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Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy
EURURO-6479; No. of Pages 6 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer
Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy Nicola Fossati a,*, R. Jeffrey Karnes b, Cesare Cozzarini c, Claudio Fiorino d, Giorgio Gandaglia a, Steven Joniau e, Stephen A. Boorjian b, Gregor Goldner f, Wolfgang Hinkelbein g, Karin Haustermans h, Bertrand Tombal i, Shahrokh Shariat j, Pierre I. Karakiewicz k, Francesco Montorsi a, Hein Van Poppel e, Thomas Wiegel l, Alberto Briganti a a
Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy;
c
Department of Radiotherapy, IRCCS Ospedale San Raffaele, Milan, Italy; d Medical Physics, San Raffaele Scientific Institute, Milan, Italy; e University Hospitals
b
Department of Urology, Mayo Clinic, Rochester, MN, USA;
Leuven, Department of Urology, Leuven, Belgium; f Klinik fu¨r Radioonkologie, Medizinische Universita¨t Wien, Vienna, Austria; g Department of Radiation Oncology, Charite´ Universita¨tsmedizin, Campus Benjamin Franklin, Berlin, Germany;
h
University Hospitals Leuven, Department of Radiation Oncology,
Leuven, Belgium; i Department of Urology, Universite´ Catholique de Louvain, Brussels, Belgium; j Department of Urology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna General Hospital, Vienna, Austria;
k
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health
Centre, Montreal, Canada; l Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany
Article info
Abstract
Article history: Accepted October 5, 2015
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
Associate Editor: James Catto Keywords: Prostatic neoplasms Neoplasm recurrence Biochemical tumour markers Radiotherapy Salvage therapy
* Corresponding author. Division of Oncology/Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Via Olgettina, 60, 20131 Milan, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298. E-mail address: [email protected] (N. Fossati). http://dx.doi.org/10.1016/j.eururo.2015.10.009 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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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. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Network guidelines [4]. All patients received eSRT that was defined as local radiation to the prostate and seminal vesicle bed delivered at PSA
Prostate cancer patients treated with radical prostatectomy (RP) have an overall risk of biochemical recurrence (BCR) of approximately 30% at 10 yr after surgery [1,2]. Among treatment modalities for patients who experience BCR, salvage radiation therapy (SRT) currently represents a recommended option for men with no evidence of distant metastasis [3,4]. The correct timing of SRT administration remains unclear. Previous studies have shown that SRT efficacy is highly dependent on the prostate-specific antigen (PSA) level at the time of salvage treatment [5–8]. Better oncologic outcomes were observed when SRT was administered at the first sign of PSA recurrence [9]. The natural history of BCR after definitive surgical treatment is highly variable and is not invariably poor [10–12]. Moreover, postoperative radiation therapy (RT) may have a detrimental effect on functional outcomes, such as urinary continence, erectile function, and bowel symptoms [13,14]. As such, the identification of the appropriate timing to initiate early salvage radiation therapy (eSRT) is of utmost importance to maximise cancer control and to avoid overtreatment. We hypothesised that the impact of PSA level on cancer control after eSRT varies according to tumour characteristics at final pathology. As such, we evaluated a large multiinstitutional cohort of patients who were treated with eSRT for BCR after RP.
0.5 ng/ml [3]. Patients with missing information for preoperative PSA (n = 24), pathologic stage (n = 73), pathologic Gleason score (n = 36), or surgical margin status (n = 106) were excluded. These selection criteria yielded 716 evaluable individuals with complete clinical, pathologic, and followup data.
2.2.
Radiation therapy technique
SRT consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 mV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 66.6 Gy (interquartile range [IQR]: 66.6–70.2). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians in defining the CTV. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error. No patient received hormonal treatment during eSRT.
2.3.
Variable definition
Clinical data consisted of patient age at eSRT, preoperative PSA level, time from surgery to eSRT, and pre-eSRT PSA level. Pathologic data included pathologic stage (pT2, pT3a, or pT3b or higher), pathologic Gleason score (6, 7, or 8), and surgical margin status (negative vs positive).
2.
Materials and methods
2.4.
Definition of outcomes
2.1.
Patient population
The outcome of the study was BCR after eSRT, defined as two consecutive PSA values 0.2 ng/ml. Follow-up time was defined as the time between
We identified 955 patients treated with eSRT for PSA rise after RP
the initiation of eSRT and BCR or last follow-up.
at seven tertiary referral centres between 1996 and 2009. All patients had histologically confirmed pT2–pT4 pN0 R0–R1 adenocarcinoma of
2.5.
