Benign Prostate-specific Antigen Bounce Research Articles

Multi-Institutional Analysis of Prostate-Specific Antigen Kinetics After Stereotactic Body Radiation Therapy

Understanding prostate-specific antigen (PSA) kinetics after radiation therapy plays a large role in the management of patients with prostate cancer (PCa). This is particularly true in establishing expectations regarding PSA nadir (nPSA) and PSA bounces, which can be disconcerting. As increasingly more patients are being treated with stereotactic body radiation therapy (SBRT) for low- and intermediate-risk PCa, it is imperative to understand the PSA response to SBRT. PSA data from 5 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2004 to 2016. Patients received 35 to 40 Gy in 5 fractions, per institutional standards. Patients who had less than 12 months of PSA data or received androgen deprivation therapy were excluded from this study. Linear and logistic multivariable analysis were performed to identify predictors of nPSA, bounce, and biochemical recurrence, and joint latent class models were developed to identify significant predictors of time to biochemical failure. A total of 1062 patients were included in this study. Median follow-up was 66 months (interquartile range [IQR], 36.4-89.9 months). Biochemical failure per the Phoenix criteria occurred in 4% of patients. Median nPSA was 0.2 ng/mL, median time to nPSA was 40 months, 84% of patients had an nPSA ≤0.5 ng/mL, and 54% of patients had an nPSA ≤0.2 ng/mL. On multivariable analysis, nPSA was a significant predictor of biochemical failure. Benign PSA bounce was noted in 26% of patients. The median magnitude of PSA bounce was 0.52 ng/mL (IQR, 0.3-1.0 ng/mL). Median time to PSA bounce was 18.1 months (IQR, 12.0-31.1 months). On multivariable analysis, age and radiation dose were significantly associated with a lower incidence of bounce. Joint latent class models modeling found that nPSA and radiation dose were significantly associated with longer time to biochemical failure. In this multi-institutional cohort of patients with long-term follow-up, we found that SBRT led to low nPSAs. In turn, lower nPSAs are associated with reduced incidence of, and longer time to, biochemical failure. Benign PSA bounces occurred in a quarter of patients, as late as several years after treatment. Further studies are needed to directly compare the PSA response of patients who receive SBRT versus other treatment modalities.

Increasing Fractional Doses Increases the Probability of Benign PSA Bounce in Patients Undergoing Definitive HDR Brachytherapy for Prostate Cancer

Prostate-specific antigen (PSA) bounce is a temporary elevation of the PSA level above a prior nadir. The purpose of this study was to determine whether the frequency of a PSA bounce following high-dose-rate (HDR) interstitial brachytherapy for the treatment of prostate cancer is associated with individual treatment fraction size. Between 1999 and 2014, 554 patients underwent treatment of low- or intermediate-risk prostate cancer with definitive HDR brachytherapy as monotherapy and had ≥3 subsequent PSA measurements. Four different fraction sizes were used: 950cGy × 4 fractions, 1200cGy × 2 fractions, 1350cGy × 2 fractions, 1900cGy × 1 fraction. Four definitions of PSA bounce were applied: ≥0.2, ≥0.5, ≥1.0, and ≥2.0ng/mL above the prior nadir with a subsequent return to the nadir. The median follow-up period was 3.7years. The actuarial 3-year rate of PSA bounce for the entire cohort was 41.3%, 28.4%, 17.4%, and 6.8% for nadir +0.2, +0.5, +1.0, and +2.0ng/mL, respectively. The 3-year rate of PSA bounce >0.2ng/mL was 42.2%, 32.1%, 41.0%, and 59.1% for the 950-, 1200-, 1350-, and 1900-cGy/fraction levels, respectively (P=.002). The hazard ratio for bounce >0.2ng/mL for patients receiving a single fraction of 1900cGy compared with those receiving treatment in multiple fractions was 1.786 (P=.024). For patients treated with a single 1900-cGy fraction, the 1-, 2-, and 3-year rates of PSA bounce exceeding the Phoenix biochemical failure definition (nadir +2ng/mL) were 4.5%, 18.7%, and 18.7%, respectively, higher than the rates for all other administered dose levels (P=.025). The incidence of PSA bounce increases with single-fraction HDR treatment. Knowledge of posttreatment PSA kinetics may aid in decision making regarding management of potential biochemical failures.

Prostate-specific antigen kinetics after stereotactic body radiotherapy as monotherapy or boost after whole pelvic radiotherapy for localized prostate cancer.

PurposeStereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate-specific antigen (PSA) kinetics after SBRT has not been well characterized. The purpose of the current study is to assess the kinetics of PSA for low- and intermediate-risk prostate cancer patients treated with SBRT using Cyberknife as both monotherapy and boost after whole pelvic radiotherapy (WPRT) in the absence of androgen deprivation therapy.MethodsA total of 61 patients with low- and intermediated-risk prostate cancer treated with SBRT as monotherapy (36.25 Gy in 5 fractions in 32 patients) and SBRT (21 Gy in 3 fractions in 29 patients) boost combined with WPRT (45 Gy in 25 fractions). Patients were excluded if they failed therapy by the Phoenix definition or had androgen deprivation therapy. PSA nadir and rate of change in PSA over time (slope) were calculated and compared.ResultsWith a median follow-up of 52.4 months (range, 14–74 months), for SBRT monotherapy, the median PSA nadir was 0.31 ng/mL (range, 0.04–1.15 ng/mL) and slopes were –0.41 ng/mL/mo, –0.17 ng/mL/mo, –0.12 ng/mL/mo, and –0.09 ng/mL/mo, respectively, for durations of 1 year, 2 years, 3 years, and 4 years postradiotherapy. Similarly, for SBRT boost after WPRT, the median PSA nadir was 0.34 ng/mL (range, 0.04–1.44 ng/mL) and slopes were –0.53 ng/mL/mo, –0.25 ng/mL/mo, –0.14 ng/mL/mo, and –0.09 ng/mL/mo, respectively. The median nadir and slopes of SBRT monotherapy did not differ significantly from those of SBRT boost after WPRT. Benign PSA bounces were common in 30.4% of all cohorts, and the median time to PSA bounce was 12 months (range, 6–25 months).ConclusionsIn this report of low- and intermediate-risk prostate cancer patients, an initial period of rapid PSA decline was followed by a slow decline, which resulted in a lower PSA nadir. The PSA kinetics of SBRT monotherapy appears to be comparable to those achieved with SBRT boost with WPRT.

Prostate specific antigen kinetics following robotic stereotactic body radiotherapy for localized prostate cancer

Background. Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate specific antigen (PSA) kinetics after prostate SBRT have not been well characterized. The purpose of this study was to analyze the trend in PSA decline following robotic SBRT from a prospective cohort of patients.Material and methods. In total 175 patients were treated definitively for localized prostate cancer to a dose of 35–36.25 Gy in 5 fractions using robotic SBRT in the absence of androgen deprivation therapy (ADT). PSA and testosterone were collected at regular intervals following treatment and patients were assessed for biochemical failure and benign PSA bounce. A PSA nadir threshold of 0.5 ng/ml was used as a predictor of long-term disease-free survival. Multivariate logistic regression was used to assess the effect of disease specific covariates on the likelihood of achieving a PSA nadir less than threshold. PSA kinetics were analyzed a multi-component exponential model accounting for benign and malignant sources of PSA.Results and conclusion. At a median follow-up of 3 years, 70% of patients achieved a PSA nadir below 0.5 ng/ml with a median PSA nadir of 0.3 ng/ml at a median time to nadir of 30 months. In our cohort, 36.2% experienced a benign PSA bounce. Absence of PSA bounce, initial PSA, and testosterone at the time of nadir proved to be significant predictors of achieving a PSA nadir below threshold. PSA kinetics after prostate SBRT were well described with a functional volume model with fitted half-lives of 4.4 and 14.8 months for malignant and benign sources of PSA, respectively. Patients treated with prostate SBRT experience an initial period of rapid PSA decline followed by a slow decline which will likely result in lower PSA nadirs after longer follow-up. The long-term disease specific impacts of these results remain to be determined.

Clinical implications of a prostate-specific antigen bounce after radiation therapy for prostate cancer.

The objectives are to determine predictors of a prostate-specific antigen (PSA) bounce, whether a PSA bounce after radiotherapy for prostate cancer is associated with biochemical disease-free survival (bDFS), and the time course to a PSA bounce versus a biochemical failure post-irradiation. Between July 2000 and December 2012, 691 prostate cancer patients without regional or distant metastases were treated with external beam radiation therapy and/or brachytherapy, and had at least 12 months of follow-up. A PSA bounce was defined as a temporary PSA increase of ≥ 0.4 ng/mL. bDFS was defined according to the nadir + 2 definition. The median follow-up was 42 months. The median time to first PSA bounce was 17 months (95% confidence interval 15-18 months). In contrast, the median time to biochemical failure was 41 months (95% confidence interval 28-53 months). Two hundred and twenty-six of 691 (33%) patients had at least one PSA bounce with a median magnitude of 1.0 ng/mL (range 0.4-17.0). A Gleason score of 6 (p < 0.0001) predicted a PSA bounce on multivariate analysis. Patients with a PSA bounce experienced improved bDFS on multivariate analysis (p = 0.002). Patients with a Gleason score of 6 were more likely to experience a PSA bounce which was associated with improved bDFS. A PSA bounce occurred sooner after radiotherapy than a biochemical failure. The authors recommend against performing prostate biopsies within 24-30 months of radiotherapy since an elevated PSA may simply represent a benign PSA bounce.

