Radiotherapy is given for salvage after RP in 3 settings: (1) for a DR-PSA after the PSA has dropped to an undetectable level immediately postprostatectomy, (2) for a persistently detectable PSA after surgery, and (3) for treatment of a palpable recurrence within the prostatic fossa. This division may be important because the initial considerations in evaluation may be different, and there are reports of a distinction in prognosis. However, many retrospective series were based on small patient numbers and did not separate these patients, making conclusions difficult.
The time to a rising PSA after prostatectomy, the prostatectomy Gleason score, and the PSA doubling time (PSADT) are independent predictors of distant metastasis and mortality.25,26 When the time to BF is <3 years (the PD-PSA patients would be included in this group), Gleason score is ≥8, and PSADT is <9 months, the risk of death due to prostate cancer at 5 years is ≥19%.26 This risk increases to ≥74% at 10 years. PSADT has taken on much more importance over the last 5 years.42,53,54 If the above parameters included a postoperative PSADT of <3 months, nearly 50% will die within 5 years. Even the PSA kinetics prior to prostatectomy may be an independent determinant of mortality.55–57 A rapidly rising PSA prior to RP or prior to RT connotes a poor prognosis, suggestive of occult metastatic disease even if the metastatic workup is negative. Although our ability to predict progression after SRT has improved, we are a long way from making conclusive judgments on whether SRT would benefit most men. There is a need to optimize treatment selection with the goal of prolonging survival without unnecessary toxicity, particularly in the setting of rapid PSA kinetics.
Factors indicating that postprostatectomy RT for a PD-PSA might be beneficial include extensive extraprostatic extension (particularly in those with high-grade disease) or positive margins. Other indicators that there may be disease in the prostatic fossa are SVI, a cut-through of the prostate (a partial prostatectomy when there is palpable, biopsy, or imaging evidence of prostate remaining), or incomplete removal of the seminal vesicles in the setting of T3 disease (especially with ECE at the base or with SVI). In the absence of these features and with a PSA that is rising quickly (doubling time <6 months), the probability of distant metastasis is high,25,53,58–60 and SRT is discouraged.
The results of SRT have been relatively poor, with 5-year FFBF rates in most series ranging from 10% to 66%.3–6,41,59,61–66 The following factors have been correlated with worse FFBF rates: Gleason score >7, SVI, high pre-RT PSA (>1 to >2.5 ng/mL), short PSADT, negative prostatectomy margins, treatment for a PD-PSA (vs. a DR-PSA), a palpable prostatic fossa mass, and RT dose <65 Gy.
In general, when the PSA remains detectable after RP, the risk of distant metastasis is greater than when the PSA goes to undetectable and then rises later. Thus, outcomes of SRT in most series have been worse for patients with a PD-PSA compared with a DR-PSA.3,4,6,63 However, some series have not found a significant difference in FFBF rates between the 2 groups.5,42,65,67 While distinguishing between the groups seems to be the most objective way of evaluating the utility of SRT, most of the studies reporting SRT outcomes do not separately analyze the DR-PSA and the PD-PSA patients. In addition, all of these studies are retrospective, and most include small numbers of patients.
As described earlier in the text, the PSADT is an important predictor of SRT outcome. The shorter it is, the greater the risk of death due to prostate cancer. A doubling time of ≤10 months in the setting of a DR-PSA or a PD-PSA indicates a higher likelihood of occult metastatic disease,25,42,53,58–60 thus rendering postoperative RT much less effective. Another study showed that a PSADT of ≥5 months predicted a response to SRT (a response was defined as a PSA nadir of ≤0.1 ng/mL).68 One caveat concerning the PSADT as a reliable predictor of distant metastasis is that when the PSA is below 1 ng/mL, the estimates may be inaccurate.60,69,70 In reports of postoperative RT, few have identified PSADT as a predictor of FFBF. In a preliminary recursive partitioning analysis of about 1200 men in a pooled multi-institutional database, PSADT was not independently related to outcome, while pre-RT PSA, Gleason score, and margin status were.71 Standards are needed for when the PSADT calculation begins (from the PSA just prior to when an accelerated rise occurs or from the time of the first detectable PSA) and the minimum number of PSA values required to accurately calculate a PSADT.
The pre-RT PSA has been found to be the most consistent predictor of FFBF in both univariate and multivariate analyses of SRT.72–75 While a clear pre-RT PSA cutpoint has not yet been defined, evidence suggests that lower pre-RT PSAs are associated with higher FFBF rates. The best results have been seen when the pre-RT PSA is ≤1 ng/mL. A significant decline in FFBF is seen when the pre-RT PSA increases from ≤1 ng/mL to 2, and then to >2 ng/mL.
