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Neoadjuvant Treatment of High-Risk, Clinically Localized Prostate Cancer Prior to Radical Prostatectomy

Abstract

Multimodal strategies combining local and systemic therapy offer the greatest chance of cure for many with men with high-risk prostate cancer who may harbor occult metastatic disease. However, no systemic therapy combined with radical prostatectomy has proven beneficial. This was in part due to a lack of effective systemic agents; however, there have been several advancements in the metastatic and castrate-resistant prostate cancer that might prove beneficial if given earlier in the natural history of the disease. For example, novel hormonal agents have recently been approved for castration-resistant prostate cancer with some early phase II neoadjuvant showing promise. Additionally, combination therapy with docetaxel-based chemohormonal has demonstrated a profound survival benefit in metastatic hormone-naïve patients and might have a role in eliminating pre-existing ADT-resistant tumor cells in the neoadjuvant setting. The Cancer and Leukemia Group B (CALGB)/Alliance 90203 trial has finished accrual and should answer the question as to whether neoadjuvant docetaxel-based chemohormonal therapy provides an advantage over prostatectomy alone. There are also several promising targeted agents and immunotherapies under investigation in phase I/II trials with the potential to provide benefit in the neoadjuvant setting.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.

    Bach C et al. The status of surgery in the management of high-risk prostate cancer. Nat Rev Urol. 2014;11(6):342–51.

    Article  PubMed  Google Scholar 

  2. 2.

    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. 2008;53(5):950–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.••

    Chang AJ et al. High-risk prostate cancer-classification and therapy. Nat Rev Clin Oncol. 2014;11(6):308–23. This excellent review provides an overview of the current state of prostate cancer management with a focus on optimal design for future studies.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Mitchell JA et al. Ability of 2 pretreatment risk assessment methods to predict prostate cancer recurrence after radical prostatectomy: data from CaPSURE. J Urol. 2005;173(4):1126–31.

    Article  PubMed  Google Scholar 

  5. 5.

    Cha EK, Eastham JA. Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer. Urol Oncol. 2015;33(5):217–25.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    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(9660):301–8.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Mason MD et al. Final report of the intergroup randomized study of combined androgen-deprivation therapy plus radiotherapy versus androgen-deprivation therapy alone in locally advanced prostate cancer. J Clin Oncol. 2015;33(19):2143–50.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bolla M et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med. 2009;360(24):2516–27.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Hanks GE et al. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92–02. J Clin Oncol. 2003;21(21):3972–8.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Wilt TJ et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203–13.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Garzotto M, Hung AY. Advances in the multimodality management of high-risk prostate cancer. Surg Oncol Clin N Am. 2013;22(2):375–94.

    Article  PubMed  Google Scholar 

  12. 12.

    Bill-Axelson A et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011;364(18):1708–17.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Silberstein JL et al. Reverse stage shift at a tertiary care center: escalating risk in men undergoing radical prostatectomy. Cancer. 2011;117(21):4855–60.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lowrance WT et al. Locally advanced prostate cancer: a population-based study of treatment patterns. BJU Int. 2012;109(9):1309–14.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol. 2014;65(6):1058–66.

    Article  PubMed  Google Scholar 

  16. 16.

    Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case–control study. J Urol. 2015;193(3):832–8.

    Article  PubMed  Google Scholar 

  17. 17.

    Thalgott M et al. Long-term results of a phase II study with neoadjuvant docetaxel chemotherapy and complete androgen blockade in locally advanced and high-risk prostate cancer. J Hematol Oncol. 2014;7:20.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Williams SB, et al. Neoadjuvant systemic therapy before radical prostatectomy in high-risk prostate cancer does not increase surgical morbidity: contemporary results using the Clavien system. Clin Genitourin Cancer. 2015.

  19. 19.

    Stephenson AJ et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol. 2009;27(26):4300–5.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Vallet BS. Radical perineal prostatectomy subsequent to bilateral orchiectomy. Del Med J. 1944;16:18–20.

    Google Scholar 

  21. 21.

    Soloway MS et al. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol. 2002;167(1):112–6.

    Article  PubMed  Google Scholar 

  22. 22.

    Shelley MD et al. A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev. 2009;35(1):9–17.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Chi KN et al. Multicenter phase II study of combined neoadjuvant docetaxel and hormone therapy before radical prostatectomy for patients with high risk localized prostate cancer. J Urol. 2008;180(2):565–70. discussion 570.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Joung JY et al. The prevalence and outcomes of pT0 disease after neoadjuvant hormonal therapy and radical prostatectomy in high-risk prostate cancer. BMC Urol. 2015;15:82.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gleave ME et al. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol. 2001;166(2):500–6. discussion 506–7.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Gleave ME, Goldenberg SL, Chin JL. Randomized comparative study of 3 versus 8-months of neoadjuvant hormonal therapy prior to radical prostatectomy(3 year PSA recurrence rates). J Urol, 2003; 169(179): p. (Abstract 690).

  27. 27.

    Mohler JL et al. Prostate cancer, version 2.2014. J Natl Compr Canc Netw. 2014;12(5):686–718.

    CAS  PubMed  Google Scholar 

  28. 28.

    Mostaghel EA et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67(10):5033–41.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Small EJ. Can targeting the androgen receptor in localized prostate cancer provide insights into why men with metastatic castration-resistant prostate cancer die? J Clin Oncol. 2014;32(33):3689–91.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Spratt DE et al. Androgen receptor upregulation mediates radioresistance after ionizing radiation. Cancer Res. 2015;75(22):4688–96.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Polkinghorn WR et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3(11):1245–53.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ryan CJ et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–48.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Beer TM et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.••

    Taplin ME et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol. 2014;32(33):3705–15. This phase II trial demostrates the potential of novel hormonal agents in the neoadjuvant setting. Phase III trials are underway and much anticipated.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Eigl BJ, Gleave ME, Chi KN. The future of systemic therapies for localised prostate cancer. Clin Oncol (R Coll Radiol). 2013;25(8):506–13.

