Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series.

BACKGROUND: Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT). OBJECTIVE: To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT. DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml. INTERVENTION: We compared aRT versus observation followed by esRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis). RESULTS AND LIMITATIONS: Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population. CONCLUSIONS: At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT. PATIENT SUMMARY: At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.

Predicting the 5-Year Risk of Biochemical Relapse After Postprostatectomy Radiation Therapy in ≥PT2, pN0 Patients With a Comprehensive Tumor Control Probability Model.

PURPOSE: To fit the individual biochemical recurrence-free survival (bRFS) data from patients treated with postprostatectomy radiation therapy (RT) with a comprehensive tumor control probability (TCP) model. METHODS AND MATERIALS: Considering pre-RT prostate-specific antigen (PSA) as a surrogate of the number of clonogens, bRFS may be expressed as a function of dose-per-fraction-dependent radiosensitivity (αeff), the number of clonogens for pre-RT PSA = 1 ng/mL (C), and the fraction of patients who relapse because of clonogens outside the treated volume (K), assumed to depend (linearly or exponentially) on pre-RT PSA and Gleason score (GS). Data from 894 node-negative, ≥pT2, pN0 hormone-naive patients treated with adjuvant (n=331) or salvage (n=563) intent were available: 5-year bRFS data were fitted grouping patients according to GS (<7:392, =7:383, >7:119). RESULTS: The median follow-up time, pre-RT PSA, and dose were 72 months, 0.25 ng/mL, and 66.6 Gy (range 59.4-77.4 Gy), respectively. The best-fit values were 0.23 to 0.26 Gy(-1) and 10(7) for αeff and C for the model considering a linear dependence between K and PSA. Calibration plots showed good agreement between expected and observed incidences (slope: 0.90-0.93) and moderately high discriminative power (area under the curve [AUC]: 0.68-0.69). Cross-validation showed satisfactory results (average AUCs in the training/validation groups: 0.66-0.70). The resulting dose-effect curves strongly depend on pre-RT PSA and GS. bRFS rapidly decreases with PSA: the maximum obtainable bRFS (defined as 95% of the maximum) declined by about 2.7% and 4.5% for each increment of 0.1 ng/mL for GS <7 and ≥7, respectively. CONCLUSIONS: Individual data were fitted by a TCP model, and the resulting best-fit parameters were radiobiologically consistent. The model suggests that relapses frequently result from clonogens outside the irradiated volume, supporting the choice of lymph-node irradiation, systemic therapy, or both for specific subgroups (GS <7: PSA >0.8-1.0 ng/mL; GS ≥7: PSA >0.3 ng/mL). Early RT should be preferred over delayed RT; the detrimental effect of PSA increase can never be fully compensated by increasing the dose, especially for patients with GS ≥7.

Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy.

BACKGROUND: Early salvage radiation therapy (eSRT) represents a treatment option for patients who experience a prostate-specific antigen (PSA) rise after radical prostatectomy (RP); however, the optimal PSA level for eSRT administration is still unclear. OBJECTIVE: To test the impact of PSA level on cancer control after eSRT according to pathologic tumour characteristics. DESIGN, SETTING, AND PARTICIPANTS: The study included 716 node-negative patients with undetectable postoperative PSA who experienced a PSA rise after RP. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at PSA ≤ 0.5 ng/ml. Biochemical recurrence (BCR) after eSRT was defined as two consecutive PSA values ≥ 0.2 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox regression analysis tested the association between pre-eSRT PSA level and BCR after eSRT. Covariates consisted of pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤ 6, 7, or ≥ 8), and surgical margin status (negative vs positive). We tested an interaction with PSA level and baseline pathologic risk for the hypothesis that BCR-free survival differed by pre-eSRT PSA level. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score ≥ 8, and negative surgical margins. RESULTS AND LIMITATIONS: Median follow-up among patients who did not experience BCR after eSRT was 57 mo (interquartile range: 27-105). At 5 yr after eSRT, BCR-free survival rate was 82% (95% confidence interval [CI], 78-85). At multivariable Cox regression analysis, pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio: 4.89; 95% CI, 1.40-22.9; p < 0.0001). When patients were stratified according to the number of risk factors at final pathology, patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR as high as 10% per 0.1 ng/ml of PSA level compared with only 1.5% in patients with one or no pathologic risk factors. CONCLUSIONS: In this retrospective study, cancer control after eSRT greatly depended on pretreatment PSA. The absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. In patients with more adverse pathologic features, eSRT conferred better cancer control when administered at the very first sign of PSA rise. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP. PATIENT SUMMARY: In this retrospective study, cancer control after early salvage radiation therapy (eSRT) was influenced by pretreatment prostate-specific antigen (PSA) level. This effect was highest in men with at least two of the following pathologic features: pT3b/pT4 disease, pathologic Gleason score ≥ 8, and negative surgical margins. In these patients, eSRT conferred better cancer control when administered at the very first sign of PSA rise.