Distinguishing Prostate-Specific Antigen Bounce from Biochemical Failure after Low-Dose-Rate Prostate Brachytherapy

Low-dose-rate (LDR) brachytherapy is a popular treatment option for men with localized prostate cancer. Patient outcomes are excellent, with minimal toxicity and excellent disease-free survival. However, temporary increases in prostate-specific antigen (PSA) levels are common after brachytherapy, a phenomenon known as a benign PSA bounce. The purpose of this study was to characterize PSA rises of at least 2.0 ng/mL as benign bounces or biochemical failures after LDR prostate brachytherapy at our institution, and to investigate distinguishing features between them.

Distinguishing prostate-specific antigen bounces from biochemical failure after low-dose-rate prostate brachytherapy.

PurposeThe purpose of this study was to characterize benign prostate-specific antigen (PSA) bounces of at least 2.0 ng/mL and biochemical failure as defined by the Phoenix definition after prostate brachytherapy at our institution, and to investigate distinguishing features between three outcome groups: patients experiencing a benign PSA bounce, biochemical failure, or neither.Material and methodsFive hundred and thirty consecutive men treated with low-dose-rate brachytherapy with follow-up of at least 3 years were divided into outcome groups experiencing bounce, failure, or neither. A benign bounce was defined as a rise of at least 2.0 ng/mL over the pre-rise nadir followed by a decline to 0.5 ng/mL or below, without intervention. Patient and tumor characteristics, treatment variables, and PSA kinetics were analyzed between groups.ResultsThirty-two (6.0%) men experienced benign bounces and 47 (8.9%) men experienced failure. Men experiencing a bounce were younger (p = 0.01), had a higher 6-month PSA level (p = 0.03), and took longer to reach a final nadir (p < 0.01). Compared to the failure group, men with bounce had a lower pre-treatment PSA level (p = 0.01) and experienced a rise of at least 2.0 ng/mL that occurred sooner after the implant (p < 0.01) with a faster PSA doubling time (p = 0.01). Only time to PSA rise independently differentiated between bounce and failure (p < 0.01), with a benign bounce not being seen after 36 months post-treatment. Prostate-specific antigen levels during a bounce reached levels as high as 12.6 ng/mL in this cohort, and in some cases took over 5 years to decline to below 0.5 ng/mL.ConclusionsAlthough there is substantial overlap between the features of benign PSA bounces and failure, physicians may find it useful to evaluate the timing, absolute PSA level, initial response to treatment, and rate of rise when contemplating management for a PSA rise after low-dose-rate brachytherapy.

Stereotactic body radiotherapy for prostate cancer: A preliminary report

We report the results of a retrospective study of stereotactic body radiotherapy (SBRT) using a Cyberknife for prostate cancer. In all 29 patients were treated with hypofractionated SBRT using a Cyberknife at median 36 Gy in five fractions. All the patients were treated with a radical aim. Prostate-specific antigen (PSA) was evaluated at baseline and after radiotherapy. Acute (≤3 months) and late (>3 months) urinary and rectal toxicities were recorded according to the CTCAE version 4.0. The median duration of follow up was 41 months. PSA values decreased in a time-dependent way. The median PSA nadir was 0.329 ng/mL, achieved after a median of 23 months' follow up. Two patients had a PSA failure according to the definition of nadir + 2 ng/mL. Eight patients (28%) had a benign PSA bounce at median 9 months after radiotherapy. CTCAE Grade 2 and 3 late urinary toxicities were reported in 3 and 3%, respectively. One patient had exacerbated urinary symptoms and received an operation. There were no severe late rectal toxicities. The preliminary findings of our study suggest SBRT is feasible for prostate cancer treatment. Further studies with more patients and longer follow-up duration are required.

