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Prostate-specific antigen kinetics following external-beam radiotherapy and temporary (Ir-192) or permanent (I-125) brachytherapy for prostate cancer
Radiotherapy and Oncology 96 (2010) 25–29
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Prostate brachytherapy
Prostate-specific antigen kinetics following external-beam radiotherapy and temporary (Ir-192) or permanent (I-125) brachytherapy for prostate cancer Michael Pinkawa a,*, Marc D. Piroth a, Richard Holy a, Karin Fischedick a, Sandra Schaar a, Holger Borchers b, Axel Heidenreich b, Michael J. Eble a a
Department of Radiation Oncology; and b Department of Urology, RWTH Aachen University, Aachen, Germany
a r t i c l e
i n f o
Article history: Received 19 August 2009 Received in revised form 21 December 2009 Accepted 14 February 2010 Available online 16 March 2010 Keywords: Prostate cancer Radiotherapy Brachytherapy Ir-192 I-125 Prostate-specific antigen Hormone therapy
a b s t r a c t Background and purpose: The aim of the study was the evaluation of PSA kinetics after different radiotherapy methods. Materials and methods: Two-hundred and ninety five patients received external-beam radiotherapy (EBRT; 70.2 Gy; n = 135), Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18 Gy + 50.4 Gy; n = 66) or I-125 brachytherapy (LDR-BT; 145 Gy; n = 94) as monotherapy. ‘‘PSA bounce” was defined as a PSA rise of P0.2 ng/ml followed by spontaneous return to prebounce level or lower, biochemical failure as ‘‘nadir + 2 ng/ml”. Results: Patients without biochemical failure reached a lower nadir after brachytherapy (median 60.05 ng/ml after LDR- and HDR-BT without NHT) in comparison to EBRT (0.55 ng/ml without NHT; p < 0.01). Not a single patient without NHT and a nadir <0.1 ng/ml failed biochemically (0% vs. 45% with a nadir P0.1 ng/ml; p < 0.01). PSA bounces were found predominantly in the LDR-BT group (42% vs. 23%/ 20% after HDR-BT/EBRT; p < 0.01). In a multivariate Cox regression analysis, LDR-BT and HDR-BT were associated with a significantly lower biochemical failure rate in comparison to EBRT. Conclusions: PSA kinetics differ significantly following different radiotherapy methods. A lower nadir and a higher biochemical control rate suggest a higher radiobiological efficiency of brachytherapy in comparison to EBRT (with a dose of 70.2 Gy). Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 96 (2010) 25–29
Prostate-specific antigen (PSA) is a cornerstone in the follow-up of prostate cancer patients after definitive therapy. Biochemical recurrence antedates metastatic disease progression and prostate cancer-specific mortality by an average of 7 and 15 years [1,2]. It is widely used as an early end point to assess treatment success and frequently prompts the initiation of secondary therapy. Following radical prostatectomy, PSA values >0.2 ng/ml are regarded as recurrent cancer [3]. Following radiotherapy (RT), a nadir is often reached after several months or years [4]. PSA kinetics in the first years after RT are sometimes difficult to interpret. Patients and their physicians fear recurrences in case of rising PSA values, though ‘‘PSA bounces” – temporary rising PSA values with subsequent decline – have not been shown to have a negative prognostic impact [5–8]. To ensure consistent reporting and comparison of treatment efficacy after radiotherapy, the American Society for Therapeutic Radiology and Oncology (ASTRO) provided a definition of biochemical failure after radiotherapy in 1997, based on three consecutive increases in PSA after a nadir [9]. This definition was * Corresponding author. Address: Department of Radiation Oncology, RWTH Aachen University, Aachen, Germany. E-mail address: [email protected] (M. Pinkawa). 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.02.010
not linked to clinical progression or survival. Despite the fact that the ASTRO definition was not developed using data from series using hormonal therapy or brachytherapy (BT), this definition came to be applied in both of these settings as well. The second definition, so-called ‘‘Phoenix definition” – a rise by 2 ng/ml or more above the nadir PSA – considered clinical outcomes in several larger patient series after external-beam radiotherapy (EBRT) and BT. It is recommended as the current standard definition for biochemical failure after RT with or without short-term hormonal therapy [10]. The most frequently used radiotherapeutic methods for prostate cancer are EBRT, interstitial permanent (LDR – low-dose-rate) BT and interstitial temporary (HDR – high-dose-rate) BT [3,11]. EBRT and BT are used as single or combined modalities. The choice of a specific method is frequently not evidence based and rather depends on the experience of a centre. Prospective randomized studies have demonstrated improved biochemical control rates of an EBRT dose escalation and an HDR-BT in combination with EBRT in comparison to EBRT alone. There is a lack of studies comparing PSA kinetics after different treatment methods with and without neoadjuvant hormonal therapy (NHT). Apart from the actual biochemical tumour control, it is
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PSA kinetics following radiotherapy
important to know the rate and magnitude of PSA bounces, the expected PSA nadir, the time to reach this nadir, and the predictive value of a specific nadir for long-term tumour control. These questions were in focus of this study.
median dose to the prostate in the reference point was 50.4 Gy at 1.8 Gy daily fractions. For EBRT without additional brachytherapy, the same technique was used up to a median dose of 70.2 Gy at 1.8 Gy fractions.
Materials and methods
Evaluation of PSA kinetics
Patients
All patients had a pre-treatment PSA measurement. The PSA levels were usually obtained every 3 or 4 months in the first 2 years and every 6 months thereafter. PSA failure (biochemical failure) was defined according to the RTOG-ASTRO Phoenix consensus [10]: (1) a rise by 2 ng/ml or more above the nadir PSA; (2) the date of failure determined ‘‘at call” (not backdated). An initiation of hormonal treatment after treatment was additionally counted as ‘‘PSA failure” for both definitions. The presence of a ‘‘PSA bounce” was defined as a PSA rise P0.2 ng/ml followed by spontaneous return to prebounce level or lower [8].
This study was based on 295 consecutive patients who were treated due to cT1-3N0M0 prostatic carcinoma with EBRT (n = 135), a combination of HDR-BT with EBRT (n = 66) or LDR-BT as monotherapy (n = 94) in the years 2000–2003. The indication for a specific treatment was frequently based on the patient’s and/or the referring urologist’s preference. Patients presenting for LDR-BT often came from long distances with a strong wish for this specific treatment. High risk patients were excluded from LDR-BT as monotherapy. Baseline patient characteristics are presented in Table 1.