The PSA-response to salvage radiotherapy after radical prostatectomy correlates with freedom from progression and overall survival.

BACKGROUND AND PURPOSE: In a retrospective analysis, we examined factors influencing the outcome of prostate cancer (PCa) patients receiving salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy (RP). MATERIAL AND METHODS: 306 patients received 3D-conformal SRT at a median pre-SRT PSA of 0.298 ng/ml. Post-SRT progression was defined as PSA ⩾0.2 ng/ml above nadir and rising further, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method and multivariable Cox regression. RESULTS: Application of SRT at a PSA <0.2 ng/ml correlated significantly with achieving a post-SRT PSA nadir <0.1 ng/ml and with improved freedom from progression (median follow-up 7.2 years). The post-SRT nadir <0.1 ng/ml correlated significantly with less recurrences and with better overall survival. In multivariable Cox analysis restricted to pre-SRT parameters, a pre-SRT PSA ⩾0.2 ng/ml had the strongest impact (hazard ratio 2.4) on progression. If the post-SRT PSA nadir was included in the model, then failing the nadir was the most important risk factor (hazard ratio 8.1). CONCLUSIONS: Early SRT at a PSA <0.2 ng/ml is a favorable treatment option for post-RP biochemical recurrence. It correlated with a post-SRT PSA-nadir <0.1 ng/ml which was associated with improved freedom from progression and overall survival.

Prostate-specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse-free survival and overall survival: 10-year data of the ARO 96-02 trial.

OBJECTIVE: The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). METHODS AND MATERIALS: For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. RESULTS: Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm-C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score ≥8 (hazard ratio [HR] 2.8), pT ≥ 3c (HR 2.4), and extraprostatic extension ≥2 mm (HR 3.6) were unfavorable risk factors of progression. CONCLUSIONS: A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups will benefit most from which treatment option.

Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial.

BACKGROUND: Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy. OBJECTIVE: To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study. DESIGN, SETTING, AND PARTICIPANTS: After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)--that is, 159 WS plus 148 ART men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease. RESULTS AND LIMITATIONS: The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p<0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred. CONCLUSIONS: Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe. PATIENT SUMMARY: Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.

Salvage radiotherapy in patients with prostate cancer and biochemical relapse after radical prostatectomy : Long-term follow-up of a single-center survey.