Other important prognostic factors include the Gleason score, margin status, and seminal vesicle invasion. Gleason scores of ≤7 predict for a better prognosis compared with scores of 8 to 10. A positive margin often indicates residual disease in the prostate bed, for which SRT is effective, and FFBF rates are higher when this is the case. Seminal vesicle invasion has been found to be a determinant of outcome in multivariate analysis in many series as well, with worse FFBF rates when the seminal vesicles were involved, due to these patients being at a higher risk of developing subsequent metastatic failure (Table 3).3,41,42
The use of concurrent ADT with ART and SRT could impact the course of the disease hypothetically by 3 principal mechanisms: (1) better disease eradication locally (recurrence in a hypoxic scar may be radioresistant), (2) improved disease control distantly (cells in microscopic metastatic deposits might retain sensitivity to ADT), and (3) the combination of ADT and RT may alter the PSA kinetics in patients who eventually relapse.76,77 The mechanism of the effect on the kinetics of BF and the delayed appearance of distant metastasis is unknown. However, any improvement upon the current results of ART and SRT is potentially worthwhile. In some reports,4,6,41,78–83 ADT had positive results in patients at high risk of experiencing a rising PSA after SRT (eg, a pre-RT PSA >1 ng/mL). Randomized trials are needed and are in progress (Table 4).
The optimal timing of ART versus SRT for patients with high-risk pathologic features remains controversial. Some have supported watchful waiting before administering SRT.84 This rationale is based on 3 points. First, half of men will be treated unnecessarily. Second, salvage rates are fairly good when the pre-RT PSA is low (≤1.0 ng/mL).61,78,85–87 Third, the progression to distant metastasis after BF may be long.25,26 It is beyond the scope of this article to compare ART to SRT in depth; however, it should be noted that the addition of SRT to patients who were originally in the observation arm of the Southwest Oncology Group randomized trial still resulted in a higher rate of metastatic failure in these patients compared with early adjuvant therapy.51 Without a randomized trial to eliminate selection bias, it is impossible to ascribe an advantage to 1 strategy over the other based on FFBF outcomes. At least ART has a proven benefit in randomized prospective studies, supporting first principles that RT treatment should be used if the risk of local failure is >20% and the side effect profile is reasonable. Local persistence leads to distant metastasis in most malignancies, and there is evidence that this is the case for prostate cancer.88–91 In younger men with a long life expectancy, ART should be considered.
LNI portends a very poor prognosis, with a high rate of distant failure. Although there are emerging data indicating that RP or RT should be used along with ADT when LNI is identified,92 there is no well-established benefit from this approach as yet. ART might be of some value when there is evidence of an appreciable locoregional tumor burden, such as extensive positive margins. There are insufficient data on the subject of pelvic nodal irradiation to make any recommendations, even when LNI has been documented (Table 5).93
1. Bottke D, de Reijke TM, Bartkowiak D, et al. Salvage radiotherapy in patients with persisting/rising PSA after radical prostatectomy for prostate cancer. Eur J Cancer
. 2009;45(suppl 1):148–157.
2. Choo R, Hruby G, Hong J, et al. (IN)-efficacy of salvage radiotherapy for rising PSA or clinically isolated local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys
3. Chawla AK, Thakral HK, Zietman AL, et al. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology
4. Taylor N, Kelly JF, Kuban DA, et al. Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys
5. Garg MK, Tekyi-Mensah S, Bolton S, et al. Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology
6. Song DY, Thompson TL, Ramakrishnan V, et al. Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology
7. Kupelian P, Katcher J, Levin H, et al. Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology
8. Epstein JI, Partin AW, Sauvageot J, et al. Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol
9. Pound CR, Partin AW, Epstein JI, et al. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Urol Clin North Am
10. Ramos C, Carvalhal G, Smith D, et al. Clinical and pathological characteristics, and recurrence rates of stage T1C versus T2A or T2B prostate cancer. J Urol
11. Gilliland FD, Hoffman RM, Hamilton A, et al. Predicting extracapsular extension of prostate cancer in men treated with radical prostatectomy: results from the population based prostate cancer outcomes study. J Urol
12. Cheng L, Slezak J, Bergstralh EJ, et al. Preoperative prediction of surgical margin status in patients with prostate cancer treated by radical prostatectomy. J Clin Oncol
13. Shah O, Robbins DA, Melamed J, et al. The New York University nerve sparing algorithm decreases the rate of positive surgical margins following radical retropubic prostatectomy. J Urol
14. Cagiannos I, Karakiewicz P, Eastham JA, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol
15. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol
16. Roehl KA, Han M, Ramos CG, et al. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3478 consecutive patients: long-term results. J Urol
17. Hull GW, Rabbani F, Abbas F, et al. Cancer control with radical prostatectomy alone in 1000 consecutive patients. J Urol
. 2002;167(2 pt 1):528–534.
