Early observed transient prostate-specific antigen elevations on a pilot study of external beam radiation therapy and fractionated MRI guided High Dose Rate brachytherapy boost
© Singh et al; licensee BioMed Central Ltd. 2006
Received: 17 May 2006
Accepted: 16 August 2006
Published: 16 August 2006
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
There are over 200,000 new cases and nearly 30,000 deaths each year from prostate cancer . External beam radiation therapy (EBRT) and/or brachytherapy are mainstays of local therapy. Low dose rate (LDR) brachytherapy, with permanently implanted radioactive seeds, [2–6] and HDR brachytherapy, with temporarily implanted catheters, has been used to treat prostate cancer [7–10].
Prostate-specific antigen (PSA) is a sensitive measure of treatment outcome after radiotherapy (RT) for prostate cancer. When RT is successful, the PSA level falls. If RT fails, the PSA increases over time. Independent of treatment, there is some natural variation in PSA levels. Given this variability, different definitions of failure have been suggested [12–15]. Though no definition is definitively superior, the ASTRO definition of failure (3 consecutive rises in PSA over the last 9 months) has been used in many large prostate cancer trials. After failure, patients may consider salvage therapy, including additional local therapies or hormone therapy.
Regardless of the definition, elevations in the PSA that rise and subsequently fall without treatment make it difficult to distinguish an actual failure from a transient and self-limited elevation. Such transient elevations, or benign 'PSA bounces', after EBRT and/or LDR brachytherapy have been described[13, 14, 16–23]. However, there is limited data on this phenomena following HDR brachytherapy.
This analysis describes early observations of the incidence of transient PSA elevation following external beam and HDR brachytherapy for prostate cancer.
Eligibility and accrual
Patient and Treatment Characteristics
Patients Without PSA Bounce (n = 4)
Patients With PSA Bounce (n = 5)
Median Age (years)
Largest Field Treated
Whole Pelvis Treated
Prostate and Seminal Vesicles
Concurrent Hormone Therapy
T2b and greater tumor stage
PSA less than 10
MRI guided HDR brachytherapy
The MRI guided HDR brachytherapy technique has been previously described[25, 26]. Briefly, dwell time optimization was performed to achieve the following dosimetric parameters: target percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) >90%, urethral V150 <2% and V125 <20%, and rectal V75 <2%. If the above-defined dosimetric parameters were achieved, a dose of 1050 cGy was prescribed to the 100% isodose. If they were not achieved, but a urethral V150 <2%, and rectal V75 <5% were obtained, 950 cGy was prescribed to the 100% isodose line.
External Beam Radiation Therapy
Computed tomography simulation was performed 1 day after the first brachytherapy procedure with the patient in the supine position. The patient was instructed to void before simulation. CT images of the pelvis were obtained, and treatment planning for EBRT was performed. For those patients with high-risk localized disease (Gleason score ≥8, PSA ≥20 ng/mL, or Stage T3a or greater disease), the CTV included the prostate gland, seminal vesicles, and regional pelvic lymph nodes at risk. For all other patients with intermediate-risk localized disease, the CTV included the prostate gland and seminal vesicles. A planning target volume was obtained by adding a margin of 1.5 cm to the CTV. A dose of 4600 cGy was prescribed to the 100% isodose in 23 fractions, 200 cGy/d. During the last week of EBRT, or the week after EBRT, a second brachytherapy fraction was delivered in the same fashion.
Hormonal therapy (with leuprolide acetate injection for 2 to 7 months following 2 weeks of oral biclutamide) was permitted during the trial at the discretion of the patient and treating physician and administered in a neoadjuvant, concurrent, and adjuvant fashion. For the purposes of this analysis, the 2 patients who received greater than 7 months of adjuvant hormone therapy were excluded. Five patients received no hormone therapy and 4 patients received neo-adjuvant and concurrent hormonal therapy, which was discontinued after RT.
