8. Huang, J. et al. Percentage of positive biopsy cores: a better risk stratification model for prostate cancer? Int. J. Radiat. Oncol. Biol. Phys. 83, 1141–1148 (2012).

    Article  PubMed  Google Scholar 

  9. Cooperberg, M. R. et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J. Urol. 173, 1938–1942 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cooperberg, M. R., Broering, J. M. & Carroll, P. R. Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis. J. Natl Cancer Inst. 101, 878–887 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kattan, M. W., Eastham, J. A., Stapleton, A. M., Wheeler, T. M. & Scardino, P. T. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J. Natl Cancer Inst. 90, 766–771 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Yossepowitch, O. et al. Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. J. Urol. 178, 493–499 (2007).

    Article  PubMed  Google Scholar 

  13. Gosselaar, C., Kranse, R., Roobol, M. J., Roemeling, S. & Schroder, F. H. The interobserver variability of digital rectal examination in a large randomized trial for the screening of prostate cancer. Prostate 68, 985–993 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. American Joint Committee on Cancer. AJCC Cancer Staging Manual, 7th edn (Springer, New York, 2011).

  15. Yakar, D. et al. Predictive value of MRI in the localization, staging, volume estimation, assessment of aggressiveness, and guidance of radiotherapy and biopsies in prostate cancer. J. Magn. Reson. Imaging 35, 20–31 (2012).

    Article  PubMed  Google Scholar 

  16. Zhang, J. Q., Loughlin, K. R., Zou, K. H., Haker, S. & Tempany, C. M. Role of endorectal coil magnetic resonance imaging in treatment of patients with prostate cancer and in determining radical prostatectomy surgical margin status: report of a single surgeon's practice. Urology 69, 1134–1137 (2007).

    Article  PubMed  Google Scholar 

  17. Peng, Y. et al. Quantitative analysis of multiparametric prostate MR images: differentiation between prostate cancer and normal tissue and correlation with Gleason score--a computer-aided diagnosis development study. Radiology 267, 787–796 (2013).

    Article  PubMed  Google Scholar 

  18. Puech, P. et al. Prostate cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy--prospective multicenter study. Radiology 268, 461–469 (2013).

    Article  PubMed  Google Scholar 

  19. Tiwari, P., Kurhanewicz, J. & Madabhushi, A. Multi-kernel graph embedding for detection, Gleason grading of prostate cancer via MRI/MRS. Med. Image Anal. 17, 219–235 (2013).

    Article  PubMed  Google Scholar 

  20. Cooperberg, M. R. et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J. Clin. Oncol. 31, 1428–1434 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Ding, Z. et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roach, M. 3rd, Waldman, F. & Pollack, A. Predictive models in external beam radiotherapy for clinically localized prostate cancer. Cancer 115, 3112–3120 (2009).

    Article  PubMed  Google Scholar 

  23. Durand, X. et al. The value of urinary prostate cancer gene 3 (PCA3) scores in predicting pathological features at radical prostatectomy. BJU Int. 110, 43–49 (2012).

    Article  PubMed  Google Scholar 

  24. Lin, D. W. et al. Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study. Clin. Cancer Res. 19, 2442–2450 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shore, N. et al. Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer. Curr. Med. Res. Opin. 30, 547–553 (2014).

    Article  PubMed  Google Scholar 

  26. Knezevic, D. et al. Analytical validation of the Oncotype DX prostate cancer assay—a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics 14, 690 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Donovan, M. J. & Cordon-Cardo, C. Predicting high-risk disease using tissue biomarkers. Curr. Opin. Urol. 23, 245–251 (2013).

    PubMed  Google Scholar 

  28. Bolla, M. et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360, 103–106 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Pilepich, M. V. et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31 Int. J. Radiat. Oncol. Biol. Phys. 61, 1285–1290 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Beckendorf, V. et al. 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 80, 1056–1063 (2011).

    Article  PubMed  Google Scholar 

  31. Creak, A. et al. Randomised pilot study of dose escalation using conformal radiotherapy in prostate cancer: long-term follow-up. Br. J. Cancer 109, 651–657 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kuban, D. A. et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int. J. Radiat. Oncol. Biol. Phys. 79, 1310–1317 (2011).