18. Oesterling JE, Epstein JI, Walsh PC. Long-term autopsy findings following radical prostatectomy. Urology
19. Saleem MD, Sanders H, Abu El Naser M, et al. Factors predicting cancer detection in biopsy of the prostatic fossa after radical prostatectomy. Urology
20. Foster LS, Jajodia P, Fournier G Jr, et al. The value of prostate specific antigen and transrectal ultrasound guided biopsy in detecting prostatic fossa recurrences following radical prostatectomy. J Urol
21. Naya Y, Okihara K, Evans RB, et al. Efficacy of prostatic fossa biopsy in detecting local recurrence after radical prostatectomy. Urology
22. Trapasso JG, deKernion JB, Smith RB, et al. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol
. 1994;152(5 pt 2):1821–1825.
23. Catalona W, Smith D. Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol
24. 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
25. Pound C, Partin A, Eisenberger M, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA
26. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA
27. Paulson DF. Impact of radical prostatectomy in the management of clinically localized disease. J Urol
. 1994;152(5 pt 2):1826–1830.
28. Zietman AL, Edelstein RA, Coen JJ, et al. Radical prostatectomy for adenocarcinoma of the prostate: the influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology
29. Epstein JI. Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am
30. Watson RB, Civantos F, Soloway MS. Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. Urology
31. Kupelian PA, Katcher J, Levin HS, et al. Stage T1–2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys
32. Kausik SJ, Blute ML, Sebo TJ, et al. Prognostic significance of positive surgical margins in patients with extraprostatic carcinoma after radical prostatectomy. Cancer
33. Karakiewicz PI, Eastham JA, Graefen M, et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi-institutional assessment of 5831 patients. Urology
34. Jones EC. Resection margin status in radical retropubic prostatectomy specimens: relationship to type of operation, tumor size, tumor grade and local tumor extension. J Urol
35. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer
36. Epstein JI, Pound CR, Partin AW, et al. Disease progression following radical prostatectomy in men with Gleason score 7 tumor. J Urol
. 1998;160:97–100; discussion 101.
37. Obek C, Sadek S, Lai S, et al. Positive surgical margins with radical retropubic prostatectomy: anatomic site-specific pathologic analysis and impact on prognosis. Urology
38. Emerson RE, Koch MO, Jones TD, et al. The influence of extent of surgical margin positivity on prostate specific antigen recurrence. J Clin Pathol
39. Freedland SJ, Aronson W, Presti JC Jr, et al. Should a positive surgical margin following radical prostatectomy be pathological stage T2 or T3? Results from the SEARCH database. J Urol
40. Wheeler TM, Dillioglugil O, Kattan MW, et al. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1–T2 prostate cancer. Hum Pathol
41. 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
42. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA
43. Valicenti RK, Gomella LG, Perez CA. Radiation therapy after radical prostatectomy: a review of the issues and options. Semin Radiat Oncol
44. Leibovich BC, Engen DE, Patterson DE, et al. Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin. J Urol
45. Do LV, Do TM, Smith R, et al. Postoperative radiotherapy for carcinoma of the prostate: impact on both local control and distant disease-free survival. Am J Clin Oncol
46. Petrovich Z, Lieskovsky G, Stein JP, et al. Comparison of surgery alone with surgery and adjuvant radiotherapy for pT3N0 prostate cancer. BJU Int
47. Vargas C, Kestin LL, Weed DW, et al. Improved biochemical outcome with adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Radiat Oncol Biol Phys
48. Lee HM, Solan MJ, Lupinacci P, et al. Long-term outcome of patients with prostate cancer and pathologic seminal vesicle invasion (pT3b): effect of adjuvant radiotherapy. Urology
49. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet
50. Swanson GP. Phase III randomized study of adjuvant radiation therapy versus observation in patients with pathologic T3 prostate cancer (SWOG 8794). Int J Radiat Oncol Biol Phys
. 2005;63(2 suppl 1):S1.
51. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term follow-up of a randomized clinical trial. J Urol
52. Wiegel T, Bottke D, Steiner U, 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
53. 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
54. 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
55. Sengupta S, Myers RP, Slezak JM, et al. Preoperative prostate specific antigen doubling time and velocity are strong and independent predictors of outcomes following radical prostatectomy. J Urol
56. Patel DA, Presti JC Jr, McNeal JE, et al. Preoperative PSA velocity is an independent prognostic factor for relapse after radical prostatectomy. J Clin Oncol
57. D'Amico AV, Chen MH, Roehl KA, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med
58. Patel A, Dorey F, Franklin J, et al. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol
59. Leventis AK, Shariat SF, Kattan MW, et al. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol
60. 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
61. Brooks JP, Albert PS, Wilder RB, et al. Long-term salvage radiotherapy outcome after radical prostatectomy and relapse predictors. J Urol
. 2005;174:2204–2208; discussion 2208.