Definition of PSA bounce
Prostate-specific antigen (PSA) bounce was defined by a rise PSA values with a subsequent fall to levels less than the nadir or below 20% of the level of the maximum post-treatment PSA rise. The ability of 6 previously published definitions of biochemical failure to distinguish true failure from bounce were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO, definition 5 nadir + 2 ng/ml; and definition 6, nadir + 3 ng/ml.
On treatment and follow-up evaluations
Patients were seen by a physician weekly while on treatment. Upon completion of therapy, follow-up visits occurred at 6 weeks, 3 months, 6 months, then every 6 months until 3 years, then annually until 5 years. The Radiation Therapy Oncology Group toxicity grades were documented at each follow-up visit. Patients with rising PSA were given the option of having monthly PSA tests.
Summary statistics, such as sample proportions, means, and median values were used to describe the patient characteristics. A two-sided Fisher's exact test was used for comparing proportions across groups. A Wilcoxon rank sum test was used to compare medians across groups for continuous variables. All analyses were performed with MATLAB software (The Mathworks Inc, Natick, MA, USA).
The incidence false positive "failures" due to such transient PSA elevation was: 56% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
For the HDR brachytherapy implants, the following dosimetric parameters were evaluated: V100, V150, V200, urethra V100, urethra V125, prostate volume, number of catheters and catheter density. There were no significant differences between the group of patients who did and not experience a definition 1 transient PSA elevation.
This is the first paper to describe the incidence, amount, and duration of transient PSA elevations which subsequently fall without further treatment in patients treated with HDR brachytherapy and EBRT, with or without hormonal therapy. Multiple definitions of biochemical failure were used and all produced some false positives. The ASTRO definition of biochemical failure, one of the most common, had a 33% false positive rate.
Demanes et al, performed a review of 209 patients, without prior androgen suppression, treated with HDR-BT plus EBRT. Using a definition of failure with endpoints of local failure (determined by DRE or positive biopsy >2 years after treatment associated with PSA progression), distant failure, hormonal therapy, or a post-treatment PSA level >25 ng/mL, the authors reported 10 of 209 patients (4.8%) had false positive diagnoses of failure using the ASTRO definition. As in this study, Demanes et al found that the nadir plus 2 ng/ml definition correlated better with actual clinical outcome than the ASTRO definition. However, the authors did not further describe the nature of the amount or duration of PSA rise .
Rising PSA values after radiation therapy are worrisome for both patients and treating physicians. There is no clear evidence that very early initiation of salvage hormone therapy improves survival . However, survival is better when hormones are initiated prior to development of distant metastases or when PSA is less than 20 . Thus, there is an understandable desire to initiate salvage hormone therapy quickly prior to further potential advancement of disease.
Transient PSA elevations, which resolve without therapy, further complicate the decision to initiate salvage hormone therapy. Such transient elevations, or benign PSA bounces, after EBRT and/or LDR brachytherapy have been described [13, 14, 16–23]. The prognostic significance of PSA bounces following EBRT remains unclear [29, 30]. PSA bounces do not appear to negatively impact long term outcome following LDR brachytherapy [13, 19].
In a cohort of patients treated with LDR brachytherapy, using definition 1, Ciezki et al reported a 46% incidence of PSA bounce with a median time to occurrence of 15 months . Using bounce definition 1, we found a similar 55% incidence but all patients had experienced bounce by 12 months. Therefore, time to bounce following HDR may be faster than following LDR.
The present study is the first to report the details of transient PSA rises in a population treated with HDR brachytherapy and EBRT. The optimal PSA-based definition to predict ultimate failure remains elusive necessitating evaluation of new definitions. Such evaluations will be facilitated if, as done here, authors graphically report the duration and magnitude of the PSA elevation.
Some patients in our study also received limited duration androgen deprivation therapy which is known to produce a high incidence of PSA bounce. The small size of the present cohort combined with brief follow-up limits our ability to interrogate the causes and consequences of this PSA bounce.
We hope that our data will encourage reviews of larger databases of patients treated with HDR brachytherapy which will illuminate more optimal management thereby reducing both patient and physician anxiety.
This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and in collaboration with Nucletron.
