IJO International Journal of Oncology 1019-6439 1791-2423 D.A. Spandidos 10.3892/ijo.2012.1694 ijo-42-01-0109 Articles Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: Single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy CORTÉS-GONZÁLEZJEFF R.12 CASTELLANOSENRIQUE1 SANDBERGKATINKA1 ERIKSSONMARIE-HJELM1 WIKLUNDPETER3 CARLSSONSTEFAN3 COHN-CEDERMARKGABRIELLA1 HARMENBERGULRIKA1 GUSTAFSSONOVE4 LEVITTSEYMOUR H.15 LENNERNÄSBO16 BRANDBERGYVONNE1 MÁRQUEZMARCELA1 KÄLKNERKARL-MIKAEL1 NILSSONSTEN1 Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Urology Service, University Hospital ‘Dr. Jose E. Gonzalez’ UANL, Monterrey, Mexico; Department of Surgery, Section of Urology, Karolinska University Hospital, Stockholm and Section of Urology, Department of Molecular Medicine and Surgery, Karolinska Institutet; Division of Urology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Radiation Oncology, University of Minnesota, Minneapolis, MN, USA; Department of Oncology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg Urology Service, Gothenburg, Sweden Correspondence to: Dr Jeff R. Cortés-González, Department of Oncology-Pathology, Karolinska Institutet, Urologic Oncology Group CCK R8:3, SE-17176 Stockholm, Sweden, E-mail: jeff.cortes-gonzalez@ki.se 1 2013 13 11 2012 42 1 109 117 13 04 2012 21 06 2012 Copyright © 2013, Spandidos Publications 2013 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

The aim of this study was to investigate the role of 70 Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48 months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8–10 in the prostatectomy specimens 17/40 (43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3–4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.

 prostate cancer salvage radiotherapy radical prostatectomy neoadjuvant hormone therapy PSA co-morbidity quality of life Introduction

Every third patient with localized prostate cancer (PCa) who undergoes radical prostatectomy (RP) will experience biochemical failure (BcF) within 10 years (1,2) and, without further treatment, one third will progress to metastatic disease within 8 years (1). Postoperative radiotherapy has been delivered to patients with recurrent PCa for the last 2–3 decades, but not until recently have data shown that adjuvant radiotherapy (ART) increases disease-free survival and also provides an appreciable survival benefit in patients with non-radically excised tumors (3–5). Definitions of BcF have varied over the years, although they have all included rising PSA after RP and no evidence of clinical or radiological residual disease. Furthermore, there is now level 1 evidence that ART plays a role after non-radical RP, but the vast majority of patients with PSA relapse have not received this treatment.

Thus, therapy decisions must be made as to whether these individuals should be offered salvage radiotherapy (SRT). Several ongoing studies include patients randomized to ART or SRT; however, data are not to be expected within the next few years, and, hence, decisions must be based on outcome data from non-randomized studies. Numerous questions concerning SRT remain to be answered, although recommendations and guidelines have emerged (6,7). Common to these is that SRT provides long-term control of the disease in approximately one third of patients with BcF, particularly those with relatively low pre-SRT PSA levels. Patients with poorly differentiated cancer and short PSA doubling time (PSADT) seem to benefit most from SRT (8). Recently, well-designed matched-pair analyses were performed to compare ART with early SRT (9,10) and these investigations, like the three large randomized adjuvant trials, suggested that ART is superior. However, it is difficult to draw extensive conclusions from the indicated observations, because, by definition, the SRT patients suffered from more advanced disease. Treatment decisions can be based on previously reported outcome data. However, knowledge is still limited regarding issues such as long-term side-effects, impact of treatment on health-related quality of life (HRQoL), influence of co-morbidity on treatment outcome, effects of neoadjuvant hormone therapy (NHT).

The aim of the present study was to evaluate the long-term outcome of SRT, with consideration paid to genitourinary (GU) and gastrointestinal (GI) toxicity, the impact on HRQoL, and the influence of co-morbidity. To our knowledge, this is the first large, single-institution study to use a uniform radiation treatment protocol combined with short-term NHT.

 Patients and methods <sec> <title>Patients

Treatment outcome was analyzed in 184 consecutive PCa patients with post-RP BcF. The patients had been referred for SRT to the Radiumhemmet and Södersjukhuset facilities at the Karolinska University Hospital (KS) in Stockholm, Sweden, between October 2001 and February 2007. Patients were available for all the following characteristics: pT stage 2–3, record of digital rectal examination (DRE), post-RP BcF, NX or N0, Gleason score (GS) of the post-RP specimen and at least 12 months post-SRT follow-up. Median age was 64 years (range 39–77), and median follow-up was 48 months (range 12–92). After SRT, all patients were monitored for BcF with periodic PSA values. If recurrence/metastases were suspected, scintigraphy and/or [F18]-FDG or acetate positron emission tomography were performed.