    Article  PubMed  Google Scholar 

  33. Peeters, S. T. et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J. Clin. Oncol. 24, 1990–1996 (2006).

    Article  PubMed  Google Scholar 

  34. Roach, M. 3rd. Dose escalated external beam radiotherapy versus neoadjuvant androgen deprivation therapy and conventional dose external beam radiotherapy for clinically localized prostate cancer: do we need both? Strahlenther. Onkol. 183, 26–28 (2007).

    Article  PubMed  Google Scholar 

  35. Widmark, A. et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 373, 301–308 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Warde, P. et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 378, 2104–2111 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bechis, S. K., Carroll, P. R. & Cooperberg, M. R. Impact of age at diagnosis on prostate cancer treatment and survival. J. Clin. Oncol. 29, 235–241 (2011).

    Article  PubMed  Google Scholar 

  38. Lu-Yao, G. L. et al. Outcomes of localized prostate cancer following conservative management. JAMA 302, 1202–1209 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roach, M. 3rd et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J. Clin. Oncol. 26, 585–591 (2008).

    Article  PubMed  Google Scholar 

  40. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  41. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  42. Nichol, A. M., Warde, P. & Bristow, R. G. Optimal treatment of intermediate-risk prostate carcinoma with radiotherapy: clinical and translational issues. Cancer 104, 891–905 (2005).

    Article  PubMed  Google Scholar 

  43. Bolla, M. et al. Duration of androgen suppression in the treatment of prostate cancer. N. Engl. J. Med. 360, 2516–2527 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Horwitz, E. M. et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J. Clin. Oncol. 26, 2497–2504 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  46. Nabid, A. et al. Duration of androgen deprivation therapy in high-risk prostate cancer: a randomized trial [abstract LBA4510]. J. Clin. Oncol. 31 (Suppl.), (2013).

  47. Ahmadi, H. & Daneshmand, S. Androgen deprivation therapy: evidence-based management of side effects. BJU Int. 111, 543–548 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Cormie, P. et al. Can supervised exercise prevent treatment toxicity in prostate cancer patients initiating androgen deprivation therapy: a randomised controlled trial. BJU Int. http://dx.doi.org/10.1111/bju.12646.

  49. Gardner, J. R., Livingston, P. M. & Fraser, S. F. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J. Clin. Oncol. 32, 335–346 (2014).

    Article  PubMed  Google Scholar 

  50. Saylor, P. J., Keating, N. L. & Smith, M. R. Prostate cancer survivorship: prevention and treatment of the adverse effects of androgen deprivation therapy. J. Gen. Intern. Med. 24 (Suppl. 2), S389–S394 (2009).

    Article  PubMed  Google Scholar 

  51. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Fizazi, K. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 13, 983–992 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

    CAS  PubMed  Google Scholar 

  57. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Zelefsky, M. J. et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 41, 491–500 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Levegrün, S. et al. Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer. Radiother. Oncol. 63, 11–26 (2002).

    Article  PubMed  Google Scholar 

  60. Dearnaley, D. P. et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol. 8, 475–487 (2007).

    Article  PubMed  Google Scholar 

  61. Sathya, J. R. et al. Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate. J. Clin. Oncol. 23, 1192–1199 (2005).

    Article  PubMed  Google Scholar 

  62. Zietman, A. L. et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J. Clin. Oncol. 28, 1106–1111 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zelefsky, M. J., Reuter, V. E., Fuks, Z., Scardino, P. & Shippy, A. Influence of local tumor control on distant metastases and cancer related mortality after external beam radiotherapy for prostate cancer. J. Urol. 179, 1368–1373 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Fang, L. C. et al. High-risk prostate cancer with Gleason score 8–10 and PSA level ≤15 ng/mL treated with permanent interstitial brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 81, 992–996 (2011).

    Article  PubMed  Google Scholar 

  65. Vargas, C. et al. High-dose radiation employing external beam radiotherapy and high-dose rate brachytherapy with and without neoadjuvant androgen deprivation for prostate cancer patients with intermediate- and high-risk features. Prostate Cancer Prostatic Dis. 9, 245–253 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. D'Amico, A. V. et al. Risk of death from prostate cancer after brachytherapy alone or with radiation, androgen suppression therapy, or both in men with high-risk disease. J. Clin. Oncol. 27, 3923–3928 (2009).

    Article  PubMed  Google Scholar 

  67. Stephenson, A. J. et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J. Clin. Oncol. 27, 4300–4305 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Eggener, S. E. et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J. Urol. 185, 869–875 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Spahn, M. 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. Eur. Urol. 58, 1–7 (2010).