Statistical analysis
the prostate. No patient received neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as
Our statistical analysis consisted of three main steps. First, multivariable
<0.1 ng/ml).
Cox regression analysis tested the association between pre-eSRT PSA
PSA rise after surgery was defined as undetectable PSA with a
level and BCR after eSRT. Covariates were selected based on two
subsequent PSA increase within two or more determinations, according
previously published predictive models that addressed the risk of BCR
to the definition provided by the National Comprehensive Cancer
after eSRT [7,8]. Specifically, covariates consisted of pathologic stage
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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(pT2, pT3a, or pT3b or higher), pathologic Gleason score (6, 7, or 8), and surgical margin status (negative vs positive). Second, we wished to assess whether BCR-free survival was different by pre-eSRT PSA level by testing an interaction with PSA level and
Table 1 – Descriptive characteristics of 716 patients treated with early salvage radiation therapy for biochemical recurrence following radical prostatectomy Variable
Overall population
baseline pathologic risk. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score 8, and negative surgical margins. The choice of interaction variables (one or fewer pathologic risk factors vs two or more) was prespecified. We evaluated the number of pathologic risk factors to give the reader a clear message easily applicable to clinical practice, instead of evaluating each variable separately. Third, locally weighted 5-yr Kaplan-Meier estimates by values of a continuous covariate (st: Lowess) method was used to explore graphically the relationship between pre-eSRT PSA level and BCR-free survival rate at 5 yr after eSRT. The same graph was developed according to the number of pathologic risk factors (one or fewer vs two or more). All statistical analyses were performed using Stata v.12 (StataCorp LP, College Station, TX, USA).
Table 1 shows the descriptive characteristics of the patient population. The median PSA level at eSRT was 0.2 ng/ml (IQR: 0.1–0.3). Median follow-up among patients who did not experience BCR after eSRT was 57 mo (IQR: 27–105). At 5 yr after eSRT, the BCR-free survival rate was 82% (95% confidence interval [CI], 78–85). At multivariable Cox regression analysis (Table 2), the pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio [HR]: 4.89; 95% CI, 1.40–22.9; p < 0.0001). Moreover, pathologic stage pT3b or higher (HR: 2.07; 95% CI, 1.22–3.52; p = 0.007), pathologic Gleason score 8 (HR: 2.69; 95% CI, 1.60–4.53; p = 0.0002), and negative surgical margins (HR: 2.50; 95% CI, 1.69–3.71; p < 0.0001) were significantly associated with BCR after eSRT. These pathologic features were considered as pathologic risk factors. The association between BCR-free survival and pre-eSRT PSA level differed by the number of pathologic risk factors (p < 0.0001 by an interaction test). Overall, using the st: Lowess method, we observed a progressive decrease of the 5-yr BCR-free survival rate from 87% to 75% for the pre-eSRT
Table 2 – Multivariable Cox regression analysis predicting biochemical recurrence after early salvage radiation therapy in 716 prostate cancer patients
Pathologic stage pT2 pT3a pT3b or higher Pathologic Gleason score 6 7 8 Surgical margin status Negative Positive PSA at eSRT, ng/ml
382 (53) 226 (32) 108 (15) 319 (45) 297 (41) 100 (14) 331 (46) 385 (54) 0.2 (0.1–0.3)
eSRT = early salvage radiation therapy; PSA = prostate-specific antigen. All values are shown as median (interquartile range) or frequency (proportion).
Results
Predictor
63 (57–67) 7.5 (5.1–11.2)
HR
95% CI
p value
1.00 2.11 2.07
Ref. 1.40–3.17 1.22–3.52
– 0.0004 0.007
1.00 1.69 2.69
Ref. 1.10–2.59 1.60–4.53
– 0.02 0.0002
1.00 0.40 4.89
Ref. 0.27–0.59 1.40–22.9
– <0.0001 <0.0001
CI = confidence interval; eSRT = early salvage radiation therapy; HR = hazard ratio; PSA = prostate-specific antigen.
BCR-free survival at 5 yr after eSRT, %
3.
Age at eSRT, yr Preoperative PSA, ng/ml Pathologic stage (%) pT2 pT3a pT3b or higher Pathologic Gleason score (%) 6 7 8 Surgical margin status (%) Negative Positive PSA at eSRT, ng/ml
PSA at eSRT, ng/ml Fig. 1 – Biochemical recurrence (BCR)-free survival at 5 yr after early salvage radiation therapy (eSRT) plotted against the prostate-specific antigen (PSA) level at salvage treatment. BCR = biochemical recurrence; eSRT = early salvage radiation therapy; PSA = prostate-specific antigen.