62. Nudell DM, Grossfeld GD, Weinberg VK, et al. Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology
63. 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
64. Mosbacher MR, Schiff PB, Otoole KM, et al. Postprostatectomy salvage radiation therapy for prostate cancer: impact of pathological and biochemical variables and prostate fossa biopsy. Cancer J
65. Macdonald OK, Schild SE, Vora SA, et al. Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J Urol
66. 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
67. Peyromaure M, Allouch M, Eschwege F, et al. Salvage radiotherapy for biochemical recurrence after radical prostatectomy: a study of 62 patients. Urology
68. Numata K, Azuma K, Hashine K, et al. Predictor of response to salvage radiotherapy in patients with PSA recurrence after radical prostatectomy: the usefulness of PSA doubling time. Jpn J Clin Oncol
69. Ng MK, Van As N, Thomas K, et al. Prostate-specific antigen (PSA) kinetics in untreated, localized prostate cancer: PSA velocity vs PSA doubling time. BJU Int
70. Swindle PW, Kattan MW, Scardino PT. Markers and meaning of primary treatment failure. Urol Clin North Am
71. Pollack A, Hanlon AL, Pisansky TM, et al. A multi-institutional analysis of adjuvant and salvage radiotherapy after radical prostatectomy. Int J Radiat Oncol Biol Phys
72. Forman JD, Meetze K, Pontes E, et al. Therapeutic irradiation for patients with an elevated postprostatectomy prostate specific antigen level. J Urol
. 1997;158:1436–1439; discussion 1439–1440.
73. Morris MM, Dallow KC, Zietman AL, et al. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys
74. Rogers R, Grossfeld GD, Roach M III, et al. Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol
75. Valicenti RK, Gomella LG, Ismail M, et al. Effect of higher radiation dose on biochemical control after radical prostatectomy for PT3N0 prostate cancer. Int J Radiat Oncol Biol Phys
76. Hanlon AL, Horwitz EM, Hanks GE, et al. Short-term androgen deprivation and PSA doubling time: their association and relationship to disease progression after radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys
77. Kaminski JM, Hanlon AL, Joon DL, et al. Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth. Int J Radiat Oncol Biol Phys
78. Cheung R, Kamat AM, de Crevoisier R, et al. Outcome of salvage radiotherapy for biochemical failure after radical prostatectomy with or without hormonal therapy. Int J Radiat Oncol Biol Phys
79. Corn BW, Winter K, Pilepich MV; Radiation Therapy Oncology Group. Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85–31. Urology
80. de la Taille A, Flam TA, Thiounn N, et al. Predictive factors of radiation therapy for patients with prostate specific antigen recurrence after radical prostatectomy. BJU Int
81. Jani AB, Sokoloff M, Shalhav A, et al. Androgen ablation adjuvant to postprostatectomy radiotherapy: complication-adjusted number needed to treat analysis. Urology
82. King CR, Presti JC Jr, Gill H, et al. Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes? Int J Radiat Oncol Biol Phys
83. Tiguert R, Rigaud J, Lacombe L, et al. Neoadjuvant hormone therapy before salvage radiotherapy for an increasing post-radical prostatectomy serum prostate specific antigen level. J Urol
. 2003;170(2 pt 1):447–450.
84. Forman JD, Velasco J. Therapeutic radiation in patients with a rising post-prostatectomy PSA level. Oncology (Williston Park)
. 1998;12:33–39; discussion 39, 43–44, 47.
85. Terai A, Matsui Y, Yoshimura K, et al. Salvage radiotherapy for biochemical recurrence after radical prostatectomy. BJU Int
86. Pazona JF, Han M, Hawkins SA, et al. Salvage radiation therapy for prostate specific antigen progression following radical prostatectomy: 10-year outcome estimates. J Urol
. 2005;174(4 pt 1):1282–1286.
87. Choo R, Morton G, Danjoux C, et al. Limited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgery. Radiother Oncol
88. Coen JJ, Zietman AL, Thakral H, et al. Radical radiation for localized prostate cancer: local persistence of disease results in a late wave of metastases. J Clin Oncol
89. Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: long term results in patients treated with I-125 implantation. Int J Radiat Oncol Biol Phys
90. Zagars GK, von Eschenbach AC, Ayala AG, et al. The influence of local control on metastatic dissemination of prostate cancer treated by external beam megavoltage radiation therapy. Cancer
91. Kuban DA, el-Mahdi AM, Schellhammer PF. Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma. Urology
92. Pollack A, Horwitz EM, Movsas B. Treatment of prostate cancer with regional lymph node (N1) metastasis. Semin Radiat Oncol
93. Galalae RM, Kovacs G, Schultze J, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys