Rossi, Carl J. Jr. MD*; Joe Hsu, I-Chow MD†; Abdel-Wahab, May MD, PhD‡; Arterbery, V. Elayne MD§; Ciezki, Jay P. MD¶; Frank, Steven J. MD∥; Hahn, Noah M. MD**; Moran, Brian J. MD††; Rosenthal, Seth A. MD‡‡; Merrick, Gregory MD§§¶¶
Radical prostatectomy (RP) and radiation therapy (RT) are the primary treatment options for organ-confined prostate cancer (T1–T2, stages I or II). Eventually, about 50% to 70% of postprostatectomy patients with high-risk pathologic features such as a positive margin, extracapsular extension (ECE), or seminal vesicle involvement (SVI) will develop biochemical failure (BF).1 Thus, RT may play a role either immediately following prostatectomy (based on various known high-risk pathologic features) or at the time of BF.
There are 3 main situations in which RT is given after RP: (1) adjuvant radiotherapy (ART) for men with an undetectable or barely detectable Prostate-Specific Antigen (PSA) (<0.2 ng/mL) who have high-risk pathologic features; (2) salvage radiotherapy (SRT) for men who had an undetectable or barely detectable PSA (<0.2 ng/mL) immediately postoperatively, but whose PSA rises at some later date—a delayed rise in PSA (DR-PSA); and (3) SRT for men whose PSA remains at 0.2 ng/mL or above postoperatively—a persistently detectable PSA (PD-PSA).
The purpose of distinguishing between ART and SRT is rooted in the observation that there are significant differences between the 2 groups in prognosis after RT, in dose of RT administered, and in prognostic factors. The further subdivision of salvage patients into 2 groups, those with a DR-PSA and those with a PD-PSA, is useful because their outcomes after RT appear to be different,2–6 with a worse prognosis for those having a PD-PSA. In general, the earlier the rise in PSA after RP, the worse the outcome because of a higher risk of metastatic disease; the PD-PSA group represents the extreme of patients being considered for SRT in this respect.
The rationale for administering ART after RP is predicated on the assumption that microscopic local disease remains. Local therapy would reduce recurrence in the prostate bed and prevent the residual nidus from disseminating distantly. The decision to administer ART is based on the presence of high-risk pathologic findings in the prostatectomy specimen. The primary high-risk features are ECE, positive margins (prostate cancer at the margin of resection), SVI, and lymph node involvement (LNI). The frequencies of occurrence are approximately 40% for ECE, 25% for margin positivity, 10% for SVI, and 5% for LNI.7–17 Another indication for ART is the presence of residual normal prostate at the inked specimen margin (a cut-through of the prostate), even without conclusive evidence that tumor remains and with an undetectable PSA. The assumption is that a cut-through of the prostate is representative of inadequate surgery and that microscopic disease could be left behind.
The prevalence of persistent local disease following RP is significant and generally under recognized. Residual disease has been documented in approximately 50% of prostatectomy cases at autopsy18 and in biopsy specimens of the prostatic fossa and urethrovesical anastomosis.19–21 Long-term follow-up has revealed that the risk of BF following prostatectomy is substantial. Various surgical series have reported that this risk continues to be present between 5 and 10 years postprostatectomy, with an average relative risk of about 2% to 3% per year without reaching a plateau.9,22–24 Late BFs are not insignificant, eventually leading to the development of painful bony metastases in 50% of patients in 7 to 8 years.25,26 ART has the potential to reduce failure and ultimately improve quality of life. Patients with a life expectancy of >10 years should benefit from ART.
A powerful predictor of biochemical and local failure after prostatectomy is margin positivity. It is estimated that approximately 40% of men with a positive surgical margin will experience a rise in PSA to detectable levels within 5 to 10 years.8,27–33 Other pathologic features that predict for BF include extraprostatic extension, Gleason score ≥7, and SVI.8,29,30,32–36 The balance of data from the available series indicates that margin status is an important determinant of outcome, along with Gleason score and PSA. The extent of margin positivity is another factor shown to influence BF,30,37,38 which has only been examined in retrospective series. ART may have less effect in the case of a small focal positive margin in the absence of other unfavorable pathologic features.39 In this setting, other factors, such as the degree of extraprostatic extension40 and/or Gleason score ≥7 disease, appear to contribute to a greater risk of BF and provide a stronger rationale for ART. Similarly, a focal area of ECE alone is associated with a lower risk of biochemical progression, as compared with more extensive ECE; but the risk will be higher when the ECE is accompanied by Gleason score ≥7 disease.
In the setting of negative margins and a rising PSA, a complete biochemical response to SRT is still achieved in the majority of cases, suggesting local disease persistence in the prostatic fossa. A rising PSA after a negative margin has been associated with a worse prognosis in some prostatectomy series41,42; however, one must consider that not every micron of tissue in the prostatectomy specimen is pathologically assessed. The RT response data suggest that tumor cells were left behind (a focal positive margin) but were not identified on pathologic evaluation. The risk of local disease persistence when there is obvious ECE in addition to Gleason ≥7 disease,40 even with negative margins, is likely high enough that ART should be considered.
Many retrospective studies have examined the role of ART.43–48 More recently, 3 prospective randomized trials comparing prostatectomy alone to prostatectomy plus ART have been described.48,49 All 3 have shown an improvement in biochemical control of about 20% with ART, with 1 trial demonstrating an improvement in both metastasis-free and overall survival. The European Organization for Research and Treatment of Cancer 22911 study included 972 patients with pT2–3 prostate cancer with at least one high-risk feature (ECE, positive margins, or SVI). Freedom from biochemical failure (FFBF) at 5 years was 53% in the RP alone group versus 74% in the RP + RT (60 Gy) group (P < 0.0001).49
A similar study was conducted by the Southwest Oncology Group and presented at the 2005 meetings of the American Urological Association and the American Society of Therapeutic Radiology and Oncology.50 There were 473 patients with pathologically determined ECE, positive margins, and/or SVI randomized to RT (60–64 Gy) versus observation. FFBF was significantly improved by the addition of radiation from 38% to 61% at 5 years and from 23% to 47% at 10 years. This benefit was shared by each of the 3 pathologic risk groups. ART also prevented the need for androgen deprivation therapy (ADT) in some patients and delayed its use significantly (by 2.5 years) in others. Perhaps most convincingly, this study is now demonstrating an improvement in metastasis-free and overall survival. With a median follow-up of 12.7 years, out of 425 evaluable patients, metastasis have developed in 114 of 211 patients on the observation arm versus 93 of 214 patients who received early adjuvant therapy (P = 0.016). In addition, there have been 110 deaths on the observation arm versus 88 deaths in the irradiated patients (P = 0.023). Although ART initially resulted in some adverse impact on quality of life, this difference disappeared by 2 years post-treatment, and the irradiated patients actually fared better beyond 3 years postradiotherapy.51
A third study (ARO, 96–02) randomized 388 men with pT3 disease after prostatectomy and an undetectable postoperative PSA to either RT (60 Gy) or observation.52 The 5-year FFBF rate was 54% in the RP-alone group versus 72% in the RP plus RT group (P = 0.0015). ART was very well tolerated, with the rate of grade 3 to 4 late adverse events being 0.3% (Tables 1, 2).
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
ANDROGEN DEPRIVATION THERAPY
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).
ADJUVANT VERSUS SRT
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.
IRRADIATION IN PATIENTS WITH POSITIVE LYMPH NODES
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
* A high percentage of radical prostatectomy patients with high-risk pathologic features (positive surgical margins, extraprostatic extension of cancer, SVI) will experience a subsequent BF, with failure often due to the progression of residual disease within the surgical bed.
* The addition of adjuvant radiation therapy directed at the prostate fossa to these patients has been shown in 3 prospective randomized trials to improve the biochemical freedom from failure rate among the irradiated patients and, in 1 trial, to provide an improvement in metastasis-free and overall survival.
* Salvage radiation therapy, in which patients with biochemically detectable disease undergo radiotherapy to the prostate bed, has also been shown to improve freedom from BF, although the impact on overall survival remains uncertain.
* The appropriate radiation dose to the prostate fossa in the adjuvant or salvage setting is 66 to 70.2 Gy. Higher doses may be appropriate if there is an evidence of gross recurrence within the prostate bed.
* The addition of pelvic radiotherapy to prostate fossa radiation is generally discouraged, although it may be appropriate in certain clinical situations (absence of lymph node dissection, evidence of nodal involvement at prostatectomy or on imaging studies, etc).
* The benefit of neoadjuvant/adjuvant ADT is the subject of ongoing clinical trials, and its use is discouraged outside of the protocol setting.
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. 2002;53:269–276.
3. Chawla AK, Thakral HK, Zietman AL, et al. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology. 2002;59:726–731.
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. 2003;56:755–763.
5. Garg MK, Tekyi-Mensah S, Bolton S, et al. Impact of postprostatectomy prostate-specific antigen nadir on outcomes following salvage radiotherapy. Urology. 1998;51:998–1002.