Statistical analysis Treatment The referring urologist decided about the indication for NHT due to prognostic risk factors or to offer an immediate treatment before the decision for a definitive curative method. As a consequence, several different agents have been used: luteinizing hormone-releasing hormone (LHRH) agonists (3-monthly depot preparations) in 92 cases (58%), antiandrogens in 31 cases (20%), a combination of LHRH agonists and antiandrogens in 21 cases (13%) and an orchiectomy in 14 cases (9%). Hormonal therapy was only rarely continued after RT (n = 26; 9% – considering the total patient population). The prescription dose to the prostate for permanent LDR-BT was 145 Gy in accordance with international recommendations [17,18]. A median number of 54 sources with a median activity of 0.64 mCi has been implanted in a modified peripheral loading technique. An Ir-192 stepping source from an afterloader with a nominal activity of 370 GBq was used for temporary HDR-BT. All patients received two fractions to deliver 18 Gy to the prostate with 7 days between each fraction. Within three weeks after brachytherapy EBRT started. Three dimensional treatment plans were calculated using a four-field box technique with 15 MeV photons and a multi-leaf collimator. The PTV (planning target volume) was required to be enclosed by the 90% isodose relative to the ICRU (International Commission on Radiation Units and Measurements) reference point with a margin of 1.5 cm in the anterior/lateral and 1 cm in the craniocaudal and dorsal directions to the CTV (clinical target volume = prostate and seminal vesicles). Image guidance techniques for prostate localization have not been used. The total
Statistical analysis was performed using the SPSS 17.0 (SPSS, Chicago, Ill), software. Contingency table analysis with the chisquare test was performed to compare treatment groups with respect to categorical variables. The matched-pairs t-test was applied to determine longitudinal PSA changes. In forward stepwise multivariate analyses, different factors (pre-treatment PSA, NHT, radiotherapy technique, PSA failure) were tested for their significance concerning ‘‘PSA nadir <0.2 ng/ml” and ‘‘PSA bounce”. Kaplan–Meier analysis was used to determine bounce free and failure free survival. Comparisons between groups were made using the log-rank test. Prognostic factors (T stage, Gleason score, pre-treatment PSA), NHT and radiotherapy technique were furthermore tested for their significance concerning ‘‘PSA failure” in a multivariate Cox regression analysis. All p-values reported are two-sided, p < 0.05 is considered significant. Results PSA nadir Considering the PSA nadir, it is important to differentiate between patients with or without NHT and patients with and without a biochemical failure (BF). The first PSA measurement within three months after treatment was <0.5 ng/ml in 53% vs. 7% of patients (p < 0.01) with vs. without NHT. Patients without BF reached a significantly lower nadir following LDR-BT and HDR-BT in comparison to EBRT (Table 2), both with and without NHT. Focusing on patients without BF and without NHT, a continuous PSA decline could be seen in the first years after treatment only
Table 1 Baseline patients characteristics.
Patient age/years median (range) mean ± SD Follow-up period/months median (range) mean ± SD T stage >2a Gleason score >6 Primary PSA/ng/ml median (range) mean ± SD Low risk patientsa Intermediate risk patientsb High risk patientsc NHT NHT/months median (range) mean ± SD a b c
All (n = 295)
LDR-BT (n = 94)
HDR-BT (n = 66)
EBRT (n = 135)
71(49–83) 70 ± 6 72(7–101) 68 ± 18 21% 13% 9(1–300) 15 ± 26 43% 29% 29% 44% 4(1–28) 6 ± 5
69(49–81) 68 ± 7 76(8–101) 73 ± 17 5% 3% 7(1–15) 8 ± 3 65% 35% 0% 35% 3(1–8) 3 ± 2
72(63–81) 73 ± 5 75(7–98) 69 ± 23 36% 18% 13(1–300) 27 ± 47 27% 24% 49% 56% 5(1–28) 8 ± 8
71(52–83) 72 ± 6 67(9–97) 64 ± 16 25% 17% 10(1–150) 15 ± 17 35% 26% 39% 47% 5(1–18) 7 ± 5
No risk factors: PSA <10 ng/ml; Gleason score <7; cT-stage <2b. One risk factor: PSA 10–20 ng/ml or Gleason score = 7 or cT-stage = 2b/c. Two risk factors or PSA >20 ng/ml or Gleason score >7 or cT-stage >2b/c.
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M. Pinkawa et al. / Radiotherapy and Oncology 96 (2010) 25–29 Table 2 Prostate-specific antigen nadir (median/mean ± standard deviation).
Nadir without BF + without NHT
PSA/ng/ml
*
*
Time to nadir/months Nadir without BF + with NHT
PSA/ng/ml* Time to nadir/months*
Nadir with BF + without NHT
PSA/ng/ml *
Time to nadir/months Nadir with BF + with NHT
PSA/ng/ml Time to nadir/months*
*
All (n = 295)
LDR-BT (n = 94)
HDR-BT (n = 66)
EBRT (n = 135)
0.10 0.41 ± 0.90 35 39 ± 22
0.04 0.14 ± 0.27 44 45 ± 20
0.05 0.18 ± 0.30 46 45 ± 24
0.55 0.86 ± 1.34 23 29 ± 20
0.00 0.17 ± 0.37 14 22 ± 22
0.01 0.08 ± 0.14 4 17 ± 21
0.00 0.07 ± 0.12 30 35 ± 21
0.04 0.29 ± 0.51 7 17 ± 20
0.8 1.6 ± 3.6 15 18 ± 12
0.55 0.95 ± 0.82 12 14 ± 9
1.00 1.42 ± 1.59 25 25 ± 17
0.96 1.93 ± 4.52 15 17 ± 10
0.62 2.42 ± 4.25 6 10 ± 12
0.10 0.36 ± 0.52 9 14 ± 12
0.80 1.34 ± 1.59 5 11 ± 17
0.80 3.72 ± 5.42 5 9±9
p < 0.05.
