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Cancer Research and Treatment > Volume 42(1); 2010 > Article
Choo: Salvage Radiotherapy for Patients with PSA Relapse Following Radical Prostatectomy: Issues and Challenges

Abstract

A progressively rising level of serum prostate specific antigen (PSA) after radical prostatectomy (RP) invariably indicates the recurrence of prostate cancer. The optimal management of patients with post-RP PSA relapse has remained uncertain due to a wide variability in the natural course of post-RP PSA relapse and the inability to separate a recurrent disease confined to the prostate bed from that with occult distant metastasis. Management uncertainty is further compounded by the lack of phase III clinical studies demonstrating which therapeutic approach, if any, would prolong life with no significant morbidity. Radiotherapy has been the main therapeutic modality with a curative potential for patients with post-RP PSA relapse. This review article depicts issues and challenges in the management of patients with post-RP PSA relapse, presents the literature data for the efficacy of salvage radiotherapy, either alone or in combination of androgen ablation therapy, and discusses future directions that can optimize treatment strategies.

Introduction

Radical prostatectomy (RP) is one of standard treatment options for clinically localized prostate cancer. In the U.S.A., about 40% of patients with newly diagnosed prostate cancer undergo RP as their primary treatment (1). In recent years, the proportion of patients diagnosed with low risk prostate cancer has significantly increased due to widely employed prostate specific antigen (PSA) screening, and the utilization of RP for low risk prostate cancer has correspondingly increased (2).
Although RP is performed with curative intent, a significant proportion of surgically treated patients face with the risk of prostate cancer recurrence. The recurrence of prostate cancer following RP is invariably heralded by a progressively rising PSA before there is any clinical or radiological manifestation - the so - called 'PSA relapse' or 'biochemical failure'. PSA relapse after RP can be due to a local tumor recurrence at the prostate bed, occult nodal or distant metastasis, or the combination of both.
The optimal management for patients with post-RP PSA relapse has remained unclear. This stems from the inability to separate patients whose recurrent disease is confined to the prostate bed from those that have already developed occult metastasis. Furthermore, the clinical course of patients with post-RP PSA relapse is highly variable. Some experience rapid clinical progression to metastasis, while others have a very indolent natural course. As a result, management options are diverse, ranging from salvage RT, either alone or in combination of androgen ablation therapy, as a definitive therapy to expectant management or androgen ablation therapy alone as a palliative therapy. Up to now, there have been no published outcomes from randomized clinical trials addressing the efficacy of salvage therapeutic modalities. As such, treatment strategies for patients with PSA relapse have been mostly derived from retrospective series and small prospective studies, or by extrapolating evidences from clinical trials of primary cancer setting.
Radiotherapy (RT) has been the main salvage therapeutic modality with a curative potential for patients with post-RP PSA relapse. The aim of this review article is to discuss the issues and challenges in the management of patients with post-RP PSA relapse and to evaluate the role of salvage RT, either alone or in combination of androgen ablation therapy. It also discusses future directions that can assist a risk assessment and optimize management approach.

Definition and Prevalence of PSA Relapse after Radical Prostatectomy

Monitoring PSA level after RP is the cornerstone of post-operative surveillance strategies to detect the recurrence of prostate cancer. Given that the half-life of PSA is 3.15 days (3), PSA usually declines to an undetectable level within 30 days after RP (4). Thus, persistently detectable or subsequent rising PSA levels after RP indicate either residual or recurrent prostate cancer.
Various PSA cut-off points, ranging from >0.1 ng/mL to >0.5 ng/mL, have been used for the definition of PSA relapse after RP (5-12). One of commonly used definitions has been PSA ≥0.2 ng/mL with one subsequent rise. The American Urological Association and the European Association of Urology put forward a guideline that recommended PSA ≥0.2 ng/mL with a second confirmatory level of >0.2 ng/mL as the definition of PSA relapse (13-15). Freeland suggested PSA >0.2 ng/mL as an appropriate cut-off for PSA relapse, and reported that the likelihood of further PSA progression was 86% at 1 year and 100% at 3 years, when a post-operative PSA was >0.2 ng/mL (12). Another commonly used PSA cut-off point for the definition of PSA relapse has been ≥0.4 ng/mL. Stephenson examined a PSA relapse definition that would best predict the development of metastatic disease among 10 definitions selected on the basis of acceptable sensitivity. PSA ≥0.4 ng/mL with one subsequent rise was the best predictor for clinical progression, and was associated with a high probability of subsequent PSA progression and the need for subsequent secondary therapy (16). Amling reported that the probability of subsequent PSA progression increased as a PSA cut-off value increased from 0.2 to 0.4 ng/mL, and recommended PSA ≥0.4 ng/mL for the definition of PSA relapse (10). The PSA Working Group recommended PSA ≥0.4 ng/mL at a minimum of 1 month after surgery followed by a subsequent PSA value equal to or greater than the first measurement to be used for clinical trials that target patients with post-RP PSA relapse (17).
The availability of an ultrasensitive PSA assay in recent years has enabled a clinician to predict PSA relapse earlier, but at the same time has further complicated how it should be incorporated into a clinical practice. Ellis compared a PSA cut-off point >0.008 ng/mL using an ultrasensitive assay with a PSA cut-off point >0.1 ng/mL on a conventional assay for the definition of PSA relapse. He reported that the ultrasensitive PSA assay could detect PSA relapse much earlier with a lead time of 12.7~22.5 months (18). Doherty reported that the likelihood of PSA relapse, defined as three consecutive PSA rises above 0.01 ng/mL on an ultrasensitive assay, was 75% for patients who failed to achieve PSA <0.01 ng/mL, compared with only 3% for those attaining PSA <0.01 ng/mL (19). The dilemma is, however, that not all patients who appear to have PSA relapse on ultrasensitive assays develop clinical progression and subsequent PSA rise (18,20). Such a low PSA level may be due to non-malignant tissues such as benign prostatic glands or periurethral glands (18,20,21). Thus, when treatment is initiated at such a low PSA level, there is concern for over-treatment. In addition, there has been no study yet supporting that therapeutic intervention at such a low PSA level using an ultrasensitive assay would provide any therapeutic gain, compared with that triggered by PSA levels via a conventional PSA assay. The European Consensus Group advised that an ultrasensitive PSA assay could be used for monitoring patients, but not for management decision-making (14).
The risk of PSA relapse after RP depends on several, well-defined, clinical and pathologic factors such as pre-operative PSA level, Gleason score, pathologic stage, and surgical margin status. In the pooled data of RP among 8 institutions (22), the risk of PSA relapse was 19% at 10 years for pathologically organ-confined disease with negative surgical margins. The risk of PSA relapse increased substantially with the presence of extracapsular tumor extension, positive surgical margins, or the combination of both. The risk of PSA relapse at 10 years was 39% for positive surgical margins with no extracapsular extension, 54% for extracapsular extension with negative surgical margins, and 75% for extracapsular extension with positive surgical margins. Kahn constructed a modelling of four prognostic groups based on Gleason score, pathologic stage, and surgical margin status for the likelihood of being free from PSA relapse after RP (23). In recent years, the outcomes of three randomized studies (24-27), comparing observation with post-operative adjuvant radiotherapy for pathologic T3 (pT3) and/or positive surgical margins, have confirmed that extracapsular tumor extension and/or positive surgical margins are associated with a high risk of PSA relapse. In the Southwest Oncology Group 8794 clinical trial, the rate of PSA relapse was 72% at 10 years in 122 patients with pT3 and/or positive surgical resection margins who had initially achieved an undetectable post-operative PSA (≤0.2 ng/mL) (25). Similarly, in the European Organization for Research and Treatment of Cancer 22911 clinical trial (26) and the German study (27), the risk of PSA relapse was high, 40% and 46% at 5 years, respectively, in those with pT3 and/or positive surgical resection margins even if they had initially attained an undetectable post-operative PSA.