BACKGROUND AND PURPOSE: In patients with prostate cancer (PC) and biochemical relapse after radical prostatectomy, salvage radiotherapy (SRT) could improve PC-specific survival (PCSS) but the timing for initiation is still under discussion. We have demonstrated a low rate of biochemical relapses in a patient series with very low pre-SRT PSA levels after a median follow-up of 42 months. Here, we present an update of that study. PATIENTS AND METHODS: Overall, 151 patients were analyzed. A biochemical relapse after SRT was diagnosed when the PSA exceeded the post-SRT nadir by 0.2 ng/ml with subsequent increase. Parameters with significant impact on biochemical progression-free survival (BPFS), PCSS, and overall survival (OS) in univariate analysis were included in a multiple Cox regression analysis. RESULTS: After a median follow-up of 82 months, 18 patients (12%) had died with 10 (6.6%) deaths being PC-related. A biochemical progression was diagnosed in 83 patients (55%). Univariate analysis revealed a significant impact of pre-SRT PSA level, Gleason score, and PSA doubling time (PSADT) on BPFS and for initial tumor stage and Gleason score on OS. Multivariate analysis confirmed the impact of pre-SRT PSA level, Gleason score, and PSADT on BPFS and tumor stage on OS. CONCLUSION: In this update, the rate of biochemical relapses increased compared with our previous data. Compared to similar studies, we found a remarkably low rate of PC-related deaths. Our data support early initiation of SRT. However, this treatment strategy, triggered by very low PSA levels, could carry the risk of overtreatment in at least a subset of patients.

Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy.

BACKGROUND: Early salvage radiotherapy (eSRT) represents the only curative option for prostate cancer patients experiencing biochemical recurrence (BCR) for local recurrence after radical prostatectomy (RP). OBJECTIVE: To develop and internally validate a novel nomogram predicting BCR after eSRT in patients treated with RP. DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional cohort, 472 node-negative patients who experienced BCR after RP were identified. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at prostate-specific antigen (PSA) ≤ 0.5 ng/ml. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: BCR after eSRT was defined as two consecutive PSA values ≥ 0.2 ng/ml. Uni- and multivariable Cox regression models predicting BCR after eSRT were fitted. Regression-based coefficients were used to develop a nomogram predicting the risk of 5-yr BCR after eSRT. The discrimination of the nomogram was quantified with the Harrell concordance index and the calibration plot method. Two hundred bootstrap resamples were used for internal validation. RESULTS AND LIMITATIONS: Mean follow-up was 58 mo (median: 48 mo). Overall, 5-yr BCR-free survival rate after eSRT was 73.4%. In univariable analyses, pathologic stage, Gleason score, and positive surgical margins were associated with the risk of BCR after eSRT (all p ≤ 0.04). These results were confirmed in multivariable analysis, where all the previously mentioned covariates as well as pre-RT PSA were significantly associated with BCR after eSRT (all p ≤ 0.04). A coefficient-based nomogram demonstrated a bootstrap-corrected discrimination of 0.74. Our study is limited by its retrospective nature and use of BCR as an end point. CONCLUSIONS: eSRT leads to excellent cancer control in patients with BCR for presumed local failure after RP. We developed the first nomogram to predict outcome after eSRT. Our model facilitates risk stratification and patient counselling regarding the use of secondary therapy for individuals experiencing BCR after RP. PATIENT SUMMARY: Salvage radiotherapy leads to optimal cancer control in patients who experience recurrence after radical prostatectomy. We developed a novel tool to identify the best candidates for salvage treatment and to allow selection of patients to be considered for additional forms of therapy.

Patterns and predictors of early biochemical recurrence after radical prostatectomy and adjuvant radiation therapy in men with pT3N0 prostate cancer: implications for multimodal therapies.