after both BT treatments. The percentage of patients with a nadir <0.5 ng/ml or <0.2 ng/ml increased after BT, but it remained stable after EBRT (Fig. 1). The mean PSA after 3 years was still significantly higher in comparison to the PSA after 4 years following BT (LDR-BT: 0.37 vs. 0.18; p < 0.01; HDR-BT: 0.31 vs. 0.17; p < 0.01). Following EBRT, the mean PSA did not change considerably comparing values after 1 vs. 5 years (1.00 vs. 1.14; not significant). A nadir was reached much sooner with NHT, so that the percentage of patients with a nadir <0.5 ng/ml or <0.2 ng/ml was not increasing as clearly as without NHT (Table 2). Mean PSA was even increasing after EBRT (0.51 vs. 0.58 after 1 vs. 5 years; p = 0.03). A multivariate analysis demonstrates the independent influence of LDR-BT vs. EBRT, HDR-BT vs. EBRT, NHT and BF on the chances to reach a nadir <0.2 ng/ml (Table 3). The nadir was of a high prognostic relevance. All patients without NHT and a nadir <0.1 ng/ml remained free of a recurrence (0% vs. 45% with a nadir P0.1 ng/ml; p < 0.01 – with NHT: 10% vs. 63%; p < 0.01). Patients with a nadir <0.5 ng/ml remained free of recurrence in 87% (LDR-BT: 94%; HDR-BT: 83%; EBRT: 78%) and 77% (LDR-BT: 77%; HDR-BT: 74%; EBRT: 77%) without and with NHT.
PSA bounce PSA bounces were predominantly found following LDR-BT (42% vs. 23% after HDR-BT and 20% after EBRT; p < 0.01). The multivari-
Table 3 Significant factors for PSA nadir <0.2 ng/ml, PSA bounce and PSA failure in multivariate analysis. Hazard ratio
95% Confidence interval
p-value
PSA nadir <0.2 ng/ml LDR-BT vs. EBRT HDR-BT vs. EBRT NHT Biochemical failure
6.3 3.7 4.2 0.1
3.2–12 1.8–7.7 2.2–7.8 0.05–0.18
<0.01 <0.01 <0.01 <0.01
PSA bounce LDR-BT vs. HDR-BT LDR-BT vs. EBRT Biochemical failure
1.9 2.1 0.1
0.9–4.1 1.1–3.9 0.02–0.19
0.09 0.02 <0.01
PSA failure T stage >2a Gleason score >6 PSA LDR-BT vs. EBRT HDR-BT vs. EBRT
1.9 1.6 1.01 0.5 0.6
1.3–3.0 0.98–2.7 1.01–1.02 0.3–0.8 0.4–0.97
<0.01 0.06 <0.01 <0.01 0.04
ate analysis has shown LDR-BT vs. EBRT, LDR-BT vs. HDR-BT and BF to be independent predisposing factors for a bounce (Table 3). PSA bounces >1 ng/ml have been observed in 9%/3%/1% of patients following LDR-BT/HDR-BT/EBRT (p < 0.01). A PSA bounce has only rarely been observed for patients with BF, i.e. PSA did not reach the prior nadir after rising. Bounces were found mainly in the first 3 years after treatment (Fig. 2).
PSA failure
Fig. 1. Percentage of patients without hormonal therapy and without biochemical failure reaching PSA <0.2 ng/ml and <0.5 ng/ml after treatment.
For the total group, the biochemical control after 5 years (BC5) has been greater for low/intermediate risk patients (79%/76%) in comparison to high risk patients (41%; p < 0.01). BT treatment was associated with a significantly higher BC5 for low/intermediate risk patients (83% vs. 69%; p = 0.03; HDR-BT: 87%; LDR-BT: 81%). A difference between low and intermediate risk patients was not found after LDR-BT (BC5 of 81% and 81%) and EBRT (BC5 of 69% and 69%), but an advantage for low risk patients was found after HDR-BT (BC5 of 94% vs. 80%; p = 0.07). EBRT and HDR-BT were equally effective for high risk patients (BC5 of 40% vs. 42%). A learning curve seems to be important for the LDR-BT treatment: BC5 of 70%, 82%, 87% and 89% resulted for patients treated in the years 2000, 2001, 2002 and 2003, respectively. Apart from well established risk factors for prostate cancer (T stage, Gleason score,
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PSA kinetics following radiotherapy
Fig. 2. Probability of prostate-specific antigen bounce free follow-up.
PSA), LDR-BT and HDR-BT proved to be independent prognostic factors in comparison to EBRT, considering recurrence free survival (Table 3). Discussion PSA has become the standard measure of disease recurrence after radical prostatectomy, external-beam radiotherapy and brachytherapy. After radiotherapy, the prolonged time to radiation-induced prostate cancer cell death and the acceptance of various amounts of normal PSA-producing epithelium as being compatible with tumour control has led to a long and difficult search for a PSA-based definition of tumour control. Most efforts have concentrated on external-beam data, for which there is extensive experience with pooled data sets and long follow-up. ASTRO consensus and RTOG–ASTRO Phoenix consensus biochemical failure definitions are mainly based on these data [9,10]. There is a lack of studies comparing PSA kinetics after different treatment methods with and without NHT. In this study, several major differences have been demonstrated. After EBRT, the expected nadir cannot be as low as after LDR-BT or HDR-BT, even concerning patients without a biochemical tumour recurrence. The nadir in the population of patients without BF was already reached after a median time <24 months. The time to reach the nadir is much longer after BT. More patients reach a PSA <0.5 ng/ml after BT in comparison to EBRT already after 12 months. The percentage increases in the following years – the majority of patients presented with a PSA <0.2 ng/ml 36 months after BT. Fractionated treatment is associated with the rationale to increase the therapeutic ratio by destroying the malignant tumour but allowing normal tissue repair. After a fractionated treatment with a total dose of 70.2 Gy some normal prostate cells survive the treatment – as indirectly demonstrated in this study. The remaining PSA levels can exceed 0.5 ng/ml for many patients without major dynamics in several subsequent measurements over years – a high probability of complete tumour destruction. With increasing doses, tumour control probability increases. Several randomized dose escalation studies could well demonstrate this effect for prostate cancer patients concerning biochemical control [12–14]. Longer follow-up periods demonstrate a survival benefit for high risk patients or patients with initial PSA >10 ng/ml [15]. The increasing tumour control probability is associated with