- Greenlee RT, Hill-Harmon MB, Murray T, et al.: Cancer statistics, 2001. CA Cancer J Clin 2001, 51: 15-36.View ArticlePubMedGoogle Scholar
- Kumar PP, Bartone FF: Transperineal percutaneous I-125 implant of prostate. Urology 1981, 17: 238-240. 10.1016/0090-4295(81)90037-6View ArticlePubMedGoogle Scholar
- Ragde H, Blasko JC, Grimm PD, et al.: Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997, 80: 442-453. 10.1002/(SICI)1097-0142(19970801)80:3<442::AID-CNCR12>3.0.CO;2-XView ArticlePubMedGoogle Scholar
- Sylvester JE, Blasko JC, Grimm PD, et al.: Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys 2003, 57: 944-952. 10.1016/S0360-3016(03)00739-9View ArticlePubMedGoogle Scholar
- Merrick GS, Butler WM, Wallner KE, et al.: Variability of prostate brachytherapy pre-implant dosimetry: a multi-institutional analysis. Brachytherapy 2005, 4: 241-251. 10.1016/j.brachy.2005.05.002View ArticlePubMedGoogle Scholar
- Critz FA, Williams WH, Levinson AK, et al.: Simultaneous irradiation for prostate cancer: intermediate results with modern techniques. J Urol 2000, 164: 738-741. discussion 741–733 10.1016/S0022-5347(05)67293-XView ArticlePubMedGoogle Scholar
- Astrom L, Pedersen D, Mercke C, et al.: Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer. Radiother Oncol 2005, 74: 157-161. 10.1016/j.radonc.2004.10.014View ArticlePubMedGoogle Scholar
- Deger S, Boehmer D, Turk I, et al.: High dose rate brachytherapy of localized prostate cancer. Eur Urol 2002, 41: 420-426. 10.1016/S0302-2838(02)00016-7View ArticlePubMedGoogle Scholar
- Martinez AA, Gustafson G, Gonzalez J, et al.: Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 2002, 53: 316-327. 10.1016/S0360-3016(02)02733-5View ArticlePubMedGoogle Scholar
- Galalae RM, Martinez A, Mate T, et al.: Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer. Int J Radiat Oncol Biol Phys 2004, 58: 1048-1055. 10.1016/j.ijrobp.2003.08.003View ArticlePubMedGoogle Scholar
- Albertsen PC, Hanley JA, Penson DF, et al.: Validation of increasing prostate specific antigen as a predictor of prostate cancer death after treatment of localized prostate cancer with surgery or radiation. J Urol 2004, 171: 2221-2225. 10.1097/01.ju.0000124381.93689.b4View ArticlePubMedGoogle Scholar
- Cheung R, Tucker SL, Lee AL, et al.: Assessing the impact of an alternative biochemical failure definition on radiation dose response for high-risk prostate cancer treated with external beam radiotherapy. Int J Radiat Oncol Biol Phys 2005, 61: 14-19. 10.1016/j.ijrobp.2004.04.064View ArticlePubMedGoogle Scholar
- Ciezki JP, Reddy CA, Garcia J, et al.: PSA kinetics after prostate brachytherapy: PSA bounce phenomenon and its implications for PSA doubling time. Int J Radiat Oncol Biol Phys 2006, 64: 512-517. 10.1016/j.ijrobp.2005.07.960View ArticlePubMedGoogle Scholar
- Zietman AL, Christodouleas JP, Shipley WU: PSA bounces after neoadjuvant androgen deprivation and external beam radiation: impact on definitions of failure. Int J Radiat Oncol Biol Phys 2005, 62: 714-718. 10.1016/j.ijrobp.2004.11.020View ArticlePubMedGoogle Scholar
- Cox JGD, Kaplan R, et al.: Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997, 37: 1035-1041. 10.1016/S0360-3016(96)00584-6Google Scholar
- Critz FA, Williams WH, Levinson AK, et al.: Prostate specific antigen bounce after simultaneous irradiation for prostate cancer: the relationship to patient age. J Urol 2003, 170: 1864-1867. 10.1097/01.ju.0000091644.41330.2aView ArticlePubMedGoogle Scholar
