Post-Operative Radiotherapy Following Radical Prostatectomy

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1 EAU Update Series EAU Update Series 3 (2005) Post-Operative Radiotherapy Following Radical Prostatectomy Charles Catton* Department of Radiation Oncology, The University of Toronto, and the Princess Margaret Hospital, 620 University Avenue, Toronto, ON, Canada, M5G 2M9 Abstract Biochemical relapse will occur in 17 64% of men who undergo radical prostatectomy, and up to a third of men with biochemical relapse will progress to develop metastatic disease, and ultimately die of prostate cancer. Postoperative radiotherapy (RT) to the prostatic fossa is well-tolerated and potentially curative treatment, and should be considered for all men who have positive margins or biochemical relapse following prostatectomy. Gleason score <8, PSA doubling time >10 months and PSA re-emergence >2 years following surgery predict for a low risk of early metastatic failure, but even men with no favourable prognostic factors may have a long-term durable response to RT, and should not be excluded from consideration of treatment on the basis of these factors alone. Improvements in radiation delivery with modern 3D conformal RT techniques and the integration of advanced imaging techniques such as MRI into the treatment planning process may improve tumor targeting and reduce normal-tissue toxicity for post-operative RT, and these require investigation. A positive anastamotic biopsy does not predict response to RT, and routine biopsy is not recommended. PSA level at time of RT is a strong indicator of durable response to RT, but no one PSA cut-point level appears to be more significant, and early RT is likely more effective than late. Adjuvant RT for a positive margin with an undetectable PSA offers the best opportunity to eradicate microscopic disease while tumor is localized and the tumor burden is lowest, but it also risks over-treating some men. Contemporary PSA assays can detect biochemical relapse in the range, and this may provide additional therapeutic advantage if treatment can be given once relapse is proven and when tumour burden is small. There is an urgent need for prospective data from randomised trials to optimally select patients for adjuvant or salvage RT, to determine the optimal time to initiate treatment and to determine the role of adjunctive hormone therapy, and all patients should be considered for entry into ongoing and future clinical trials. # 2005 Elsevier B.V. All rights reserved. Keywords: Post-operative radiotherapy 1. Introduction Radical prostatectomy is an effective and commonly employed curative treatment for localized prostate cancer, although biochemical relapse will occur in 17 64% of men who undergo radical prostatectomy depending upon selection criteria used, and up to a third of these men will progress to develop metastatic disease and ultimately die of prostate cancer [1 5]. * Tel ; Fax: address: charles.catton@rmp.uhn.on.ca. In the pre-psa era, recurrence following radical prostatectomy usually presented as a palpable nodule in the prostate bed, skeletal metastases or both, and treatment was limited to palliative hormonal ablation. Radiotherapy (RT) was sometimes offered for effective symptomatic treatment of bulky local relapses, but cure or long-term disease control was rarely obtained [6,7]. The recognition that patients at increased risk of relapse following radical prostatectomy could be identified according to the known pathologic prognostic factors of the time- high tumor grade, extra-prostatic tumor extension or positive surgical margins, led to the /$ see front matter # 2005 Elsevier B.V. All rights reserved. doi: /j.euus

2 108 C. Catton / EAU Update Series 3 (2005) use of adjuvant post-operative radiotherapy to the tumor bed for identified high-risk patients in an attempt to reduce the risk of relapse and improve survival. This assumed that potential residual microscopic disease was limited to the prostate bed without systemic spread, and that local disease could be accurately targeted and eradicated with radiation doses that could be safely given in the post-operative setting. This hypothesis is being tested in three randomized trials of adjuvant post-operative radiotherapy that are either ongoing (German Cancer Society ARO 96-02) or recently completed and not reported (EORTC 22911, SWOG 8794). The advent of prostate specific antigen (PSA) testing has provided