PSA level ranging from 0.1 to 0.5 ng/ml; therefore, the 5-yr BCR risk increased by 3.0% per 0.1 ng/ml of PSA level (Fig. 1). However, when patients were stratified according to the number of risk factors at final pathology (one or fewer vs two or more), the effect of increasing PSA at eSRT on cancer control was dramatically higher in men with more advanced and/or aggressive disease. Patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR equal to 10% per 0.1 ng/ml of PSA level versus 1.5% in patients with few or no pathologic risk factor (Fig. 2). 4.
Discussion
The hypothesis of the current study was that the impact of PSA level on cancer control after eSRT varies according to tumour characteristics at final pathology. Our results
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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BCR-free survival at 5 yr after eSRT, %
EUROPEAN UROLOGY XXX (2015) XXX–XXX
PSA at eSRT, ng/ml Fig. 2 – Biochemical recurrence (BCR)-free survival at 5 yr after early salvage radiation therapy (eSRT) plotted against the prostate-specific antigen (PSA) level at salvage treatment. Patients were stratified according to the number of pathologic risk factors. Green dashed line: one risk factor or fewer; red dotted line: two or more risk factors. BCR = biochemical recurrence; eSRT = early salvage radiation therapy; PSA = prostate-specific antigen.
confirmed our hypothesis because PSA level conferred a different BCR risk after SRT based on pathologic features. Several facets of our findings deserve attention. First, the absolute PSA level was confirmed to have prognostic significance, even in the eSRT setting for values <0.5 ng/ml. This result was in line with previous studies [5–7,15–20]; however, we showed that PSA level after RP has different prognostic weights depending on pathologic characteristics of the tumour. Previous studies focused on the optimal PSA cut-off for the initiation of SRT [21,22]. Conversely, our results suggested the need for an accurate interpretation of postoperative PSA level based on pathologic characteristics. In other words, the identification of a specific and unique PSA cut-off seems to be incorrect and improper because the prognostic significance of PSA level varies importantly according to pathologic characteristics. Our results may suggest a potential benefit of immediate adjuvant RT, especially for patients with more adverse pathologic features; however, this study included only patients who experienced a PSA rise after surgery. As such, we did not compare the outcomes with those patients who underwent a wait-and-see approach and did not experience a PSA rise. A more precise answer to this question will arise only from a randomised clinical trial comparing adjuvant RT versus eSRT. Second, we identified three pathologic risk factors according to recently published predictive models (ie, pathologic stage pT3b or higher, pathologic Gleason 8, and negative surgical margins) [6–8]. These risk factors were confirmed as significant predictors at multivariable analysis for the outcome of BCR after eSRT. We observed that patients with more adverse pathologic features showed an increased risk of 5-yr BCR of 10% per 0.1 ng/ml of PSA level. In this setting, our results highlighted the need for
eSRT administration at the very first sign of PSA increase to maximise cancer control. On the contrary, the 5-yr BCR risk increased by only 1.5% per 0.1 ng/ml of PSA in patients with one or no pathologic risk factors. In this patient category, a wait-and-see approach appears to be a reasonable option to avoid overtreatment. It has been shown that not all patients in whom two consecutive and rising post-RP PSA values >0.20 ng/ml are documented will develop a clinically evident relapse [10,23]. Third, our results were not altered by hormonal therapy because no patient received neoadjuvant, adjuvant, or salvage androgen deprivation therapy before and during eSRT. The correct timing of hormonal therapy has not yet been clearly demonstrated in this setting. Two currently ongoing prospective clinical trials (the GETUG-16 and the RADICALS) are addressing this topic. The first results of GETUG-16 suggested a benefit of adding hormonal therapy to SRT. However, because biochemical outcome was the main end point of this study, the lack of hormonal therapy administration in our patient population represents an important strength of the study. Fourth, the current study included a large (n = 716) multi-institutional series of patients with a median followup of 57 mo (IQR: 27–105). To the best of our knowledge, this represents one of the largest series of patients treated with SRT after surgery. Despite the multi-institutional nature of the study, CTVs and RTs dose were similar among centres. These points represent additional strengths of the study. Finally, RT was not significantly associated with the probability of cancer control