Management of rising serum PSA following radical prostatectomy for prostate cancer: Salvage radiation therapy INTRODUCTION — Prostate specific antigen (PSA) is a sensitive and specific marker for prostate cancer. Serum levels are elevated in 95 percent of men with advanced disease. Furthermore, in men treated for advanced disease, posttherapy PSA changes correlate with time to progression and survival in most studies. As a result, serum PSA is used by most clinicians as an intermediate endpoint to define treatment benefit. Largely due to the sensitivity of serum PSA as a marker for prostate cancer, serial PSA measurements are routinely obtained to detect early disease recurrence in men who have had aggressive primary therapy for localized disease One consequence of the routine adoption of PSA monitoring after treatment of early stage prostate cancer is the identification of men with a PSA-only (also termed serologic or biochemical) recurrence. In this situation, increases in serum PSA over the pretreatment baseline are not accompanied by symptoms or signs of progressive disease. Since a significant number of these men are relatively young and otherwise healthy, intense interest has been focused upon their treatment, with particular attention to survival, and the impact of therapy on quality of life. There are several treatment options for men who have a biochemical recurrence after radical prostatectomy. These include external beam radiation therapy (RT) to the pelvis and/or prostatic bed, traditional androgen deprivation therapy (orchiectomy, gonadotropin releasing hormone [GnRH] agonists, or combined therapy), nontraditional hormone therapy (ie, intermittent androgen deprivation therapy, antiandrogen monotherapy, a combination of an antiandrogen and a 5-alpha reductase inhibitor), a combination of RT plus androgen deprivation therapy (ADT), or observation. An area of major controversy is the method for ascertaining clinical benefit from therapeutic strategies that are applied to this population. The majority of published studies focus on biochemical relapse-free survival as a primary endpoint. However, in guidelines from the National Cancer Institute-sponsored Prostate-Specific Antigen Working Group, the preferred endpoints are prostate cancer-specific survival, and alternatively, time to develop metastatic disease. This topic is addressed in more detail elsewhere. This topic review will cover the use of salvage RT for men who have a rising PSA following radical prostatectomy for early stage disease. The use of systemic therapy in these men, treatment options for men who fail initial RT, the definition and diagnostic assessment for men with a rising PSA after local therapy, and the role of PSA in prostate cancer screening are discussed separately. EXTERNAL BEAM RT ALONE — For men failing radical prostatectomy, salvage external beam RT can provide long-term disease control if the recurrence is localized within an encompassable field, and a sufficient dose can be delivered to eradicate the residual/recurrent cancer. In addition to RT dose, the success of salvage RT also depends on treatment volume (ie, prostate bed with or without pelvis) and optimal patient selection according to pretreatment prognostic factors. Published biochemical relapse-free survival (bRFS) rates after salvage RT, as defined by undetectable levels of serum PSA after RT, are widely variable, ranging from 18 to 68 percent. Much of the variability in outcomes can be accounted for by differences in pretreatment prognostic factors (eg, tumor or T stage, serum PSA at the time of treatment initiation, duration of the recurrence-free interval), the wide range of RT doses, and the short duration of follow-up in most of the studies. The impact of salvage RT on survival remains unknown because randomized trials comparing RT to observation or ADT in this setting have not been conducted. A large randomized trial from Europe showed a survival advantage to postprostatectomy RT for men with high-risk features, but most of the men had an undetectable PSA at the time of treatment Patient selection — We select men for salvage RT if they are likely to have a clinically localized recurrence in the prostate bed without distant spread. Optimal candidates are men who meet all of the following criteria:
Positive surgical margins — The optimal management of men with positive surgical margins and an undetectable PSA level after prostatectomy is controversial. Whether immediate adjuvant RT is superior to salvage therapy at the time of biochemical failure remains unclear. Despite the lack of a clear survival benefit, adjuvant RT is often recommended for men with diffusely positive resection margins and for those with pathologic T3a disease (extraprostatic extension). For men who do not undergo immediate adjuvant RT, a positive surgical margin at the time of radical prostatectomy is a powerful predictor of a durable response from salvage RT. A positive margin suggests a greater likelihood that a disease recurrence is due to residual pelvic tumor rather than a distant recurrence. Seminal vesicle invasion — Outcomes are less favorable in men who had seminal vesicle invasion at the time of prostatectomy as compared to other clinical stages, including pT3a disease. However, some of these men benefit from salvage RT. Three to five-year bRFS rates of 10 to 38 percent are reported Preradiotherapy
PSA — The preradiotherapy PSA level is the most consistent variable
related to outcomes after salvage RT. In general, the best