Radiological Inverstigations for PSA Relapse

Radiological investigations are usually considered for patients with post-RP PSA relapse in order to evaluate the site of tumor recurrence and to rule out any distant metastasis. Radiological studies can complement clinical and pathologic information to guide management approach. However, there has been no reliable radiological tool up to now to accurately identify the site of tumor recurrence for patients with post-RP PSA relapse.
The yield of conventional investigations such as bone scan and computed tomography (CT) of the abdomen and pelvis has been very low for patients with post-RP PSA relapse. Nevertheless, these tests are commonly performed, as the detection of any distant metastasis obviates the need for local salvage treatment. Cher reported in a series of 93 patients with PSA relapse that the probability of a positive bone scan was <5%, unless a PSA level was above 40 ng/mL (28). In the Dotan's series of 414 bone scans, the rate of a positive scan was 4%, 36%, 50%, and 79% for PSA <10, 10.1~20, 20.1~50, and >50 ng/mL, respectively (29). Gomez described a very low probability of a positive bone scan with PSA <7 ng/mL (30). Similarly, the sensitivity of abdominopelvic CT scan has been limited, when PSA levels are low. Okotie reported that when PSA was <10 ng/mL, the probability of a positive CT scan was non-existent (31). Given this very limited sensitivity and an additional risk of false positive, the routine application of bone scan and abdominopelvic CT scan has been questioned in the setting of low PSA levels. It has been suggested that the incorporation of other PSA parameters such as PSA velocity and PSA doubling time, in conjunction with PSA level, could augment the judicious use of these tests (29,31,32). Kane suggested that low PSA velocities of <0.5 ng/mL/month and <0.7 ng/mL/month were associated with negative bone scan and abdominopelvic CT scan, respectively (32). In another series, a short PSA doubling time of <6 months was associated with a higher likelihood of a positive bone scan and abdominopelvic CT scan (31).
The usefulness of routine transrectal ultrasonography (TRUS) of the prostatic fossa is unclear. Several studies have suggested a poor sensitivity of TRUS for patients with low PSA levels (33-38). In addition, Koppie questioned a predictive value of TRUS-guided biopsy of the prostatic fossa, since a positive anastomotic biopsy was not associated with an improved outcome after salvage RT (39).
Magnetic resonance imaging (MRI) has gained increasing favor in recent years for the evaluation of patients with post-RP PSA relapse for several reasons (40-42). First, MRI has enabled a clinician to assess local recurrence in the prostate bed more accurately. Sella reported that endorectal coil MRI demonstrated at least one soft tissue mass in the prostatic bed in 39 of 41 patients with clinical evidence of local recurrence (40). In a series by Miralbell, MRI was capable of documenting a recurrent or residual disease in the setting of PSA levels ranging from 0.05 to 13.3 ng/mL (median: 0.87), typically in the inferior and posterior region of the vesicourethral anastomosis (41). Sciarra suggested that the sensitivity and specificity of MRI could be further improved by the combined use of dynamic contrast-enhanced MRI and MR spectroscopic imaging (42). This combined approach yielded a sensitivity of 87% and a specificity of 94% for local recurrence in a series of 50 patients with PSA relapse (PSA range: 0.9~1.9 ng/mL). Second, MRI can assist to evaluate pelvic lymph nodes and bone metastasis in visualized bones. Third, another potential benefit of MRI is to enable a clinician to treat areas of identified local recurrence with an escalated radiation dose, which can, in turn, potentially enhance the efficacy of salvage RT.
111In-capromab pendetide scan (ProstaScint®) has shown some promise in a primary cancer setting, but its utility for patients with post-RP PSA relapse has not been validated. In a primary prostate cancer setting, a multi-center study reported that ProstaScint had a sensitivity of 75%, a specificity of 86%, and an overall accuracy of 81% in detecting extraprostatic lymph node metastasis, when it was tested for patients with a high risk prostate cancer (43). However, in the setting of post-RP PSA relapse, ProstaScint has been reported with a wide range of specificity, sensitivity, and predictive values (44-47). Raj estimated in a subset of 95 patients with post-RP PSA relapse that the sensitivity, specificity, and positive predictive value of ProstaScint were 73%, 53%, and 89%, respectively (44). Nagda reported, on the other hand, that the positive predictive value of ProstaScint in detecting recurrent disease outside the prostatic bed was only 27% (47). Furthermore, in his study of 58 patients who underwent salvage RT for PSA relapse, PSA relapse-free survival rates at 4 years were not different among patients with negative scan (53%) vs. those with positive uptake in the prostate bed alone (45%) vs. those with positive uptake outside the prostate bed (74%). Koontz and Thomas similarly reported that a positive vs. negative result of ProstaScint did not predict the treatment outcome after salvage RT (48,49).
The use of conventional positron emission tomography (PET) tracers such as 18F-fluorodeoxyglucose (FDG) is limited for prostate cancer due to a low glycolysis rate in most prostate cancer and the renal excretion of the isotope into the bladder, thus obscuring any local uptake. 11C-choline has been studied as a PET tracer for prostate cancer and has shown some promise. Rinnab reported that 11C-choline PET/CT had a sensitivity of 89% and specificity of 40% for patients with post-RP PSA levels <2.5 ng/mL (50). Castelluci reported that PSA level, PSA velocity and PSA doubling time were predictive factors for the outcome of 11C-choline PET/CT for patients with post-RP PSA relapse (51). Scattoni, in a series of 21 patients with post-RP PSA relapse (median PSA: 1.98 ng/mL), correlated the outcome of 11C-choline PET/CT for the detection of lymph node metastases with pelvic +/- retroperitoneal lymph node dissection (52). Nineteen of 21 patients (90%) with positive 11C-choline PET/CT had histologically confirmed nodal metastases. On a nodal site-based analysis, it was estimated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 11C-choline PET/CT was 64%, 90%, 86%, 72%, and 77%, respectively. However, Schilling cautioned a limited positive predictive value of 11C-choline PET/CT, as 3 of 10 patients deemed to have pelvic nodal metastases on 11C-choline PET/CT turned out no malignancy on pathology (53). Also, a recent study raised some doubt over the sensitivity of PET in the clinical setting of low PSA levels. Vees reported, in a series of 20 patients with post-RP PSA levels <1 ng/mL, that only 11 were found to have a positive PET/CT using either 18F-choline or 11C-acetate, while 15 of 18 who also underwent endorectal MRI examinations had an evidence of local recurrence (54).
In summary, the ultimate aim of radiological investigations is to differentiate the tumor recurrence confined locally to the prostate bed from that with regional or distant metastasis; thereby, identifying patients who are likely to benefit from a definitive local salvage treatment, while sparing those least likely to respond. Currently, there is no reliable radiological tool to accurately identify the site of tumor recurrence for patients with post-RP PSA relapse. The sensitivity of current imaging techniques in detecting the site of tumor recurrence falls short of the sensitivity of PSA detection. Further study is warranted to examine the utility of various radiological modalities including functional imaging techniques.