    Article  PubMed  Google Scholar 

  70. Zwergel, U. et al. Outcome of prostate cancer patients with initial PSA > or = 20 ng/ml undergoing radical prostatectomy. Eur. Urol. 52, 1058–1065 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Klein, E. A. et al. Surgeon experience is strongly associated with biochemical recurrence after radical prostatectomy for all preoperative risk categories. J. Urol. 179, 2212–2216 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Begg, C. B. et al. Variations in morbidity after radical prostatectomy. N. Engl. J. Med. 346, 1138–1144 (2002).

    Article  PubMed  Google Scholar 

  73. Valicenti, R. K. et al. Adjuvant and salvage radiation therapy after prostatectomy: American Society for Radiation Oncology/American Urological Association guidelines. Int. J. Radiat. Oncol. Biol. Phys. 86, 822–828 (2013).

    Article  PubMed  Google Scholar 

  74. Thompson, I. M. et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J. Urol. 190, 441–449 (2013).

    Article  PubMed  Google Scholar 

  75. Boorjian, S. A. et al. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer 117, 2883–2891 (2011).

    Article  PubMed  Google Scholar 

  76. Briganti, A. et al. Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer. Eur. Urol. 61, 584–592 (2012).

    Article  PubMed  Google Scholar 

  77. Ward, J. F., Slezak, J. M., Blute, M. L., Bergstralh, E. J. & Zincke, H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int. 95, 751–756 (2005).

    Article  PubMed  Google Scholar 

  78. Yossepowitch, O. et al. Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy. Eur. Urol. 53, 950–959 (2008).

    Article  PubMed  Google Scholar 

  79. Bill-Axelson, A. et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N. Engl. J. Med. 364, 1708–1717 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Wilt, T. J. et al. Radical prostatectomy versus observation for localized prostate cancer. N. Engl. J. Med. 367, 203–213 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Briganti, A. et al. Pelvic lymph node dissection in prostate cancer. Eur. Urol. 55, 1251–1265 (2009).

    Article  PubMed  Google Scholar 

  82. Stone, N. N., Stock, R. G. & Unger, P. Laparoscopic pelvic lymph node dissection for prostate cancer: comparison of the extended and modified techniques. J. Urol. 158, 1891–1894 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Briganti, A. et al. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur. Urol. 50, 1006–1013 (2006).

    Article  PubMed  Google Scholar 

  84. Bader, P., Burkhard, F. C., Markwalder, R. & Studer, U. E. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J. Urol. 168, 514–518 (2002).

    Article  PubMed  Google Scholar 

  85. Keller, H., Lehmann, J. & Beier, J. Radical perineal prostatectomy and simultaneous extended pelvic lymph node dissection via the same incision. Eur. Urol. 52, 384–388 (2007).

    Article  PubMed  Google Scholar 

  86. Wyler, S. F. et al. Laparoscopic extended pelvic lymph node dissection for high-risk prostate cancer. Urology 68, 883–887 (2006).

    Article  PubMed  Google Scholar 

  87. Liss, M. A. et al. Outcomes and complications of pelvic lymph node dissection during robotic-assisted radical prostatectomy. World J. Urol. 31, 481–488 (2013).

    Article  PubMed  Google Scholar 

  88. World Health Organization. International Clinical Trials Registry Program; German Clinical Trials Register [online], (2014).

  89. Feifer, A. H. et al. Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy. Cancer 117, 3933–3942 (2011).

    Article  PubMed  Google Scholar 

  90. Gandaglia, G. et al. The impact of robot-assisted radical prostatectomy on the use and extent of pelvic lymph node dissection in the “post-dissemination” period. Eur. J. Surg. Oncol. http://dx.doi.org/10.1016/j.ejso.2013.12.016.

  91. Yuh, B. et al. The role of robot-assisted radical prostatectomy and pelvic lymph node dissection in the management of high-risk prostate cancer: A systematic review. Eur. Urol. 65, 918–927 (2014).

    Article  PubMed  Google Scholar 

  92. Weingartner, K. et al. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J. Urol. 156, 1969–1971 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Heidenreich, A., Ohlmann, C. H. & Polyakov, S. Anatomical extent of pelvic lymphadenectomy in patients undergoing radical prostatectomy. Eur. Urol. 52, 29–37 (2007).