results have been seen when the preradiotherapy PSA was Although a standard cutpoint has not been established, a consensus panel convened by the American Society for Therapeutic Radiology and Oncology (ASTRO) recommended that if salvage RT is selected, treatment should be instituted before the serum PSA rises above 1.5 ng/mL. Others suggest that salvage RT be strongly considered as soon as an increasing PSA level is detected post radical prostatectomy. Immediate adjuvant RT in men with pT3 disease or positive surgical margins is discussed elsewhere. Others emphasize the duration of the recurrence-free interval as a better predictor of successful outcome than the PSA value at the time of RT. As an example, in a report of 82 men undergoing salvage RT (57 for a rising PSA post radical prostatectomy, and the remainder for biopsy-documented local recurrence), the likelihood of successful salvage increased as the interval between initial therapy and PSA recurrence increased. Only one of 16 men (6 percent) with a PSA-recurrence in the first year after radical prostatectomy was rendered disease-free by salvage RT, while 44 percent of men with a five-year recurrence-free interval achieved long-term disease control. In keeping with these data, when men with a persistently detectable PSA have been segregated from those with a delayed rise in PSA, the outcomes have usually been worse (at least in univariate analyses) for those with persistently elevated PSA values On the other hand, the difference in freedom from biochemical failure has been either minimal or not seen in multivariate analysis Regardless of whether the serum PSA is persistently elevated or the rise is delayed, men with a rapidly rising PSA (particularly a PSA doubling time of 6 months or less) early after radical prostatectomy are most likely to have systemic disease, and do not stand to benefit from salvage RT. In contrast, if levels remain undetectable for two to four years and then gradually rise, the likelihood of an isolated local recurrence in the prostate bed is higher Importance of dose — There are no randomized trials that explore the issue of dose in salvage RT. However, retrospective series report better outcomes when doses above 65 Gy are used. The recommendation of a consensus panel convened by ASTRO recommended a threshold dose of 64 Gy for salvage RT following prostatectomy Volume of the treated field — The optimal treatment volume is controversial. However, extrapolating from the results of a randomized trial conducted in men undergoing definitive RT for localized disease, when ADT is used, we also treat the pelvic nodes.. Contemporary outcomes — Contemporary outcomes of modern salvage RT in appropriately selected patients can be illustrated by the experience of two groups
With a median follow-up of 45 months, 250 (50
percent) progressed, 49 (10 percent) with distant metastases; however, only 20 (4 percent)
died from prostate cancer. In multivariate analysis, predictors of disease progression
were a Gleason score of 8 to 10, preradiotherapy PSA level >2 ng/mL, PSA doubling time
of
A nomogram to predict outcomes from salvage RT
based upon factors such as these may be a potentially useful tool to select appropriate
candidates for this approach. One such nomogram was based on a series of 500 men followed
for an average of 36 months after salvage RT, and included the pretreatment variables
Gleason score, preradiotherapy PSA level and PSA doubling time, preprostatectomy serum PSA
level, margin status, interval from radical prostatectomy to biochemical recurrence, use
of neoadjuvant ADT, and RT dose. In a preliminary report, the nomogram predicted a
two-year progression-free probability between 65 and 95 percent for a typical patient with
a pre-RT PSA <2 ng/mL, PSA doubling time more than 10 months, Gleason score RT PLUS ANDROGEN DEPRIVATION THERAPY — The addition of ADT to definitive or adjuvant RT benefits men with high-risk clinically localized prostate cancer as well as those with locally advanced disease. There are no randomized trials of RT with and without ADT in men with a rising PSA after radical prostatectomy. The benefit of ADT in men undergoing salvage RT has been addressed in two retrospective reports
These retrospective, historical comparisons
suggest that ADT may benefit some men who are receiving salvage RT. A randomized trial to
answer this question (Radiation Therapy Oncology Group [RTOG] trial 96-01, RT with or
without bicalutamide) has been completed, although the results are not yet available. At present, it seems reasonable to suggest short-term ADT (two months
before and then throughout salvage RT) for men who had unfavorable risk factors at the
time of radical prostatectomy (eg, PSA>10 ng/mL, Gleason score SUMMARY AND RECOMMENDATION — The routine adoption of PSA monitoring after treatment of early stage prostate cancer has led to the identification of men with a PSA-only (also termed serologic or biochemical) recurrence. In this situation, increases in serum PSA over pretreatment baseline are not accompanied by symptoms or signs of progressive disease. Salvage RT using adequate RT doses ( The success of salvage RT depends on RT dose, and optimal patient selection. Although the only true contraindication to attempting salvage RT for men with a rising serum PSA following radical prostatectomy is unequivocal evidence of distant metastatic spread, the best candidates are men who had a positive surgical margin, Gleason score <8, and no evidence of lymph node involvement at the time of prostatectomy, a postprostatectomy recurrence-free interval of at least one year, and a low serum PSA (<1.5 ng/ml) at recurrence The following represents our approach to salvage RT in men with a rising PSA after radical prostatectomy:
We suggest treatment of the pelvic nodes in addition to prostate RT rather than prostate RT alone in men who have an indication for ADT
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1.5 ng/mL) at the
time of recurrence 
12 months (66
versus 48 percent), although the difference was no longer evident by 10 years (33 versus
34 percent, respectively). However, men with a short PSA doubling time developed clinical
metastases at a higher rate at both five (10 versus 0 percent) and ten years (29 versus 17
percent, respectively).