Management Options for Patients with PSA Relapse

The optimal management for patients with post-RP PSA relapse has remained unclear. This uncertainty is due to the inability to separate patients who have the recurrent disease confined to the prostate bed from those that have already developed occult metastasis. Another factor complicating the management decision is a wide variation in the natural course of post-RP PSA relapse. Furthermore, there has been no published phase III study addressing the efficacy of salvage therapeutic modalities. As such, management options are diverse, ranging from salvage RT, either alone or in combination with androgen ablation therapy, as a definitive therapeutic intervention to expectant management or androgen ablation therapy alone as a palliative treatment.
Management decision must be based on not only tumor factors but also patient factors. Predictive tumor factors for prognosis include Gleason grade of malignancy, initial pathologic stage, surgical margin status, pre-operative PSA level, the time from RP to the first sign of PSA relapse, PSA level prior to salvage radiotherapy, and PSA doubling time. In addition, patient factors associated with life expectancy, such as age, medical co-morbidity, and family history of longevity, must be taken into consideration for management decision, given that the natural course of post-RP PSA relapse is quite heterogeneous and that a patient with PSA relapse is often old and has other medical illness. The heterogeneity of the natural course of post-RP PSA relapse has been reported by Freeland (55). In his study of 379 patients with post-RP PSA relapse who were managed expectantly or androgen ablation therapy only at the time of distant metastasis, significant prognostic factors for prostate cancer-specific mortality were Gleason score, time from surgery to PSA relapse and PSA doubling time. When PSA doubling time was ≥15 months along with Gleason score <8 and time from surgery to PSA relapse >3 years, the estimated risk of prostate cancer death at 15 years was only 6%. In contrast, when PSA doubling time was <3 months in conjunction with Gleason score ≥8 and time from surgery to PSA relapse <3 years, a median survival was only 3 years and the estimated risk of prostate cancer death at 10 years was 99%. This wide variation in the natural course of post-RP PSA relapse indicates that the management decision for patients with post-RP PSA relapse should be based on not only clinicopathologic features of malignancy but also an individual patient's life expectancy. For example, a conservative management of observation alone with delayed androgen ablation therapy at the of time of distant metastasis or symptomatic local progression can be a reasonable option for a patient with a short life expectancy <5 years and favorable clinicopathologic features such as a long PSA doubling time. On the other hand, an aggressive salvage therapeutic intervention should be considered for a patient with a life expectancy >10 years and/or adverse clinicopathologic features such as a short PSA doubling time and a high Gleason score.
There has been no published data of phase III clinical studies demonstrating which therapeutic approach, if any, would prolong life with no significant morbidity for patients with post-RP PSA relapse. Androgen ablation therapy alone is considered palliative, since castration-refractory disease invariably develops in almost all patients. There has been no randomized study that can guide the optimal timing to introduce androgen ablation therapy for patients with post-RP PSA relapse. While there are some retrospective studies suggesting the benefit of early androgen ablation therapy vs. delayed implementation for patients with PSA relapse after primary therapy (56,57), the early institution of androgen ablation therapy should be carefully weighed in due to its potential long-term adverse effects such as lethargy, metabolic syndrome, potential cardiovascular effect, and osteoporosis. There has been no published data from phase III studies to address the effectiveness of salvage RT. It remains uncertain whether salvage RT confers a survival benefit compared with observation or androgen ablation therapy. However, RT is considered the only therapeutic modality that offers a potential of cure for patients with post-RP PSA relapse. Recently, the benefit of salvage RT, compared with expectant management, is suggested by two retrospective studies (58,59). Trock reported, in a series of 635 patients with post-RP PSA relapse, that salvage RT was associated with a statistically significant improvement in both prostate cancer-specific survival and overall survival, in comparison with observation alone. Among 511 patients with no pelvic node metastases, the hazard ratio for prostate cancer-specific death was 0.34 for salvage RT vs. observation alone, and 0.35 for salvage RT plus androgen ablation therapy vs. observation alone (58). Similarly, in a retrospective series of 2,657 patients with post-RP PSA relapse, Boorjian reported that salvage RT was associated with 90% reduction in the risk of local recurrence, 20% reduction in the need of androgen ablation therapy, and 75% decrease in the risk of distant metastasis, in comparison with no salvage RT (59).

Salvage Radiotherapy for PSA Relapse

RT remains the only therapeutic intervention that offers a potential of cure for patients with post-RP PSA relapse. A PSA response rate of salvage RT, defined as any incremental decrease of PSA in response to RT, has been reported up to 90% (60). A high PSA response rate to RT suggests that a majority of patients with post-RP PSA relapse have at least an element of local tumor recurrence at the prostate bed, although they may also have occult distant metastasis simultaneously. A complete PSA response rate, defined as a decline of PSA to an undetectable level, has been reported 57% by Choo (PSA cut-off: <0.2 ng/mL) (60), and 55% by Stephenson (PSA cut-off: ≤0.1 ng/mL) (61). Choo reported that up to 10% of patients did not show any PSA response to RT (60). The most plausible explanation for the lack of PSA response to RT would be the presence of occult nodal or distant metastasis that is beyond the radiotherapy field.
The ability to provide an excellent local tumor control is one of the important factors when salvage RT is considered for patients with post-RP PSA relapse, although it may not be as critical as other end points such as relapse-free and overall survival benefit. Almost all the published studies reported that salvage RT could provide excellent local tumor control at the prostate bed for patients with post-RP PSA relapse including those presenting with clinically palpable local recurrence (60,62,63). Whether equally good local control can be achieved with androgen ablation therapy alone remains unknown. It is worthwhile to note that a few studies reported that RT was effective in controlling local recurrence which had progressed on androgen ablation therapy (64,65).
The ultimate goal of salvage RT is to keep a PSA level undetectable in post-RT follow-up, in which case a claim that salvage RT has been curative can be made. The vast majority of published series evaluating the efficacy of salvage RT have been retrospective studies, and limited by a relatively small sample size, a short follow-up, and inherent shortcomings associated with a retrospective study. Table 1 shows selected studies published in the last 10 years. The outcomes of salvage RT have been variable among published series. The difference in outcomes is, in part, due to the variation in PSA cut-off levels used to define freedom from PSA relapse, and the heterogeneity of patient and tumor characteristics among studies. For example, in the series by Loeb (66), De Meerleer (67), and Stephenson (61), PSA ≥0.2 ng/mL followed by another higher value was used for the definition of PSA relapse after salvage RT. On the other hand, Buskirk (68) and Pisansky (69) used a PSA cut-off of ≥0.4 and ≥0.3 ng/mL for the definition of PSA relapse, respectively. Neuhof (70), and Wiegel (71) used yet another definition for PSA relapse after salvage RT - three consecutive PSA increases. Another significant variation is patient and tumor characteristics among studies. Some series, compared with others, had a higher PSA level prior to salvage RT and a higher proportion of patient with poor prognostic factors such as a high Gleason score, and seminal vesicle invasion. For instance, Leventis reported in a series of 49 patients that a 5-year PSA relapse-free probability after salvage RT was 24%. In his series, median PSA prior to salvage RT was 2.1 ng/mL (72). In contrast, in the Pisansky's series, which reported a 5-year PSA relapse-free probability of 46%, median PSA prior to salvage RT was 0.9 ng/mL (69).
The efficacy of salvage RT for patients with post-RP PSA relapse has been suboptimal, as shown in Table 1. In the pooled data of 17 North American tertiary referral centers, Stephenson examined the efficacy of salvage RT for a retrospective cohort of 1,540 patients with post-RP PSA relapse. With a median follow-up of 53 months, the overall progression-free probability (defined as PSA <0.2 ng/mL) at 6 years was 32% (61). In the Buskirk series, the estimated PSA relapse-free rate (defined as PSA <0.4 ng/mL) at 8 years was 35% (68). Pazona reported that only 25% remained free of PSA relapse (defined as PSA <0.3 ng/mL) at 10 years (73).
Why the efficacy of salvage RT has been mediocre? The main reason stems most likely from the underlying adverse pathologic and/or clinical features that patients with post-RP PSA relapse often possess. In the Stephenson's series (61), 65%, 24%, and 74% of the pooled cohort of 1,540 patients had extracapsular tumor extension, seminal vesicle invasion, and Gleason score ≥7, respectively, on RP specimens. In addition, 29% of the patients had persistently detectable PSA after RP. In another salvage RT series by Buskirk (68), 62% and 53% of the patients displayed pT3-T4 disease and Gleason score ≥7, respectively, on RP specimens. These underlying adverse pathological features predict inherently aggressive biological disposition with a high probability of developing distant metastasis and locoregional relapse. Thus, it is not a surprise, to some extent, that a significant proportion of patients undergoing salvage RT exhibit a second wave of PSA relapse on a follow-up, even if they initially show a very favorable PSA response to RT.
Many series evaluated prognostic factors for PSA relapse-free outcome following salvage RT. Reported prognostic variables include pathologic stage, seminal vesicle involvement, Gleason score, surgical margin status, the interval between RP and the first sign of PSA relapse, PSA level prior to salvage RT, radiation dose, the use of neoadjuvant and/or concurrent androgen ablation therapy, and PSA doubling time. However, these variables were not consistently reported or correlated with treatment outcomes among published series. One of consistent variables associated with PSA relapse-free outcome has been PSA levels prior to salvage RT. Multiple studies examined various PSA cut-off levels and showed that the lower the PSA level at the time of salvage RT, the better the treatment outcome (61,68-70,72,74-84). No specific PSA cut-off level has been identified as being superior to others at predicting treatment outcome. In the Stephenson's series of the pooled cohort of 1,540 patients, a nomogram was constructed to predict treatment outcomes following salvage RT (61). Significant predictive factors associated with progression-free outcome were PSA levels prior to salvage RT, Gleason grade, PSA doubling time, surgical margin status, androgen ablation therapy before or during RT, and lymph node metastasis. The predictive accuracy of the nomogram as measured by c-index was 0.69 in internal validation. Recently, Moreira reported, using the outcome of 102 patients treated with salvage RT in other institutions, that the concordance index of the nomogram was 0.65 (77).
Optimal radiation dose required for patients with post-RP PSA relapse remains unknown. Most published studies used a radiation dose <70 Gy for salvage RT, due to the concern for radiation morbidity. It is plausible that a higher radiation dose may yield better treatment outcome. King suggested a dose-response relationship in salvage RT setting (85). He estimated that 66.8 Gy would give a 50% chance of achieving PSA relapse-free rate at 5 years and that the proportional gain in PSA relapse-free rate would be 3.8% per additional Gray within the steep part of the tumor control probability curve. Bernard (86) and King (76) described in their retrospective series that a higher radiation dose was associated with improved PSA relapse-free rates. In recent years, the adaptation of more sophisticated techniques in radiation delivery such as intensity-modulated radiotherapy has allowed escalating radiation dose to the target, while minimizing toxicity to the surrounding normal tissues. De Meerleer recently reported, using intensity-modulated radiotherapy, that a dose of 75 Gy could be delivered with a low risk of serious acute and late radiation toxicity in a salvage RT setting (67).