    Article  PubMed  Google Scholar 

  94. Wagner, M., Sokoloff, M. & Daneshmand, S. The role of pelvic lymphadenectomy for prostate cancer--therapeutic? J. Urol. 179, 408–413 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Touijer, K. A., Mazzola, C. R., Sjoberg, D. D., Scardino, P. T. & Eastham, J. A. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur. Urol. 65, 20–25 (2014).

    Article  PubMed  Google Scholar 

  96. Engel, J. et al. Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer. Eur. Urol. 57, 754–761 (2010).

    Article  PubMed  Google Scholar 

  97. Ji, J., Yuan, H., Wang, L. & Hou, J. Is the impact of the extent of lymphadenectomy in radical prostatectomy related to the disease risk? A single center prospective study. J. Surg. Res. 178, 779–784 (2012).

    Article  PubMed  Google Scholar 

  98. Bolla, M. et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 366, 572–578 (2005).

    Article  PubMed  Google Scholar 

  99. Bolla, M. et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 380, 2018–2027 (2012).

    Article  PubMed  Google Scholar 

  100. Thompson, I. M. et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J. Urol. 181, 956–962 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Wiegel, T. et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95. J. Clin. Oncol. 27, 2924–2930 (2009).

    Article  PubMed  Google Scholar 

  102. Thompson, I. M. Jr et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 296, 2329–2335 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Moinpour, C. M. et al. Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J. Clin. Oncol. 26, 112–120 (2008).

    Article  PubMed  Google Scholar 

  104. Briganti, A. et al. Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis. Eur. Urol. 62, 472–487 (2012).

    Article  PubMed  Google Scholar 

  105. Nam, R. K. et al. Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol. 15, 223–231 (2014).

    Article  PubMed  Google Scholar 

  106. Bhojani, N. et al. The rate of secondary malignancies after radical prostatectomy versus external beam radiation therapy for localized prostate cancer: a population-based study on 17,845 patients. Int. J. Radiat. Oncol. Biol. Phys. 76, 342–348 (2010).

    Article  PubMed  Google Scholar 

  107. Bostrom, P. J. & Soloway, M. S. Secondary cancer after radiotherapy for prostate cancer: should we be more aware of the risk? Eur. Urol. 52, 973–982 (2007).

    Article  PubMed  Google Scholar 

  108. Moon, K., Stukenborg, G. J., Keim, J. & Theodorescu, D. Cancer incidence after localized therapy for prostate cancer. Cancer 107, 991–998 (2006).

    Article  PubMed  Google Scholar 

  109. Stephenson, A. J. et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J. Clin. Oncol. 25, 2035–2041 (2007).

    Article  PubMed  Google Scholar 

  110. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  111. Current Controlled Trials Ltd. International Standard Randomised Controlled Trial Number Register [online], (2011).

  112. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  113. Keating, N. L., O'Malley, A. J. & Smith, M. R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J. Clin. Oncol. 24, 4448–4456 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Nguyen, P. L. et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306, 2359–2366 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Punnen, S., Cooperberg, M. R., Sadetsky, N. & Carroll, P. R. Androgen deprivation therapy and cardiovascular risk. J. Clin. Oncol. 29, 3510–3516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Arcangeli, G. et al. Retrospective comparison of external beam radiotherapy and radical prostatectomy in high-risk, clinically localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 75, 975–982 (2009).

    Article  PubMed  Google Scholar 

  117. Zelefsky, M. J. et al. 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. 28, 1508–1513 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zelefsky, M. J. et al. Predicting biochemical tumor control after brachytherapy for clinically localized prostate cancer: The Memorial Sloan-Kettering Cancer Center experience. Brachytherapy 11, 245–249 (2012).

    Article  PubMed  Google Scholar 

  119. Kattan, M. W. et al. Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer. J. Clin. Oncol. 21, 4568–4571 (2003).

    Article  PubMed  Google Scholar 

  120. Hsu, C. C. et al. Feasibility of MR imaging/MR spectroscopy-planned focal partial salvage permanent prostate implant (PPI) for localized recurrence after initial PPI for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 85, 370–377 (2013).

    Article  PubMed  Google Scholar 

  121. Chen, C. P. et al. Salvage HDR brachytherapy for recurrent prostate cancer after previous definitive radiation therapy: 5-year outcomes. Int. J. Radiat. Oncol. Biol. Phys. 86, 324–329 (2013).