 Treatment

Radical prostatectomy was retropubic in 161 (87%), laparoscopic in 3 (2%), and robot-assisted in 20 (11%). Three different clinical target radiotherapy volumes (CTVs) were used according to individual factors: A) inclusion of the prostatic fossa (PF) and seminal vesicles (SVs) in the 78 (43%) patients with SV invasion (SVI) at surgery; B) inclusion of only the PF in 19 (10%) patients whose SVs had been removed completely; C) a shrinking field in 87 (47%) patients with residual distal parts of the SVs after RP. The planning target volume (PTV) was defined as CTV plus 20 mm in all directions except posteriorly, where 15 mm was used. The daily fraction was 2 Gy delivered 5 days/week. For CTVs A and B, the prescribed dose was 70 Gy; in C, the PF and the SVs were irradiated to 54 Gy, and thereafter only the PF to 70 Gy. At least 95% of the PTV received the prescribed doses. Less than 15% of the outlined rectal volume received doses >70 Gy. All patients were given 3D conformal therapy with high-energy linear accelerators equipped with multi-leaf collimators, and they were treated in the supine position. The external beam radiation was performed with a four-field at Radiumhemmet, whereas a three-field technique (one anterior and two lateral fields) was used at Södersjukhuset; all fields were equally weighted at both facilities.

A median of 3 months of NHT was given to 165 (90%) of the patients. Of these, 151 (92%) received antiandrogens (bicalutamide 50 mg × 1 or flutamide 250 mg × 3) combined with a gonadotropin-releasing hormone (GnRH) analogue, and 14 (8%) were given antiandrogens or GnRH analogue as monotherapy.

 Data collection

Clinical data were collected from electronic medical records (KS database). Side-effects were reported according to the GU-GI toxicity scale of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) (11). The Charlson co-morbidity index adjusted for age was analyzed to correlate co-morbidities and RTOG toxicity (12,13). DRE was performed during the regular follow-up after RP. A palpable post-RP recurrence was found in 46 (25%) patients; 35 (76%) of these underwent transrectal ultrasound guided fine-needle aspiration cytology. Pathological evidence of local post-RP recurrence was found in 10 (29%). The patient characteristics are described in Table I. The investigation was approved by the local ethics committee (approval number 2006/620-31/1).

 RTOG score and Charlson co-morbidity index adjusted for age (CCIAA) (<xref rid="t2-ijo-42-01-0109" ref-type="table">Table II</xref>) HRQoL EORTC QLQ-C30 and PR-25 (prostate specific) (<xref rid="b14-ijo-42-01-0109" ref-type="bibr">14</xref>,<xref rid="b15-ijo-42-01-0109" ref-type="bibr">15</xref>)

Up to October 2009, 9 of the 184 consecutive patients had died during follow-up. To each of the remaining 175, an envelope containing both questionnaires, a letter inviting participation in the study, and a prepaid return envelope was sent. In all, 148 (85%) patients returned the questionnaires; four were blank, which left 144 (83%) for evaluation.

 Statistical analysis

Pre-SRT BcF was defined as follows: a rise in PSA >0.1 ng/dl when nadir was undetectable, or any rise in PSA above nadir. Clinical characteristics such as pre-RP PSA and pT stage (extracapsular extension), pre-RT PSADT, post-RP GS, pre-SRT PSA, were dichotomized. Post-SRT BcF was defined as any detectable PSA with an undetectable nadir or an elevation of 0.1 ng/ml above nadir. Undetectable PSA was reported as <0.05 ng/ml, and an approximation to 0.04 ng/ml was done in the statistical calculation. The PSADT calculation was done according to Pound et al(1) The pT stage was defined according to the 1997 TNM classification system.

No biochemical evidence of disease (bNED), overall survival (OS), PCa-specific survival, and metastasis-free survival (MFS) were estimated by using the Kaplan-Meier and log-rank methods to demonstrate differences. Time to event was calculated from the date of SRT to the date of the event or death. A univariate regression was performed in which BcF was evaluated as an outcome variable. The multivariate regressions were conducted with stepwise variable elimination, using BcF and bone metastases as outcome variables. Both univariate and multivariate analyses were performed using Cox proportional hazards regression and were compared with the results presented by Stephenson et al(16) as listed in Table III. Logarithmic transformation of the pre-SRT PSA was performed to run a logistic regression.

The raw scores of the questionnaires were linearly transformed into a 100-point scale, and missing values were imputed according to the EORTC scoring manual (17). Mean questionnaire scores for patients with bNED and with BcF were calculated with 95% confidence intervals.

To compare means, the Student’s t-test was used when data were normally distributed, and the Mann-Whitney U test when skewed. Fisher’s exact test was utilized for the count/frequency analyses. The tests were performed using STATA 9, and p-values <0.05 were considered statistically significant.

 Using the nomogram

The pre-treatment data of patients were used in the nomogram for radiotherapy as described by Stephenson et al(7) to create an individual probability for PSA bNED at 3 years. Thereafter, the means were calculated.