after SRT (data not shown). This result was in contrast with previous studies that found a significant association between doses 70 Gy with better BCR-free survival [21,24] as well as metastasis-free survival [20]. A possible explanation of this discordance may be the similar dose administered to patients within the current series because the median dose was 66 Gy (IQR: 66–70) highlighting its skewed distribution. The current study has important clinical implications regarding the administration of postoperative RT. Several previous studies addressed the question of whether and when to administer SRT; however, conflicting results have been published, and a clear-cut answer is still lacking. Siegmann et al, for example, showed that even a relatively small shift from 0.28 to 0.2 ng/ml for initiation of an RT treatment improved the 2-yr BCR-free survival rate by 5% [21]. In contrast, lowering the PSA cut-off from 0.5 to 0.3 ng/ml for RT did not improve 5-yr BCR-free survival in a recently published study [8], suggesting that the optimal threshold for initiating eSRT may possibly be <0.5 ng/ml. In this study, for the first time, we showed the importance of contextualising the absolute value of postoperative PSA according to tumour characteristics. In other words, the administration of SRT appears to be a decision step similar to whether or not to perform a prostate biopsy for an elevated PSA value at the time of diagnosis. If our findings are confirmed by future studies, urologists and radiation oncologists should integrate the PSA value after surgery with further information (ie, pathologic characteristics). In
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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EUROPEAN UROLOGY XXX (2015) XXX–XXX
the future, the use of ultrasensitive PSA assays for close monitoring will allow for further precision of PSA-based thresholds for eSRT initiation. Despite its strengths, our study is not devoid of limitations. First, the evaluated outcome was BCR after eSRT. Data about more clinically significant end points, such as metastases-free, cancer-specific, and/or overall survival, were not available in our series. The evaluation of hard clinical end points is necessary to draw definitive conclusions and requires further studies. Second, other factors in addition to PSA and pathologic features might guide the optimal timing of early RT administration. Specifically, PSA doubling time (PSA DT) has been shown as a significant prognostic factor for patients who experienced BCR after RP. Indeed, a short PSA DT identifies patients at the highest risk for progression to distant metastasis [6,7] and cancer-specific mortality [11]. Consequently, the evaluation of PSA DT in the current study might help identify the optimal timing for eSRT administration according to pathologic features; however, due to the retrospective nature of our study, we were unable to retrieve this information. Third, a significant selection bias could exist for the early administration of SRT. Patients with more favourable disease may have received SRT later (eg, PSA >0.5 ng/ml). At the same time, physicians could have particular reasons to select patients for eSRT including unfavourable characteristics from the RP specimens, rapid PSA rise, and/or short PSA DT. In this case, however, such selection bias probably attenuated our results. In fact, the limited effect of eSRT in this patient category may have been more evident if eSRT had been administered to patients with favourable characteristics.
Drafting of the manuscript: Fossati, Karnes, Cozzarini, Fiorino, Gandaglia, Joniau, Boorjian, Goldner, Hinkelbein, Haustermans, Tombal, Shariat, Karakiewicz, Montorsi, Van Poppel, Wiegel, Briganti. Critical revision of the manuscript for important intellectual content: Fossati, Karnes, Cozzarini, Fiorino, Gandaglia, Joniau, Boorjian, Goldner, Hinkelbein, Haustermans, Tombal, Shariat, Karakiewicz, Montorsi, Van Poppel, Wiegel, Briganti. Statistical analysis: Fossati, Gandaglia, Fiorino. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Fossati, Karnes, Cozzarini, Fiorino, Gandaglia, Joniau, Boorjian, Goldner, Hinkelbein, Haustermans, Tombal,
Shariat,
Karakiewicz,
Montorsi, Van Poppel, Wiegel, Briganti. Other (specify): None. Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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In this retrospective study, we found that cancer control after eSRT greatly depended on pretreatment PSA, and the absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. 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 administered at the very first sign of PSA rise conferred better cancer control. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP despite PSA rise. Prospective randomised clinical trials are needed to corroborate our findings. Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fossati, Karnes, Briganti.