PURPOSE: The aim of our study was to evaluate patterns and predictors of early biochemical recurrence (eBCR) after radical prostatectomy (RP) and adjuvant radiation therapy (aRT) in order to identify which individuals might benefit from additional treatments. METHODS AND MATERIALS: We evaluated 390 patients with pT3N0 prostate cancer (PCa) receiving RP and aRT at 6 European centers between 1993 and 2006. Patients who were free from BCR at <2 years' follow-up were excluded. This resulted in 374 assessable patients. Early BCR was defined as 2 consecutive prostate-specific antigen (PSA) test values >0.2 ng/mL within 2 or 3 years after aRT. Uni- and multivariable Cox regression analyses predicting overall and eBCR after aRT were fitted. Covariates consisted of preoperative PSA results, surgical margins, pathological stage, Gleason score, and aRT dose. RESULTS: Overall, 5- and 8-year BCR-free survival rates were 77.1% and 70.8%, respectively. At a median follow-up of 86 months after aRT, 33 (8.8%) and 55 (14.6%) men experienced BCR within 2 or 3 years after aRT, respectively. In multivariable analyses, Gleason scores of 8 to 10 represented the only independent predictor of eBCR after aRT (all, P≤.01). The risk of BCR was significantly higher in patients with a Gleason score of 8 to 10 disease than in those with Gleason 2 to 6 within 24 months after treatment, after adjusting for all covariates (all, P≤.04). However, given a 24-month BCR free period, the risk of subsequent BCR for men with poorly differentiated disease was equal to that of men with less aggressive disease (all, P≥.3). CONCLUSIONS: High Gleason score represents the only predictor of eBCR after RP and aRT in patients affected by pT3N0 PCa. Given the association between early PSA recurrence, clinical progression, and mortality, these patients might be considered candidates for adjuvant medical therapy and/or prophylactic whole-pelvis radiation therapy in addition to aRT, delivered to the prostatic bed.

Phase 3 study of adjuvant radiotherapy versus wait and see in pT3 prostate cancer: impact of pathology review on analysis.

BACKGROUND: In a randomised trial, radical prostatectomy (RP) followed by adjuvant radiotherapy (aRT) was compared with RP alone in patients with pT3 pN0 prostate cancer with or without positive margin at local pathology (German Cancer Society trial numbers ARO 96-02/AUO AP 09/95). OBJECTIVE: A pathology review was performed on 85% of RP specimens of patients to investigate the influence of pathology review on the analysis. DESIGN, SETTING, AND PARTICIPANTS: Patients post-RP (n=385) were randomised before achieving an undetectable prostate-specific antigen (PSA) level to either wait and see (n=192) or 60Gy aRT (n=193). Of 307 patients with undetectable PSA after RP, 262 had pathology review. These results were included prospectively into the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Agreement between local and review pathology was measured by the total percentage of agreement and by simple kappa statistics. The prognostic reliability for the different parameters was analysed by Cox regression model. Event-free rates were determined by Kaplan-Meier analysis with a median follow-up of 40 mo for the wait-and-see arm and 38.5 mo for the aRT arm. RESULTS AND LIMITATIONS: There was fair concordance between pathology review and local pathologists for seminal vesicle invasion (pT3c: 91%; κ=0.76), surgical margin status (84%; κ=0.65), and for extraprostatic extension (pT3a/b: 75%; κ=0.74). Agreement was much less for Gleason score (47%; κ=0.42), whereby the review pathology resulted in a shift to Gleason score 7. In contrast to the analysis of progression-free survival with local pathology, the multivariate analysis including review pathology revealed PSMs and Gleason score >6 as significant prognostic factors. CONCLUSIONS: Phase 3 studies of postoperative treatment of prostate cancer should be accomplished in the future with a pathology review. In daily practice, a second opinion by a pathologist experienced in urogenital pathology would be desirable, in particular, for high-risk patients after RP.

Salvage radiotherapy in patients with persistently detectable PSA or PSA rising from an undetectable range after radical prostatectomy gives comparable results.

PURPOSE: Salvage radiotherapy (SRT) is applied routinely in patients with a biochemical relapse after radical prostatectomy (RP). Although the detection threshold for relapse after RP has steadily been lowered, only about 30% of the SRT patients achieve a durable response. We have previously shown the association between a PSA decrease below detectable levels after SRT and biochemical progression-free survival (BPFS). After recalculating our data according to a more recent definition of biochemical failure after SRT, we now show the significance of the post-RP PSA nadir. MATERIALS AND METHODS: Among 159 prostate cancer patients without hormonal treatment after RP, SRT was given to 72 patients with persistently detectable PSA after RP and to 87 whose PSA increased out of an undetectable range. The median pre-SRT PSA was 0.29 ng/ml for the former group and 0.34 ng/ml for the latter group. A radiation dose of 66.6 Gy was applied to the prostate bed. RESULTS: The overall median follow-up time was 41.7 months. The probability for BPFS after this period was 52.8% in 72 patients with persistently detectable PSA after RP and 65.4% in 87 patients who had a post-RP PSA nadir below detection limit. Univariate and multivariate analyses showed no significant difference in BPFS of both patient groups (p > 0.05). CONCLUSION: Our findings suggest that SRT is a viable treatment option for patients with persistently detectable PSA, giving similar results as in patients whose PSA increases out of an undetectable range after RP.

