Korean J Urol.  2014 Mar;55(3):153-160. 10.4111/kju.2014.55.3.153.

Nonmetastatic Castration-Resistant Prostate Cancer

Affiliations
  • 1Department of Urology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
  • 2Urologic Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. kimiy@cinj.rutgers.edu

Abstract

After the introduction of prostate cancer screening with the prostate-specific antigen (PSA) test, we have witnessed a dramatic stage migration. As a result, an increasing number of patients are diagnosed at earlier stages and receive local treatments including surgery or radiation. When these local treatments fail by the definition of increasing PSA levels, patients are usually treated with androgen-deprivation therapy. A fraction of these patients will finally reach a state of castration-resistant prostate cancer (CRPC) even without radiological evidence of metastasis, which is referred to as nonmetastatic CRPC (NM-CRPC). Most men with advanced or metastatic prostate cancer initially respond to various types of androgen ablation, but a considerable portion of them eventually progress to NM-CRPC. Among patients with NM-CPRC, about one-third will develop bone metastasis within 2 years. In these patients, PSA kinetics is the most powerful indicator of progression and is usually used to trigger further imaging studies and enrollment in clinical trials. Although CRPC remains largely driven by the androgen receptor, the benefit of second-line hormonal manipulations, including first-generation antiandrogens, adrenal synthesis inhibitors, and steroids, has not been investigated in men with NM-CRPC. To date, denosumab is the only agent that has been shown to delay the onset of bone metastasis. However, overall survival did not differ. In treating NM-CRPC patients, physicians should recognize the heterogeneity of the disease and acknowledge that the recently approved second-line treatments have been studied only in advanced stages of the disease.

Keyword

Castration-resistant prostatic neoplasm; Neoplasm metastasis; Prostate-specific antigen

MeSH Terms

Androgen Antagonists
Humans
Kinetics
Male
Mass Screening
Neoplasm Metastasis
Population Characteristics
Prostate*
Prostate-Specific Antigen
Prostatic Neoplasms*
Prostatic Neoplasms, Castration-Resistant
Receptors, Androgen
Steroids
Androgen Antagonists
Prostate-Specific Antigen
Receptors, Androgen
Steroids