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Prostate Cancer
Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy Nicola Fossati a,*, R. Jeffrey Karnes b, Cesare Cozzarini c, Claudio Fiorino d, Giorgio Gandaglia a, Steven Joniau e, Stephen A. Boorjian b, Gregor Goldner f, Wolfgang Hinkelbein g, Karin Haustermans h, Bertrand Tombal i, Shahrokh Shariat j, Pierre I. Karakiewicz k, Francesco Montorsi a, Hein Van Poppel e, Thomas Wiegel l, Alberto Briganti a a
Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy;
c
Department of Radiotherapy, IRCCS Ospedale San Raffaele, Milan, Italy; d Medical Physics, San Raffaele Scientific Institute, Milan, Italy; e University Hospitals
b
Department of Urology, Mayo Clinic, Rochester, MN, USA;
Leuven, Department of Urology, Leuven, Belgium; f Klinik fu¨r Radioonkologie, Medizinische Universita¨t Wien, Vienna, Austria; g Department of Radiation Oncology, Charite´ Universita¨tsmedizin, Campus Benjamin Franklin, Berlin, Germany;
h
University Hospitals Leuven, Department of Radiation Oncology,
Leuven, Belgium; i Department of Urology, Universite´ Catholique de Louvain, Brussels, Belgium; j Department of Urology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna General Hospital, Vienna, Austria;
k
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health
Centre, Montreal, Canada; l Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany
Article info
Abstract
Article history: Accepted October 5, 2015
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
Associate Editor: James Catto Keywords: Prostatic neoplasms Neoplasm recurrence Biochemical tumour markers Radiotherapy Salvage therapy
* Corresponding author. Division of Oncology/Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Via Olgettina, 60, 20131 Milan, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298. E-mail address: [email protected] (N. Fossati). http://dx.doi.org/10.1016/j.eururo.2015.10.009 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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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. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Network guidelines [4]. All patients received eSRT that was defined as local radiation to the prostate and seminal vesicle bed delivered at PSA
Prostate cancer patients treated with radical prostatectomy (RP) have an overall risk of biochemical recurrence (BCR) of approximately 30% at 10 yr after surgery [1,2]. Among treatment modalities for patients who experience BCR, salvage radiation therapy (SRT) currently represents a recommended option for men with no evidence of distant metastasis [3,4]. The correct timing of SRT administration remains unclear. Previous studies have shown that SRT efficacy is highly dependent on the prostate-specific antigen (PSA) level at the time of salvage treatment [5–8]. Better oncologic outcomes were observed when SRT was administered at the first sign of PSA recurrence [9]. The natural history of BCR after definitive surgical treatment is highly variable and is not invariably poor [10–12]. Moreover, postoperative radiation therapy (RT) may have a detrimental effect on functional outcomes, such as urinary continence, erectile function, and bowel symptoms [13,14]. As such, the identification of the appropriate timing to initiate early salvage radiation therapy (eSRT) is of utmost importance to maximise cancer control and to avoid overtreatment. We hypothesised that the impact of PSA level on cancer control after eSRT varies according to tumour characteristics at final pathology. As such, we evaluated a large multiinstitutional cohort of patients who were treated with eSRT for BCR after RP.
0.5 ng/ml [3]. Patients with missing information for preoperative PSA (n = 24), pathologic stage (n = 73), pathologic Gleason score (n = 36), or surgical margin status (n = 106) were excluded. These selection criteria yielded 716 evaluable individuals with complete clinical, pathologic, and followup data.
2.2.
Radiation therapy technique
SRT consisted of local radiation to the prostate and seminal vesicle bed. All patients were treated with high-energy photon beams (10–25 mV) at conventional fractionation (1.8–2 Gy per fraction), with a median dose of 66.6 Gy (interquartile range [IQR]: 66.6–70.2). Conventional nonconformal treatment was delivered, and rectangular or minimally blocked beams were used. Alternatively, a three-dimensional conformal approach was used. The clinical target volume (CTV) was delineated on computed tomography (CT) images and included the prostatic fossa and periprostatic tissue. Clinical findings, presurgery CT scan, and surgical clips guided the clinicians in defining the CTV. The planned target volume was defined as CTV plus a 0.8- to 1.0-cm margin to account for organ motion and setup error. No patient received hormonal treatment during eSRT.
2.3.
Variable definition
Clinical data consisted of patient age at eSRT, preoperative PSA level, time from surgery to eSRT, and pre-eSRT PSA level. Pathologic data included pathologic stage (pT2, pT3a, or pT3b or higher), pathologic Gleason score (6, 7, or 8), and surgical margin status (negative vs positive).
2.
Materials and methods
2.4.
Definition of outcomes
2.1.
Patient population
The outcome of the study was BCR after eSRT, defined as two consecutive PSA values 0.2 ng/ml. Follow-up time was defined as the time between
We identified 955 patients treated with eSRT for PSA rise after RP
the initiation of eSRT and BCR or last follow-up.
at seven tertiary referral centres between 1996 and 2009. All patients had histologically confirmed pT2–pT4 pN0 R0–R1 adenocarcinoma of
2.5.
Statistical analysis
the prostate. No patient received neoadjuvant or adjuvant hormonal therapy. All patients had an undetectable postoperative PSA (defined as
Our statistical analysis consisted of three main steps. First, multivariable
<0.1 ng/ml).
Cox regression analysis tested the association between pre-eSRT PSA
PSA rise after surgery was defined as undetectable PSA with a
level and BCR after eSRT. Covariates were selected based on two
subsequent PSA increase within two or more determinations, according
previously published predictive models that addressed the risk of BCR
to the definition provided by the National Comprehensive Cancer
after eSRT [7,8]. Specifically, covariates consisted of pathologic stage
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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(pT2, pT3a, or pT3b or higher), pathologic Gleason score (6, 7, or 8), and surgical margin status (negative vs positive). Second, we wished to assess whether BCR-free survival was different by pre-eSRT PSA level by testing an interaction with PSA level and
Table 1 – Descriptive characteristics of 716 patients treated with early salvage radiation therapy for biochemical recurrence following radical prostatectomy Variable
Overall population
baseline pathologic risk. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score 8, and negative surgical margins. The choice of interaction variables (one or fewer pathologic risk factors vs two or more) was prespecified. We evaluated the number of pathologic risk factors to give the reader a clear message easily applicable to clinical practice, instead of evaluating each variable separately. Third, locally weighted 5-yr Kaplan-Meier estimates by values of a continuous covariate (st: Lowess) method was used to explore graphically the relationship between pre-eSRT PSA level and BCR-free survival rate at 5 yr after eSRT. The same graph was developed according to the number of pathologic risk factors (one or fewer vs two or more). All statistical analyses were performed using Stata v.12 (StataCorp LP, College Station, TX, USA).
Table 1 shows the descriptive characteristics of the patient population. The median PSA level at eSRT was 0.2 ng/ml (IQR: 0.1–0.3). Median follow-up among patients who did not experience BCR after eSRT was 57 mo (IQR: 27–105). At 5 yr after eSRT, the BCR-free survival rate was 82% (95% confidence interval [CI], 78–85). At multivariable Cox regression analysis (Table 2), the pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio [HR]: 4.89; 95% CI, 1.40–22.9; p < 0.0001). Moreover, pathologic stage pT3b or higher (HR: 2.07; 95% CI, 1.22–3.52; p = 0.007), pathologic Gleason score 8 (HR: 2.69; 95% CI, 1.60–4.53; p = 0.0002), and negative surgical margins (HR: 2.50; 95% CI, 1.69–3.71; p < 0.0001) were significantly associated with BCR after eSRT. These pathologic features were considered as pathologic risk factors. The association between BCR-free survival and pre-eSRT PSA level differed by the number of pathologic risk factors (p < 0.0001 by an interaction test). Overall, using the st: Lowess method, we observed a progressive decrease of the 5-yr BCR-free survival rate from 87% to 75% for the pre-eSRT
Table 2 – Multivariable Cox regression analysis predicting biochemical recurrence after early salvage radiation therapy in 716 prostate cancer patients
Pathologic stage pT2 pT3a pT3b or higher Pathologic Gleason score 6 7 8 Surgical margin status Negative Positive PSA at eSRT, ng/ml
382 (53) 226 (32) 108 (15) 319 (45) 297 (41) 100 (14) 331 (46) 385 (54) 0.2 (0.1–0.3)
eSRT = early salvage radiation therapy; PSA = prostate-specific antigen. All values are shown as median (interquartile range) or frequency (proportion).
Results
Predictor
63 (57–67) 7.5 (5.1–11.2)
HR
95% CI
p value
1.00 2.11 2.07
Ref. 1.40–3.17 1.22–3.52
– 0.0004 0.007
1.00 1.69 2.69
Ref. 1.10–2.59 1.60–4.53
– 0.02 0.0002
1.00 0.40 4.89
Ref. 0.27–0.59 1.40–22.9
– <0.0001 <0.0001
CI = confidence interval; eSRT = early salvage radiation therapy; HR = hazard ratio; PSA = prostate-specific antigen.
BCR-free survival at 5 yr after eSRT, %
3.