Early salvage radiation therapy does not compromise cancer control in patients with pT3N0 prostate cancer after radical prostatectomy: results of a match-controlled multi-institutional analysis.

BACKGROUND: Previous randomised trials demonstrated that adjuvant radiation therapy (aRT) improves cancer control in patients with pT3 prostate cancer (PCa). However, there is currently no evidence supporting early salvage radiation therapy (eSRT) as equivalent to aRT in improving freedom from biochemical recurrence (BCR) after radical prostatectomy (RP). OBJECTIVE: To evaluate BCR-free survival for aRT versus observation followed by eSRT in cases of relapse in patients undergoing RP for pT3pN0, R0-R1 PCa. DESIGN, SETTING, AND PARTICIPANTS: Using a European multi-institutional cohort, 890 men with pT3pN0, R0-R1 PCa were identified. INTERVENTION: All patients underwent RP. Subsequently, patients were stratified into two groups: aRT versus initial observation followed by eSRT in cases of relapse. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Propensity-matched analysis was employed, and patients were stratified into two groups: aRT versus observation and eventual eSRT, defined as RT given at a postoperative serum prostate-specific antigen (PSA) ≤ 0.5 ng/ml at least 6 mo after RP. BCR, defined as PSA >0.20 ng/ml and rising after administration of RT, was compared between aRT and initial observation followed by eSRT in cases of relapse using Kaplan-Meier and Cox regression methods. RESULTS AND LIMITATIONS: Overall, 390 (43.8%) and 500 (56.2%) patients were treated with aRT and initial observation, respectively. Within the latter group, 225 (45.0%) patients experienced BCR and underwent eSRT. In the postpropensity-matched cohort, the 2- and 5-yr BCR-free survival rates were 91.4% and 78.4% in aRT versus 92.8% and 81.8% in patients who underwent initial observation and eSRT in cases of relapse, respectively (p=0.9). No differences in the 2- and 5-yr BCR-free survival rates were found, even when patients were stratified according to pT3 substage and surgical margin status (all p ≥ 0.4). These findings were also confirmed in multivariable analyses (p=0.6). Similar results were achieved when the cut-off to define eSRT was set at 0.3 ng/ml (all p ≥ 0.5). CONCLUSIONS: The current study suggests that timely administration of eSRT is comparable to aRT in improving BCR-free survival in the majority of pT3pN0 PCa patients. Therefore, eSRT may not compromise cancer control but significantly reduces overtreatment associated with aRT.

Salvage radiotherapy after prostatectomy - what is the best time to treat?

PURPOSE: Salvage radiotherapy (SRT) is applied routinely in patients with biochemical relapse after radical prostatectomy (RP). However, only ∼30% of these patients achieve a durable response after 10 years. As a standard, 66 Gy are given, ideally with a PSA below 0.5 ng/ml. We tried to determine more precisely the optimal PSA for starting SRT. MATERIAL AND METHODS: In 301 prostate cancer patients without hormonal treatment, we analysed the impact on the biochemical response (bNED) to SRT of two pre-SRT PSA levels, namely below or above the median of 0.28 ng/ml. RESULTS: The median follow-up time for the entire group was 30 months. In 151 patients, SRT commenced at a PSA ≤ 0.28 ng/ml, in 150 at > 0.28 ng/ml. Eighty-two patients (27%) developed biochemical progression during follow up. The calculated two-year bNED was 74% for the entire group, 78% versus 61% for a PSA ≤ or > 0.28 ng/ml, respectively. In multivariate analysis, pT(3b), resection status, pre-SRT PSA dichotomized at median, PSA post-SRT undetectable, and PSA doubling time were statistically significant independent predictors of progression after SRT. CONCLUSIONS: Our findings suggest that a PSA of ≤ 0.28 ng/ml improves bNED compared with a PSA before SRT of > 0.28 ng/ml.