Toxicity of Salvage RT

Salvage RT to the prostate bed is generally well tolerated with a low risk of severe acute and late gastrointestinal (GI) and genitourinary (GU) toxicity. Most of toxicity information in the literature has been, however, hampered by a retrospective nature of analysis, a small sample size, and the lack of baseline evaluation prior to salvage RT. In the retrospective database of 959 patients who were treated at 11 academic centers with either adjuvant RT or salvage RT (81% treated with salvage RT), 4% and 0.4% had Grade 2 and Grade 3 late GI toxicity at 5 years, respectively, using the Radiation Therapy Oncology Group (RTOG) toxicity scoring system (87). 10% and 1% had Grade 2 and Grade 3 late GU toxicity at 5 years, respectively. Peterson estimated in a retrospective study of 308 patients that the cumulative rate of Grade 3 or 4 late GI or GU complication was 0.7% at 5 years, using the RTOG toxicity scoring system (88).
The comprehensive information on the toxicity of salvage RT has been recently reported by Pearse (89). In this study, which was a phase I/II clinical trial evaluating the efficacy of salvage RT plus 2-year adjuvant androgen ablation therapy for patients with post-RP PSA relapse, acute and late GI and GU toxicity was prospectively assessed using the National Cancer Institute (NCI) Expanded Common Toxicity Criteria version 2 (http://ctep.info.nih.gov). Toxicity assessment was administered prior to salvage RT (baseline), 3 and 6 weeks into RT, 10 weeks after the completion of RT, then four monthly for the first two years, and then six monthly. The study comprised of a cohort of 75 patients treated with radiation doses ranging from 60 Gy to 66 Gy (median: 66 Gy; 2 Gy per fraction). The clinical target volume of radiotherapy was limited to the prostate bed. It noted that 30 patients (40%) had pre-existing GU dysfunction prior to RT, mainly due to urinary incontinence (28/30 patients). Four patients (5%) experienced Grade 3 acute GI or GU toxicity. With the median follow-up of 45.1 months, cumulative incidences of Grade 3 late GI and GU toxicity at 36 months were 1.6% and 2.6%, respectively; 8.7% and 22.6% for Grade ≥2 late GI and GU toxicity, respectively. None had Grade 4 late toxicity. The severity of acute GU toxicity (Grade <2 vs. ≥2) was a significant predictor factor for Grade ≥2 late GU toxicity after adjusting for pre-existing GU dysfunction. Five patients (7%) reported Grade 3 late GI or GU toxicity. One patient had Grade 3 radiation proctitis requiring argon plasma coagulation. Two patients developed self-limiting gross hematuria. One patient had Grade 3 incontinence at baseline, which persisted throughout the follow-up. The remaining one patient developed Grade 3 urinary frequency and Grade 3 urethral stricture requiring dilatation.
Compromising urinary continence and exacerbating urethral stricture by RT are major concerns to both patients and clinicians, given that patients may have already suffered some degree of urinary incontinence and/or urethral stricture after surgery. The prevalence of pre-existing urinary incontinence prior to salvage RT was illustrated by the Pearse's series (89), in which 28/75 patients (37%) reported Grade 1 to 3 incontinence before salvage RT. The study reported that the cumulative incidence of urinary incontinence at 36 months was 16.8% for Grade ≥2 incontinence, and that pre-existing urinary incontinence was associated with a higher incidence of Grade ≥2 incontinence at 36 months (35.0% for patients with pre-existing incontinence vs. 9.6% for patients with complete continence at baseline) (89). Pearse also examined the prevalence of urinary incontinence at one specific time point of follow-up. At 30-month post-RT, 71 patients were available for this analysis. Of these patients, 45 were fully continent at baseline, and 26 had some degree of underlying urinary incontinence (23 with Grade 1, 2 with Grade 2, and 1 with Grade 3) prior to salvage RT. Of the 45 patients with complete continence at baseline, 31 remained totally continent, while 13 had Grade 1 and 1 had Grade 2 incontinence at 30 months. None had Grade 3 incontinence. Of the 26 patients with pre-existing incontinence prior to salvage RT, incontinence was unchanged in 11, worsened in 2, and improved in 13 at 30 months (89).