- Critz FA, Williams WH, Benton JB, et al.: Prostate specific antigen bounce after radioactive seed implantation followed by external beam radiation for prostate cancer. J Urol 2000, 163: 1085-1089. 10.1016/S0022-5347(05)67698-7View ArticlePubMedGoogle Scholar
- Rosser CJ, Kamat AM, Wang X, et al.: Is patient age a factor in the occurrence of prostate-specific antigen bounce phenomenon after external beam radiotherapy for prostate cancer? Urology 2005, 66: 327-331. 10.1016/j.urology.2005.02.026View ArticlePubMedGoogle Scholar
- Stock RG, Stone NN, Cesaretti JA: Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: descriptions and implications. Int J Radiat Oncol Biol Phys 2003, 56: 448-453. 10.1016/S0360-3016(02)04470-XView ArticlePubMedGoogle Scholar
- Patel C, Elshaikh MA, Angermeier K, et al.: PSA bounce predicts early success in patients with permanent iodine-125 prostate implant. Urology 2004, 63: 110-113. 10.1016/j.urology.2003.08.025View ArticlePubMedGoogle Scholar
- Pickles T: Prostate-specific antigen (PSA) bounce and other fluctuations: which biochemical relapse definition is least prone to PSA false calls? An analysis of 2030 men treated for prostate cancer with external beam or brachytherapy with or without adjuvant androgen deprivation therapy. Int J Radiat Oncol Biol Phys 2006.Google Scholar
- Merrick GS, Butler WM, Wallner KE, et al.: Prostate-specific antigen (PSA) velocity and benign prostate hypertrophy predict for PSA spikes following prostate brachytherapy. Brachytherapy 2003, 2: 181-188. 10.1016/S1538-4721(03)00130-2View ArticlePubMedGoogle Scholar
- Merrick GS, Butler WM, Wallner KE, et al.: Prostate-specific antigen spikes after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002, 54: 450-456. 10.1016/S0360-3016(02)02948-6View ArticlePubMedGoogle Scholar
- Demanes DJ, Rodriguez RR, Schour L, et al.: High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy's 10-year results. Int J Radiat Oncol Biol Phys 2005, 61: 1306-1316. 10.1016/j.ijrobp.2004.08.014View ArticlePubMedGoogle Scholar
- Menard C, Susil RC, Choyke P, et al.: MRI-guided HDR prostate brachytherapy in standard 1.5 T scanner. Int J Radiat Oncol Biol Phys 2004, 59: 1414-1423. 10.1016/j.ijrobp.2004.01.016PubMed CentralView ArticlePubMedGoogle Scholar
- Citrin D, Ning H, Guion P, et al.: Inverse treatment planning based on MRI for HDR prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005, 61: 1267-1275. 10.1016/j.ijrobp.2004.11.024View ArticlePubMedGoogle Scholar
- D'Amico AV, Moul JW, Carroll PR, et al.: Intermediate end point for prostate cancer-specific mortality following salvage hormonal therapy for prostate-specific antigen failure. J Natl Cancer Inst 2004, 96: 509-515.View ArticlePubMedGoogle Scholar
- Shipley WU, Desilvio M, Pilepich MV, et al.: Early initiation of salvage hormone therapy influences survival in patients who failed initial radiation for locally advanced prostate cancer: A secondary analysis of RTOG protocol 86-10. Int J Radiat Oncol Biol Phys 2006.Google Scholar
- Hanlon AL, Pinover WH, Horwitz EM, et al.: Patterns and fate of PSA bouncing following 3D-CRT. Int J Radiat Oncol Biol Phys 2001, 50: 845-849. 10.1016/S0360-3016(01)01557-7View ArticlePubMedGoogle Scholar
- Sengoz M, Abacioglu U, Cetin I, et al.: PSA bouncing after external beam radiation for prostate cancer with or without hormonal treatment. Eur Urol 2003, 43: 473-477. 10.1016/S0302-2838(03)00138-6View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.