Dose escalation for patients with decreasing PSA during radiotherapy for elevated PSA after radical prostatectomy improves biochemical progression-free survival: results of a retrospective study.

PURPOSE: The optimal dose for salvage radiotherapy (SRT) after radical prostatectomy (RP) is still not defined. It should be at least 66 Gy. In the present study, the suitability of PSA regression as a selection criterion for an SRT dose escalation to 70.2 Gy was examined. PATIENTS AND METHODS: Between 1997 and 2007, 301 prostate cancer patients received SRT after RP at the Charité - University Medicine Berlin, Campus Benjamin Franklin. None of the patients had antihormone therapy prior to SRT. A total of 234 patients received 66.6 Gy. From 2002 on, 67 patients with a PSA decrease during SRT were irradiated with 70.2 Gy. The influence of this selection and dose escalation on freedom from biochemical progression (bNED) was analyzed. RESULTS: The median follow-up of the whole group was 30 months, the median pre-SRT PSA was 0.28 ng/ml. Of the patients, 27% (82/301) developed biochemical progression, 31% from the 66.6 Gy cohort (73/292) and 13% from the 70.2 Gy cohort (9/67) (p = 0.01). The calculated 2-years bNED was 74% for the whole group, 88% vs. 71% after 70.2 Gy and 66.6 Gy, respectively (p = 0.01). In a multivariate analysis, the total dose (p = 0.017), the re-achievement of an undetectable PSA after SRT (p = 0.005), and the infiltration of the seminal vesicles (p = 0.049) were independent parameters of bNED. CONCLUSION: Our analysis suggests that patient selection during SRT for a dose escalation to 70.2 Gy can improve the freedom from biochemical progression in patients with SRT after RP.

The German S3 guideline prostate cancer: aspects for the radiation oncologist.

This report summarizes the relevant aspects of the S3 guideline prostate cancer for the radiation oncologist. Treatment decision and dose prescription are discussed, as well as technical performance of external beam radiotherapy and brachytherapy. The relevant literature is cited to allow an overview of the current recommendations.

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.

PURPOSE: Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. METHODS: After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. RESULTS: Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. CONCLUSION: Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

Achieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome--results of a retrospective study.

PURPOSE: Salvage radiotherapy (SRT) is commonly used to treat patients with biochemical failure after radical prostatectomy (RP). Retrospective series have demonstrated biochemical response in approximately 60-75% of patients, but only a significantly lower rate of patients achieves a response with a decrease of the prostate-specific antigen (PSA) to a value below the limits of detectability. Therefore, long-term response at 10 years is only about 20-25% in all of these patients. The purpose of this study was to determine prognostic factors with impact on achieving the undetectable PSA range after SRT and to define the role of this end point. METHODS AND MATERIALS: Between 1997 and 2004, 162 patients received SRT at the Charité Universitätsmedizin, Berlin. No patient had hormonal treatment before SRT and 90% of the patients (143) had a SRT dose of 66 Gy. We analyzed the impact of nine potential risk factors on achieving an undetectable PSA after RT and on biochemical relapse-free survival (bNED) after SRT. RESULTS: Median follow-up time was 41.5 months and median PSA pre-RT was 0.33 ng/mL. Calculated bNED for 3.5 years was 54%. A total of 60% of the patients achieved an undetectable PSA after SRT. Univariate analysis demonstrated statistically significant predictors of biochemical progression after SRT: Gleason score (p = 0.01), PSA pre-SRT (p = 0.031), tumor stage (p = 0.047), and persistent detectable PSA after RT (p < 0.00005). In multivariate analysis, margin status (p = 0.017) and PSA pre-SRT (p = 0.002) were significant predictors of an undetectable PSA after SRT. The most significant independent predictor of bNED was "PSA undetectable after RT" (p < 0.0005) with a hazard ratio of 8.4, thus leading to a calculated bNED at 3.5 years of 75% compared with only 18% for those patients, who did not achieve an undetectable PSA after SRT. The rate of severe Grade 3-4 side effects was below 2.5%. CONCLUSIONS: The study represents one of the largest retrospective single-institution series of SRT for increasing PSA after RP in patients without any hormonal treatment before the initiation of SRT. Our findings suggest that achieving an undetectable PSA after RT is an important prognosticator for a high chance of cure and patients with a low PSA pre-SRT, positive surgical margins, and low tumor stage at the time of RP are best candidates for SRT.