 Results <sec> <title>Nine patients died during follow-up and one of PCa

This gave a 99% PCa-specific survival and 95% OS. Seven (4%) developed bone metastases. No statistically significant differences in OS were found between patients with low/medium and high CCIAA scores. Using the patients’ pre-treatment data and the Stephenson nomogram, a mean 3-year bNED probability of 53% (95% CI 49.21; 56.71) was calculated.

PSA levels after SRT + NHT were undetectable in 171 (93%) patients. BcF developed in 68 (37%). Kaplan-Meier bNED, MFS, curves are shown in Fig. 1.

In the univariate analyses, post-RP GS, pre-SRT PSA, pT stage, SVI, and detectable post-SRT PSA were statistically significant prognostic factors for BcF. In the multivariate analyses for BcF, statistical significance was found for the same variables as in the univariate analysis, except for pT stage. In the multivariate analysis for metastases, only SVI was found to be significant (Table III). After a logistic regression, pre-SRT PSA was a positive prognostic factor for BcF (p<0.001, OR 5.48 95% CI 2.27; 13.23). The area under the curve was 0.68 (95% CI 0.61; 0.75), and the z-test statistic 4.30 (p<0.001).

Grade 1–2 acute toxicities were observed in the GU and the GI region in 100 (54%) and 132 (72%) patients, respectively, and the former proportion, tended to diminish over time (Fig. 2). Corresponding proportions showing RTOG acute toxicity grade 3–4 were observed 5 (3%) and 0 (0%) patients, respectively. An increment in the frequency of grade over time was observed for both GU and GI toxicity, although it was more evident for the former. At the 2- and 5-year follow-ups, respectively, the numbers of patients with grade 3–4 toxicities were 1 (1%) and 5 (5%) as regards the GI tract, and 5 (3%) and 11 (9%) as regards the GU region.

The CCIAA score was low/medium for 115 (63%) patients and high for 69 (38%). No statistically significant association was found between RTOG toxicity and CCIAA scores (Table II).

In Table IV, the results for each domain of the two questionnaires are shown together with predicted values for the general population in Sweden and values obtained in a Swedish long-term follow-up of men with localized prostate cancer ≥5 years after brachytherapy (18,19).

 Discussion

One of the aims of the present study was to identify prognostic variables for patients who may derive long-term benefit from SRT at a dose of 70 Gy combined with short-term NHT. Stephenson et al(16) analyzed retrospectively the outcome of 501 patients who were treated with SRT at five different academic centres with a median follow-up of 45 months. These patients had received a heterogeneous pelvic radiation dose (PRD) with a mean absorbed dose of 64.8 Gy. In that study, GS 8–10, pre-SRT PSA >2.0 ng/ml, positive surgical margins, PSADT ≤10 months, and SVI were all significant predictors of disease progression. In the present study, 184 consecutive patients were included in the study and treated with SRT at a single institution with a homogeneous PRD and NHT (median 3 months). The median follow-up time was 48 months. None of the patients were lost to follow-up. Our results show that the significant factors for treatment failure were post-RP GS, pre-SRT PSA ≥1.0 ng/ml, SVI, and detectable post-SRT PSA, the latter in accordance with data presented by Wiegel et al(5). We interpret these findings as indicating that the importance of some of the poor prognostic factors identified by Stephenson and colleagues can be diminished by using higher SRT doses combined with short-term NHT.

Once post-RP BcF has been diagnosed, SRT remains the only potentially curative therapy (16). For SRT, the American Society for Therapeutic Radiology and Oncology consensus guidelines recommend the use of the highest dose of radiation that can be delivered with acceptable morbidity, and suggest a minimum of 64 Gy with conventional fractionation (20). However, doses >66.6 Gy have been described to result in decreased risk of BcF (21). With the advent of conformal radiotherapy techniques, the maximally tolerated and effective PRD for recurrent PCa is still unclear (22) and late toxicity, especially rectal, is the dose-limiting factor.

MacDonald et al(23) and Choo et al(24) have reported that PCa patients with palpable recurrence after RP respond poorly to SRT. In our study, this was not statistically significant as an independent prognostic factor and no difference between the patients with positive and negative pathological disease was detected as regards the risk of BcF or metastasis. However, this is difficult to compare, since the PRD used in previous studies have been lower and, in many instances, heterogeneous in terms of dosing and fractionation. Also, some other previous studies have indicated that routine biopsies taken at the anastomotic site before treatment are not advisable, since a negative biopsy does not exclude local recurrence, and a positive biopsy does not exclude systemic disease (21,25). Thus, it remains to be determined whether a negative or positive biopsy, with no evidence of metastatic disease, would change the treatment approach used in patients with BcF after RP. Nevertheless, in the present study, the PRD may have had an impact on DRE as a prognostic factor. Caution must be taken when interpreting these results due the following: the numbers of patients with positive and negative, respectively, DRE differed and both groups showed statistically significant differences in clinical characteristics (data not shown).