Salvage Radiotherapy Plus Androgen Ablation Therapy for PSA Relapse

There has been a paucity of data in the literature examining the efficacy of a combined approach of salvage RT plus androgen ablation therapy. Furthermore, there has been no published phase III study demonstrating the benefit of adding androgen ablation therapy to salvage RT for patients with post-RP PSA relapse.
Choo recently reported the outcome of a phase I/II study evaluating the combined approach of salvage RT plus 2-year androgen ablation therapy (90). In the study, a total of 75 patients with post-RP PSA relapse were treated with salvage RT followed by 2-year androgen ablation therapy. Androgen ablation therapy started within 1 month after the completion of salvage RT, and consisted of nilutamide for 4 weeks and buserelin acetate depot for 2 years. All completed RT. Sixty-five patients completed the planned 2-year of androgen ablation therapy, while 10 terminated it prematurely. The median duration of androgen ablation therapy for these 10 patients was 19 months. The median age of the cohort was 63 years at the time of salvage RT. The study used a PSA rise above 0.2 ng/mL with two consecutive increases over a minimum of three months as the definition of PSA relapse post-therapy. All achieved initially complete PSA response (<0.2 ng/mL) with the protocol treatment. With the median follow-up of 6.4 years (range: 2.0~9.8) from salvage RT, the study reported that a relapse-free rate including the freedom from PSA relapse was 91.5% at 5 years and 78.6% at 7 years, and overall survival rate was 93.2% at both 5 and 7 years. These study outcomes were encouraging and more favorable than those of published series of salvage RT alone. A confirmatory phase III or another large prospective study is, however, needed to demonstrate the benefit of adding androgen ablation therapy to salvage RT.
There have been a few retrospective studies, which suggested a possible benefit of adding androgen ablation therapy to salvage RT. Katz reported in a retrospective series of 115 patients that a PSA relapse-free rate at 4 years appeared better for 45 patients receiving a median duration of 3 months of neoadjuvant androgen ablation therapy prior to salvage RT, compared with 70 patients treated with salvage RT alone (59% vs. 39%) (91). In another retrospective study with a median follow-up of 38 months, Tiguert reported that a 5-year PSA relapse-free rate was 50% at 5 years for 81 patients treated with 3 months of neoadjuvant androgen ablation therapy followed by salvage RT (92). King compared treatment outcomes between salvage RT plus 4-month androgen ablation therapy (2-month before and 2-month during RT) and salvage RT alone in a retrospective study of 122 patients (93). A 5-year PSA relapse-free rate was better for those treated with salvage RT plus 4-month androgen ablation therapy than for those receiving salvage RT alone (57% vs. 31%). In a retrospective series of 71 patients undergoing salvage RT, Taylor explored a potential benefit of adding adjuvant androgen ablation therapy to salvage RT (94). In his series, 35/71 received adjuvant androgen ablation therapy for a median duration of 24 months. The study reported, with a median follow-up of 39 months, that a 5-year PSA relapse-free rate was 81% for patients receiving adjuvant androgen ablation therapy, compared with 54% for those treated with salvage RT alone.

Past and Current Phase III Studies for PSA Relapse

The Radiation Therapy Oncology Group completed a phase III clinical trial (RTOG 9601) comparing salvage RT with salvage RT plus 2 years of a high dose bicalutamide (150 mg per day) for patients with post-RP PSA relapse. The study closed in 2003 after accruing a total of 840 patients. Its outcome is pending at present. Currently, the RTOG is conducting another phase III, 3-arm, study (RTOG 0534) to examine the potential benefit of adding 4~6 months of androgen ablation therapy to salvage RT and to address a potential role of treating pelvic lymph nodes. The United Kingdom is conducing a phase III study called RADICALS (Radiotherapy and Androgen Deprivation in Combination After Local Surgery), and part of this study is to assess the benefit of adding 6-month or 24-month androgen ablation therapy to salvage RT. The Japan Clinical Oncology Group is conducting a phase III study comparing androgen ablation therapy alone with salvage RT+/- androgen ablation therapy (androgen ablation therapy limited to patients with PSA relapse after salvage RT) (95). A French group is conducting a phase III study comparing salvage RT with salvage RT plus 6-month androgen ablation therapy (Clinical Trials Gov. Identifier: NCT00423475).

Future Directions

There is a need to further study radiological means and molecular markers that can separate local tumor recurrence from regional or distant metastasis for patients with PSA relapse. These tools will assist clinicians to identify patients who are likely to benefit from definitive local salvage treatment such as radiotherapy, while sparing those least likely to benefit. In addition, molecular markers, along with clinicopathologic features, which can separate indolent disease from biologically aggressive disease that is likely destined to progress need to be explored to facilitate an individualized management decision.
For salvage RT, further study is needed to address optimal radiation dose required for patients with PSA relapse. In parallel, more advanced techniques in radiation simulation and delivery need to be explored in order to minimize radiation toxicity to the surrounding normal tissues, while escalating radiation dose to the target. Another unresolved question is whether regional pelvic nodes should be irradiated along with the prostate bed, and the current RTOG 0534 study is addressing this question.
Strategies that optimize the control of systemic disease and the local prostate bed need to be explored, particularly for patients with adverse clinicopathologic features such as a high Gleason score, a short PSA doubling time, and a high PSA level at the time of salvage RT. The efficacy of salvage RT alone for patients with adverse clinicopathologic features has been suboptimal in spite of a high initial PSA response rate and an excellent local control achieved by RT. The limited efficacy of salvage RT is likely, in part, due to occult distant metastasis at the time of referral for salvage RT and/or radio-resistant clones. Thus, therapeutic approaches that target occult systemic disease as well as the local prostate bed need to be examined. Such approaches include combining androgen ablation therapy and/or chemotherapy with salvage RT.

Conclusion

PSA relapse after RP presents a difficult clinical dilemma for both patients and clinicians. For the patient, it is a sign that the initial surgery was not successful and brings a sense of anxiety and burden to consider a second-line therapy. For the clinician, it presents management challenges that do not have definitive answers to many unresolved questions. In particular, management decision has been complicated by a wide variation in the natural course of post-RP PSA relapse and the lack of clear evidences demonstrating which therapeutic approach, if any, prolongs life with no significant morbidity.
RT has been the main therapeutic modality with a curative potential for patients with post-RP PSA relapse. Its efficacy has been, however, adversely affected by the underlying adverse pathological and/or clinical features that patients with post-RP PSA relapse often present with. Clinical studies are in progress to evaluate various therapeutic approaches including a combined approach of salvage RT plus androgen ablation therapy.