an additional powerful prognostic indicator for prostate cancer. In the pre-operative setting the PSA level at time of surgery predicts the risk of relapse. In the post-operative setting a rising PSA level is an early indicator of relapse, and there is evidence that the PSA doubling time (PSADT) and the PSA level at the time of re-treatment predict for the biochemical response rate and durability of biochemical response to post-operative radiotherapy. The additional prognostic information provided by PSA testing has led to the concept of early postoperative salvage therapy. It is hypothesized that post-operative PSA testing permits early identification of biochemical relapse and the need for additional therapy. Since current imaging techniques cannot distinguish between patients with only microscopic local residual tumor, or with systemic micrometastases, or with both, prognostic factors such as the pre-treatment PSA, the PSADTand the PSA level at time of treatment and the traditional pathologic prognostic factors may help identify those who are potentially curable with early implementation of additional local treatment, and those who also require systemic hormonal ablative therapy as part of their salvage treatment. These hypotheses have not been tested in randomized trials, and practice pattern surveys of both urologists and radiation oncologists show that no consensus exists on the optimal treatment approach in the absence of data from randomised trials [8,9]. The present understanding of the role of salvage RT is derived from identification of prognostic factors predictive of biochemical relapse-free rates in retrospective series of patients treated with post-operative RT for clinical or biochemical failure following radical prostatectomy. These retrospective series suffer from the expected problems of small patient numbers, treatment selection bias and changes in patient evaluation and treatment techniques over time. However, when taken together, they support the concept that complete and durable biochemical responses following postoperative salvage RT to the prostate bed are possible for selected patients who exhibit biochemical failure following radical prostatectomy, that early treatment is preferable to delayed treatment, and that the probability of long-term biochemical control following radiotherapy can be predicted from the above-mentioned prognostic factors. While it is clear that post-operative RT will benefit selected patients judged to be at risk of clinical disease progression following radical prostatectomy and provides the only curative option for those who exhibit biochemical relapse following surgery, there is an urgent need for prospective data from randomized trials to optimally select patients for adjuvant or salvage RT, to determine the optimal time to initiate treatment and to determine the role of adjuvant hormone therapy, and all patients should be considered for entry into ongoing and future clinical trials. This section will review the evidence for postoperative therapy following radical prostatectomy and offer treatment recommendations based upon the available evidence. 2. Prediction of relapse following radical prostatectomy Large series with long follow-up exist of patients treated with prostatectomy alone, and these reports provide useful insight into the prognostic factors for relapse after surgery for the design of post-operative clinical trials and selection of patients for post-operative therapy. Partin et al. [10] reported the Johns Hopkins experience of 1058 men treated with radical prostatectomy. Multivariate analysis was used to investigate the contribution of the factors time from surgery to a serum PSA level of 0.5 ng/ml, the PSA level one year following surgery, pathologic stage, Gleason score, and the rate of change of PSA as predictors of local versus distant metastases. A combination of PSA velocity, pathologic stage, and Gleason score were found to best distinguish local from distant metastases, and these factors were incorporated into a predictive nomogram for local and metastatic disease. Pound et al. [11] updated the experience from this same centre to include 1997 men treated with radical prostatectomy and followed for a mean of 5.3 years. The actuarial likelihood of developing metastatic disease after PSA progression in 304 men was greatest in those with a Gleason score >7, a PSA recurrence 2 years from surgery and a PSADT of <10 months.

