Today, because of prostate-specific antigen (PSA) screening, prostate cancer in most patients is detected earlier and at younger ages than in the past. Despite this early detection and after definitive therapy, whether by radical prostatectomy (RP) or radiation therapy (RT), a biochemical recurrence will develop within 10 years of treatment in about 35% of men.1,2 With about 230,000 cases of prostate cancer diagnosed each year in the United States, it is estimated that a PSA-only recurrence develops in more than 50,000 men per year.3
Although the natural history of PSA recurrence can be long,4 recent studies have helped us stratify men for varying risk of clinical progression and prostate cancer death with ever-increasing accuracy.4-7 In this review, we discuss PSA recurrence after primary therapy. We focus on the definition of recurrence, the natural history and risk factors for progression, the role of salvage therapies aimed at cure or palliation, and the timing of these therapies. We also offer advice on how to incorporate this information into clinical practice.
PSA RECURRENCE DEFINED
During RP, essentially all PSA-producing cells should have been removed. Therefore, slight elevations in PSA levels are used to indicate cancer recurrence. The exact level that defines PSA recurrence is debated, however. In general, a PSA level higher than 0.4 or 0.2 ng/mL has been used in most studies.8,9
PSA levels do not fall to undetectable levels after RT as they do after RP. Rather, radiation induces a slow and not always steady decline in PSA level. The median time to PSA nadir is about 18 months--and possibly longer following brachytherapy. In addition, slight transient upswings in PSA levels (PSA bounce) are not uncommon. Therefore, defining recurrence in this setting is more challenging.
In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) convened a consensus panel whose members defined recurrence after RT as 3 consecutive elevated PSA values after reaching a nadir, or a single elevated value significant enough to trigger the initiation of hormone therapy.10 The failure date is backdated to the midpoint between PSA nadir and the first of the 3 elevated PSA values. This backdating introduces a bias that overestimates the success at shorter follow-up times (not enough follow-up has occurred to document failure). Moreover, in long-term follow-up studies, the failures are backdated to an earlier point in time, resulting in a leveling of the Kaplan-Meier curve, in contrast to outcomes after RP in which PSA-free survival continues to decline over time.11
Because of the concerns mentioned above, ASTRO recently convened a new consensus panel that redefined recurrence: a PSA value higher than absolute nadir plus 2 ng/mL or a PSA value higher than absolute nadir plus 3 ng/mL.12 Both define the failure date as that when recurrence was met (ie, failure time is no longer backdated).
NATURAL HISTORY OF PSA RECURRENCE
The natural history of PSA recurrence can be quite long but varies. In a classic study at Johns Hopkins University, Pound and associates4 described 315 men with PSA failure following RP who did not receive hormonal therapy until the time of metastasis. The median time from PSA recurrence to metastasis was 8 years, and the median time from metastasis to death was 5 years.
In a recent follow-up study from Johns Hopkins that included a slightly larger cohort, the median time from PSA recurrence to prostate cancer death was not reached after 16 years of follow-up.6 However, prostate cancer deaths were seen as early as 1 year after PSA recurrence, although with very rare frequency. Thus, the natural history of recurrent prostate cancer is one of a slowly progressing disease, but in some men the progression can be quite rapid.
1. Han M, Partin AW, Pound CR, et al. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. 2001;28:555-565.
2. Djavan B, Moul JW, Zlotta A, et al. PSA progression following radical prostatectomy and radiation therapy: new standards in the new millennium. Eur Urol. 2003;43:12-27.
3. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol. 2000;163:1632-1642.
4. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281: 1591-1597.
5. D'Amico AV, Moul JW, Carroll PR, et al. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95:1376-1383.
6. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294:433-439.
7. Ward JF, Blute ML, Slezak J, et al. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol. 2003;170:1872-1876.
8. Amling CL, Bergstralh EJ, Blute ML, et al. Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol. 2001;165:1146-1151.
9. Freedland SJ, Sutter ME, Dorey F, Aronson WJ. Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology. 2003;61:365-369.
10. Horwitz EM, Vicini FA, Ziaja EL, et al. The correlation between the ASTRO Consensus Panel definition of biochemical failure and clinical outcome for patients with prostate cancer treated with external beam irradiation. American Society of Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys. 1998;41:267-272.
11. Amling CL, Blute ML, Bergstralh EJ, et al. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol. 2000; 164:101-105.
12. Horwitz EM, Thames HD, Kuban DA, et al. Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis. J Urol. 2005;173:797-802.
13. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992;267:2215-2220.
14. Zagars GK, Pollack A. The fall and rise of prostate-specific antigen. Kinetics of serum prostate-specific antigen levels after radiation therapy for prostate cancer. Cancer. 1993;72:832-842.
15. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol. 1994;152:1821-1825.
16. Okotie OT, Aronson WJ, Wieder JA, et al. Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. J Urol. 2004;171:2260-2264.
17. Kane CJ, Amling CL, Johnstone PA, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology. 2003;61:607-611.
18. Sartor CI, Strawderman MH, Lin XH, et al. Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy. Int J Radiat Oncol Biol Phys. 1997;38:941-947.
19. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology. 1994;43:649-659.
20. Albertsen PC, Hanley JA, Penson DF, Fine J. Validation of increasing prostate specific antigen as a predictor of prostate cancer death after treatment of localized prostate cancer with surgery or radiation. J Urol. 2004;171:2221-2225.
21. D'Amico AV, Cote K, Loffredo M, et al. Determinants of prostate cancer-specific survival after radiation therapy for patients with clinically localized prostate cancer. J Clin Oncol. 2002;20:4567-4573.