The current results demonstrate that a substantial proportion of patients in our study achieved a durable response in terms of bNED, despite having a high GS, advanced pT stage, positive DRE, positive surgical margins, rapid PSADT, and SVI, all of which have been considered to be incurable (Table V). In addition, our observations indicate 63% bNED (99% of those with still undetectable PSA), 99% PCa-specific survival, 95% OS, and 96% MFS at 4-year (median) follow-up. These findings are in contrast to the 4-year progression-free probability of 45% reported by Stephenson et al. The data concerning MFS in the present study have to be interpreted with caution since radiologic follow-up was not performed systematically and due to the fact that some patients actively asked for hormone therapy although metastatic disease could not be verified radiologically.

In a study by Tzou et al(26), mean radiation doses of 60–70 and ≥70 Gy were found to be associated with bNED in 25–57% and 58–67% of cases, respectively. The definition of BcF after RP has been a matter of debate. The American Urological Association and the European Association of Urology designate it as a PSA level of 0.2 ng/ml or higher, with a second confirmatory value of >0.2 ng/ml (27–29). The use of a too low PSA threshold for SRT involves the risk of over-treating patients. Some investigators have described that ≤50% of patients with a single PSA elevation <0.4 ng/ml after RP may be regarded as having stable non-progressive disease. This is based on the assumption that residual benign prostatic tissue might be responsible for the rise in PSA (16,30). However, recent data suggest that residual benign prostatic elements after RP are an unlikely source of elevated PSA (31), a finding which has led to a decision to administer early SRT at our institute.

The nomogram presented by Stephenson et al was used in the present study to compare the actual and the expected outcome of SRT. A substantially higher bNED was found in the present study, 63% at 4 years, compared with 53% at 3 years when using the Stephenson nomogram. The reasons for the improved outcome in our series may be explained by the use of a higher SRT total dose combined with the use of short-term NHT. However, there may also exist other plausible explanations for the discrepancies seen.

Stephenson et al(32) stated that the potential for morbidity associated with RT argues against indiscriminate use of this treatment in the salvage setting. The incidence of RTOG GI/GU grade 3–4 acute toxicity has been reported to be <4% (3,33–37), which is in agreement with the results obtained in the present series. GI/GU grade 1–2 and grade 3–4 late toxicities have been reported to occur in 5–20% and <4% of SRT patients, respectively (33–36,38). We observed GU/GI late toxicities as grade 1–2 in 23 and 9%, respectively, and as grade 3–4 in 9 and 5%, respectively. This slight increase in GU/GI complications is most probably dose-related. It may, thus, be possible to reduce the frequency of these toxicities further by the use of modern techniques such as intensity-modulated radiation therapy (IMRT) (39). Interestingly, the incidence of toxicity was not more pronounced in patients with a high, as compared with low/intermediate, CCIAA score. The occurrence of co-morbidity often influences the choice of treatment and it is generally agreed that men with severe comorbidities receive less aggressive treatment (40). To our knowledge, the present study is the first to describe the co-morbidity pattern and the influence of this in patients undergoing treatment with 70 Gy SRT + NHT.

The data presented in this report support the idea that patients with a rise in PSA after RP should be offered 70 Gy SRT with a curative intention. Although there are numerous reports concerning SRT, ours is one of the largest single-institution reports describing treatment using a high and homogeneous PRD + NHT, given to consecutive patients for a delimited period of time during which no major alterations were done in treatment policies. Androgen deprivation before radiotherapy has shown improvement in DSS and OS in patients with locally advanced and high risk tumours (41). The role for NHT in combination with SRT still unclear although recent data from other treatment series have, in addition to ours, shown promising results in patients undergoing SRT (42,43). The role for NHT in combination with SRT is currently being addressed in ongoing randomized studies.

The patients in the current investigation had slightly better scores on almost all items of the HRQoL (EORTC QLQ-C30) after 4-year follow-up compared with predicted values from an age-matched healthy population and the results presented by Wahlgren et al and Michelson et al(18,19). Surprisingly, sexual functioning was not poorer in patients evaluated in the present series. No statistical differences were found between patients with or without BcF, although some complications, such as diarrhoea, may be clinically relevant. The PR-25 results in our study show slightly higher negative impact than those presented by van Andel et al(15), a finding that was also more or less anticipated. To our knowledge, the present study is one of the largest that assesses long-term HRQoL in patients treated with SRT.

In conclusion, salvage radiotherapy with 70 Gy delivered in fractions of 2 Gy/day combined with a 3-month NHT results in long-term undetectable PSA in more than half of patients presenting with biochemical and/or clinical recurrence after radical prostatectomy.