References

1. Cooperberg MR, Broering JM, Litwin MS, Lubeck DP, Mehta SS, Henning JM, 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. 2004;171:1393–1401. PMID: 15017184
crossref pmid
2. Cooperberg MR, Broering JM, Kantoff PW, Carroll PR. Contemporary trends in low risk prostate cancer: risk assessment and treatment. J Urol. 2007;178:S14–S19. PMID: 17644125
crossref pmid pmc
3. Oesterling JE, Chan DW, Epstein JI, Kimball AW Jr, Bruzek DJ, Rock RC, et al. Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol. 1988;139:766–772. PMID: 2451037
crossref pmid
4. Partin AW, Oesterling JE. The clinical usefulness of prostate specific antigen: update 1994. J Urol. 1994;152:1358–1368. PMID: 7523702
crossref pmid
5. Presti JC Jr, Shinohara K, Bacchetti P, Tigrani V, Bhargava V. Positive fraction of systematic biopsies predicts risk of relapse after radical prostatectomy. Urology. 1998;52:1079–1084. PMID: 9836558
crossref pmid
6. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591–1597. PMID: 10235151
crossref pmid
7. Freedland SJ, Wieder JA, Jack GS, Dorey F, deKernion JB, Aronson WJ. Improved risk stratification for biochemical recurrence after radical prostatectomy using a novel risk group system based on prostate specific antigen density and biopsy Gleason score. J Urol. 2002;168:110–115. PMID: 12050502
crossref pmid
8. Moul JW, Connelly RR, Lubeck DP, Bauer JJ, Sun L, Flanders SC, et al. Predicting risk of prostate specific antigen recurrence after radical prostatectomy with the Center for Prostate Disease Research and Cancer of the Prostate Strategic Urologic Research Endeavor databases. J Urol. 2001;166:1322–1327. PMID: 11547066
crossref pmid
9. Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol. 2002;167:528–534. PMID: 11792912
crossref pmid
10. Amling CL, Bergstralh EJ, Blute ML, Slezak JM, Zincke H. Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol. 2001;165:1146–1151. PMID: 11257657
crossref pmid
11. Iselin CE, Robertson JE, Paulson DF. Radical perineal prostatectomy: oncological outcome during a 20-year period. J Urol. 1999;161:163–168. PMID: 10037390
crossref pmid
12. Freedland SJ, Sutter ME, Dorey F, Aronson WJ. Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology. 2003;61:365–369. PMID: 12597949
crossref pmid
13. Cookson MS, Aus G, Burnett AL, Canby-Hagino ED, D'Amico AV, Dmochowski RR, 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. 2007;177:540–545. PMID: 17222629
crossref pmid
14. Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, et al. EAU guidelines on prostate cancer. Eur Urol. 2008;53:68–80. PMID: 17920184
crossref pmid
15. Boccon-Gibod L, Djavan WB, Hammerer P, Hoeltl W, Kattan MW, Prayer-Galetti T, et al. Management of prostate-specific antigen relapse in prostate cancer: a European Consensus. Int J Clin Pract. 2004;58:382–390. PMID: 15161124
crossref pmid
16. Stephenson AJ, Kattan MW, Eastham JA, Dotan ZA, Bianco FJ Jr, Lilja H, et al. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition. J Clin Oncol. 2006;24:3973–3978. PMID: 16921049
crossref pmid
17. Scher HI, Eisenberger M, D'Amico AV, Halabi S, Small EJ, Morris M, 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. 2004;22:537–556. [Erratum appears in J Clin Oncol. 2004;22:3205]PMID: 14752077
crossref pmid
18. Ellis WJ, Vessella RL, Noteboom JL, Lange PH, Wolfert RL, Rittenhouse HG. Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate-specific antigen assay. Urology. 1997;50:573–579. PMID: 9338734
crossref pmid
19. Doherty AP, Bower M, Smith GL, Miano R, Mannion EM, Mitchell H, et al. Undetectable ultrasensitive PSA after radical prostatectomy for prostate cancer predicts relapse-free survival. Br J Cancer. 2000;83:1432–1436. PMID: 11076649
crossref pmid pmc
20. Ornstein DK, Oh J, Herschman JD, Andriole GL. Evaluation and management of the man who has failed primary curative therapy for prostate cancer. Urol Clin North Am. 1998;25:591–601. PMID: 10026768
crossref pmid
21. Diamandis EP, Yu H. Nonprostatic sources of prostate-specific antigen. Urol Clin North Am. 1997;24:275–282. PMID: 9126224
crossref pmid
22. Karakiewicz PI, Eastham JA, Graefen M, Cagiannos I, Stricker PD, Klein E, et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi-institutional assessment of 5,831 patients. Urology. 2005;66:1245–1250. PMID: 16360451
crossref pmid
23. Khan MA, Partin AW, Mangold LA, Epstein JI, Walsh PC. Probability of biochemical recurrence by analysis of pathologic stage, Gleason score, and margin status for localized prostate cancer. Urology. 2003;62:866–871. PMID: 14624910
crossref pmid
24. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, 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. 2009;181:956–962. PMID: 19167731
crossref pmid pmc
25. Swanson GP, Hussey MA, Tangen CM, Chin J, Messing E, Canby-Hagino E, et al. Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol. 2007;25:2225–2229. PMID: 17538167
crossref pmid
26. Bolla M, van Poppel H, Collette L, van Cangh P, Vekemans K, Da Pozzo L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. 2005;366:572–578. PMID: 16099293
crossref pmid
27. Wiegel T, Bottke D, Steiner U, Siegmann A, Golz R, Storkel S, 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. PMID: 19433689
crossref pmid
28. Cher ML, Bianco FJ Jr, Lam JS, Davis LP, Grignon DJ, Sakr WA, et al. Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy. J Urol. 1998;160:1387–1391. PMID: 9751361
crossref pmid
29. Dotan ZA, Bianco FJ Jr, Rabbani F, Eastham JA, Fearn P, Scher HI, et al. Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy. J Clin Oncol. 2005;23:1962–1968. PMID: 15774789
crossref pmid pmc
30. Gomez P, Manoharan M, Kim SS, Soloway MS. Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated? BJU Int. 2004;94:299–302. PMID: 15291855
crossref pmid
31. Okotie OT, Aronson WJ, Wieder JA, Liao Y, Dorey F, DeKernion JB, et al. Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. J Urol. 2004;171:2260–2264. PMID: 15126798
crossref pmid
32. Kane CJ, Amling CL, Johnstone PA, Pak N, Lance RS, Thrasher JB, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology. 2003;61:607–611. PMID: 12639656
crossref pmid
33. Saleem MD, Sanders H, Abu El Naser M, El-Galley R. Factors predicting cancer detection in biopsy of the prostatic fossa after radical prostatectomy. Urology. 1998;51:283–286. PMID: 9495712
crossref pmid
34. Connolly JA, Shinohara K, Presti JC Jr, Carroll PR. Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins. Urology. 1996;47:225–231. PMID: 8607239
crossref pmid
35. Shekarriz B, Upadhyay J, Wood DP Jr, Hinman J, Raasch J, Cummings GD, et al. Vesicourethral anastomosis biopsy after radical prostatectomy: predictive value of prostate-specific antigen and pathologic stage. Urology. 1999;54:1044–1048. PMID: 10604706
crossref pmid
36. Scattoni V, Montorsi F, Picchio M, Roscigno M, Salonia A, Rigatti P, et al. Diagnosis of local recurrence after radical prostatectomy. BJU Int. 2004;93:680–688. PMID: 15009088
crossref pmid
37. Naya Y, Okihara K, Evans RB, Babaian RJ. Efficacy of prostatic fossa biopsy in detecting local recurrence after radical prostatectomy. Urology. 2005;66:350–355. PMID: 16040095
crossref pmid
38. Deliveliotis C, Manousakas T, Chrisofos M, Skolarikos A, Delis A, Dimopoulos C. Diagnostic efficacy of transrectal ultrasound-guided biopsy of the prostatic fossa in patients with rising PSA following radical prostatectomy. World J Urol. 2007;25:309–313. PMID: 17440730
crossref pmid
39. Koppie TM, Grossfeld GD, Nudell DM, Weinberg VK, Carroll PR. Is anastomotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol. 2001;166:111–115. PMID: 11435834
crossref pmid
40. Sella T, Schwartz LH, Swindle PW, Onyebuchi CN, Scardino PT, Scher HI, et al. Suspected local recurrence after radical prostatectomy: endorectal coil MR imaging. Radiology. 2004;231:379–385. PMID: 15064390