Reference

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014; 64:9–29.
2. Jung KW, Won YJ, Kong HJ, Oh CM, Seo HG, Lee JS. Cancer statistics in Korea: incidence, mortality, survival and prevalence in 2010. Cancer Res Treat. 2013; 45:1–14.
3. Kim D, Choi D, Lim JH, Yoon JH, Jeong IG, You D, et al. Changes in prostate cancer aggressiveness over a 12-year period in Korea. Korean J Urol. 2012; 53:680–685.
4. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008; 26:1148–1159.
5. Akaza H. Asian trends in primary androgen depletion therapy on prostate cancer. Cancer Biol Med. 2013; 10:187–191.
6. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011; 65:1180–1192.
7. Kim SJ, Kim SI. Current treatment strategies for castration-resistant prostate cancer. Korean J Urol. 2011; 52:157–165.
8. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU Guidelines on Prostate Cancer. Part II: Treatment of Advanced, Relapsing, and Castration-Resistant Prostate Cancer. Eur Urol. 2014; 65:467–479.
9. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 1999; 17:3461–3467.
10. Smith MR, Kabbinavar F, Saad F, Hussain A, Gittelman MC, Bilhartz DL, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005; 23:2918–2925.
11. Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer. 2011; 117:2077–2085.
12. Tombal B, Lecouvet F. Modern detection of prostate cancers bone metastasis: is the bone scan era over? Adv Urol. 2012; 2012:893193.
13. Yu EY, Miller K, Nelson J, Gleave M, Fizazi K, Moul JW, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol. 2012; 188:103–109.
14. Smith MR, Saad F, Oudard S, Shore N, Fizazi K, Sieber P, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013; 31:3800–3806.
15. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351:1502–1512.
16. Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol. 2012; 23:Suppl 10. x251–x258.
17. NCCN clinical practice guideline in oncology: prostate cancer, version 4.2013 [Internet]. Fort Wathington: National Comprehensive Cancer Network;c2012. cited 2014 Jan 14. Available from: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.
18. Cookson MS, Roth BJ, Dahm P, Engstrom C, Freedland SJ, Hussain M, et al. Castration-resistant prostate cancer: AUA Guideline. J Urol. 2013; 190:429–438.
19. Botticella A, Guarneri A, Filippi AR, Levra NG, Munoz F, Ragona R, et al. May non-metastatic clinically localized castration-resistant prostate cancer after primary androgen ablation benefit from salvage prostate radiotherapy? J Cancer Res Clin Oncol. 2013; 139:1955–1960.
20. Gontero P, Spahn M, Marchioro G, Karnes JR, Briganti A, Frea B, et al. Salvage radical prostatectomy in nonmetastatic castration-resistant prostate cancer patients who received previous radiotherapy: a feasibility study. Eur Urol. 2014; 65:254–255.
21. Chade DC, Eastham J, Graefen M, Hu JC, Karnes RJ, Klotz L, 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; 61:961–971.
22. Kelly WK, Scher HI. Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol. 1993; 149:607–609.
23. Small EJ, Carroll PR. Prostate-specific antigen decline after casodex withdrawal: evidence for an antiandrogen withdrawal syndrome. Urology. 1994; 43:408–410.
24. Sartor AO, Tangen CM, Hussain MH, Eisenberger MA, Parab M, Fontana JA, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. 2008; 112:2393–2400.
25. Suzuki H, Okihara K, Miyake H, Fujisawa M, Miyoshi S, Matsumoto T, et al. Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade. J Urol. 2008; 180:921–927.
26. Narimoto K, Mizokami A, Izumi K, Mihara S, Sawada K, Sugata T, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010; 17:337–345.
27. Lodde M, Lacombe L, Fradet Y. Salvage therapy with bicalutamide 150 mg in nonmetastatic castration-resistant prostate cancer. Urology. 2010; 76:1189–1193.
28. Sartor O, Gomella LG, Gagnier P, Melich K, Dann R. Dutasteride and bicalutamide in patients with hormone-refractory prostate cancer: the Therapy Assessed by Rising PSA (TARP) study rationale and design. Can J Urol. 2009; 16:4806–4812.
29. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole [Internet]. London: European medicines agency;c2013. updated 2013 Jul 26. cited 2014 Jan 19. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001855.jsp.
30. Tombal B, Berges R. Optimal control of testosterone: a clinical case-based approach of modern androgen-deprivation therapy. Eur Urol Suppl. 2008; 7:15–21.
31. Morote J, Orsola A, Planas J, Trilla E, Raventos CX, Cecchini L, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007; 178:1290–1295.
32. Lawrentschuk N, Fernandes K, Bell D, Barkin J, Fleshner N. Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. J Urol. 2011; 185:848–854.
33. Mason MD, Sydes MR, Glaholm J, Langley RE, Huddart RA, Sokal M, et al. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst. 2007; 99:765–776.
34. Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol. 2009; 10:872–876.
35. Nelson JB, Love W, Chin JL, Saad F, Schulman CC, Sleep DJ, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008; 113:2478–2487.
36. Miller K, Moul JW, Gleave M, Fizazi K, Nelson JB, Morris T, et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2013; 16:187–192.
37. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012; 379:39–46.
38. Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. 2008; 14:4526–4531.
39. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009; 115:3670–3679.
40. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010; 363:411–422.
41. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006; 24:3089–3094.
42. Kawalec P, Paszulewicz A, Holko P, Pilc A. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. A systematic review and meta-analysis. Arch Med Sci. 2012; 8:767–775.
43. Attard G, Reid AH, AHern R, Parker C, Oommen NB, Folkerd E, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009; 27:3742–3748.
44. Safety and efficacy study of enzalutamide in patients with nonmetastatic castration-resistant prostate cancer (PROSPER) [Internet]. Bethesda: U.S. National Institutes of Health;c2013. updated 2014 Jan 7. cited 2014 Jan 16. Available from: http://clinicaltrials.gov/show/NCT02003924.
45. A study of ARN-509 in men with non-metastatic castration-resistant prostate cancer (SPARTAN) [Internet]. Bethesda: U.S. National Institutes of Health;c2013. updated 2014 Jan 9. cited 2014 Jan 18. Available from: http://clinicaltrials.gov/show/NCT01946204.
46. Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2013; 31:3525–3530.
47. Safety and efficacy study of TAK-700 in patients with nonmetastatic castration-resistant prostate cancer and a rising prostate-specific antigen [Internet]. Bethesda: U.S. National Institutes of Health;c2010. updated 2013 Nov 15. cited 2014 Jan 18. Available from: http://clinicaltrials.gov/show/NCT01046916.
48. Heath EI, Heilbrun LK, Li J, Vaishampayan U, Harper F, Pemberton P, et al. A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3'-Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res. 2010; 2:402–411.
49. Morris MJ, Huang D, Kelly WK, Slovin SF, Stephenson RD, Eicher C, et al. Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer. Eur Urol. 2009; 56:237–244.
50. Manni A, Bartholomew M, Caplan R, Boucher A, Santen R, Lipton A, et al. Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. J Clin Oncol. 1988; 6:1456–1466.
51. Gardiner RA, Sweeney C, Tilley WD. Testosterone therapy in castrate-resistant prostate cancer: a possible new approach. Eur Urol. 2009; 56:245–246.
52. A randomized, double blind, placebo-controlled phase II study of testosterone replacement in men with non-metastatic castrate resistant prostate cancer [Internet]. Bethesda: U.S. National Institutes of Health;c2007. updated 2014 Jan 16. cited 2014 Jan 25. Available from: http://clinicaltrials.gov/ct2/show/NCT00515112.
53. Ogita S, Tejwani S, Heilbrun L, Fontana J, Heath E, Freeman S, et al. Pilot phase II trial of bevacizumab monotherapy in nonmetastatic castrate-resistant prostate cancer. ISRN Oncol. 2012; 2012:242850.
54. Gravis G, Bladou F, Salem N, Goncalves A, Esterni B, Walz J, et al. Results from a monocentric phase II trial of erlotinib in patients with metastatic prostate cancer. Ann Oncol. 2008; 19:1624–1628.
55. Nabhan C, Lestingi TM, Galvez A, Tolzien K, Kelby SK, Tsarwhas D, et al. Erlotinib has moderate single-agent activity in chemotherapy-naive castration-resistant prostate cancer: final results of a phase II trial. Urology. 2009; 74:665–671.
56. Study of erlotinib in patients with non-metastatic prostate cancer with a rising prostate specific antigen (PSA) on hormone therapy [Internet]. Bethesda: U.S. National Institutes of Health;c2005. updated 2011 Jun 24. cited 2014 Jan 25. Available from: http://clinicaltrials.gov/ct2/show/study/NCT00148772.
57. Study of lanreotide in non metastatic castration-resistant prostate cancer patients (POSEIDON) [Internet]. Bethesda: U.S. National Institutes of Health;c2011. updated 2013 Apr 23. cited 2014 Jan 18. Available from: http://clinicaltrials.gov/show/NCT01313273.
58. Friedlander TW, Weinberg VK, Small EJ, Sharib J, Harzstark AL, Lin AM, et al. Effect of the somatostatin analog octreotide acetate on circulating insulin-like growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: results of a phase II study. Urol Oncol. 2012; 30:408–414.
59. Alva A, Slovin S, Daignault S, Carducci M, Dipaola R, Pienta K, et al. Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735 A study by the DOD/PCF prostate cancer clinical trials consortium. Invest New Drugs. 2012; 30:749–757.
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