3 C. Catton / EAU Update Series 3 (2005) The highest actuarial risk of metastatic progression was 79% at 7 years for men with all 3 adverse features. Involvement of seminal vesicles or pelvic lymph nodes, or capsular penetration in those with uninvolved seminal vesicles and pelvic lymph nodes, predicted for a shorter time to development of metastatic disease. Patel et al. [12] found that clinical relapse correlated better with the post-operative PSADT than with Gleason score, pathologic stage or margin status. Long PSADT greater than 6 months was associated with local recurrence in 18%, distant metastasis in 2% and persistent occult disease in 80% at a mean followup of 45 months in 44 patients. Of the 9 patients with proved local recurrence 8 had a long PSADTwhile 11 of the 12 with recurrence at distant sites had a short PSADT. A positive surgical margin increases the risk of biochemical relapse independently of the serum PSA at diagnosis, pathological T stage, prostatectomy Gleason score, adjuvant treatment or DNA ploidy [13,14], and in one report a positive bladder neck margin was an independent predictor of survival [15]. The relationship of a positive surgical margin to the risk of local recurrence is not clear. Kupelian et al. [16] reported margin involvement to be an independent predictor of local recurrence. No similar relationship between margin status and pattern of failure has been found by others [10,17], and furthermore, the response to salvage radiotherapy has not consistently been shown to be associated with margin status [18 24]. 3. Adjuvant radiotherapy following radical prostatectomy Since local tumor burden is smallest immediately following surgery, there may be an advantage to treating patients as soon as possible after surgery, before the PSA becomes detectable if the pathological features indicate a risk of residual microscopic disease. The disadvantage to this approach is the lack of evidence that the pathologic features predict biochemical progression with any certainty. Retrospective series of immediate post-operative RT for pt3 disease (Table 1) report higher 5-year relapse free rates than expected for salvage RT [6,25 33], but the predictive value of surgical margin status is not well established in patients treated with surgery alone, and some of these men may not require radiation. Three randomized trials are designed to address this question. Two are either ongoing (German Cancer society ARO 96-02) or recently completed and not reported (SWOG 8794), and the third (EORTC 22911) was recently reported in abstract form [34]. In this trial 1005 men with positive surgical margins, capsular penetration or seminal vesicle involvement were randomized to receive immediate post-operative RT to the prostate bed or deferred treatment. Immediate radiotherapy was associated with a significant improvement in the 5-year biochemical and clinical progression free rates [72.2% (CI: ) vs. 51.5% (CI: ) and 83.3% vs. 74.8% respectively]. Not surprisingly, patients who received immediate RT had a higher risk of immediate and late grade 1 2 side effects, although the risk of more serious grade 3 effects was low, and under 5% in both groups. These preliminary results are very encouraging, however longer follow-up is required to determine if a reduction in the relapse rate with immediate radiotherapy leads to improved survival. Further analysis of this trial, and the other trials will provide important data about the prognostic factors for relapse and survival and for treatment toxicity and Table 1 A selected literature summary of treatment outcome for men treated with adjuvant post-operative radiotherapy Author Number Median radiation dose (Gy) Median follow-up Actuarial relapse-free rate Petrovich et al. [28] years 51% (10-year) a a Syndikus et al. [26] ( Gy fractions) Not stated 75% (7-year) a b Schild et al. [27] months 57% (5-year) b b Catton et al. [6] months 57% (5-year) b Valicenti et al. [50] months 90% >61.2 Gy 64% 61.2 Gy (36-month) b b Hagan et al. [32] months 79% (5-year) b a Anscher et al. [51] 46 Range years 55% (10-year) a 48% (15-year) b Morris et al. [30] 40 Range months (mean) 88% (3-year) b b Tsien et al. [33] years 45% (8-year) b a Elias et al. [29] 31 Not stated 8.1 years 70% (5-year) a a These studies report only clinical, or partly clinical and biochemical evidence of relapse. b These studies report biochemical evidence of relapse.