    Article  PubMed  Google Scholar 

  122. Giordano, S. H. et al. Limits of observational data in determining outcomes from cancer therapy. Cancer 112, 2456–2466 (2008).

    Article  PubMed  Google Scholar 

  123. Eifler, J. B. et al. Causes of death after radical prostatectomy at a large tertiary center. J. Urol. 188, 798–801 (2012).

    Article  PubMed  Google Scholar 

  124. Lane, J. A. et al. Latest results from the UK trials evaluating prostate cancer screening and treatment: the CAP and ProtecT studies. Eur. J. Cancer 46, 3095–3101 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Jang, T. L. et al. Physician visits prior to treatment for clinically localized prostate cancer. Arch. Intern. Med. 170, 440–450 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Sommers, B. D. et al. Predictors of patient preferences and treatment choices for localized prostate cancer. Cancer 113, 2058–2067 (2008).

    Article  PubMed  Google Scholar 

  127. Bastian, P. J. et al. High-risk prostate cancer: from definition to contemporary management. Eur. Urol. 61, 1096–1106 (2012).

    Article  PubMed  Google Scholar 

  128. Bellmunt, J. et al. Advances in the management of high-risk localised and metastatic prostate cancer. BJU Int. 109 (Suppl. 2), 8–13 (2012).

    Article  PubMed  Google Scholar 

  129. Gomella, L. G. et al. Enhancing prostate cancer care through the multidisciplinary clinic approach: a 15-year experience. J. Oncol. Pract. 6, e5–e10 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Bianco, F. J. Jr, Scardino, P. T. & Eastham, J. A. Radical prostatectomy: long-term cancer control and recovery of sexual and urinary function (“trifecta”). Urology 66, 83–94 (2005).

    Article  PubMed  Google Scholar 

  131. Jacobs, E. F., Boris, R. & Masterson, T. A. Advances in robotic-assisted radical prostatectomy over time. Prostate Cancer 2013, 902686 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Turpen, R., Atalah, H. & Su, L. M. Technical advances in robot-assisted laparoscopic radical prostatectomy. Ther. Adv. Urol. 1, 251–258 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Taplin, M.-E. et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study [abstract]. J. Clin. Oncol. 30 (Suppl.), a4521 (2012).

    Google Scholar 

  134. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  135. Tollefson, M. K. et al. A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer. [Abstract, 168], ASCO Genitourinary Cancers Symposium, March 5–7, San Francisco, CA. http://meetinglibrary.asco.org/content/30897.73 (2010).

  136. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  137. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  138. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  139. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  140. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  141. Heidenreich, A. et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur. Urol. 59, 61–71 (2011).

    Article  PubMed  Google Scholar 

  142. Cooperberg, M. R., Hilton, J. F. & Carroll, P. R. The CAPRA-S score: A straightforward tool for improved prediction of outcomes after radical prostatectomy. Cancer 117, 5039–5046 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Amy Plofker, MSKCC editor, for her superb editorial assistance. This work was supported at Memorial Sloan–Kettering Cancer Center by The Sidney Kimmel Center for Prostate and Urologic Cancers, the MSKCC SPORE in Prostate Cancer (P50 CA92629) (H.I.S.), the Department of Defense Prostate Cancer Research Program (PC051382, PC121111) (H.I.S.), and The Prostate Cancer Foundation (H.I.S.). This work was supported at the University of California, San Francisco by the Helen Diller Family Cancer Center (M.R.), NRG Oncology (M.R.), University of California San Francisco Resource Allocation Program (A.J.C.), and General Electric ISR (A.J.C.).

Author information

Authors and Affiliations

Authors

Contributions

All authors researched the data for the article, contributed substantially to discussion of content, wrote and reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Mack Roach III or Howard I. Scher.

Ethics declarations

Competing interests

M.R. declares associations with Astellas, Bayer and Varian. H.I.S. declares associations with Astellas, Bristol-Myers Squibb, Janssen, Medivation, Millennium, and Sanofi. The other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chang, A., Autio, K., Roach, M. et al. High-risk prostate cancer—classification and therapy. Nat Rev Clin Oncol 11, 308–323 (2014). https://doi.org/10.1038/nrclinonc.2014.68

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2014.68

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing