Prostate cancer is the second most common cause of cancer death in American men, with 192,289 new cases and 27,360 deaths expected in 2009. While radical prostatectomy provides excellent control for clinically localized disease, approximately one-third of patients undergoing surgery will have positive surgical margins and another 9% will have seminal vesicle invasion.[2-5] Around one-third of patients will also have extracapsular extension. These adverse pathological risk factors, in addition to the Gleason score and initial PSA level, are independent predictors of biochemical recurrence of cancer. Indeed, 40%-50% of high-risk patients have a biochemical recurrence after surgery, and many of those patients eventually develop metastases.[6-11] Currently, the majority of post-surgical patients without high-risk features are observed for signs of disease progression without active treatment. However, recently updated randomized trials have shown a very significant benefit to immediate "adjuvant" radiation therapy for prostate cancer at high risk of recurrence, such as pT3 disease.[12-14] Controversy surrounds the issue of what to do when prostate cancer recurs months or years after initial prostatectomy, and whether the risks and morbidity of radiation therapy in the "salvage" setting outweigh the intended benefits.
This review outlines the evidence for the use of salvage external beam radiotherapy for patients with biochemical relapse, and discusses current recommendations for a treatment target and dose prescription. In addition, we highlight why the treatment of prostate cancer recurrence is important as it relates to the cost and disability associated with metastatic disease. Though the relative cost, benefit, and risks are less defined than in the adjuvant setting, multiple studies have shown an excellent quality of life and low complication rates with salvage radiotherapy. Selected patients may have an improved likelihood of benefiting from salvage radiotherapy.
Definition of Biochemically Recurrent Prostate Cancer
Prostate cancer presents a unique situation in which physicians have the capability to oversee treatment response with a serologic marker that predicts treatment failure years before clinical progression. Given the extended period between prostate cancer recurrence after radical prostatectomy and death, the use of PSA progression is commonplace in monitoring treatment success.[16,17] In principle, the PSA level should become undetectable within 6 weeks of radical prostatectomy (RP), as the prostate tissue has been removed, and the half-life of PSA is around 3 days. Therefore, a detectable serum PSA suggests either remaining prostate tissue or cancer, and is recognized as evidence of cancer recurrence.[19-21]
The American Urological Association (AUA) defines biochemical recurrence following radical prostatectomy as an initial serum PSA of ≥ 0.2 ng/mL, with a second confirmatory level of > 0.2 ng/mL. The initial postoperative PSA is measured 6-12 weeks after surgery, and after confirmation the date of failure is the date of the first value above the 0.2 ng/mL. Although the AUA established this definition for the purpose of reporting information in a consistent manner and not as a standard for when to begin salvage therapy, this value also represents the threshold at which patients are at very high risk of developing additional PSA increases. In a retrospective evaluation of 358 men undergoing RP, they found that when PSA levels rose to levels
> 0.2 ng/mL after RP, the 1- and 3-year risks of additional PSA progression were 86% (95% CI 69%-97%) and 100% (95% CI 87%-100%), respectively. Using this definition of PSA recurrence rather than a definition of failure that includes any detectable PSA decreases the likelihood of a falsely positive PSA due to retained benign prostate tissue.
Though a major cooperative group advocated an optimal value to define PSA relapse of > 0.4, the two PSA levels have similar specificity. As the lower PSA cutoff (> 0.2 and rising) is necessarily more sensitive, it could potentially lead to earlier initiation of salvage radiotherapy, at a lower disease burden and decreased likelihood for distant disease. This is especially true since the benefit of salvage radiation has been demonstrated to be inversely correlated to the serum PSA level at the time of radiation therapy (RT).[6,25]
Definition of Salvage Radiotherapy (SRT), and the Distinction Between SRT and Adjuvant RT (ART)
Generally, "salvage" radiotherapy (SRT) is defined as radiation treatment given for suspected recurrent malignant disease after a period of observation after prostatectomy. In contrast, "adjuvant" radiotherapy (ART) refers to treatment directly after prostatectomy in patients potentially without residual disease and with an undetectable PSA. There are several important distinctions between SRT and ART: 1) There is a higher likelihood of local residual disease without distant metastatic disease for patients in whom ART is indicated immediately post-prostatectomy versus a patient for whom SRT is being considered; 2) The burden of disease may be higher for SRT vs ART; and 3) Multiple prospective randomized trials have shown a benefit to ART, whereas similar evidence is lacking for SRT [12-14] (although a randomized trial comparing SRT and ART is underway).
ART is given for patients at high risk of localized recurrence, generally defined as: evidence for prostate cancer outside the capsule (extracapsular extension), positive surgical margins, or seminal vesicle invasion. In contrast, SRT patients can have recurrence years after RP, and it is often unclear whether the detected PSA represents recurrence locally within the prostate bed, seminal vesicle remnants, pelvis, or at a distant site. This is obviously important for RT planning, as delivering RT to the prostate bed is useless if no disease remains locally.
In general, the burden of disease may be different for ART patients versus SRT patients. Though ART patients can have gross residual disease remaining after radical prostatectomy, they also often have an undetectable PSA indicative of, at most, microscopic residual disease. In contrast, all patients who undergo SRT for a biochemical recurrence have either a large enough burden of disease to cause a detectable PSA, a palpable nodule on digital rectal exam, or gross disease detected on CT or MRI. Therefore, some authors suggest that in general, SRT patients have roughly ten times the disease burden of ART patients.
Immediate "adjuvant" radiotherapy for patients at high risk of recurrence (pT3, etc.) has proven to be beneficial in three randomized trials. The European Organisation for Research and Treatment of Cancer (EORTC) 22911 clinical trial showed a biochemical progression-free survival (74.0% vs 52.6%; P <.0001), improved clinical progression-free survival (P = .0009), and a significantly lower rate of cumulative locoregional failure (P = .0005) with ART. It is also worth noting that deferred postoperative radiation was given to almost half of relapsing patients in the observation group and there was still a demonstrated advantage to ART. The second randomized trial, the ARO96-02/AUO AP 09/95 study, compared ART after radical RP to RP alone in patients with pT3N0 tumors and an undetectable (< 0.1 ng/mL) postoperative PSA. Biochemical progression-free survival in the ART arm was significantly improved over the observation group (72% vs 54%; HR = 0.53, P = .0015), even in this group of men with an undetectable PSA at the time of RT. Although the EORTC 22911 trial demonstrated a treatment effect for all subgroups, analysis in this study revealed only positive surgical margins; Gleason score 6 or less; PSA level > 10 ng/mL before surgery; and extracapsular extension without infiltration of the seminal vesicles to be predictors of improved recurrence-free survival. Longer follow-up is needed for both the EORTC and ARO96-02 studies to assess the impact of ART on metastasis-free and overall survival.
The third randomized trial that assessed the benefit of ART was the Southwest Oncology Group (SWOG) study, which randomized 425 men with one of three pathologic features: extracapsular extension, positive surgical margins, or seminal vesicle invasion to observation (n=211) or ART arms (n=214). Like the first two studies, the SWOG group found a significant 60% reduction in the risk for biochemical recurrence (hazard ratio 0.43 (95% CI: 0.38–0.58, P < .001), which was similar in magnitude to the risk reduction for biochemical failure observed in both the EORTC (hazard ratio: 0.48, 98% CI 0·37–0·62, P < .001) and ARO96-02 studies (hazard ratio: 0.53; 95% CI, 0.37–0.79; P = .0015). In distinction from the other two randomized trials, with a much longer follow-up of median >12 years, the SWOG study also found a significant benefit to ART in metastasis-free survival (93 of 214 events in the ART arm vs 114 of 211 events in observation arm; HR 0.71, P = .016) and improved overall survival (88 deaths of 214 in the ART arm vs 110 deaths of 211 in observation arm; HR 0.72, P = .023). These findings are particularly noteworthy since of those men under observation—approximately one-third—ultimately received SRT. Furthermore, the use of hormonal therapy in the observation arm was almost twice that of the ART group. Subset analysis revealed that even though men with a detectable PSA after surgery benefit from ART, this group's metastasis rate is higher than that of men who had ART with an undetectable PSA (P = .03).
Whether an equivalent survival benefit can be attained with close surveillance and early initiation of SRT for patients with biochemical recurrence after RP is still an area of debate. However, a new study known as the Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial has been designed to clarify the timing of radiation therapy after prostate surgery. In the trial, patients with adverse pathological features and an undetectable PSA after RP are randomized to RT within 2 months of surgery (ART) or treatment as soon as their PSA rises > 0.1 ng/mL (SRT). Patients will also be randomized to 0, 6, or 24 months of hormonal therapy to determine the role of androgen deprivation. The investigators aim to recruit more than 4,000 patients and the primary outcome is cause-specific survival.
1. Jemal A, et al: Cancer statistics, 2009. CA Cancer J Clin 59:225-249, 2009.
2. Underwood W, 3rd, et al: Racial treatment trends in localized/regional prostate carcinoma: 1992-1999. Cancer 103:538-545, 2005.
3. Bill-Axelson A, et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352:1977-1984, 2005.
4. Cooperberg MR, et al: The contemporary management of prostate cancer in the United States: Lessons from the cancer of the prostate strategic urologic research endeavor (CapSURE), a national disease registry. J Urol 171: 1393-1401, 2004.
5. Klein EA, et al: Surgeon experience is strongly associated with biochemical recurrence after radical prostatectomy for all preoperative risk categories. J Urol 179: 2212-2216; discussion 2216-2217, 2008.
6. Swanson GP, Riggs M, Hermans M: Pathologic findings at radical prostatectomy: Risk factors for failure and death. Urol Oncol 25:110-114, 2007.
7. Vis AN, Schroder FH, van der Kwast TH: The actual value of the surgical margin status as a predictor of disease progression in men with early prostate cancer. Eur Urol 50: 258-265, 2006.
8. Dahl DM, et al: Pathologic outcome of laparoscopic and open radical prostatectomy. Urology 68:1253-1256, 2006.
9. Katz MS, et al: Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol 21:483-489, 2003.
10. Roehl KA, et al: Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: Long-term results. J Urol 172: 910-914, 2004.
11. Freedland SJ, et al: Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433-439, 2005.
12. Bolla M, et al: Postoperative radiotherapy after radical prostatectomy: A randomised controlled trial (EORTC trial 22911). Lancet 366:572-578, 2005.
13. Thompson IM, et al: Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. J Urol 181:956-962, 2009.
14. Wiegel T, 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 27:2924-2930, 2009.
15. Pound CR, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1597, 1999.
16. Trapasso JG, et al: The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 152(5 pt 2):1821-1825, 1994.
17. Zincke H, et al: Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer.J Urol 152(5 pt 2):1850-1857, 1994.
18. Stamey TA, et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317:909-916, 1987.
19. Consensus statement: Guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37:1035-1041, 1997.
20. Lange PH, et al: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol 141:873-879, 1989.
21. Moul JW: Prostate specific antigen only progression of prostate cancer. J Urol 163:1632-1642, 2000.
22. Cookson MS, et al: Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: The American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol 177: 540-545, 2007.
23. Freedland SJ, et al: Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology 61:365-369, 2003.
24. Scher HI, et al: Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: Recommendations from the Prostate- Specific Antigen Working Group. J Clin Oncol 22:537-556, 2004.
25. Stephenson AJ, et al: Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 25:2035-2041, 2007.
26. Parker C, et al: Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): A new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy. BJU Int 99:1376-1379, 2007.
27. King CR, Kapp DS: Radiotherapy after prostatectomy: Is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys 71:346-350, 2008.
28. Feng M, et al: Predictive factors for late genitourinary and gastrointestinal toxicity in patients with prostate cancer treated with adjuvant or salvage radiotherapy. Int J Radiat Oncol Biol Phys 68:1417-1423, 2007.
29. Trock BJ, et al: Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 299: 2760-2769, 2008.
30. Kuban D, Pagliaro L: Salvage radiotherapy or observation after radical prostatectomy in the PSA era. Am J Hem Onc 8:136-138, 2009.
31. Lee AK, D’Amico AV: Utility of prostate-specific antigen kinetics in addition to clinical factors in the selection of patients for salvage local therapy. J Clin Oncol 23:8192-8197, 2005.
32. Losa A, et al: Salvage brachytherapy for local recurrence after radical prostatectomy and subsequent external beam radiotherapy. Urology 62:1068-1072, 2003.
33. Niehoff P, et al: Feasibility and preliminary outcome of salvage combined HDR brachytherapy and external beam radiotherapy (EBRT) for local recurrences after radical prostatectomy. Brachytherapy 4:141-145, 2005.
34. Poortmans P, et al: Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother Oncol 84:121-127, 2007.
35. Michalski JM, et al: Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys 76:361-368, 2010.
36. Wiltshire KL, et al: Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy. Int J Radiat Oncol Biol Phys 69:1090-1099, 2007.
37. Miralbell R, et al: Endorectal MRI assessment of local relapse after surgery for prostate cancer: A model to define treatment field guidelines for adjuvant radiotherapy in patients at high risk for local failure. Int J Radiat Oncol Biol Phys 67:356-361, 2007.
38. Silverman JM, Krebs TL: MR imaging evaluation with a transrectal surface coil of local recurrence of prostatic cancer in men who have undergone radical prostatectomy. AJR Am J Roentgenol 168:379-385, 1997.
39. Sella T, et al: Suspected local recurrence after radical prostatectomy: Endorectal coil MR imaging. Radiology 231:379-385, 2004.
40. Wang K, et al: The uncertainties in target localization for prostate and prostate-bed radiotherapy with Calypso 4D. Int J Radiat Oncol Biol Phys 75:S594, 2009.
41. Schiffner DC, et al: Daily electronic portal imaging of implanted gold seed fiducials in patients undergoing radiotherapy after radical prostatectomy. Int J Radiat Oncol Biol Phys 67:610-619, 2007.