Radiotherapy in biochemical recurrences after surgery for prostate cancer.

A biochemical recurrence following prostatectomy is often diagnosed in relatively young and healthy men, and hence deemed very relevant concerning life, given the generally high life expectancy of these patients. Therefore, there is a need for a therapy that offers a long-term chance of cure. Following salvage radiotherapy in large multicenter series, about 45% of the patients treated are in biochemical complete remission 4 years after radiotherapy. The best chances of response are in those patients in whom none of the established risk factors, that will be discussed, are present. Given the established curative potential of salvage radiotherapy and the fact that there are no therapeutic alternatives with a realistic chance of cure, the rather moderate rates of side effects seem acceptable.

Hormone-refractory and metastatic prostate cancer - palliative radiotherapy.

Prostate cancer progression is commonly manifested by obstructive uropathy, regional lymphatic metastases and hematogenous metastases to the axial skeleton. Radiotherapy is a mainstay in the palliation of symptomatic metastatic prostate cancer and is most often used for the palliation of painful metastatic bone lesions, resulting in a relief of pain in about 80-90% of patients and a reduction of analgesics. In metastatic disease compromising the integrity of the spinal cord or a nerve root, radiotherapy can be used as an urgent intervention to minimize neurological dysfunction and local progression or as an adjunct to surgical decompression. Local progression is often associated with hematuria, ureteric obstruction and perineal discomfort. Symptoms of metastatic lymphadenopathy like leg edema and back discomfort caused by pelvic or paraaortic metastases are related to the immediate anatomic structures affected. Radiotherapy for localized hormone-refractory prostate cancer has an excellent local control rate; nevertheless, the prognosis is poor, the majority of patients failing with distant metastasis within few years. The role of radiotherapy in hormone-refractory and metastatic prostate cancer, considering the patient's individual situation, are presented and discussed.

Fractionated irradiation can induce functionally relevant multidrug resistance gene and protein expression in human tumor cell lines.

The molecular basis of radiotherapy-related multidrug resistance (MDR) is still unclear. Here we report on a study investigating the effect of fractionated irradiation on expression of the MDR-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance-related protein (LRP), the respective mRNAs, and the functional consequences. Cells of six colon and five breast cancer cell lines were irradiated with a total dose of 27 Gy, five fractions of 1.8 Gy per week. The mRNA expression was measured by quantitative RT-PCR, protein levels and drug sensitivity to cisplatin, doxorubicin and bendamustine were assessed by flow cytometry. Breast cancer cell lines showed enhancement of the mRNAs encoding for P-gp, MRP1 and LRP in comparison to nonirradiated cells. No up-regulation of the three mRNA species was observed in the colon cancer cell lines. After irradiation, three breast cancer cell lines showed an up-regulation of LRP, one line an up-regulation of MRP1, and four lines a small up-regulation of P-gp. In the colon cancer cell lines, radiation induced significant enhancement of all three proteins. In comparison to controls, the irradiated cells lines showed a significant resistance to cisplatin, doxorubicin and bendamustine. This study confirms the prior reports of enhancement of P-gp and MRP1 after irradiation, which is accompanied by a multidrug resistance phenomenon, but in addition proposes a novel mechanism in the appearance of MDR after radiation-induced enhancement of LRP.