The data obtained in the present study show that non-metastatic patients should not be routinely disqualified from receiving SRT although per se presenting with poor prognostic factors at surgery such as SVI and/or high GS or having a pre-SRT PSA level >1.0 ng/ml and/or a short pre-SRT PSADT. SRT combined with short-term NHT is associated with acceptable rectal-genitourinary toxicity. No obvious association was found between the occurrence of co-morbidity (assessed with CCIAA) and acute/long-term toxicities. The treatment can be safely delivered without any major negative effects on long-term QoL.

We would like to acknowledge Dr Hemming Johansson for biostatistical expertise. This study was supported by the Swedish Cancer Society, the National Council of Science and Technology (Consejo Nacional de Ciencia y Tecnologia, CONACyT), UANL, Radiumhemmets Research Funds, and The Af Jochnick Research Foundation.

 References PoundCRPartinAWEisenbergerMAChanDWPearsonJDWalshPCNatural history of progression after PSA elevation following radical prostatectomyJAMA281159115971999 WardJFBluteMLSlezakJBergstralhEJZinckeHThe long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomyJ Urol170187218762003 BollaMvan PoppelHColletteLPostoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)Lancet3665725782005 ThompsonIMTangenCMParadeloJAdjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term follow-up of a randomized clinical trialJ Urol1819569622009 WiegelTLohmGBottkeDAchieving an undetectable PSA after radiotherapy for biochemical progression after radical prostatectomy is an independent predictor of biochemical outcome - results of a retrospective studyInt J Radiat Oncol Biol Phys73100910162009 BuskirkSJPisanskyTMSchildSESalvage radiotherapy for isolated prostate specific antigen increase after radical prostatectomy: evaluation of prognostic factors and creation of a prognostic scoring systemJ Urol1769859902006 StephensonAJSlawinKMThe value of radiotherapy in treating recurrent prostate cancer after radical prostatectomyNat Clin Pract Urol190962004 MoreiraDMBanezLLPrestiJCJrPredictors of secondary treatment following biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital databaseBJU Int10528332010 OstPDe TroyerBFonteyneVOosterlinckWDe MeerleerGA matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancerInt J Radiat Oncol Biol Phys80131613222011 TrabulsiEJValicentiRKHanlonALA multi-institutional matched-control analysis of adjuvant and salvage postoperative radiation therapy for pT3-4N0 prostate cancerUrology72129813042008 CoxJDStetzJPajakTFToxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC)Int J Radiat Oncol Biol Phys31134113461995 CharlsonMEPompeiPAlesKLMacKenzieCRA new method of classifying prognostic comorbidity in longitudinal studies: development and validationJ Chronic Dis403733831987 ExtermannMMeasuring comorbidity in older cancer patientsEur J Cancer364534712000 AaronsonNKAhmedzaiSBergmanBThe European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncologyJ Natl Cancer Inst853653761993 van AndelGBottomleyAFossaSDAn international field study of the EORTC QLQ-PR25: a questionnaire for assessing the health-related quality of life of patients with prostate cancerEur J Cancer44241824242008 StephensonAJShariatSFZelefskyMJSalvage radiotherapy for recurrent prostate cancer after radical prostatectomyJAMA291132513322004 FayersPAaronsonNBjordalKGroenvoldMCurranDBottomleyAEORTC QLQ-C30 scoring manualEuropean Organization for Research and Treatment of Cancer3rd edition2001 MichelsonHBolundCNilssonBBrandbergYHealth-related quality of life measured by the EORTC QLQ-C30-reference values from a large sample of Swedish populationActa Oncol394774842000 WahlgrenTNilssonSLennernasBBrandbergYPromising long-term health-related quality of life after high-dose-rate brachytherapy boost for localized prostate cancerInt J Radiat Oncol Biol Phys696626702007 CoxJDGallagherMJHammondEHKaplanRSSchellhammerPFConsensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology ConsensusPanel J Clin Oncol1711551999 BernardJRJrBuskirkSJHeckmanMGSalvage radiotherapy for rising prostate-specific antigen levels after radical prostatectomy for prostate cancer: dose-response analysisInt J Radiat Oncol Biol Phys767357402010 KupelianPAWilloughbyTRReddyCAKleinEAMahadevanAHypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experienceInt J Radiat Oncol Biol Phys68142414302007 MacDonaldOKSchildSEVoraSSalvage radiotherapy for men with isolated rising PSA or locally palpable recurrence after radical prostatectomy: do outcomes differ?Urology647607642004 ChooRMortonGDanjouxCHongESzumacherEDeBoerGLimited efficacy of salvage radiotherapy for biopsy confirmed or clinically palpable local recurrence of prostate carcinoma after surgeryRadiother Oncol741631672005 NeulanderEZSolowayMSFailure after radical prostatectomyUrology6130362003 TzouKTanWWBuskirkSTreatment of men with rising prostate-specific antigen levels following radical prostatectomyExpert Rev Anticancer Ther111251362011 Boccon-GibodLDjavanWBHammererPManagement of prostate-specific antigen relapse in prostate cancer: a European ConsensusInt J Clin Pract583823902004 CooksonMSAusGBurnettALVariation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomesJ Urol1775405452007 HeidenreichAAusGBollaMEAU guidelines on prostate cancerEur Urol5368802008 AmlingCLBergstralhEJBluteMLSlezakJMZinckeHDefining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point?J Urol165114611512001 GodoyGTareenBULeporHDoes benign prostatic tissue contribute to measurable PSA levels after radical prostatectomy?Urology741671702009 StephensonAJScardinoPTKattanMWPredicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomyJ Clin Oncol25203520412007 CattonCGospodarowiczMWardePAdjuvant and salvage radiation therapy after radical prostatectomy for adenocarcinoma of the prostateRadiother Oncol5951602001 KatzMSZelefskyMJVenkatramanESFuksZHummerALeibelSAPredictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancerJ Clin Oncol214834892003 MaierJFormanJTekyi-MensahSBoltonSPatelRPontesJESalvage radiation for a rising PSA following radical prostatectomyUrol Oncol2250562004 PacholkeHDWajsmanZAlgoodCBMorrisCGZloteckiRAPostoperative adjuvant and salvage radiotherapy for prostate cancer: impact on freedom from biochemical relapse and survivalUrology649829862004 ValicentiRKGomellaLGIsmailMDurable efficacy of early postoperative radiation therapy for high-risk pT3N0 prostate cancer: the importance of radiation doseUrology52103410401998 AnscherMSCloughRDodgeRRadiotherapy for a rising prostate-specific antigen after radical prostatectomy: the first 10 yearsInt J Radiat Oncol Biol Phys483693752000 AlongiFFiorinoCCozzariniCIMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients treated with post-operative adjuvant or salvage radiotherapy after radical prostatectomyRadiother Oncol932072122009 BerglundAGarmoHTishelmanCHolmbergLStattinPLambeMComorbidity, treatment and mortality: a population based cohort study of prostate cancer in PCBaSe SwedenJ Urol1858338402011 WidmarkAKleppOSolbergAEndocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trialLancet3733013082009 ChooRDanjouxCGardnerSEfficacy of salvage radiotherapy plus 2-year androgen suppression for postradical prostatectomy patients with PSA relapseInt J Radiat Oncol Biol Phys759839892009 PaiHHEldridgeBBishopDDoes neoadjuvanthormone therapy improve outcome in prostate cancer patients receiving radiotherapy after radical prostatectomy?Can J Urol16454145522009 Figures and Tables