42. Nath SK, Sandhu AP, Rose BS, et al: Toxicity analysis of postoperative image-guided intensity- modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2009 Nov 23 [e-pub ahead of print].
43. 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 48:369-375, 2000.
44. Valicenti RK, et al: Effect of higher radiation dose on biochemical control after radical prostatectomy for PT3N0 prostate cancer. Int J Radiat Oncol Biol Phys 42:501-506, 1998.
45. Macdonald OK, et al: Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J Urol 170:1833-1837, 2003.
46. Pollack A, et al: Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097-1105, 2002.
47. Zietman AL, et al: Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 294:1233-1239, 2005.
48. Kupelian P, et al: Improved biochemical relapse-free survival with increased external radiation doses in patients with localized prostate cancer: The combined experience of nine institutions in patients treated in 1994 and 1995. Int J Radiat Oncol Biol Phys 61:415-419, 2005.
49. King CR, Spiotto MT: Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys 71:23-27, 2008.
50. Cox JD, 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 17:1155, 1999.
51. Wong GW, et al: Salvage hypofractionated radiotherapy for biochemically recurrent prostate cancer after radical prostatectomy. Int J Radiat Oncol Biol Phys 70:449-455, 2008.
52. Abramowitz MC, Pollack A: Postprostatectomy radiation therapy for prostate cancer. Semin Radiat Oncol 18:15-22, 2008.
53. Bolla M, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phaseIII randomised trial. Lancet 360:103-106, 2002.
54. D’Amico AV, et al: 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: A randomized controlled trial. JAMA 292:821-827, 2004.
55. Lawton CA, et al: Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 49:937-946, 2001.
56. Moinpour CM, et al: Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 26:112-120, 2008.
57. Pearse M, et al: Prospective assessment of gastrointestinal and genitourinary toxicity of salvage radiotherapy for patients with prostate specific antigen relapse or local recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 72:792-798, 2008.
58. Peterson JL, et al: Late toxicity after postprostatectomy salvage radiation therapy. Radiother Oncol 93:203-206, 2009.
59. Pinkawa M, et al: Health-related quality of life after adjuvant and salvage postoperative radiotherapy for prostate cancer—a prospective analysis. Radiother Oncol 88:135-139, 2008.
60. Sanda MG, et al: Quality of life and satisfaction with outcome among prostate cancer survivors. N Engl J Med 358:1250-1261, 2008.
61. Hedestig O, et al: Living after radical prostatectomy for localized prostate cancer: A qualitative analysis of patient narratives. Acta Oncol 44:679-686, 2005.
62. Bokhour BG, et al: Sexuality after treatment for early prostate cancer: Exploring the meanings of “erectile dysfunction”. J Gen Intern Med 16:649-655, 2001.
63. Katz A: What happened? Sexual consequences of prostate cancer and its treatment. Can Fam Physician 51:977-982, 2005.
64. Miller DC, et al: Long-term outcomes among localized prostate cancer survivors: Health-related quality-of-life changes after radical prostatectomy, external radiation, and brachytherapy. J Clin Oncol 23:2772-2780, 2005.
65. van der Wielen GJ, Mulhall JP, Incrocci L: Erectile dysfunction after radiotherapy for prostate cancer and radiation dose to the penile structures: A critical review. Radiother Oncol 84:107-113, 2007.
66. Wittmann D, et al: Counseling patients about sexual health when considering postprostatectomy radiation treatment. Int J Impot Res 21:275-284, 2009.
67. Hu JC, et al: The effect of postprostatectomy external beam radiotherapy on quality of life: Results from the Cancer of the Prostate Strategic Urologic Research Endeavor. Cancer 107:281-288, 2006.
68. Formenti SC, et al: Update on impact of moderate dose of adjuvant radiation on urinary continence and sexual potency in prostate cancer patients treated with nerve-sparing prostatectomy. Urology 56:453-458, 2000.
69. Schulman KL, Kohles J: Economic burden of metastatic bone disease in the U.S. Cancer 109:2334-2342, 2007.
70. American Cancer Society: Cancer Facts and Figures 2009. Available at http://www.cancer.org/docroot/ STT/content/STT_1x_Cancer_Facts__ Figures_2009.asp.
71. Zubek VB, Konski A: Cost effectiveness of risk-prediction tools in selecting patients for immediate post-prostatectomy treatment. Mol Diagn Ther 13:31-47, 2009.
72. EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy 16:199-208, 1990.
73. Stephenson AJ, et al: Salvage therapy for locally recurrent prostate cancer after external beam radiotherapy. Curr Treat Options Oncol 5:357-365, 2004.
74. Moreira DM, et al: Validation of a nomogram to predict disease progression following salvage radiotherapy after radical prostatectomy: Results from the SEARCH database. BJU Int 104:1452-1456, 2009.