ABSTRACT: Prostate cancer is the second most common cause of cancer death in American men. What to do when prostate cancer recurs months or years after a patient undergoes radical prostatectomy is an area of active research. Patients who underwent radical prostatectomy without immediate adjuvant radiation therapy (ART) but subsequently have evidence of recurrent disease are candidates for Salvage Radiation Therapy (SRT). Though there are three prospective randomized trials illustrating the efficacy of post-operative ART for selected patients, similarly strong evidence is lacking for SRT. In this article, we define the biochemical recurrence of prostate cancer, distinguish SRT from ART, outline the evidence for SRT, and make recommendations with regard to radiotherapy volume and dose. We discuss the known side effects from SRT, weigh the cost and benefit of SRT, and discuss possible tools that may improve the cost/benefit ratio for SRT by helping to select patients whom SRT may be more likely to benefit.
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.