Metastasis-free and bNED survival curves. Patients with BcF had a median bNED period of 30 months (4–88).

Gastrointestinal (GI) and genitourinary (GU) RTOG toxicity after ≤7 years of follow-up.

Baseline clinical characteristics.

Characteristics No. (%)a
Total no. of patients 184
Pre-prostatectomy age, median (range), ng/ml 64 (39–77)
Pre-prostatectomy PSA level, median (range), ng/ml 9.5(1.8–48)
  PSA <10 101 (55)
  PSA 10–20 68 (37)
  PSA >20 15 (8)
Pathological stage
  pT2 63 (34)
  pT3 121 (66)
Gleason score after radical prostatectomy
  ≤6 42 (23)
  7 112 (61)
  8–10 30 (16)
Digital rectal examination
  Positive 46 (25)
  Biopsy 35 (76)
  Positive 10 (29)
Pre-radiotherapy PSA level, median (range), ng/ml 0.47 (0.1–6.3)
PSA doubling time, median (range), months 6 (0.4–78)
PSA doubling time <10 months 134 (73)
Positive surgical margins 121 (66)
Seminal vesicle invasion 40 (22)
Disease-free interval between prostatectomy and radiotherapy, median (range), months 14 (2–89)
Persistent detectable PSA level after radical prostatectomy 85 (46)
Neoadjuvant androgen deprivation therapy before salvage radiotherapy 165 (90)
Radiation dose 70 Gy
  Entire seminal vesicles 78 (43)
  Shrinking field after 54 Gy 87 (47)
  Only prostate bed 19 (10)
Follow-up after radiotherapy, median (range), months 48 (12–92)

PSA, prostate-specific antigen.

Except where otherwise indicated.

Association of rectal (GI)/genitourinary (GU) toxicity and comorbidities based on the RTOG toxicity score and the Charlson co-morbidity index adjusted for age (CCIAA) at different time-points.

GU RTOG score CCIAA L/M n (%) CCIAA High n (%) p-value GI RTOG score CCIAA L/M n (%) CCIAA High n (%) p-value
Acute 0 48 (42) 31(45) 0.75 Acute 0 28 (24) 24 (35) 0.13
Acute 1–2 65 (57) 36 (52) 0.64 Acute 1–2 87 (76) 45 (65) 0.13
Acute 3–4 2 (2) 2 (3) 0.63 Acute 3–4 0 0
At 2 years 0 89 (77) 42 (61) 0.01 At 2 years 0 88 (77) 52 (75) 0.86
At 2 years 1–2 24 (21) 24 (35) 0.06 At 2 years 1–2 27 (23) 15 (22) 0.85
At 2 years 3–4 2 (2) 3 (4) 0.36 At 2 years 3–4 0 (0) 2 (3) 0.13
At 5 years 0 48 (72) 27 (60) 0.22 At 5 years 0 56 (86) 39 (87) 1.00
At 5 years 1–2 13 (19) 13 (29) 0.26 At 5 years 1–2 6 (9) 4 (9) 1.00
At 5 years 3–4 6 (9) 5 (11) 0.75 At 5 years 3–4 3 (5) 2 (4) 1.00

GU/GI toxicity was graded 0–4 (RTOG/EORTC scale) (11). For further comparisons, patients were divided into three subgroups, with grades 0, 1–2, and 3–4, respectively. Prevalence of the highest toxicity score during different time frames was recorded. Toxicity was considered to be late if it occurred at >6 months after SRT, and acute if it arose earlier. Any post-RP GU symptoms were recorded only if they had become worse after SRT. The Charlson co-morbidity index (CCI) evaluates 19 conditions (12). To calculate the CCI, a weight to each disease category is assigned, based on all discharge diagnoses (KS database) that were present before and/or during the SRT. The cancer variable was weighted when a second malignancy was present (13). To adjust for age, each decade (starting at 50 years) was counted as an extra point. Weights were summed, and a total score was obtained (12). Two subgroups were delineated for further comparisons: 0–2 and ≥3 as low/medium and high scores, respectively. L/M, low-medium score.

Univariate and multivariate regression analysis.

Univariate Stephenson et al(16)
Present study
HR 95% CI p-value HR 95% CI p-value
Pre-prostatectomy PSA level, ng/ml >10 0.04 0.90 0.55; 1.45 0.66
Gleason score <0.001 0.39 0.23; 0.68 <0.001
Pre-radiotherapy PSA level <0.001 0.39 0.23; 0.67 <0.001
Surgical margins 0.002 1.13 0.69; 1.85 0.48
PSA doubling time, <10 months <0.001 0.80 0.45; 1.43 0.44
Seminal vesicle invasion <0.001 0.41 0.25; 0.67 <0.001
Extracapsular extension (pathological T stage) 0.07 0.56 0.32; 0.99 0.046
Lymph node involvement 0.12 -
Disease-free interval, <12 months 0.31 1.01 0.62; 1.65 0.95
Detectable PSA after radical prostatectomy 0.005 0.73 0.45; 1.18 0.20
NHT prior to salvage radiotherapy 0.77 0.84 0.40; 1.78 0.60
Radiotherapy dose 0.24 -
Detectable PSA after SRT - 4.96 1.36; 18.53 <0.001
Multivariate Stephenson et al(16)
Present study (BcF, stepwise)
Present study (Mets, stepwise)
HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value
Positive DRE - NS NS
Pre-prostatectomy PSA level, ng/ml >10 1.1 0.8; 1.4 0.73 NS NS
Gleason score 7 1.5 0.98; 2.2 0.06 - -
Gleason score 8–10 2.6 1.7; 4.1 <0.001 2.06 1.15; 3.67 0.015 NS
Pre-radiotherapy PSA level 1–2 1.2 0.8; 1.7 0.31 2.07 1.20; 3.56 0.009 NS
Pre-radiotherapy PSA level >2 2.3 1.7; 3.2 <0.001 - -
Surgical margins 1.9 1.4; 2.5 <0.001 NS NS
PSA doubling time, <10 months 1.7 1.2; 2.2 0.001 NS NS
Seminal vesicle invasion 1.4 1.1; 1.9 0.02 1.92 1.14; 3.23 0.015 18.20 2.21; 149.83 0.007
Extracapsular extension (pathological T stage) 1.2 0.9; 1.6 0.21 NS NS
Lymph node involvement 1.5 0.7; 3.0 0.32 NS NS
Disease-free interval, <12 months 1.0 0.7; 1.3 0.71 NS NS
Detectable PSA after radical prostatectomy - NS NS
NHT prior to salvage radiotherapy 0.8 0.5; 1.1 0.16 NS NS
Radiotherapy dose 1.0 0.7; 1.3 0.96 - -
Detectable PSA after SRT - 3.38 1.64; 6.96 0.001 NS

NS, not significant.

Total, predicted values (PV), bNED, and BcF: patients’ mean scores on the various items of the quality of life and prostate-specific questionnaires vs reference values.