4 110 C. Catton / EAU Update Series 3 (2005) quality of life. Outcome interpretation for the primary question (adjuvant vs. salvage RT) will be complicated by the fact that most patients were entered onto the SWOG and EORTC trials at a time when the lower limit of PSA detection was about 0.2 ng/ml. The undetectable control arms contain patients with post-operative PSA levels as high as 0.19, and these trials are actually a comparison of adjuvant +early salvage RT vs. later treatment. A positive result for adjuvant treatment wouldn t preclude benefit to observation with salvage RT using lower contemporary levels of PSA detectability. The results of these trials should promote further randomized studies comparing adjuvant RT vs. early salvage RT using contemporary PSA assays. The preliminary results of EORTC do support the need for and value of early post-operative RT, whether or not treatment is instituted with an undetectable PSA or at the first indication of biochemical relapse. If a decision is made to defer adjuvant treatment in patients with an undetectable PSA immediately postoperative then they should be closely followed with serial PSA measurements and reconsidered for RT at the first sign of PSA elevation, when presumably the disease bulk is still small and localized to the prostate bed. 4. Prognostic indicators and results of salvage radiotherapy As stated above, there are no published prospective trials of adjuvant or salvage post-operative radiotherapy for prostate cancer, and small patient numbers and imbalances in important prognostic factors complicate evaluation of the retrospective literature. High Gleason score, nodal and seminal vesicle involvement and high PSA level at time of RT have all been reported to predict for a higher likelihood of systemic relapse and failure of salvage RT [6,19,21,23,24]. As discussed earlier, the PSADT or the time to post-operative biochemical failure is an important predictor of early systemic failure in surgical series, and this has been considered as a prognostic factor in only some reports of salvage radiotherapy [7,20,24,35,36]. Other confounding factors for interpretation of treatment outcome in the literature include inconsistency in the choice of when to implement salvage RT with resulting differences in the local tumour burden, the use of concomitant hormone therapy in some patients and short follow-up in some series. Most reports are of patients treated in the PSA era and report biochemical relapse free rates (brfr), however the definition of complete response (undetectable PSA) varies with the sensitivity of the PSA assay used, and some authors consider a detectable and stable PSA as a complete response [7,21]. Complete and partial responses to post-operative RT determined by a decline in the post-rt PSA are between 51 90% in series that have reported these rates [7,18,24,30,35,37 39]. Responses are usually not durable, with a pattern of continued relapse over time. Reported actuarial biochemical relapse-free rates are 46 51% at 3 years, 14 50% at 4 years and 10 46% at 5 years (Table 2). Durable responses of 10 30% beyond 5 years are seen for men followed long enough, but relapse continues to occur beyond 5 years from RT [18,19,24,37]. The high initial response rates to local RT confirm that the majority of patients with persistent or subsequent PSA elevation post-prostatectomy are harbouring residual or recurrent disease in their prostatic fossa. The failure of salvage RT to achieve a durable response may be caused by local disease progression following an inadequate radiation dose or improperly located radiation fields, by progression of micrometastases initially present beyond the radiation fields, or due to both factors. The rather poor overall long-term results of salvage RT are difficult to interpret in view of the selection factors discussed earlier, and probably underestimate the benefit of RT in patients with a low risk of metastatic disease who are treated early after PSA relapse when the bulk of local tumor is small. Radiation doses higher than 64 Gy, 64.8 Gy or 65 Gy have been associated with improved brfr in three reports [25] [18,21], although Crane et al. found no difference in brfr for patients treated with more or less than 60 Gy [37]. A recent large multi-institutional study of 501 men showed no difference outcome for those treated with radiation doses greater or less than 64.8 Gy [24]. Again, differences in selection factors and the presence of occult metastatic disease may diminish any potential benefit of RT and obscure a dose-response relationship. Extrapolating from the treatment of the intact prostate, dose may well be an important determinant of local control, and the role of conformal RT techniques need to be explored in this situation. Surgical margin status, capsular penetration or the presence of a positive anastamotic biopsy was not predictive of brfr after salvage RT in many of the reports that investigated these factors [7,18 22,37], although the multi-institutional series reported by Ste-

