State of the Art in Locally Advanced and Recurrent Non-metastatic Prostate Cancer

Oncology & Hematology Review, 2014;10(2):123–32


Prostate cancer (PC) is the second leading cause of cancer-related death in men in the US. Biochemical relapse is a significant problem, due to the eventual progression to metastatic disease. It is also an opportunity to explore interventions that may have the potential to prevent or delay the occurrence of metastases. Multiple therapies with diverse mechanisms of action have become available for use in metastatic castrateresistant PC and are currently under active investigation in the non-metastatic disease state. The intent of this article is to discuss currently approved therapy in localized and locally advanced PC and to review the state of the art in clinical management within this disease state. We also discuss the novel agents and targets in development, especially for recurrent, non-metastatic PC.

Keywords: Prostate cancer, PSA relapse, localized prostate cancer, locally advanced prostate cancer, castrate resistance
Disclosure: Hema Vankayala, MD, and Ulka Vaishampayan, MD, have no conflicts of interest to declare. No funding was received in the publication of this article.
Received: September 04, 2014 Accepted October 20, 2014 Citation Oncology & Hematology Review, 2014;10(2):123–32
Correspondence: Ulka Vaishampayan, MD, Professor of Oncology, Karmanos Cancer institute/Wayne State University, 4100 John R, 4233 HWCRC, Detroit MI 48201, US. E:

Prostate cancer (PC) is the second most common malignancy in American men and the second leading cause of cancer-related death in men in the US. It is estimated that in 2014 nearly 233,000 men will be diagnosed with PC, with 29,480 dying from the disease.1,2 The majority of them are diagnosed as a result of screening, so symptomatic presentation is unusual. Since the introduction of prostate-specific antigen (PSA) screening in US, more than 1.3 million men have been diagnosed with PC and one million of these have undergone treatment.3

Over 95 % of PCs are adenocarcinomas and the median age at diagnosis is 66 years. As per the Surveillance, Epidemiology, and End Results (SEER) 18 database, 80 % have localized disease and only 12 % have regional disease at diagnosis. In the same database, 5-year survival rates vary significantly with stage and have been noted to be 100 % for localized and regional stage disease. The risk factors for PC are increasing age, African American descent, and a family history of PC.

Localized Prostate Cancer
The current clinical management of localized PC depends on the risk features associated with the cancer and a patient’s life expectancy. The cancer risk is dependent on the clinical stage, PSA, highest Gleason Score (GS), and disease burden. The prostate volume also affects the treatment choice in some situations. Treatment options vary from watchful waiting (WW) and active surveillance (AS), to radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy, cryoablation, androgen deprivation therapy (ADT), and high-intensity focused ultrasound.

Treatment recommendations and selection are dependent on disease and patient characteristics, along with patient and physician preferences. Several studies have shown that patients with low-grade, localized PC have a low risk for clinical progression within the first 10 to 15 years of diagnosis, so AS and WW are reasonable options. This strategy is also best suited to men with a shorter life expectancy.4–7

First-line ADT is seldom indicated in patients with localized PC. The outcomes of men treated with primary ADT, compared with those who were not, was evaluated in a large, retrospective cohort study. ADT is not associated with increased risk for all-cause mortality, or with reduced PC-specific mortality. However, the risk for PC progression on primary ADT was not studied. The likely explanation for the 40 % decline in PCspecific mortality during this time period is earlier detection and definitive curative intervention. ADT is not curative. This study re-affirms that ADT should be reserved for its established role: as palliation for metastatic PC, in men with node-positive PC after RP, or in combination with RT in intermediate- or high-risk PC.8,9

The treatment options for low-risk and very-low-risk patients include AS, WW, or monotherapies such as interstitial prostate brachytherapy, RT, and RP, depending on the life expectancy. The data do not provide clearcut evidence for the superiority of one over another. Hence, a balanced discussion, carefully weighing the risks and benefits, and making a decision after factoring in patient and physician choices, is reasonable.

Radical Prostatectomy in Localized Disease
The role of RP was evaluated by two randomized clinical trials (RCTs) in the pre-PSA era. In both these studies, RP was compared with observation. The updated results from the Veterans’ Administration Cooperative Urological Research Group (VACURG), reporting after 20 years of follow-up, failed to show a difference in mortality.10 In contrast to this, the recently reported 23.2 year follow-up results from the Scandinavian Prostate Cancer Group-4 trial (SPCG-4 trial) demonstrated an 11 % absolute reduction in PC-related mortality in the RP arm compared with WW. This benefit is seen mainly in men younger than 65 years of age and in those with intermediate risk cancer.11

PC screening underwent a revolutionary change with the advent of PSA testing in addition to digital rectal exams. (DREs) It is noteworthy that only 5 % of SPCG-4 patients were diagnosed with the PSA test as compared with contemporary cases where the majority are diagnosed due to an elevated PSA. Hence the current application of the SPCG-4 results is questionable as >80 % of them were diagnosed with a DRE. Most of today’s newly diagnosed PCs are likely to have lower risk disease than that studied by SPCG-4.