crossref pmid
41. Miralbell R, Vees H, Lozano J, Khan H, Molla M, Hidalgo A, 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. 2007;67:356–361. PMID: 17236961
crossref pmid
42. Sciarra A, Panebianco V, Salciccia S, Osimani M, Lisi D, Ciccariello M, et al. Role of dynamic contrast-enhanced magnetic resonance (MR) imaging and proton MR spectroscopic imaging in the detection of local recurrence after radical prostatectomy for prostate cancer. Eur Urol. 2008;54:589–600. PMID: 18226441
crossref pmid
43. Hinkle GH, Burgers JK, Neal CE, Texter JH, Kahn D, Williams RD, et al. Multicenter radioimmunoscintigraphic evaluation of patients with prostate carcinoma using indium-111 capromab pendetide. Cancer. 1998;83:739–747. PMID: 9708939
crossref pmid
44. Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer. 2002;94:987–996. PMID: 11920467
crossref pmid
45. Petronis JD, Regan F, Lin K. Indium-111 capromab pendetide (ProstaScint) imaging to detect recurrent and metastatic prostate cancer. Clin Nucl Med. 1998;23:672–677. PMID: 9790041
crossref pmid
46. Elgamal AA, Troychak MJ, Murphy GP. ProstaScint scan may enhance identification of prostate cancer recurrences after prostatectomy, radiation, or hormone therapy: analysis of 136 scans of 100 patients. Prostate. 1998;37:261–269. PMID: 9831223
crossref pmid
47. Nagda SN, Mohideen N, Lo SS, Khan U, Dillehay G, Wagner R, et al. Long-term follow-up of 111In-capromab pendetide (ProstaScint) scan as pretreatment assessment in patients who undergo salvage radiotherapy for rising prostate-specific antigen after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys. 2007;67:834–840. PMID: 17293236
crossref pmid
48. Koontz BF, Mouraviev V, Johnson JL, Mayes J, Chen SH, Wong TZ, et al. Use of local (111)in-capromab pendetide scan results to predict outcome after salvage radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;71:358–361. PMID: 18164863
crossref pmid
49. Thomas CT, Bradshaw PT, Pollock BH, Montie JE, Taylor JMG, Thames HD, et al. Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol. 2003;21:1715–1721. PMID: 12721246
crossref pmid
50. Rinnab L, Simon J, Hautmann RE, Cronauer MV, Hohl K, Buck AK, et al. [(11)C]choline PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy. World J Urol. 2009;27:619–625. PMID: 19234708
crossref pmid
51. Castellucci P, Fuccio C, Nanni C, Santi I, Rizzello A, Lodi F, et al. Influence of trigger PSA and PSA kinetics on 11C-Choline PET/CT detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med. 2009;50:1394–1400. [Erratum appears in J Nucl Med. 2009; 50:1578]PMID: 19690023
crossref pmid
52. Scattoni V, Picchio M, Suardi N, Messa C, Freschi M, Roscigno M, et al. Detection of lymph-node metastases with integrated [11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: results confirmed by open pelvicretroperitoneal lymphadenectomy. Eur Urol. 2007;52:423–429. PMID: 17397992
crossref pmid
53. Schilling D, Schlemmer HP, Wagner PH, Bottcher P, Merseburger AS, Aschoff P, et al. Histological verification of 11C-choline-positron emission/computed tomography-positive lymph nodes in patients with biochemical failure after treatment for localized prostate cancer. BJU Int. 2008;102:446–451. PMID: 18410442
crossref pmid
54. Vees H, Buchegger F, Albrecht S, Khan H, Husarik D, Zaidi H, et al. 18F-choline and/or 11C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostate-specific antigen values (<1 ng/mL) after radical prostatectomy. BJU Int. 2007;99:1415–1420. PMID: 17428249
crossref pmid
55. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294:433–439. PMID: 16046649
crossref pmid
56. Moul JW, Wu H, Sun L, McLeod DG, Amling C, Donahue T, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol. 2004;171:1141–1147. [Reprint in J Urol. 2008;179(5 Suppl):S53-9; PMID: 18405753]PMID: 14767288
crossref pmid
57. Shipley WU, Desilvio M, Pilepich MV, Roach M 3rd, Wolkov HB, Sause WT, et al. Early initiation of salvage hormone therapy influences survival in patients who failed initial radiation for locally advanced prostate cancer: A secondary analysis of RTOG protocol 86-10. Int J Radiat Oncol Biol Phys. 2006;64:11621167[Erratum appears in Int J Radiat Oncol Biol Phys. 2006;65:313]PMID: 16427211
crossref pmid
58. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760–2769. PMID: 18560003
crossref pmid pmc
59. Boorjian SA, Karnes RJ, Crispen PL, Rangel LJ, Bergstralh EJ, Blute ML. Radiation therapy after radical prostatectomy: impact on metastasis and survival. J Urol. 2009;182:2708–2714. PMID: 19836762
crossref pmid
60. Choo R, Hruby G, Hong J, Bahk E, Hong E, Danjoux C, 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. PMID: 12023129
crossref pmid
61. Stephenson AJ, Scardino PT, Kattan MW, Pisansky TM, Slawin KM, Klein EA, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035–2041. [Erratum appears in J Clin Oncol. 2007;25:4153]PMID: 17513807
crossref pmid pmc
62. Choo R, Morton G, Danjoux C, Hong E, Szumacher E, DeBoer G. Limited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgery. Radiother Oncol. 2005;74:163–167. PMID: 15734204
crossref pmid
63. Macdonald OK, Schild SE, Vora SA, Andrews PE, Ferrigni RG, Novicki DE, et al. Salvage radiotherapy for palpable, locally recurrent prostate cancer after radical prostatectomy. Int J Radiat Oncol Biol Phys. 2004;58:1530–1535. PMID: 15050333
crossref pmid
64. Ray GR, Bagshaw MA, Freiha F. External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. J Urol. 1984;132:926–930. PMID: 6436511
crossref pmid
65. Rosen EM, Cassady JR, Connolly J, Chaffey JT. Radiotherapy for localized prostate carcinoma. Int J Radiat Oncol Biol Phys. 1984;10:2201–2210. PMID: 6439698
crossref pmid
66. Loeb S, Roehl KA, Viprakasit DP, Catalona WJ. Long-term rates of undetectable PSA with initial observation and delayed salvage radiotherapy after radical prostatectomy. Eur Urol. 2008;54:88–94. PMID: 18400368
crossref pmid
67. De Meerleer G, Fonteyne V, Meersschout S, Van den Broecke C, Villeirs G, Lumen N, et al. Salvage intensity-modulated radiotherapy for rising PSA after radical prostatectomy. Radiother Oncol. 2008;89:205–213. PMID: 18771809
crossref pmid
68. Buskirk SJ, Pisansky TM, Schild SE, Macdonald OK, Wehle MJ, Kozelsky TF, et al. Salvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring system. J Urol. 2006;176:985–990. PMID: 16890677
crossref pmid
69. Pisansky TM, Kozelsky TF, Myers RP, Hillman DW, Blute ML, Buskirk SJ, et al. Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer. J Urol. 2000;163:845–850. PMID: 10687990
crossref pmid
70. Neuhof D, Hentschel T, Bischof M, Sroka-Perez G, Hohenfellner M, Debus J. Long-term results and predictive factors of three-dimensional conformal salvage radiotherapy for biochemical relapse after prostatectomy. Int J Radiat Oncol Biol Phys. 2007;67:1411–1417. PMID: 17275204
crossref pmid
71. Wiegel T, Lohm G, Bottke D, Hocht S, Miller K, Siegmann A, et al. Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study. Int J Radiat Oncol Biol Phys. 2009;73:1009–1016. PMID: 18963539
crossref pmid
72. Leventis AK, Shariat SF, Kattan MW, Butler EB, Wheeler TM, Slawin KM. Prediction of response to salvage radiation therapy in patients with prostate cancer recurrence after radical prostatectomy. J Clin Oncol. 2001;19:1030–1039. [Erratum appears in J Clin Oncol. 2001;19:2109]PMID: 11181666
crossref pmid
73. Pazona JF, Han M, Hawkins SA, Roehl KA, Catalona WJ. Salvage radiation therapy for prostate specific antigen progression following radical prostatectomy: 10-year outcome estimates. J Urol. 2005;174:1282–1286. PMID: 16145393
crossref pmid
74. Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325–1332. PMID: 15026399
crossref pmid