22. Patel A, Dorey F, Franklin J, deKernion JB. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol. 1997;158:1441-1445.
23. Zagars GK, Pollack A. Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer. Radiother Oncol. 1997;44:213-221.
24. Kim-Sing C, Pickles T; Prostate Cohort Outcomes Initiative. Intervention after PSA failure: examination of intervention time and subsequent outcomes from a prospective patient database. Int J Radiat Oncol Biol Phys. 2004;60:463-469.
25. Pinover WH, Horwitz EM, Hanlon AL, et al. Validation of a treatment policy for patients with prostate specific antigen failure after three-dimensional conformal prostate radiation therapy. Cancer. 2003;97:1127-1133.
26. Roberts SG, Blute ML, Bergstralh EJ, et al. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin Proc. 2001;76: 576-581.
27. Hanlon AL, Diratzouian H, Hanks GE. Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer. Int J Radiat Oncol Biol Phys. 2002;53:297-303.
28. Leventis AK, Shariat SF, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy [published correction appears in J Clin Oncol. 2001;19:2109]. J Clin Oncol. 2001;19: 1030-1039.
29. Chawla AK, Thakral HK, Zietman AL, Shipley WU. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology. 2002;59:726-731.
30. Cadeddu JA, Partin AW, DeWeese TL, Walsh PC. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol. 1998;159:173-178.
31. Koppie TM, Grossfeld GD, Nudell DM, et al. Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol. 2001;166: 111-115.
32. Nudell DM, Grossfeld GD, Weinberg VK, et al. Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology. 1999;54: 1049-1057.
33. Liauw SL, Webster WS, Pistenmaa DA, Roehrborn CG. Salvage radiotherapy for biochemical failure of radical prostatectomy: a single-institution experience. Urology. 2003;61:1204-1210.
34. Katz MS, Zelefsky MJ, Venkatraman ES, et al. Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol. 2003;21:483-489.
35. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291: 1325-1332.
36. Vanuytsel L, Janssens G, Van Poppel H, et al. Radiotherapy for PSA recurrence after radical prostatectomy. Eur Urol. 2001;39:425-429.
37. Anscher MS, Clough R, Dodge R. Radiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys. 2000;48:369-375.
38. Ward JF, Zincke H, Bergstralh EJ, et al. Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy. J Urol. 2004;172:2244-2248.
39. MacDonald OK, Schild SE, Vora S, et al. Salvage radiotherapy for men with isolated rising PSA or locally palpable recurrence after radical prostatectomy: do outcomes differ? Urology. 2004;64:760-764.
40. Cox JD, Gallagher MJ, Hammond EH, et al. Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel. J Clin Oncol. 1999;17:1155.
41. Ward JF, Sebo TJ, Blute ML, Zincke H. Salvage surgery for radiorecurrent prostate cancer: contemporary outcomes. J Urol. 2005;173:1156-1160.
42. Gheiler EL, Tefilli MV, Tiguert R, et al. Predictors for maximal outcome in patients undergoing salvage surgery for radio-recurrent prostate cancer. Urology. 1998;51:789-795.
43. Garzotto M, Wajsman Z. Androgen deprivation with salvage surgery for radiorecurrent prostate cancer: results at 5-year followup. J Urol. 1998;159: 950-955.
44. Bianco FJ Jr, Scardino PT, Stephenson AJ, et al. Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62: 448-453.
45. Stephenson AJ, Scardino PT, Bianco FJ Jr, et al. Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol. 2004;172:2239-2243.
46. Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol. 2003;170:1126-1130.
47. Anastasiadis AG, Sachdev R, Salomon L, et al. Comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer. J Cancer Res Clin Oncol. 2003;129:676-682.
48. Huggins C, Hodges CV. Studies on prostatic cancer, I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168:9-12.
49. Bhandari MS, Crook J, Hussain M. Should intermittent androgen deprivation be used in routine clinical practice? J Clin Oncol. 2005;23:8212-8218.
50. Penson DF, Litwin MS. The physical burden of prostate cancer. Urol Clin North Am. 2003;30:305-313.
51. Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA. 2005; 294:238-244.
52. Bayoumi AM, Brown AD, Garber AM. Cost- effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst. 2000; 92:1731-1739.
53. Labrie F, Belanger A, Luu-The V, et al. Gonadotropin-releasing hormone agonists in the treatment of prostate cancer. Endocr Rev. 2005;26:361-379.
54. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Prostate Cancer Trialists' Collaborative Group. Lancet. 1995;346: 265-269.
55. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. 2000;355:1491-1498.
56. Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer. 2002;95:361-376.
57. Klotz L, Schellhammer P. Combined androgen blockade: the case for bicalutamide. Clin Prostate Cancer. 2005;3:215-219.
58. Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr. 1988;7:165-170.
59. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol. 1997;79:235-246.
60. Kirk D. Immediate vs deferred hormone treatment for prostate cancer: how safe is androgen deprivation? Br J Urol. 2000;86(suppl 3):S220.
61. Walsh PC. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. J Urol. 1997;158:1623-1624.
62. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:1781-1788.
63. Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol. 2004;171:1141-1147.
64. Bales GT, Chodak GW. A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology. 1996;47(suppl 1A): 38-43.
65. Iversen P, Tyrrell CJ, Kaisary AV, et al. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup. J Urol. 2000;164:1579- 1582.
66. Wirth MP, See WA, McLeod DG, et al; Casodex Early Prostate Cancer Trialists' Group. Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years. J Urol. 2004;172:1865-1870.
67. Di Lorenzo G, Perdona S, De Placido S, et al. Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy. J Urol. 2005;174:2197-2203.