5 C. Catton / EAU Update Series 3 (2005) Table 2 A selected literature summary of patient characteristics and treatment outcome for men treated for biochemical or clinical local relapse of prostate cancer with post-operative radiotherapy Author N Median/mean Pre-RT a PSA (range) %Gleason score >7 %SV b or node positive Median RT a dose (range) Median/mean FU c (range) Actuarial bned d rate (time) Stephenson et al. [24] (0.1 26) 76% 31% 64.8 Gy ( Gy) 45 months (5 192 months) 45% (4 years) Pisansky et al. [21] ( ) 16% 31% 64 Gy ( Gy) 52 months (5 131 months) 46% (5 years) Katz et al. [23] ( ) 25% 27% ) 42 46% (4 years) Choo et al. [7] 98 e 0.8 (group A) 28% 22% (60 66 Gy) 4.21 years (group A) 26% (A) 1.2 (group B) 3.32 years (group B) 39% (B) 3.7 (group C) 3.95 years (group C) 14% (C) (4 years) Anscher et al. [18] ( ) 26% 34% 66 Gy ( Gy) 48 months 50% (4 years) Cadeddu et al. [19] % 15% 64 Gy (50 75 Gy) 8.3 years (1 13 years) 10% (5 years) Garg et al. (41) (0.1 30) 35% 38% 66 Gy 25 months 57/78 f Song et al. [39] 73 g 0.8 (0.1 63) 23% 25% 66.6 Gy ( Gy) 36 months (6 92 months) 39% (4 years) Nudell et al. [38] 69 ( ) 22% 10% (60 74 Gy) 37 months 55% i 35% j (4 years) Do et al. [52] 60 na h 17% 37% 64.8 Gy ( Gy) 36 months (9 96 months) 30/60 Catton et al. [6] 59 ( ) 15% 35% 60 Gy (54 65 Gy) 43 months (3 108 months) 30% k 5% l (5 years) Chawla et al. [35] (0.5 30) 35% 26% 64.8 Gy ( Gy) 45 months 35% (5 years) Vanuystel et al. [40] ( ) na h 0% 66 Gy 33 months 46% (3 years) De la Taille et al. [22] ( ) 37% 27% 68 Gy (45 70 Gy) 27.7 months (6 69 months) 51% (3 years) Leventis et al. [20] % 27% 66 Gy ( Gy) 29 months 24% (5 years) Morris et al. [30] ( ) 34% 25% (60 64 Gy) 32 months 47% (3 years) Crane et al. [37] % 29% 60 Gy (58 66 Gy) 55 months (36 96 months) 8/41 f a RT- radiotherapy. SV-seminal vesicle. FU- follow-up. d bned-biochemical relapse free. e Prognostic groups analysed separately. Group A, persistently detectable PSA; group B, delayed PSA rise; Group C, local recurrence. f acturarial rate not provided. g 12 patients excluded from analysis. h na-data not provided. i PSA only surgical failures. j biopsy proven failures analyzed separately. k Relapse rates quoted for pre-rt PSA < 2.0. l Relapse rates quoted for pre-rt PSA 2.0. phenson et al. [24] did show a significantly better 4- year progression free probability for patients with positive surgical margins compared to those without (53% vs. 34%). This was also independently predictive in a multivariate analysis. The absence of extracapsular extension was associated with a non-significant improvement in progression free probability at 4 years. Katz et al. [23] also reported that negative margins and absence of extracapsular penetration were significant independent predictors of PSA relapse after RT in a multivariate analysis of men treated without hormonal ablation. The contradictory literature is likely explained in part by differences between centres and between eras in the assessment of surgical margins, and by small patient numbers that can only detect large differences in outcome between variables and are not amenable to analysis of multiple variables. Bulky disease as evidenced by a palpable nodule is associated with poor long-term biochemical control. Our own experience [6] with 16 patients treated for palpable recurrence was that only 7/16 had a complete biochemical response to RT, with an actuarial clinical local control rate of 60% at 5 years. None stayed in biochemical remission beyond 4 years. Morris et al. [30] reported that 5/7 patients with palpable nodules experienced biochemical failure within 3 years of RT, and Choo et al. [7] reported a 90% biochemical relapse rate at 5 years for 36 patients treated for clinical local recurrence. Factors that predict for local or systemic relapse following radical prostatectomy also predict the response to salvage radiotherapy. Gleason score >7 [6,19,21,22,24,35,40], seminal vesicle involvement [19,21,23,24,35] and nodal involvement [19] predict for reduced brfr after salvage RT in a number of series that have evaluated these factors. The PSADT and its surrogate factor timing of PSA failure from surgery are important indicators for local

6 112 C. Catton / EAU Update Series 3 (2005) or metastatic failure in patients managed with surgery alone, and those with short PSADT are more likely to fail distantly than locally. Egawa et al. [36] found no association between PSADT and biochemical control after salvage RT in 35 patients, using PSADT as a categorical variable with a 12-month cut-off. Stephenson et al. [24] showed that a PSADT of 10 months was a significant predictor of progression (HR 1.7, ) after salvage RT on multivariate analysis of over 500 patients. Leventis et al. [20] demonstrated that pre-rt PSA level and PSADT modelled as a continuous variable to be independent determinants of biochemical outcome on uni and multivariate analysis. Time to PSA relapse of >6 months, >12 months and >5 years predicted improved brfr after salvage RT on univariate analysis in 3 reports [18,19,35], but was not a significant factor in three others [7,24,41]. The PSA level at the time of RT is determined by the PSADT and the interval from surgery to when treatment is initiated, and likely reflects the total tumour burden at that time. Pre-RT PSA cut-point levels of 1.0, 1.7, 2.0, 2.5, 2.7 have all been shown as significant determinants of brfr on univariate analysis [6,30,37,42,43]. Pisansky et al. [21] demonstrated in a multivariate analysis of data from their large series of 166 patients that the risk of relapse after salvage RT increases continuously with the rise in the pre-rt PSA, rather than in a stepwise fashion. Stephenson et al. [24] demonstrated that a cutpoint of greater than 2.0 ng/ml was significant on multivariate analysis, but also showed that patients with very low PSA levels of 0.6 ng/ml had improved outcome compared to patients with pre-treatment PSA levels of ng/ml. The available evidence supports the view that tumor grade, seminal vesicle involvement, pre-rt PSA level, and the PSADT are prognostic factors that predict the outcome of salvage radiation, and the timing of PSA failure may do so. There is more limited evidence from two studies to show that margin status is important, and there is little evidence to show that capsular penetration or a positive biopsy or the use of radiation doses >65 Gy predict outcome. Confirmation of these findings will only come from formal evaluation in much larger prospective studies that are able to control for the variables of patient selection, treatment delivery and endpoint evaluation, and which have sufficient power to perform the necessary multivariate analysis of co-variates. The current understanding of the way prognostic variables influence outcome in these patients provides valuable help to clinicians faced with the task of advising men with post-prostatectomy biochemical failure on the most appropriate course of action to take. It should not be the sole criterion used to exclude patients from treatment, since some men with adverse features such as seminal vesicle involvement, high Gleason score or persistently detectable PSA post-prostatectomy will attain long term biochemical control with salvage RT. This further highlights the need for prospective trials to better identify these patients. In the absence of these trials, RT should be considered in all men with a rising PSA following prostatectomy. It is the only treatment option that offers the potential for cure in this setting, and toxicity is modest. Many men, even those predicted to have a higher than average risk of occult metastatic disease view the risk-benefit ratio of post-operative RT quite favorably and are willing to accept the possibility that it may not extend survival. Those at high risk of metastatic disease should be considered for treatment with concurrent adjuvant therapy, extrapolating from experience treating prostate cancer in the intact gland, although at present there are no randomised data to support this approach. 5. Radiation treatment technique and treatment-related toxicity Radiation morbidity is related to both radiation dose and radiation treatment technique employed. Safe radiation delivery to the prostate bed is complicated by the presence of bladder and rectum that fills the empty prostatic fossa postoperatively. The clinical target volume may actually surround these normal tissues and it is technically challenging to exclude them from the high dose radiation volume. The usual way to protect the bladder and rectum from acute and late radiation injury is to limit the post-operative radiation dose to no more than 65 Gy, which is considerably less than the standard of Gy used to treat the intact gland with 3-D conformal radiotherapy [44,45]. Katz et al. [23] identified 3% acute grade 3 GU complications in 115 patients treated with higher dose post-operative 3-D conformal techniques to a median dose of 66.6 Gy ( Gy). The 4-year actuarial rates of late grade 2 and 3 GU toxicity was 9% and 10% respectively, and consisted of hematuria (grade 2) and bladder neck stricture (grade 3). The 4-year actuarial rate of late grade 2 GI toxicity was 12% and consisted of moderate proctitis. No late grade 3 or greater GI toxicity was observed.

7 C. Catton / EAU Update Series 3 (2005) Parker et al. [46] recently provided a comprehensive summary of the retrospective literature of treatment morbidity of conventional post-operative RT, consisting of 12 reports comprising 799 men treated with conventionally fractionated adjuvant or salvage RT. Acute complications of diarrhea, urinary frequency and urgency were reported as common events, and no grade 3 or 4 acute morbidity was reported. Late grade 3 or 4 complications were identified in less than 2% of the patients. Late GI complications included chronic tenesmus and diarrhea, rectal bleeding, rectal ulceration and rectal incontinence, and late GU complications included urethral stricture requiring dilation, chronic cystitis, hematuria and worsening urinary incontinence. A single series [26] of 115 patients reported 24 (21%) cases of grade 3 or 4 late bladder toxicity following hypofractionated treatment of Gy in fractions, and this technique should not be used. Within the admitted limitations of retrospectively evaluated treatment toxicity, the evidence is that conventionally fractionated post-operative radiation to the prostatic fossa is well tolerated in the Gy range. The delivery of high precision post-operative radiotherapy is presently limited by the inability to identify the volume at risk with the same precision with which it can be treated. Integrating advanced imaging techniques such as MRI into the treatment planning process warrants investigation as this may improve the identification and targeting of anatomic areas at higher risk of harbouring residual disease, such as retained seminal vesicles and neurovascular bundles following conservative resections, and the urethrovesicle anastamosis. Some degree of safe dose escalation is likely with conformal RT, but it is unlikely that radiation doses approaching those used in primary radical RT are attainable in the post-operative setting, although the optimal post-operative radiation dose is unknown and must be determined in clinical trials. For the reasons stated above it may not be technically possible to administer doses much beyond 70 Gy to the prostatic fossa even with conformal techniques, and the most obvious advantage to developing high-precision postoperative conformal RT techniques will be to reduce acute and late treatment toxicity in the Gy range. Furthermore, very high radiation doses of >75 Gy may not be necessary to control microscopic disease. This difficulty with delivering high dose post-operative RT provides an additional argument for treating patients with recurrence as early as possible, and to avoid uncontrolled expansion of the local tumor burden. The role of pelvic nodal irradiation in the postoperative setting has been explored in only a very limited fashion, and was not shown to be beneficial in one report [47]. Wider fields will add to the acute morbidity of treatment, and adjuvant pelvic nodal fields are not employed routinely at our centre. Our post-operative adjuvant and salvage RT treatment technique is to give 66 Gy in 33 fractions using a conformal technique to a clinical target volume comprising the surgical bed defined by the presence of surgical clips, and the urethro- vesicle anastamosis identified by a single fiducial marker inserted under ultrasound guidance. MRI treatment planning to improve anatomic targeting is under investigation. 6. Hormonal therapy The role of adjuvant hormone therapy to RT is the subject of investigation in the recently closed and unreported RTOG trial that randomised over 800 men to receive either 2 years of concurrent and adjuvant bicalutamide (150 mg) or delayed hormonal therapy for those receiving salvage RT to the prostate bed. A subgroup analysis of RTOG 85-31, which included 139 patients who were randomized to receive adjuvant postoperative RT immediate androgen suppression demonstrated a significant improvement in biochemical freedom from failure (65% vs. 42%) for immediate androgen suppression with median followup of 5 years. There was no overall survival advantage seen [48]. Neo-adjuvant androgen ablation prior to RT did not predict for freedom from PSA progression on univariate analysis in a large retrospective series of 501 men treated with post-operative salvage radiotherapy [24]. However, a smaller retrospective study of 115 men who received salvage RT showed improved freedom from biochemical failure for men with one or more adverse risk factors of seminal vesicle involvement, positive margins, extracapsular extension or pre RT PSA >0.6 who also received neo-adjuvant androgen ablation [23]. There is an urgent need for prospective data concerning the role of neo-adjuvant and adjuvant androgen ablation with RT in the post-operative adjuvant and salvage settings. In the absence of studies specifically for these patients, it is reasonable to extrapolate from studies of the intact prostate [49] and consider concurrent and adjuvant hormone therapy for those at high risk of having occult metastatic disease (persistently elevated post-operative PSA, seminal vesicle involvement, short PSADT), and also for those with gross disease in the prostatic fossa, for whom salvage radiotherapy has