75. Maier J, Forman J, Tekyi-Mensah S, Bolton S, Patel R, Pontes JE. Salvage radiation for a rising PSA following radical prostatectomy. Urologic Oncology. 2004;22:50–56. PMID: 14969805
crossref pmid
76. King CR, Spiotto MT. Improved outcomes with higher doses for salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys. 2008;71:23–27. PMID: 18207668
crossref pmid
77. Moreira DM, Jayachandran J, Presti JC Jr, Aronson WJ, Terris MK, Kane CJ, et al. Validation of a nomogram to predict disease progression following salvage radiotherapy after radical prostatectomy: results from the SEARCH database. BJU Int. 2009;104:1452–1456. PMID: 19466946
crossref pmid
78. MacDonald OK, Schild SE, Vora S, Andrews PE, Ferrigni RG, Novicki DE, 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. PMID: 15491716
crossref pmid
79. Song DY, Thompson TL, Ramakrishnan V, Harrison R, Bhavsar N, Onaodowan O, et al. Salvage radiotherapy for rising or persistent PSA after radical prostatectomy. Urology. 2002;60:281–287. PMID: 12137827
crossref pmid
80. Macdonald OK, Schild SE, Vora SA, Andrews PE, Ferrigni RG, Novicki DE, et al. Radiotherapy for men with isolated increase in serum prostate specific antigen after radical prostatectomy. J Urol. 2003;170:1833–1837. PMID: 14532786
crossref pmid
81. Catton C, Gospodarowicz M, Warde P, Panzarella T, Catton P, McLean M, et al. Adjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostate. Radiother Oncol. 2001;59:51–60. PMID: 11295206
crossref pmid
82. Quero L, Mongiat-Artus P, Ravery V, Maylin C, Desgrandchamps F, Hennequin C. Salvage radiotherapy for patients with PSA relapse after radical prostatectomy: a single institution experience. BMC Cancer. 2008;8:26PMID: 18230130
crossref pmid pmc
83. Sasaki T, Nakamura K, Shioyama Y, Ohga S, Toba T, Urashima Y, et al. Low preradiotherapy prostate-specific antigen level is a significant predictor of treatment success for postoperative radiotherapy in patients with prostate cancer. Anticancer Res. 2006;26:2367–2374. PMID: 16821618
pmid
84. Symon Z, Kundel Y, Sadetzki S, Oberman B, Ramon J, Laufer M, et al. Radiation rescue for biochemical failure after surgery for prostate cancer: predictive parameters and an assessment of contemporary predictive models. Am J Clin Oncol. 2006;29:446–450. PMID: 17023777
crossref pmid
85. King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys. 2008;71:346–350. PMID: 18234451
crossref pmid
86. Bernard JR Jr, Buskirk SJ, Heckman MG, Diehl NN, Ko SJ, Macdonald OK, et al. Salvage Radiotherapy for Rising Prostate-Specific Antigen Levels After Radical Prostatectomy for Prostate Cancer: Dose-Response Analysis. Int J Radiat Oncol Biol Phys. 2010;76:735–740. PMID: 19464818
crossref pmid
87. Feng M, Hanlon AL, Pisansky TM, Kuban D, Catton CN, Michalski JM, 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. 2007;68:1417–1423. PMID: 17418972
crossref pmid
88. Peterson JL, Buskirk SJ, Heckman MG, Crook JE, Ko SJ, Wehle MJ, et al. Late toxicity after postprostatectomy salvage radiation therapy. Radiother Oncol. 2009;93:203–206. PMID: 19766337
crossref pmid
89. Pearse M, Choo R, Danjoux C, Gardner S, Morton G, Szumacher E, 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. 2008;72:792–798. PMID: 18707818
crossref pmid
90. Choo R, Danjoux C, Gardner S, Morton G, Szumacher E, Loblaw DA, et al. Efficacy of salvage radiotherapy plus 2-year androgen suppression for postradical prostatectomy patients with PSA relapse. Int J Radiat Oncol Biol Phys. 2009;75:983–989. PMID: 19409726
crossref pmid
91. Katz MS, Zelefsky MJ, Venkatraman ES, Fuks Z, Hummer A, Leibel SA. Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer. J Clin Oncol. 2003;21:483–489. PMID: 12560439
crossref pmid
92. Tiguert R, Rigaud J, Lacombe L, Laverdiere J, Fradet Y. Neoadjuvant hormone therapy before salvage radiotherapy for an increasing post-radical prostatectomy serum prostate specific antigen level. J Urol. 2003;170:447–450. PMID: 12853796
crossref pmid
93. King CR, Presti JC Jr, Gill H, Brooks J, Hancock SL. Radiotherapy after radical prostatectomy: does transient androgen suppression improve outcomes? Int J Radiat Oncol Biol Phys. 2004;59:341–347. PMID: 15145146
crossref pmid
94. Taylor N, Kelly JF, Kuban DA, Babaian RJ, Pisters LL, Pollack A. Adjuvant and salvage radiotherapy after radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys. 2003;56:755–763. PMID: 12788182
crossref pmid
95. Yokomizo A, Kawamoto H, Nihei K, Ishizuka N, Kakehi Y, Tobisu KI, et al. Randomized controlled trial to evaluate radiotherapy +/- endocrine therapy versus endocrine therapy alone for PSA failure after radical prostatectomy: Japan Clinical Oncology Group Study JCOG 0401. Jpn J Clin Oncol. 2005;35:34–36. PMID: 15681602
crossref pmid
96. Ward JF, Zincke H, Bergstralh EJ, Slezak JM, Blute ML. Prostate specific antigen doubling time subsequent to radical prostatectomy as a prognosticator of outcome following salvage radiotherapy. J Urol. 2004;172:2244–2248. PMID: 15538240
crossref pmid
97. Brooks JP, Albert PS, Wilder RB, Gant DA, McLeod DG, Poggi MM. Long-term salvage radiotherapy outcome after radical prostatectomy and relapse predictors. J Urol. 2005;174:2204–2208. PMID: 16280764
crossref pmid
98. 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. PMID: 10974449
crossref pmid
99. Peyromaure M, Allouch M, Eschwege F, Verpillat P, Debre B, Zerbib M. Salvage radiotherapy for biochemical recurrence after radical prostatectomy: a study of 62 patients. Urology. 2003;62:503–507. PMID: 12946755
crossref pmid
100. Chawla AK, Thakral HK, Zietman AL, Shipley WU. Salvage radiotherapy after radical prostatectomy for prostate adenocarcinoma: analysis of efficacy and prognostic factors. Urology. 2002;59:726–731. PMID: 11992848
crossref pmid
101. De la Taille A, Flam TA, Thiounn N, Pontvert D, Saighi D, Zerbib M, et al. Predictive factors of radiation therapy for patients with prostate specific antigen recurrence after radical prostatectomy. BJU Int. 2002;90:887–892. PMID: 12460351
crossref pmid
102. Liauw SL, Webster WS, Pistenmaa DA, Roehrborn CG. Salvage radiotherapy for biochemical failure of radical prostatectomy: a single-institution experience. Urology. 2003;61:1204–1210. PMID: 12809898
crossref pmid
103. Tomita N, Kodaira T, Furutani K, Tachibana H, Nakahara R, Mizoguchi N, et al. Early salvage radiotherapy for patients with PSA relapse after radical prostatectomy. J Cancer Res Clin Oncol. 2009;135:1561–1567. PMID: 19479278
crossref pmid
104. Delongchamps NB, Zerbib M, Mejean A, Rouach Y, Debre B, Peyromaure M. Conformal radiotherapy for detectable PSA following radical prostatectomy: efficacy and predictive factors of recurrence. Can J Urol. 2009;16:4813–4819. PMID: 19796456
pmid
105. Jacinto AA, Fede AB, Fagundes LA, Salvajoli JV, Castilho MS, Viani GA, et al. Salvage radiotherapy for biochemical relapse after complete PSA response following radical prostatectomy: outcome and prognostic factors for patients who have never received hormonal therapy. Radiat Oncol. 2007;2:8PMID: 17316430
crossref pmid pmc
Table 1
Selected series of salvage radiotherapy for PSA relapse after radical prostatectomy
crt-42-1-i001.jpg

*included patients receiving androgen ablation therapy for variable duration in addition to RT, pooled data from multi-institutions, 149 patients with photon irradiation, 21 with a combination of photon and neutron irradiation, §photons, photons plus neutrons, subgroups analyzed separately, **persistently detectable PSA, ††delayed PSA rise, ‡‡local recurrence, §§year, ∥∥month, ¶¶prostate specific antigen, ***prostate specific antigen doubling time, †††positive surgical margin, ‡‡‡extracapsular extension, §§§seminal vesicles invasion.

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