    CAS  Article  Google Scholar 

  36. 36.

    Shore ND. Experience with degarelix in the treatment of prostate cancer. Ther Adv Urol. 2013;5(1):11–24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Tannock IF et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–12.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Petrylak DP et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–20.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Eigl BJ et al. Timing is everything: preclinical evidence supporting simultaneous rather than sequential chemohormonal therapy for prostate cancer. Clin Cancer Res. 2005;11(13):4905–11.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Dumontet C, Jordan MA. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010;9(10):790–803.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Santer FR, Erb HH, McNeill RV. Therapy escape mechanisms in the malignant prostate. Semin Cancer Biol. 2015;35:133–44.

    Article  PubMed  Google Scholar 

  42. 42.

    Konety BR et al. Feasibility of radical prostatectomy after neoadjuvant chemohormonal therapy for patients with high risk or locally advanced prostate cancer: results of a phase I/II study. J Urol. 2004;171(2 Pt 1):709–13.

    Article  PubMed  Google Scholar 

  43. 43.

    Silberstein JL et al. Long-term oncological outcomes of a phase II trial of neoadjuvant chemohormonal therapy followed by radical prostatectomy for patients with clinically localised, high-risk prostate cancer. BJU Int. 2015;116(1):50–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Prayer-Galetti T et al. Long-term follow-up of a neoadjuvant chemohormonal taxane-based phase II trial before radical prostatectomy in patients with non-metastatic high-risk prostate cancer. BJU Int. 2007;100(2):274–80.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Sella A et al. Neoadjuvant chemohormonal therapy in poor-prognosis localized prostate cancer. Urology. 2008;71(2):323–7.

    Article  PubMed  Google Scholar 

  46. 46.

    Mellado B et al. Phase II trial of short-term neoadjuvant docetaxel and complete androgen blockade in high-risk prostate cancer. Br J Cancer. 2009;101(8):1248–52.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Womble PR et al. A phase II clinical trial of neoadjuvant ketoconazole and docetaxel chemotherapy before radical prostatectomy in high risk patients. J Urol. 2011;186(3):882–7.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Narita S et al. Short-term clinicopathological outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade, followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with high-risk localized prostate cancer. World J Surg Oncol. 2012;10:1.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Zurita AJ et al. Integrating chemohormonal therapy and surgery in known or suspected lymph node metastatic prostate cancer. Prostate Cancer Prostatic Dis. 2015;18(3):276–80.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Tzelepi V et al. Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment. J Clin Oncol. 2011;29(18):2574–81.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.••

    Sweeney CJ et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737–46. This landmark trial demonstrated a substantial survival advantage for docetaxel-based chemohormonal therapy in metastatic hormone-sensitive prostate cancer.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    James ND. et al., Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: first overall survival results from STAMPEDE (NCT00268476). J Clin Oncol. 2015; 33: p. (suppl; abstr 5001).

  53. 53.

    Gravis G et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(2):149–58.

    CAS  Article  PubMed  Google Scholar 

  54. 54.••

    Fizazi K et al. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015;16(7):787–94. This recent trial demonstrated a significant improvement in the composite primary endpoint “relapse-free survival” for docetaxel-based chemohormonal therapy as neoadjuvant therapy in mostly radiation treated patients.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Fizazi K et al. A phase III trial of docetaxel-estramustine in high-risk localised prostate cancer: a planned analysis of response, toxicity and quality of life in the GETUG 12 trial. Eur J Cancer. 2012;48(2):209–17.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Eastham JA et al. Cancer and Leukemia Group B (CALGB) 90203: a randomized phase 3 study of radical prostatectomy alone versus estramustine and docetaxel before radical prostatectomy for patients with high-risk localized disease. Urology. 2003;62 Suppl 1:55–62.

    Article  PubMed  Google Scholar 

  57. 57.

    Lou DY, L Fong. Neoadjuvant therapy for localized prostate cancer: examining mechanism of action and efficacy within the tumor. Urol Oncol, 2014.

  58. 58.

    Arrowsmith J, Miller P. Trial watch: phase II and phase III attrition rates 2011–2012. Nat Rev Drug Discov. 2013;12(8):569.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Rajan P et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. Eur Urol. 2014;66(1):32–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Grasso CS et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239–43.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Cancer Genome Atlas Research Network. Cancer Genome Atlas Research, The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015;163(4):1011–25.

    Article  Google Scholar 

  62. 62.

    Robinson D et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Barnett CM et al. Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer. Clin Cancer Res. 2014;20(5):1306–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Rajpar S, et al. A study of ERG, PTEN, and ki-67 in a phase III trial assessing docetaxel and estramustine in high-risk localized prostate cancer (GETUG 12). J Clin Oncol. 2014; 32(5s): p. (suppl; abstr 5063).

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Acknowledgments

The study was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, funds provided by David H. Koch through the Prostate Cancer Foundation, and the National Institutes of Health/National Cancer Institute Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center under award number P30 CA008748.

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Correspondence to Eugene J. Pietzak or James A. Eastham.

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Eugene J. Pietzak and James A. Eastham each declare no potential conflicts of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Prostate Cancer

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Pietzak, E.J., Eastham, J.A. Neoadjuvant Treatment of High-Risk, Clinically Localized Prostate Cancer Prior to Radical Prostatectomy. Curr Urol Rep 17, 37 (2016). https://doi.org/10.1007/s11934-016-0592-4

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Keywords

  • Chemohormonal therapy
  • Neoadjuvant therapy
  • Prostate cancer
  • Radical prostatectomy