increasing normal tissue complication probability, if the target volume remains unchanged. In our patient population, a lower nadir in the patient population without BF suggests a stronger effect on benign prostate cells, so that PSA is hardly detectable several years after LDR-BT or HDR-BT. With a longer cell cycle of benign cells in comparison to malignant cells, a mitotic cell death can ensue several years after radiation exposure, explaining the longer time to reach a PSA nadir. The effect on the PSA nadir has to be differentiated from the effect on PSA progression, namely a rise by 2 ng/ml above the nadir. The Cox regression analysis has demonstrated an advantage of LDR-BT and HDR-BT in comparison to EBRT, independently of well established prognostic parameters. As a consequence, a higher radiobiological efficiency has been demonstrated in respect of normal prostate tissue (PSA nadir for patients without BF) and malignant prostate cells (PSA failure). LDR-BT was predominantly applied for low risk patients – as recommended in current guidelines [16,17] – while a HDR-BT boost was used particularly for the high risk population. Patients of all risk groups were considered for EBRT. No differences have been shown for high risk patients between the HDR-BT and EBRT populations. For these patients, distant tumour spread can frequently occur, so that – depending on the patient selection – local tumour control might not have an impact on the actual cure. There was no absolute PSA limit in our patient population (49%/63% of high risk patients treated with EBRT/ HDR-BT as a boost to EBRT with initial PSA >20 ng/ml), so that distant failures were presumably an important factor for relatively low biochemical control rates <50% after 5 years. Prospective randomized studies evaluating EBRT vs. HDR-BT as a boost to EBRT demonstrated improved biochemical tumour control rates with the application of HDR-BT [18,19], comparably to the EBRT dose escalation studies [12–14]. Thus, dose escalation can be performed by increasing the total EBRT dose or by applying BT as a method of reaching very high doses in the prostate – with a steeply declining dose in the vicinity of the target volume. Applying the linear-quadratic model with an alpha/beta ratio of 3 for prostate cancer, the dose of the combined EBRT and HDR-BT treatment – as used in this study – corresponds to a dose exceeding 90 Gy in 1.8 Gy fractions. A total dose of 70.2 Gy for EBRT appears to be insufficient nowadays, comparably to the EBRT dose schedules in the mentioned randomized studies comparing EBRT with HDR-BT as a boost to EBRT (50 Gy in 20 fractions [18] and 66 Gy in 33 fractions [19]). Associated with improved biochemical control rates, lower PSA nadir values could also be expected after higher EBRT doses. PSA bounces have been predominantly reported after LDR-BT in the literature [7–9,20–22]. Actual PSA bounce rates can differ considerably in dependence on the definition used [5]. In our definition, a decrease at least to the PSA level before the spike was required. In other definitions, the required rise can vary (between 0.1 and 0.5 ng/ml). Furthermore, any decline or a decline >0.2 ng/ ml is required after the transient PSA maximum [5,6,8,23]. Using the same definition for all treatment groups, we could demonstrate a considerably larger frequency of PSA bounces in the LDR-BT group in comparison to the HDR-BT or EBRT groups. PSA rises >1 ng/ml were found more frequently after LDR-BT. Similar comparisons of PSA bounce rates after different treatments are not available in the literature. PSA bounces can be idiopathic or induced by rising testosterone levels, for example after NHT, prostatitis, proctitis, recent instrumentation [4,5,20]. These factors have a strong impact in the first months after treatment (implantation causing local trauma, NHT often only until radiotherapy, inflammatory effects due to radiation) and explain the predominance of PSA bounces in the first three years after treatment. A prior study demonstrated temporarily rising PSA levels for most patients after primary radiotherapy
M. Pinkawa et al. / Radiotherapy and Oncology 96 (2010) 25–29
(BT and/or EBRT) and NHT. The highest values were found a median time of 16 months after treatment [4]. Thus, PSA values can be higher after one year in comparison to subsequent measurements. Local inflammatory effects may play a major role for the predominant induction of bounces after LDR-BT – even in contrast to HDRBT. PSA bounces do not have a negative impact on the prognosis [5–8]. Using the definition in this study (decline to the prebounce level or lower), patients with a bounce only rarely (5% of the total population) had a BF in the subsequent years. Conclusions PSA kinetics following treatment differ significantly between LDR-BT, HDR-BT with supplemental EBRT and EBRT as a single modality. A higher radiobiological efficiency of BT in comparison to EBRT (with a total dose of 70.2 Gy) has been demonstrated in respect of normal prostate tissue (lower PSA nadir for patients without BF) and malignant prostate cells (lower PSA failure rate). PSA bounces occur predominantly in the first three years after treatment, particularly after LDR-BT. References [1] Pound CR, Partin AW, Eisnberger MA, et al. Natural history of progression after PSA evaluation following radical prostatectomy. JAMA 1999;281:1591–7. [2] Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005;294:433–9. [3] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53:68–80. [4] Pinkawa M, Fischedick K, Piroth MD, et al. Prostate-specific antigen kinetics after brachytherapy or external beam radiotherapy and neoadjuvant hormonal therapy. Urology 2007;69:129–33. [5] Akyol F, Ozyigit G, Selek U, Karabulut E. PSA bouncing after short term anndrogen deprivation and 3D-conformal radiotherapy for localized prostate adenocarcinoma and the relationship with the kinetics of testosterone. Eur Urol 2005;48:40–5. [6] Sengoz M, Abacioglu U, Cetin I, Turkeri L. PSA bouncing after external beam radiation for prostate cancer with or without hormonal treatment. Eur Urol 2003;43:473–7. [7] Mitchell DM, Swindell R, Elliott T, et al. Analysis of prostate-specific antigen bounce after I125 permanent seed implant for localised prostate cancer. Radiother Oncol 2008;88:102–7.
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[8] Crook J, Gillan C, Yeung I, et al. PSA kinetics and psa bounce following permanent seed prostate brachytherapy. Int J Radiat Oncol Biol Phys 2007;69:426–33. [9] ASTRO Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1035–41. [10] Roach III M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG–ASTRO Phoenix consensus conference. Int J Radiat Oncol Biol Phys 2006;65:965–74. [11] Kovacs G, Potter R, Loch T, et al. GEC/ESTRO-EAU recommendations on temporary brachytherapy using stepping sources for localised prostate cancer. Radiother Oncol 2005;74:137–48. [12] Al-Mamgani A, van Putten WL, Heemsbergen WD, et al. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72:980–8. [13] Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:67–74. [14] Zietman AL, DeSilvio M, Slater JD, et al. Comparison of conventional-dose vs. high-dose radiation therapy in clinically localized adenocarcinoma of the prostate. JAMA 2005;294:1233–9. [15] Kuban DA, Levy LB, Tucker SL, et al. Long-term patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of the disease? Int J Radiat Oncol Biol Phys 2008;72:S93. [16] Salembier C, Lavagnini P, Nickers P, et al. Tumour and target volumes in permanent prostate brachytherapy: a supplement to the ESTRO/EAU/EORTC recommendations on prostate brachytherapy. Radiother Oncol 2007;83:3–10. [17] Ash D, Flynn A, Battermann J, et al. ESTRO/EAU/EORTC recommendations on permanent seed implantation for localized prostate cancer. Radiother Oncol 2000;57:315–21. [18] Hoskin PJ, Motohashi K, Bownes P, et al. High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial. Radiother Oncol 2007;84:114–20. [19] Sathya JR, Davis IR, Julian JA, et al. Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate. J Clin Oncol 2005;23:1192–9. [20] Das P, Chen MH, Valentine K, et al. Using the magnitude of PSA bounce after MRI-guided prostate brachytherapy to distinguish recurrence, benign precipitating factors, and idiopathic bounce. Int J Radiat Oncol Biol Phys 2002;54:698–702. [21] Merrick GS, Butler WM, Wallner KE, Galbreath RW, Anderson RL. Prostatespecific antigen spikes after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;54:450–6. [22] Patel C, Elshaikh MA, Angermeier K, et al. PSA bounce predicts early success in patients with permanent iodine-125 prostate implant. Urology 2004;63:110–3. [23] Zietman AL, Christodouleas JP, Shipley WU, et al. PSA bounces after neoadjuvant androgen deprivation and external beam radiation: impact on definitions of failure. Int J Radiat Oncol Biol Phys 2005;62:714–8.
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Prostate brachytherapy
Prostate-specific antigen kinetics following external-beam radiotherapy and temporary (Ir-192) or permanent (I-125) brachytherapy for prostate cancer Michael Pinkawa a,*, Marc D. Piroth a, Richard Holy a, Karin Fischedick a, Sandra Schaar a, Holger Borchers b, Axel Heidenreich b, Michael J. Eble a a
Department of Radiation Oncology; and b Department of Urology, RWTH Aachen University, Aachen, Germany
a r t i c l e
i n f o
Article history: Received 19 August 2009 Received in revised form 21 December 2009 Accepted 14 February 2010 Available online 16 March 2010 Keywords: Prostate cancer Radiotherapy Brachytherapy Ir-192 I-125 Prostate-specific antigen Hormone therapy
a b s t r a c t Background and purpose: The aim of the study was the evaluation of PSA kinetics after different radiotherapy methods. Materials and methods: Two-hundred and ninety five patients received external-beam radiotherapy (EBRT; 70.2 Gy; n = 135), Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18 Gy + 50.4 Gy; n = 66) or I-125 brachytherapy (LDR-BT; 145 Gy; n = 94) as monotherapy. ‘‘PSA bounce” was defined as a PSA rise of P0.2 ng/ml followed by spontaneous return to prebounce level or lower, biochemical failure as ‘‘nadir + 2 ng/ml”. Results: Patients without biochemical failure reached a lower nadir after brachytherapy (median 60.05 ng/ml after LDR- and HDR-BT without NHT) in comparison to EBRT (0.55 ng/ml without NHT; p < 0.01). Not a single patient without NHT and a nadir <0.1 ng/ml failed biochemically (0% vs. 45% with a nadir P0.1 ng/ml; p < 0.01). PSA bounces were found predominantly in the LDR-BT group (42% vs. 23%/ 20% after HDR-BT/EBRT; p < 0.01). In a multivariate Cox regression analysis, LDR-BT and HDR-BT were associated with a significantly lower biochemical failure rate in comparison to EBRT. Conclusions: PSA kinetics differ significantly following different radiotherapy methods. A lower nadir and a higher biochemical control rate suggest a higher radiobiological efficiency of brachytherapy in comparison to EBRT (with a dose of 70.2 Gy). Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 96 (2010) 25–29
Prostate-specific antigen (PSA) is a cornerstone in the follow-up of prostate cancer patients after definitive therapy. Biochemical recurrence antedates metastatic disease progression and prostate cancer-specific mortality by an average of 7 and 15 years [1,2]. It is widely used as an early end point to assess treatment success and frequently prompts the initiation of secondary therapy. Following radical prostatectomy, PSA values >0.2 ng/ml are regarded as recurrent cancer [3]. Following radiotherapy (RT), a nadir is often reached after several months or years [4]. PSA kinetics in the first years after RT are sometimes difficult to interpret. Patients and their physicians fear recurrences in case of rising PSA values, though ‘‘PSA bounces” – temporary rising PSA values with subsequent decline – have not been shown to have a negative prognostic impact [5–8]. To ensure consistent reporting and comparison of treatment efficacy after radiotherapy, the American Society for Therapeutic Radiology and Oncology (ASTRO) provided a definition of biochemical failure after radiotherapy in 1997, based on three consecutive increases in PSA after a nadir [9]. This definition was * Corresponding author. Address: Department of Radiation Oncology, RWTH Aachen University, Aachen, Germany. E-mail address: [email protected] (M. Pinkawa). 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.02.010
not linked to clinical progression or survival. Despite the fact that the ASTRO definition was not developed using data from series using hormonal therapy or brachytherapy (BT), this definition came to be applied in both of these settings as well. The second definition, so-called ‘‘Phoenix definition” – a rise by 2 ng/ml or more above the nadir PSA – considered clinical outcomes in several larger patient series after external-beam radiotherapy (EBRT) and BT. It is recommended as the current standard definition for biochemical failure after RT with or without short-term hormonal therapy [10]. The most frequently used radiotherapeutic methods for prostate cancer are EBRT, interstitial permanent (LDR – low-dose-rate) BT and interstitial temporary (HDR – high-dose-rate) BT [3,11]. EBRT and BT are used as single or combined modalities. The choice of a specific method is frequently not evidence based and rather depends on the experience of a centre. Prospective randomized studies have demonstrated improved biochemical control rates of an EBRT dose escalation and an HDR-BT in combination with EBRT in comparison to EBRT alone. There is a lack of studies comparing PSA kinetics after different treatment methods with and without neoadjuvant hormonal therapy (NHT). Apart from the actual biochemical tumour control, it is
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PSA kinetics following radiotherapy
important to know the rate and magnitude of PSA bounces, the expected PSA nadir, the time to reach this nadir, and the predictive value of a specific nadir for long-term tumour control. These questions were in focus of this study.
median dose to the prostate in the reference point was 50.4 Gy at 1.8 Gy daily fractions. For EBRT without additional brachytherapy, the same technique was used up to a median dose of 70.2 Gy at 1.8 Gy fractions.
Materials and methods
Evaluation of PSA kinetics
Patients
All patients had a pre-treatment PSA measurement. The PSA levels were usually obtained every 3 or 4 months in the first 2 years and every 6 months thereafter. PSA failure (biochemical failure) was defined according to the RTOG-ASTRO Phoenix consensus [10]: (1) a rise by 2 ng/ml or more above the nadir PSA; (2) the date of failure determined ‘‘at call” (not backdated). An initiation of hormonal treatment after treatment was additionally counted as ‘‘PSA failure” for both definitions. The presence of a ‘‘PSA bounce” was defined as a PSA rise P0.2 ng/ml followed by spontaneous return to prebounce level or lower [8].
This study was based on 295 consecutive patients who were treated due to cT1-3N0M0 prostatic carcinoma with EBRT (n = 135), a combination of HDR-BT with EBRT (n = 66) or LDR-BT as monotherapy (n = 94) in the years 2000–2003. The indication for a specific treatment was frequently based on the patient’s and/or the referring urologist’s preference. Patients presenting for LDR-BT often came from long distances with a strong wish for this specific treatment. High risk patients were excluded from LDR-BT as monotherapy. Baseline patient characteristics are presented in Table 1.
Statistical analysis Treatment The referring urologist decided about the indication for NHT due to prognostic risk factors or to offer an immediate treatment before the decision for a definitive curative method. As a consequence, several different agents have been used: luteinizing hormone-releasing hormone (LHRH) agonists (3-monthly depot preparations) in 92 cases (58%), antiandrogens in 31 cases (20%), a combination of LHRH agonists and antiandrogens in 21 cases (13%) and an orchiectomy in 14 cases (9%). Hormonal therapy was only rarely continued after RT (n = 26; 9% – considering the total patient population). The prescription dose to the prostate for permanent LDR-BT was 145 Gy in accordance with international recommendations [17,18]. A median number of 54 sources with a median activity of 0.64 mCi has been implanted in a modified peripheral loading technique. An Ir-192 stepping source from an afterloader with a nominal activity of 370 GBq was used for temporary HDR-BT. All patients received two fractions to deliver 18 Gy to the prostate with 7 days between each fraction. Within three weeks after brachytherapy EBRT started. Three dimensional treatment plans were calculated using a four-field box technique with 15 MeV photons and a multi-leaf collimator. The PTV (planning target volume) was required to be enclosed by the 90% isodose relative to the ICRU (International Commission on Radiation Units and Measurements) reference point with a margin of 1.5 cm in the anterior/lateral and 1 cm in the craniocaudal and dorsal directions to the CTV (clinical target volume = prostate and seminal vesicles). Image guidance techniques for prostate localization have not been used. The total
Statistical analysis was performed using the SPSS 17.0 (SPSS, Chicago, Ill), software. Contingency table analysis with the chisquare test was performed to compare treatment groups with respect to categorical variables. The matched-pairs t-test was applied to determine longitudinal PSA changes. In forward stepwise multivariate analyses, different factors (pre-treatment PSA, NHT, radiotherapy technique, PSA failure) were tested for their significance concerning ‘‘PSA nadir <0.2 ng/ml” and ‘‘PSA bounce”. Kaplan–Meier analysis was used to determine bounce free and failure free survival. Comparisons between groups were made using the log-rank test. Prognostic factors (T stage, Gleason score, pre-treatment PSA), NHT and radiotherapy technique were furthermore tested for their significance concerning ‘‘PSA failure” in a multivariate Cox regression analysis. All p-values reported are two-sided, p < 0.05 is considered significant. Results PSA nadir Considering the PSA nadir, it is important to differentiate between patients with or without NHT and patients with and without a biochemical failure (BF). The first PSA measurement within three months after treatment was <0.5 ng/ml in 53% vs. 7% of patients (p < 0.01) with vs. without NHT. Patients without BF reached a significantly lower nadir following LDR-BT and HDR-BT in comparison to EBRT (Table 2), both with and without NHT. Focusing on patients without BF and without NHT, a continuous PSA decline could be seen in the first years after treatment only
Table 1 Baseline patients characteristics.
Patient age/years median (range) mean ± SD Follow-up period/months median (range) mean ± SD T stage >2a Gleason score >6 Primary PSA/ng/ml median (range) mean ± SD Low risk patientsa Intermediate risk patientsb High risk patientsc NHT NHT/months median (range) mean ± SD a b c
All (n = 295)
LDR-BT (n = 94)
HDR-BT (n = 66)
EBRT (n = 135)
71(49–83) 70 ± 6 72(7–101) 68 ± 18 21% 13% 9(1–300) 15 ± 26 43% 29% 29% 44% 4(1–28) 6 ± 5
69(49–81) 68 ± 7 76(8–101) 73 ± 17 5% 3% 7(1–15) 8 ± 3 65% 35% 0% 35% 3(1–8) 3 ± 2
72(63–81) 73 ± 5 75(7–98) 69 ± 23 36% 18% 13(1–300) 27 ± 47 27% 24% 49% 56% 5(1–28) 8 ± 8
71(52–83) 72 ± 6 67(9–97) 64 ± 16 25% 17% 10(1–150) 15 ± 17 35% 26% 39% 47% 5(1–18) 7 ± 5
No risk factors: PSA <10 ng/ml; Gleason score <7; cT-stage <2b. One risk factor: PSA 10–20 ng/ml or Gleason score = 7 or cT-stage = 2b/c. Two risk factors or PSA >20 ng/ml or Gleason score >7 or cT-stage >2b/c.
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M. Pinkawa et al. / Radiotherapy and Oncology 96 (2010) 25–29 Table 2 Prostate-specific antigen nadir (median/mean ± standard deviation).
Nadir without BF + without NHT
PSA/ng/ml
*
*
Time to nadir/months Nadir without BF + with NHT
PSA/ng/ml* Time to nadir/months*
Nadir with BF + without NHT
PSA/ng/ml *
Time to nadir/months Nadir with BF + with NHT
PSA/ng/ml Time to nadir/months*
*
All (n = 295)
LDR-BT (n = 94)
HDR-BT (n = 66)
EBRT (n = 135)
0.10 0.41 ± 0.90 35 39 ± 22
0.04 0.14 ± 0.27 44 45 ± 20
0.05 0.18 ± 0.30 46 45 ± 24
0.55 0.86 ± 1.34 23 29 ± 20
0.00 0.17 ± 0.37 14 22 ± 22
0.01 0.08 ± 0.14 4 17 ± 21
0.00 0.07 ± 0.12 30 35 ± 21
0.04 0.29 ± 0.51 7 17 ± 20
0.8 1.6 ± 3.6 15 18 ± 12
0.55 0.95 ± 0.82 12 14 ± 9
1.00 1.42 ± 1.59 25 25 ± 17
0.96 1.93 ± 4.52 15 17 ± 10
0.62 2.42 ± 4.25 6 10 ± 12
0.10 0.36 ± 0.52 9 14 ± 12
0.80 1.34 ± 1.59 5 11 ± 17
0.80 3.72 ± 5.42 5 9±9
p < 0.05.
after both BT treatments. The percentage of patients with a nadir <0.5 ng/ml or <0.2 ng/ml increased after BT, but it remained stable after EBRT (Fig. 1). The mean PSA after 3 years was still significantly higher in comparison to the PSA after 4 years following BT (LDR-BT: 0.37 vs. 0.18; p < 0.01; HDR-BT: 0.31 vs. 0.17; p < 0.01). Following EBRT, the mean PSA did not change considerably comparing values after 1 vs. 5 years (1.00 vs. 1.14; not significant). A nadir was reached much sooner with NHT, so that the percentage of patients with a nadir <0.5 ng/ml or <0.2 ng/ml was not increasing as clearly as without NHT (Table 2). Mean PSA was even increasing after EBRT (0.51 vs. 0.58 after 1 vs. 5 years; p = 0.03). A multivariate analysis demonstrates the independent influence of LDR-BT vs. EBRT, HDR-BT vs. EBRT, NHT and BF on the chances to reach a nadir <0.2 ng/ml (Table 3). The nadir was of a high prognostic relevance. All patients without NHT and a nadir <0.1 ng/ml remained free of a recurrence (0% vs. 45% with a nadir P0.1 ng/ml; p < 0.01 – with NHT: 10% vs. 63%; p < 0.01). Patients with a nadir <0.5 ng/ml remained free of recurrence in 87% (LDR-BT: 94%; HDR-BT: 83%; EBRT: 78%) and 77% (LDR-BT: 77%; HDR-BT: 74%; EBRT: 77%) without and with NHT.
PSA bounce PSA bounces were predominantly found following LDR-BT (42% vs. 23% after HDR-BT and 20% after EBRT; p < 0.01). The multivari-
Table 3 Significant factors for PSA nadir <0.2 ng/ml, PSA bounce and PSA failure in multivariate analysis. Hazard ratio
95% Confidence interval
p-value
PSA nadir <0.2 ng/ml LDR-BT vs. EBRT HDR-BT vs. EBRT NHT Biochemical failure
6.3 3.7 4.2 0.1
3.2–12 1.8–7.7 2.2–7.8 0.05–0.18
<0.01 <0.01 <0.01 <0.01
PSA bounce LDR-BT vs. HDR-BT LDR-BT vs. EBRT Biochemical failure
1.9 2.1 0.1
0.9–4.1 1.1–3.9 0.02–0.19
0.09 0.02 <0.01
PSA failure T stage >2a Gleason score >6 PSA LDR-BT vs. EBRT HDR-BT vs. EBRT
1.9 1.6 1.01 0.5 0.6
1.3–3.0 0.98–2.7 1.01–1.02 0.3–0.8 0.4–0.97
<0.01 0.06 <0.01 <0.01 0.04
ate analysis has shown LDR-BT vs. EBRT, LDR-BT vs. HDR-BT and BF to be independent predisposing factors for a bounce (Table 3). PSA bounces >1 ng/ml have been observed in 9%/3%/1% of patients following LDR-BT/HDR-BT/EBRT (p < 0.01). A PSA bounce has only rarely been observed for patients with BF, i.e. PSA did not reach the prior nadir after rising. Bounces were found mainly in the first 3 years after treatment (Fig. 2).
PSA failure
Fig. 1. Percentage of patients without hormonal therapy and without biochemical failure reaching PSA <0.2 ng/ml and <0.5 ng/ml after treatment.
For the total group, the biochemical control after 5 years (BC5) has been greater for low/intermediate risk patients (79%/76%) in comparison to high risk patients (41%; p < 0.01). BT treatment was associated with a significantly higher BC5 for low/intermediate risk patients (83% vs. 69%; p = 0.03; HDR-BT: 87%; LDR-BT: 81%). A difference between low and intermediate risk patients was not found after LDR-BT (BC5 of 81% and 81%) and EBRT (BC5 of 69% and 69%), but an advantage for low risk patients was found after HDR-BT (BC5 of 94% vs. 80%; p = 0.07). EBRT and HDR-BT were equally effective for high risk patients (BC5 of 40% vs. 42%). A learning curve seems to be important for the LDR-BT treatment: BC5 of 70%, 82%, 87% and 89% resulted for patients treated in the years 2000, 2001, 2002 and 2003, respectively. Apart from well established risk factors for prostate cancer (T stage, Gleason score,
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PSA kinetics following radiotherapy
Fig. 2. Probability of prostate-specific antigen bounce free follow-up.
PSA), LDR-BT and HDR-BT proved to be independent prognostic factors in comparison to EBRT, considering recurrence free survival (Table 3). Discussion PSA has become the standard measure of disease recurrence after radical prostatectomy, external-beam radiotherapy and brachytherapy. After radiotherapy, the prolonged time to radiation-induced prostate cancer cell death and the acceptance of various amounts of normal PSA-producing epithelium as being compatible with tumour control has led to a long and difficult search for a PSA-based definition of tumour control. Most efforts have concentrated on external-beam data, for which there is extensive experience with pooled data sets and long follow-up. ASTRO consensus and RTOG–ASTRO Phoenix consensus biochemical failure definitions are mainly based on these data [9,10]. There is a lack of studies comparing PSA kinetics after different treatment methods with and without NHT. In this study, several major differences have been demonstrated. After EBRT, the expected nadir cannot be as low as after LDR-BT or HDR-BT, even concerning patients without a biochemical tumour recurrence. The nadir in the population of patients without BF was already reached after a median time <24 months. The time to reach the nadir is much longer after BT. More patients reach a PSA <0.5 ng/ml after BT in comparison to EBRT already after 12 months. The percentage increases in the following years – the majority of patients presented with a PSA <0.2 ng/ml 36 months after BT. Fractionated treatment is associated with the rationale to increase the therapeutic ratio by destroying the malignant tumour but allowing normal tissue repair. After a fractionated treatment with a total dose of 70.2 Gy some normal prostate cells survive the treatment – as indirectly demonstrated in this study. The remaining PSA levels can exceed 0.5 ng/ml for many patients without major dynamics in several subsequent measurements over years – a high probability of complete tumour destruction. With increasing doses, tumour control probability increases. Several randomized dose escalation studies could well demonstrate this effect for prostate cancer patients concerning biochemical control [12–14]. Longer follow-up periods demonstrate a survival benefit for high risk patients or patients with initial PSA >10 ng/ml [15]. The increasing tumour control probability is associated with
increasing normal tissue complication probability, if the target volume remains unchanged. In our patient population, a lower nadir in the patient population without BF suggests a stronger effect on benign prostate cells, so that PSA is hardly detectable several years after LDR-BT or HDR-BT. With a longer cell cycle of benign cells in comparison to malignant cells, a mitotic cell death can ensue several years after radiation exposure, explaining the longer time to reach a PSA nadir. The effect on the PSA nadir has to be differentiated from the effect on PSA progression, namely a rise by 2 ng/ml above the nadir. The Cox regression analysis has demonstrated an advantage of LDR-BT and HDR-BT in comparison to EBRT, independently of well established prognostic parameters. As a consequence, a higher radiobiological efficiency has been demonstrated in respect of normal prostate tissue (PSA nadir for patients without BF) and malignant prostate cells (PSA failure). LDR-BT was predominantly applied for low risk patients – as recommended in current guidelines [16,17] – while a HDR-BT boost was used particularly for the high risk population. Patients of all risk groups were considered for EBRT. No differences have been shown for high risk patients between the HDR-BT and EBRT populations. For these patients, distant tumour spread can frequently occur, so that – depending on the patient selection – local tumour control might not have an impact on the actual cure. There was no absolute PSA limit in our patient population (49%/63% of high risk patients treated with EBRT/ HDR-BT as a boost to EBRT with initial PSA >20 ng/ml), so that distant failures were presumably an important factor for relatively low biochemical control rates <50% after 5 years. Prospective randomized studies evaluating EBRT vs. HDR-BT as a boost to EBRT demonstrated improved biochemical tumour control rates with the application of HDR-BT [18,19], comparably to the EBRT dose escalation studies [12–14]. Thus, dose escalation can be performed by increasing the total EBRT dose or by applying BT as a method of reaching very high doses in the prostate – with a steeply declining dose in the vicinity of the target volume. Applying the linear-quadratic model with an alpha/beta ratio of 3 for prostate cancer, the dose of the combined EBRT and HDR-BT treatment – as used in this study – corresponds to a dose exceeding 90 Gy in 1.8 Gy fractions. A total dose of 70.2 Gy for EBRT appears to be insufficient nowadays, comparably to the EBRT dose schedules in the mentioned randomized studies comparing EBRT with HDR-BT as a boost to EBRT (50 Gy in 20 fractions [18] and 66 Gy in 33 fractions [19]). Associated with improved biochemical control rates, lower PSA nadir values could also be expected after higher EBRT doses. PSA bounces have been predominantly reported after LDR-BT in the literature [7–9,20–22]. Actual PSA bounce rates can differ considerably in dependence on the definition used [5]. In our definition, a decrease at least to the PSA level before the spike was required. In other definitions, the required rise can vary (between 0.1 and 0.5 ng/ml). Furthermore, any decline or a decline >0.2 ng/ ml is required after the transient PSA maximum [5,6,8,23]. Using the same definition for all treatment groups, we could demonstrate a considerably larger frequency of PSA bounces in the LDR-BT group in comparison to the HDR-BT or EBRT groups. PSA rises >1 ng/ml were found more frequently after LDR-BT. Similar comparisons of PSA bounce rates after different treatments are not available in the literature. PSA bounces can be idiopathic or induced by rising testosterone levels, for example after NHT, prostatitis, proctitis, recent instrumentation [4,5,20]. These factors have a strong impact in the first months after treatment (implantation causing local trauma, NHT often only until radiotherapy, inflammatory effects due to radiation) and explain the predominance of PSA bounces in the first three years after treatment. A prior study demonstrated temporarily rising PSA levels for most patients after primary radiotherapy
M. Pinkawa et al. / Radiotherapy and Oncology 96 (2010) 25–29
(BT and/or EBRT) and NHT. The highest values were found a median time of 16 months after treatment [4]. Thus, PSA values can be higher after one year in comparison to subsequent measurements. Local inflammatory effects may play a major role for the predominant induction of bounces after LDR-BT – even in contrast to HDRBT. PSA bounces do not have a negative impact on the prognosis [5–8]. Using the definition in this study (decline to the prebounce level or lower), patients with a bounce only rarely (5% of the total population) had a BF in the subsequent years. Conclusions PSA kinetics following treatment differ significantly between LDR-BT, HDR-BT with supplemental EBRT and EBRT as a single modality. A higher radiobiological efficiency of BT in comparison to EBRT (with a total dose of 70.2 Gy) has been demonstrated in respect of normal prostate tissue (lower PSA nadir for patients without BF) and malignant prostate cells (lower PSA failure rate). PSA bounces occur predominantly in the first three years after treatment, particularly after LDR-BT. References [1] Pound CR, Partin AW, Eisnberger MA, et al. Natural history of progression after PSA evaluation following radical prostatectomy. JAMA 1999;281:1591–7. [2] Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005;294:433–9. [3] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53:68–80. [4] Pinkawa M, Fischedick K, Piroth MD, et al. Prostate-specific antigen kinetics after brachytherapy or external beam radiotherapy and neoadjuvant hormonal therapy. Urology 2007;69:129–33. [5] Akyol F, Ozyigit G, Selek U, Karabulut E. PSA bouncing after short term anndrogen deprivation and 3D-conformal radiotherapy for localized prostate adenocarcinoma and the relationship with the kinetics of testosterone. Eur Urol 2005;48:40–5. [6] Sengoz M, Abacioglu U, Cetin I, Turkeri L. PSA bouncing after external beam radiation for prostate cancer with or without hormonal treatment. Eur Urol 2003;43:473–7. [7] Mitchell DM, Swindell R, Elliott T, et al. Analysis of prostate-specific antigen bounce after I125 permanent seed implant for localised prostate cancer. Radiother Oncol 2008;88:102–7.
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