8 114 C. Catton / EAU Update Series 3 (2005) been shown to be ineffective in preventing biochemical progression. There is little data concerning the use of intermittent or continuous hormone therapy as primary salvage treatment of post-operative biochemical failure in the absence of nodal metastases. As stated above, prolonged survival after PSA relapse has been demonstrated with observation alone, and primary hormonal suppressive therapy of PSA relapse would necessarily be long-term and associated with the complications of prolonged castration. RT to the prostate bed is potentially curative and should be the initial treatment consideration for men who wish to pursue treatment of PSA relapse. There is no evidence for a curative effect of hormonal ablation, and intermittent or continuous hormonal therapy should be reserved as second line treatment for men who progress after salvage RT. For those not eligible for RT or who decline RT, an initial period of observation to determine the PSADT is useful to predict who would most benefit from observation alone. 7. Summary Post-operative RT to the prostatic fossa is welltolerated and potentially curative, and should be considered for all men judged to be at risk of clinical progression following prostatectomy. Long-term results are disappointing, and the optimal selection of patients, timing of RT and the role of adjunctive hormone therapy remain to be determined in ongoing and future clinical trials, and all patients should be considered for trial entry. Preliminary prospective data, and retrospective data show that there is an advantage to giving salvage radiation earlier rather than later, and no one pre-rt PSA cut-point level is most significant. Immediate adjuvant post-operative RT for positive margins and an undetectable PSA offers the best opportunity to eradicate microscopic disease while tumor is localized and the tumor burden smallest, but it risks over-treating some men. More sensitive contemporary assays will detect PSA recurrence in range, and may provide additional therapeutic advantage if treatment can be implemented once relapse is proven and tumour burden is small. Modern 3D conformal radiotherapy techniques and the integration of advanced imaging techniques into post-operative radiation treatment planning offer the potential for reduced treatment-related morbidity and improved tumor targeting and should be the subject of future studies. References [1] Han M, Partin A, Pound C, Epstein J, Walsh P. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001;28: [2] Jhaveri F, Zippe C, Klein E, Kupelian P. Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer: 10-year results. Urology 1999;54: [3] Lau W, Bergstralh E, Blute M, Slezak J, Zincke H. Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitant pathological variables. J Urol 2002;167: [4] Trapasso J, dekernion J, Smith R, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994;152(5 Pt 2): [5] Catalona W, Smith D. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994; 152(5 Pt 2): [6] 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: [7] 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: [8] Ornstein D, Colberg J, Virgo K, Chan D, Johnson E, Oh J, et al. Evaluation and management of men whose radical prostatectomies failed: results of an international survey. Urology 1998;52: [9] Duchesne G, Millar J, Moraga V, Rosenthal M, Royce P, Snow R. What to do for prostate cancer patients with a rising PSA? A survey of Australian practice Int J Radiat Oncol Biol Phys 2003;55: [10] Partin A, Pearson J, Landis P, Carter H, Pound C, Clemens J, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43: [11] Pound C, Partin A, Eisenberger M, Chan D, Pearson J, Walsh P. 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10 116 C. Catton / EAU Update Series 3 (2005) CME questions Please visit to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. The earliest indication of treatment failure following radical prostatectomy will be obtained from: A. MRI imaging. B. PET scanning. C. Serum PSA testing. D. Prostascint 1 scanning. 2. The optimal time to offer radiotherapy following radical prostatectomy is: A. To treat high-risk patients with positive margins before the PSA becomes detectable. B. The optimal time to start post-operative radiotherapy is not presently known. C. To treat patients at the first indication of PSA relapse. D. To wait until the PSA goes beyond 0.5, to obtain the PSA doubling time. 3. The predictors of response to post-operative radiotherapy include: A. PSA level at the time of treatment. B. PSA doubling time. C. Gleason score. D. All of the above. 4. High-risk patients with persistently elevated PSA immediately post-operatively should be offered which of the following options: A. Hormonal ablation therapy. B. Radiotherapy. C. Taxanes. D. Should be encouraged to enter into clinical trials investigating the role of each of these therapies.