QLQ-C30 Total n=144
PV bNED n=91
BcF n=53
p-value Reference values
Mean 95% CI Mean 95% CI Mean 95% CI Wahlgren et al(19) Michelson et al(18)
QL2 77.9 (74.7–81.1) 77.2 78.0 (74.1–81.9) 77.7 (71.8–83.6) 0.71 75.9 (72.4–79.3) 76.6 (76.6–76.7)
PF2 91.6 (89.4–93.9) 87.8 92.3 (90.6–95.2) 89.4 (84.7–94.2) 0.54 90.4 (87.8–93.0) 83.7 (83.2–84.2)
RF2 91.4 (88.1–94.8) 86.1 94.0 (90.8–97.1) 87.1 (79.7–94.5) 0.32 89.8 (86.5–93.1) 83.9 (83.6–84.2)
EF 86.9 (83.8–90.1) 86.0 89.6 (86.5–92.7) 82.3 (75.7–89.0) 0.12 87.0 (83.9–90.1) 87.5 (97.3–87.7)
SF 81.8 (77.8–85.9) 90.3 84.6 (80.4–88.8) 77.0 (68.5–85.6) 0.44 84.3 (80.7–87.9) 89.5 (89.4–89.6)
FA 16.8 (13.5–20.1) 19.3 14.8 (11.1–18.4) 20.3 (13.7–27.0) 0.30 19.1 (15.7–22.5) 20.8 (20.6–21.0)
PA 9.4 (6.0–12.8) 18.2 8.6 (4.5–12.7) 10.7 (4.4–16.9) 0.63 10.2 (7.1–13.3) 18.8 (18.7–18.9)
SL 16.2 (12.3–20.1) 15.2 15.4 10.8–19.9) 17.6 (10.1–25.2) 0.98 21.6 (17.5–25.7) 13.1 (12.8–13.5)
CO 7.4 (4.6–10.2) 4.1 7.0 (3.2–10.8) 8.2 (3.8–12.6) 0.28 7.7 (4.8–10.7) 5.8 (5.6–6.0)
DI 7.9 (5.0–10.7) 4.7 5.5 (2.7–8.3) 11.9 (5.7–18.2) 0.08 10.8 (7.5–14.1) 4.4 (4.3–4.4)
PR-25 Total n Mean 95% CI bNED n Mean 95% CI BcF n Mean 95% CI p-value Reference values Van Andel et al(15)
URI 140 24.7 (21.2–28.8) 91 24.0 (19.8–28.2) 49 25.9 (19.3–32.5) 0.51 22.7
AID 42 29.4 (19.6–39.1) 22 24.2 (11.2–37.3) 20 35.0 (18.6–51.4) 0.31 22.6
BOW 142 9.4 (7.2–11.7) 89 9.1 (6.8–11.4) 53 10.1 (5.4–14.8) 0.55 5.4
HTS 144 16.3 (14.3–18.4) 91 15.2 (13.0–17.3) 53 18.3 (13.9–22.8) 0.65 11.9
SAC 144 31.6 (27.6–35.6) 91 31.1 (26.0–36.2) 53 32.4 (25.4–39.3) 0.72 27.8
SFU 89 50.4 (46.0–54.8) 56 52.1 (46.3–58.0) 33 47.5 (40.4–54.5) 0.42 53.6

The QLQ-C30 is a questionnaire that explores functional areas and global health status. It also includes multi-item scales and single items that assess physical symptoms as well as financial difficulties Each item is scored in four categories (except for the the global QoL scale) and range from 1 to 7. EORTC QLQ-PR25 is a 25-item questionnaire designed for use in patients with localized and metastatic PCa (15). This instrument includes subscales that assess urinary symptoms, bowel symptoms, treatment-related symptoms, and sexual functioning. Responses are given in four categories as in QLQ-C30. Abbreviations for the HRQoL QLQ-C30 questionnaire core module: CI, confidence interval; GH, global health status; PF, physical functioning; RF, role functioning; EF, emotional functioning; SF, social functioning; FA, fatigue; PA, pain; SL, sleep disturbance; CO, constipation; DI, diarrhea. Abbreviations for the PR-25 (prostate specific): URI, urinary symptoms; AID, incontinence aid; BOW, bowel symptoms; HTR, hormonal treatment-related symptoms; SAC, sexually active; SFU, sexual functioning. A higher mean score for functional scales and general health reflects a better level of functioning, and whereas a higher mean score for symptoms indicates more problems. Cognitive functioning, nausea and vomiting, dyspnoea, loss of appetite, financial difficulties were excluded from the analysis because they were not considered relevant for the study group.

Proportion of patients with poor prognostic factors who still had undetectable PSA values after SRT.

DRE + Biopsy + SV + Gleason 8–10 pre-SRT PSA >1 PSADT <10
Total n 46 10 40 29 31 134
Undetectable PSA, n (%) 25 (54.3) 6 (60) 17 (42.5) 13 (44.8) 11 (35.5) 80 (59.7)
Median follow-up (months)
Total (range) 50 (12–92) 41 (30–83) 54 (28–92) 42 (13–90) 46 (24–92) 50 (1–92)
Median follow-up (months)
Patients with undetectable 44 (12–79) 38 (30–42) 55 (17–83) 42 (13–83) 44 (41–64) 49 (13–84)
PSA (range)