Age at eSRT, yr Preoperative PSA, ng/ml Pathologic stage (%) pT2 pT3a pT3b or higher Pathologic Gleason score (%) 6 7 8 Surgical margin status (%) Negative Positive PSA at eSRT, ng/ml
PSA at eSRT, ng/ml Fig. 1 – Biochemical recurrence (BCR)-free survival at 5 yr after early salvage radiation therapy (eSRT) plotted against the prostate-specific antigen (PSA) level at salvage treatment. BCR = biochemical recurrence; eSRT = early salvage radiation therapy; PSA = prostate-specific antigen.
PSA level ranging from 0.1 to 0.5 ng/ml; therefore, the 5-yr BCR risk increased by 3.0% per 0.1 ng/ml of PSA level (Fig. 1). However, when patients were stratified according to the number of risk factors at final pathology (one or fewer vs two or more), the effect of increasing PSA at eSRT on cancer control was dramatically higher in men with more advanced and/or aggressive disease. Patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR equal to 10% per 0.1 ng/ml of PSA level versus 1.5% in patients with few or no pathologic risk factor (Fig. 2). 4.
Discussion
The hypothesis of the current study was that the impact of PSA level on cancer control after eSRT varies according to tumour characteristics at final pathology. Our results
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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BCR-free survival at 5 yr after eSRT, %
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PSA at eSRT, ng/ml Fig. 2 – Biochemical recurrence (BCR)-free survival at 5 yr after early salvage radiation therapy (eSRT) plotted against the prostate-specific antigen (PSA) level at salvage treatment. Patients were stratified according to the number of pathologic risk factors. Green dashed line: one risk factor or fewer; red dotted line: two or more risk factors. BCR = biochemical recurrence; eSRT = early salvage radiation therapy; PSA = prostate-specific antigen.
confirmed our hypothesis because PSA level conferred a different BCR risk after SRT based on pathologic features. Several facets of our findings deserve attention. First, the absolute PSA level was confirmed to have prognostic significance, even in the eSRT setting for values <0.5 ng/ml. This result was in line with previous studies [5–7,15–20]; however, we showed that PSA level after RP has different prognostic weights depending on pathologic characteristics of the tumour. Previous studies focused on the optimal PSA cut-off for the initiation of SRT [21,22]. Conversely, our results suggested the need for an accurate interpretation of postoperative PSA level based on pathologic characteristics. In other words, the identification of a specific and unique PSA cut-off seems to be incorrect and improper because the prognostic significance of PSA level varies importantly according to pathologic characteristics. Our results may suggest a potential benefit of immediate adjuvant RT, especially for patients with more adverse pathologic features; however, this study included only patients who experienced a PSA rise after surgery. As such, we did not compare the outcomes with those patients who underwent a wait-and-see approach and did not experience a PSA rise. A more precise answer to this question will arise only from a randomised clinical trial comparing adjuvant RT versus eSRT. Second, we identified three pathologic risk factors according to recently published predictive models (ie, pathologic stage pT3b or higher, pathologic Gleason 8, and negative surgical margins) [6–8]. These risk factors were confirmed as significant predictors at multivariable analysis for the outcome of BCR after eSRT. We observed that patients with more adverse pathologic features showed an increased risk of 5-yr BCR of 10% per 0.1 ng/ml of PSA level. In this setting, our results highlighted the need for
eSRT administration at the very first sign of PSA increase to maximise cancer control. On the contrary, the 5-yr BCR risk increased by only 1.5% per 0.1 ng/ml of PSA in patients with one or no pathologic risk factors. In this patient category, a wait-and-see approach appears to be a reasonable option to avoid overtreatment. It has been shown that not all patients in whom two consecutive and rising post-RP PSA values >0.20 ng/ml are documented will develop a clinically evident relapse [10,23]. Third, our results were not altered by hormonal therapy because no patient received neoadjuvant, adjuvant, or salvage androgen deprivation therapy before and during eSRT. The correct timing of hormonal therapy has not yet been clearly demonstrated in this setting. Two currently ongoing prospective clinical trials (the GETUG-16 and the RADICALS) are addressing this topic. The first results of GETUG-16 suggested a benefit of adding hormonal therapy to SRT. However, because biochemical outcome was the main end point of this study, the lack of hormonal therapy administration in our patient population represents an important strength of the study. Fourth, the current study included a large (n = 716) multi-institutional series of patients with a median followup of 57 mo (IQR: 27–105). To the best of our knowledge, this represents one of the largest series of patients treated with SRT after surgery. Despite the multi-institutional nature of the study, CTVs and RTs dose were similar among centres. These points represent additional strengths of the study. Finally, RT was not significantly associated with the probability of cancer control after SRT (data not shown). This result was in contrast with previous studies that found a significant association between doses 70 Gy with better BCR-free survival [21,24] as well as metastasis-free survival [20]. A possible explanation of this discordance may be the similar dose administered to patients within the current series because the median dose was 66 Gy (IQR: 66–70) highlighting its skewed distribution. The current study has important clinical implications regarding the administration of postoperative RT. Several previous studies addressed the question of whether and when to administer SRT; however, conflicting results have been published, and a clear-cut answer is still lacking. Siegmann et al, for example, showed that even a relatively small shift from 0.28 to 0.2 ng/ml for initiation of an RT treatment improved the 2-yr BCR-free survival rate by 5% [21]. In contrast, lowering the PSA cut-off from 0.5 to 0.3 ng/ml for RT did not improve 5-yr BCR-free survival in a recently published study [8], suggesting that the optimal threshold for initiating eSRT may possibly be <0.5 ng/ml. In this study, for the first time, we showed the importance of contextualising the absolute value of postoperative PSA according to tumour characteristics. In other words, the administration of SRT appears to be a decision step similar to whether or not to perform a prostate biopsy for an elevated PSA value at the time of diagnosis. If our findings are confirmed by future studies, urologists and radiation oncologists should integrate the PSA value after surgery with further information (ie, pathologic characteristics). In
Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009
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the future, the use of ultrasensitive PSA assays for close monitoring will allow for further precision of PSA-based thresholds for eSRT initiation. Despite its strengths, our study is not devoid of limitations. First, the evaluated outcome was BCR after eSRT. Data about more clinically significant end points, such as metastases-free, cancer-specific, and/or overall survival, were not available in our series. The evaluation of hard clinical end points is necessary to draw definitive conclusions and requires further studies. Second, other factors in addition to PSA and pathologic features might guide the optimal timing of early RT administration. Specifically, PSA doubling time (PSA DT) has been shown as a significant prognostic factor for patients who experienced BCR after RP. Indeed, a short PSA DT identifies patients at the highest risk for progression to distant metastasis [6,7] and cancer-specific mortality [11]. Consequently, the evaluation of PSA DT in the current study might help identify the optimal timing for eSRT administration according to pathologic features; however, due to the retrospective nature of our study, we were unable to retrieve this information. Third, a significant selection bias could exist for the early administration of SRT. Patients with more favourable disease may have received SRT later (eg, PSA >0.5 ng/ml). At the same time, physicians could have particular reasons to select patients for eSRT including unfavourable characteristics from the RP specimens, rapid PSA rise, and/or short PSA DT. In this case, however, such selection bias probably attenuated our results. In fact, the limited effect of eSRT in this patient category may have been more evident if eSRT had been administered to patients with favourable characteristics.
Drafting of the manuscript: Fossati, Karnes, Cozzarini, Fiorino, Gandaglia, Joniau, Boorjian, Goldner, Hinkelbein, Haustermans, Tombal, Shariat, Karakiewicz, Montorsi, Van Poppel, Wiegel, Briganti. Critical revision of the manuscript for important intellectual content: Fossati, Karnes, Cozzarini, Fiorino, Gandaglia, Joniau, Boorjian, Goldner, Hinkelbein, Haustermans, Tombal, Shariat, Karakiewicz, Montorsi, Van Poppel, Wiegel, Briganti. Statistical analysis: Fossati, Gandaglia, Fiorino. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Fossati, Karnes, Cozzarini, Fiorino, Gandaglia, Joniau, Boorjian, Goldner, Hinkelbein, Haustermans, Tombal,
Shariat,
Karakiewicz,
Montorsi, Van Poppel, Wiegel, Briganti. Other (specify): None. Financial disclosures: Nicola Fossati certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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In this retrospective study, we found that cancer control after eSRT greatly depended on pretreatment PSA, and the absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. 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 administered at the very first sign of PSA rise conferred better cancer control. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP despite PSA rise. Prospective randomised clinical trials are needed to corroborate our findings. Author contributions: Nicola Fossati had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fossati, Karnes, Briganti.
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Please cite this article in press as: Fossati N, et al. Assessing the Optimal Timing for Early Salvage Radiation Therapy in Patients with Prostate-specific Antigen Rise After Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.10.009