6. Song DY, Thompson TL, Ramakrishnan V, et al. Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology. 2002;60:281–287.
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. 1996;48:249–260.
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. 1996;20:286–292.
9. Pound CR, Partin AW, Epstein JI, et al. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Urol Clin North Am. 1997;24:395–406.
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. 1999;161:1525–1529.
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. 1999;162:1341–1345.
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. 2000;18:2862–2868.
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. 2003;169:2147–2152.
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. 2003;170:1798–1803.
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. 2003;169:517–523.
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. 2004;172:910–914.
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. 1987;29:584–588.
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. 1998;51:283–286.
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. 1993;149:1024–1028.
21. Naya Y, Okihara K, Evans RB, et al. Efficacy of prostatic fossa biopsy in detecting local recurrence after radical prostatectomy. Urology. 2005;66:350–355.
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. 1998;160:2428–2434.
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. 2000;164:101–105.
25. Pound C, Partin A, Eisenberger M, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591–1597.
26. 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.
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. 1994;43:828–833.
29. Epstein JI. Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am. 1996;23:651–663.
30. Watson RB, Civantos F, Soloway MS. Positive surgical margins with radical prostatectomy: detailed pathological analysis and prognosis. Urology. 1996;48:80–90.
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. 1997;37:1043–1052.
32. Kausik SJ, Blute ML, Sebo TJ, et al. Prognostic significance of positive surgical margins in patients with extraprostatic carcinoma after radical prostatectomy. Cancer. 2002;95:1215–1219.
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. 2005;66:1245–1250.
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. 1990;144:89–93.
35. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer. 1993;71:3582–3593.
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. 1999;54:682–688.
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. 2005;58:1028–1032.
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. 2003;169:2142–2146.
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. 1998;29:856–862.
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. 2003;21:483–489.
42. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325–1332.
43. Valicenti RK, Gomella LG, Perez CA. Radiation therapy after radical prostatectomy: a review of the issues and options. Semin Radiat Oncol. 2003;13:130–140.
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. 2000;163:1178–1182.
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. 2002;25:1–8.
46. Petrovich Z, Lieskovsky G, Stein JP, et al. Comparison of surgery alone with surgery and adjuvant radiotherapy for pT3N0 prostate cancer. BJU Int. 2002;89:604–611.
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. 2005;61:714–724.
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. 2004;64:84–89.
49. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. 2005;366:572–578.
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. 2009;181:956–962.
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. 2009;27:2924–2930.
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. 2003;95:1376–1383.
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. 2003;170:1872–1876.
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. 2005;174:2191–2196.
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. 2005;23:6157–6162.
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. 2004;351:125–135.
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. 1997;158:1441–1445.
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. 2001;19:1030–1039.
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. 2001;76:576–581.
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. 1999;54:1049–1057.
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. 2000;48:369–375.
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. 2002;8:242–246.
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. 2003;170:1833–1837.
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. 2004;64:760–764.
67. Peyromaure M, Allouch M, Eschwege F, et al. Salvage radiotherapy for biochemical recurrence after radical prostatectomy: a study of 62 patients. Urology. 2003;62:503–507.
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. 2005;35:256–259.
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. 2009;103:872–876.
70. Swindle PW, Kattan MW, Scardino PT. Markers and meaning of primary treatment failure. Urol Clin North Am. 2003;30:377–401.
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. 2004;60(suppl):S186–S187.
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. 1997;38:731–736.
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. 1998;160:1748–1753.
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. 1998;42:501–506.
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. 2004;58:43–52.
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. 2003;57:24–28.
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. 2005;63:134–140.
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. 1999;54:495–502.
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. 2002;90:887–892.
81. Jani AB, Sokoloff M, Shalhav A, et al. Androgen ablation adjuvant to postprostatectomy radiotherapy: complication-adjusted number needed to treat analysis. Urology. 2004;64:976–981.
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. 2004;59:341–347.
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. 2005;96:1009–1013.
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. 2005;74:163–167.
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. 2002;20:3199–3205.
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. 1991;21:537–547.
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. 1991;68:2370–2377.
91. Kuban DA, el-Mahdi AM, Schellhammer PF. Effect of local tumor control on distant metastasis and survival in prostatic adenocarcinoma. Urology. 1987;30:420–426.
92. Pollack A, Horwitz EM, Movsas B. Treatment of prostate cancer with regional lymph node (N1) metastasis. Semin Radiat Oncol. 2003;13:121–129.
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. 2002;52:81–90.