  1. Rullis I, Shaeffer JA, Lilien OM, Incidence of prostatic carcinoma in the elderly, Urology, 1975;6:295–7.
  2. Sakr WA, et al., High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases, In Vivo, 1994;8:439–43.
  3. Welch HG, Albertsen PC, Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986–2005, J Natl Cancer Inst, 2009;101:325–9.
  4. Klotz L, Active surveillance with selective delayed intervention for favorable risk prostate cancer, Urol Oncol, 2006;4:46–50.
  5. Johansson JE, et al., Natural history of early, localized prostate cancer, JAMA, 2004;291:2713–9.
  6. Zietman AL, et al., Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy, J Urol, 2001;166:1702–6.
  7. Adolfsson J, et al., Localized prostate cancer and 30 years of follow-up in a population-based setting, Prostate Cancer Prostatic Dis, 2000;3:37–42.
  8. Potosky AL, et al., Effectiveness of primary androgendeprivation therapy for clinically localized prostate cancer, J Clin Oncol, 2014;32:1324–30.
  9. Nelson JB, Observation for Clinically Localized Prostate Cancer, J Clin Oncol, 2014;32:1295–8.
  10. Iversen P, Madsen PO, Corle DK, Radical prostatectomy versus expectant treatment for early carcinoma of the prostate. Twenty-three year follow-up of a prospective randomized study, Scand J Urol Nephrol Suppl, 1995;172:65–72.
  11. Bill-Axelson A, et al., Radical prostatectomy or watchful waiting in early prostate cancer, N Engl J Med, 2014;370:932–42.
  12. Wilt TJ, et al., Radical prostatectomy versus observation for localized prostate cancer, N Engl J Med, 2012;367:203–13.
  13. Lau WK, et al., Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitant pathological variables, J Urol, 2002;167:117–22.
  14. Zelefsky MJ, 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, 2010;28:1508–13.
  15. Abdollah F, et al., A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988–2006, Eur Urol, 2011;59:88–95.
  16. Hu JC, et al., Comparative effectiveness of minimally invasive vs open radical prostatectomy, JAMA, 2009;302:1557–64.
  17. Hu JC, et al., Comparative effectiveness of robot-assisted versus open radical prostatectomy cancer control, Eur Urol, 2014;66:666–72.
  18. 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, 2014;65:918-927.
  19. Sundi D, et al., Very-high-risk localized prostate cancer: definition and outcomes, Prostate Cancer Prostatic Dis, 2014;17:57–63.
  20. Davidson MT, et al., Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer, Int J Radiat Oncol Biol Phys, 2011;80:1550–8.
  21. Kuban DA, et al., Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer, Int J Radiat Oncol Biol Phys, 2008;70:67–74.
  22. Pilepich MV, 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, 2005;61:1285–90.
  23. 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, 2009;373:301–8.
  24. Warde P, et al., Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase III trial, Lancet, 2011;378:2104–11.
  25. Horwitz EM, 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, 2008;26:2497–504.
  26. Bolla M, et al., Duration of androgen suppression in the treatment of prostate cancer, N Engl J Med, 2009;360:2516–27.
  27. Roach M, 3rd, et al., Predicting long-term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials, Int J Radiat Oncol Biol Phys, 2000;47:617–27.
  28. Denham J.W, et al., Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial, Lancet Oncol, 2011;12:451–9.
  29. Armstrong JG, et al., A randomized trial (Irish clinical oncology research group 97-01) comparing short versus protracted neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer, Int J Radiat Oncol Biol Phys, 2011;81:35–45.
  30. Crook J, et al., Final report of multicenter Canadian phase III randomized trial of three versus eight months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer, Int J Radiat Oncol Biol Phys, 2009;73:327–33.
  31. D’Amico AV, et al., Six-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial, JAMA, 2004;292:821–7.
  32. D’Amico AV, et al., Duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer, J Clin Oncol, 2011;29:4682–7.
  33. Boorjian SA, et al., Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer, Cancer, 2011;117:2883–91.
  34. Hoffman RM, et al., Mortality after radical prostatectomy or external beam radiotherapy for localized prostate cancer, J Natl Cancer Inst, 2013;105:711–8.
  35. Dearnaley DP, et al., Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial, Lancet Oncol, 2014;15:464–73.
  36. Zietman AL, et al., Randomized trial comparing conventionaldose 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, 2010;28:1106–11.
  37. Al-Mamgani A, et al., Update of Dutch multicenter doseescalation trial of radiotherapy for localized prostate cancer, Int J Radiat Oncol Biol Phys, 2008;72:980–8.
  38. Beckendorf V, et al., 70 Gy versus 80 Gy in localized prostate cancer: five-year results of GETUG 06 randomized trial, Int J Radiat Oncol Biol Phys, 2011;80:1056–63.
  39. Rosenthal SA, et al., Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02, Int J Radiat Oncol Biol Phys, 2009;73:672–8.
  40. Dorff TB, et al., Adjuvant androgen deprivation for high-risk prostate cancer after radical prostatectomy: SWOG S9921 study, J Clin Oncol, 2011;29:2040–5.
  41. Fizazi K, et al., A randomized phase III, factorial design, of cabazitaxel and pelvic radiotherapy in patients with localized prostate cancer and high-risk features of relapse, ASCO Meeting Abstracts, 2014;32(Suppl. 15):TPS5098.
  42. D’Amico AV, et al., Surrogate endpoints for prostate cancerspecific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials, Lancet Oncol, 2012:13;189–95.
  43. Cury FL, et al., Prostate-specific antigen response after shortterm hormone therapy plus external-beam radiotherapy and outcome in patients treated on Radiation Therapy Oncology Group study 9413, Cancer, 2013;119:1999–2004.
  44. Crawford ED, Barqawi A, Targeted focal therapy: a minimally invasive ablation technique for early prostate cancer, Oncology (Williston Park), 2007;21:27–32; discussion 33–4, 39.
  45. Ward JF, Jones JS, Focal cryotherapy for localized prostate cancer: a report from the national Cryo On-Line Database (COLD) Registry, BJU Int, 2012;109:1648–54.
  46. Babaian RJ, et al., Best practice statement on cryosurgery for the treatment of localized prostate cancer, J Urol, 2008;180:1993–2004.
  47. Onik G, et al., The “male lumpectomy”: focal therapy for prostate cancer using cryoablation results in 48 patients with at least two-year follow-up, Urol Oncol, 2008;26:500–5.
  48. Antonarakis ES, et al., The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up, BJU Int, 2012;109:32–9.
  49. Buyyounouski MK, et al., Interval to biochemical failure highly prognostic for distant metastasis and prostate cancer-specific mortality after radiotherapy, Int J Radiat Oncol Biol Phys, 2008;70:59–66.
  50. Antonarakis ES, et al., Changes in PSA kinetics predict metastasis-free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of four phase II trials, Cancer, 2012;118:533–42.
  51. Antonarakis ES, et al., The effect of PSA doubling time (PSADT) and Gleason score on the PSA at the time of initial metastasis in men with biochemical recurrence after prostatectomy, ASCO Meeting Abstracts, 2011;29(Suppl. 7):16.
  52. Castellucci P, et al., Influence of trigger PSA and PSA kinetics on 11C-Choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy, J Nucl Med, 2009;50:1394–400.
  53. Spiotto MT, Hancock SL, King CR, Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients, Int J Radiat Oncol Biol Phys, 2007;69:54–61.
  54. Stephenson AJ, et al., Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy, J Clin Oncol, 2007;25:2035–41.
  55. Trock BJ, et al., Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy, JAMA, 2008;299:2760–9.
  56. Boorjian SA, et al., Radiation therapy after radical prostatectomy: impact on metastasis and survival, J Urol, 2009;182:2708–14.
  57. King CR, The timing of salvage radiotherapy after radical prostatectomy: a systematic review, Int J Radiat Oncol Biol Phys, 2012;84:104–11.
  58. 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, 2012;380:2018–27.
  59. Shipley WU, et al., Initial report of RTOG 9601, a phase III trial in prostate cancer: Effect of anti-androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy (RP) with pT2-3,N0 disease and elevated PSA levels, ASCO Meeting Abstracts, 2011;29(Suppl. 7):1
  60. Quon H, et al., Population-based referrals for adjuvant radiotherapy after radical prostatectomy in men with prostate cancer: impact of randomized trials, Clin Genitourin Cancer, 2014;12:e1–5.
  61. Hoffman KE, et al., Recommendations for post-prostatectomy radiation therapy in the United States before and after the presentation of randomized trials, J Urol, 2011;185:116–20.
  62. Cipolla BG, et al., First double-blind placebo-controlled, multicenter, randomized trial of stabilized natural sulforaphane in men with rising PSA following radical prostatectomy, ASCO Meeting Abstracts, 2014;32(Suppl. 15):5032.
  63. Stephenson AJ, et al., Salvage therapy for locally recurrent prostate cancer after external beam radiotherapy, Curr Treat Options Oncol, 2004;5:357–65.
  64. Chade DC, et al., Salvage radical prostatectomy for radiationrecurrent prostate cancer: a multi-institutional collaboration, Eur Urol, 2011;60:205–10.
  65. Rocco B, et al., Current status of salvage robot-assisted laparoscopic prostatectomy for radiorecurrent prostate cancer, Curr Urol Rep, 2012;13:195–201.
  66. Gotto GT, et al., Impact of prior prostate radiation on complications after radical prostatectomy, J Urol, 2010;184:136–42.
  67. Chade DC, et al, Cancer control and functional outcomes of salvage radical prostatectomy for radiation-recurrent prostate cancer: a systematic review of the literature, Eur Urol, 2012;61:961–71.
  68. Ramey SJ, Marshall DT, Re-irradiation for salvage of prostate cancer failures after primary radiotherapy, World J Urol, 2013;31:1339–45.
  69. Spiess PE, et al., Outcomes of salvage prostate cryotherapy stratified by pre-treatment PSA: update from the COLD registry, World J Urol, 2013;31:1321–5.
  70. Mouraviev V, Spiess PE, Jones JS, Salvage cryoablation for locally recurrent prostate cancer following primary radiotherapy, Eur Urol, 2012;61:1204–11.
  71. Antonarakis ES, et al., Long-term overall survival and metastasis-free survival for men with prostate-specific antigenrecurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database, BJU Int, 2011;108:378–85.
  72. Paller CJ, et al., The effect of PSA frequency and duration on PSA doubling time (PSADT) calculations in men with biochemically recurrent prostate cancer (BRPC) after definitive local therapy, ASCO Meeting Abstracts, 2012;30(Suppl. 15):4559.
  73. Garcia-Albeniz X, et al., Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse, ASCO Meeting Abstracts, 2014;32(Suppl. 15):5003.
  74. Crook JM, et al., Intermittent androgen suppression for rising PSA level after radiotherapy, N Engl J Med, 2012;367:895–903.
  75. Figg WD, et al., A double-blind randomized crossover study of oral thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation, J Urol, 2009;181:1104–13; discussion 1113.
  76. Spisek R, et al., Cancer immunotherapy of patients with the biochemical relapse of the prostate cancer using dendritic cell-based vaccine DCVAC/PCa, ASCO Meeting Abstracts, 2014,32(Suppl. 15):3099.
  77. Liu G, et al., Eastern Cooperative Oncology Group Phase II Trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer, Urol Oncol, 2013;31:211–8.
  78. Paller CJ, et al., A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer, Prostate Cancer Prostatic Dis, 2013;16:50–5.
  79. Pantuck AJ, et al., Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer, Clin Cancer Res, 2006;12:4018–26.
  80. Paller CJ, et al., A phase I trial of muscadine grape skin in men with biochemically recurrent prostate cancer, ASCO Meeting Abstracts, 2014;32(Suppl. 4):263.
  81. Dorai T, Gehani N, Katz A,Therapeutic potential of curcumin in human prostate cancer. II. Cumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein, Mol Urol, 2000;4:1–6.
  82. Thomas R, et al., A double-blind, placebo-controlled randomised trial evaluatin the effect if a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer the U.K. NCRN Pomi-T study, Prostate Cancer Prostatic Dis, 2014;17:180–6.
  83. Smith MR, et al., ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC), ASCO Meeting Abstracts, 2013;31(Suppl. 6):7.
  84. McLeod DG, et al., Phase I dose escalation trial of MVA-BN-PRO in men with nonmetastatic castration-resistant prostate cancer, ASCO Meeting Abstracts, 2013;31(Suppl. 6):193.
  85. Ryan CJ, et al., Effect of abiraterone acetate and low-dose prednisone on PSA in patients with nonmetastatic castrationresistant prostate cancer: The results from IMAAGEN core study, ASCO Meeting Abstracts, 2014;32(Suppl. 15):5086.
Keywords: Prostate cancer, PSA relapse, localized prostate cancer, locally advanced prostate cancer, castrate resistance