Interpreting a rising prostate‐specific antigen after brachytherapy for prostate cancer

The aim of the present study was to review the English language literature on the topic of prostate-specific antigen bounce after brachytherapy and present a summary of the current knowledge. Although ultimately prostate-specific antigen is a reliable measure of success after prostate brachytherapy, it can be very misleading in the first 3 years because of the frequency with which temporary benign rises in prostate-specific antigen occur. We have reviewed the English language literature on the topic of prostate-specific antigen bounce under the following headings: prostate neoplasms, brachytherapy, biochemical definition of prostate-specific antigen failure, "benign prostate-specific antigen bounce" and "prostate-specific antigen spike". We included brachytherapy delivered as either low dose rate or high dose rate, and either as monotherapy or as a boost combined with external beam radiotherapy. A benign self-limited rise in prostate-specific antigen after prostate brachytherapy is seen in an average of 35% of patients, but increases in frequency with younger age. In patients aged less than 55 years, it is observed in up to 68%. Other factors, such as sexual activity, dose, prostate volume and the use of high dose rate versus low dose rate have been implicated in affecting the frequency of the benign bounce. Benign increases in prostate-specific antigen are frequent after prostate brachytherapy. It is important to recognize and correctly diagnose this phenomenon in order to avoid unnecessary salvage treatment.

Outcomes after prostate brachytherapy are even better than predicted.

During the first 3 years after prostate cancer treatment with radiation therapy, benign prostate-specific antigen (PSA) bounces are difficult for clinicians to distinguish from a biochemical recurrence, which can result in unnecessary interventions and erroneous predictions of outcomes. The objective of this study was to evaluate a commonly used PSA failure definition in a multinational, multi-institutional study after monotherapy with prostate brachytherapy. Participants were selected from 2919 men who underwent permanent prostate brachytherapy at the University Medical Center Utrecht, Princess Margaret Hospital, or Seattle Prostate Institute between 1998 and 2006. Inclusion required not having received androgen-deprivation therapy and having at least 30 months of follow-up. Failure was defined as any post-treatment use of hormone therapy, clinical relapse, or prostogram-defined biochemical (PSA) failure. Cases in which the nomogram predicted biochemical failure were evaluated at each institution to verify biochemical status over time and the actual clinical outcome at 5 years. The median follow-up for the 1816 patients was 5.2 years. Concordance between the prostogram-predicted and actual outcomes, as measured by the Harrell c statistic, was 0.655 (95% confidence interval [CI], 0.536-0.774; P = .010) for the Princess Margaret group, 0.493 (95% CI, 0.259-0.648; P = .955) for the Seattle group, and 0.696 (95% CI, 0.648-0.744, P < .001) for the Utrecht group. The overall mean difference in biochemical recurrence-free survival at 5 years between actual outcomes and prostogram-defined outcomes was 9.2% (95% CI, 7.7%-10.6%). The total numbers of prostogram-defined and actual biochemical failures were 312 and 157, respectively (P = .001). The widely used prostogram could not adequately distinguish a benign PSA bounce from a biochemical recurrence after prostate brachytherapy and could not be used to counsel patients about their predicted outcomes after treatment. The authors conclude that, to avoid unnecessary active interventions after treatment, clinicians should monitor PSA levels for at least 3 years and provide reassurance to patients that a PSA rise during this time is common and may not indicate a treatment failure.

Evaluating the Phoenix Definition of Biochemical Failure After 125I Prostate Brachytherapy: Can PSA Kinetics Distinguish PSA Failures From PSA Bounces?

To evaluate the prostate-specific antigen (PSA) kinetics of PSA failure (PSAf) and PSA bounce (PSAb) after permanent (125)I prostate brachytherapy (PB). The study included 1,006 consecutive low and "low tier" intermediate-risk patients treated with (125)I PB, with a potential minimum follow-up of 4 years. Patients who met the Phoenix definition of biochemical failure (nadir + 2 ng/mL(-1)) were identified. If the PSA subsequently fell to ≤0.5 ng/mL(-1)without intervention, this was considered a PSAb. All others were scored as true PSAf. Patient, tumor and dosimetric characteristics were compared between groups using the chi-square test and analysis of variance to evaluate factors associated with PSAf or PSAb. Median follow-up was 54 months. Of the 1,006 men, 57 patients triggered the Phoenix definition of PSA failure, 32 (56%) were true PSAf, and 25 PSAb (44%). The median time to trigger nadir + 2 was 20.6 months (range, 6-36) vs. 49 mo (range, 12-83) for PSAb vs. PSAf groups (p < 0.001). The PSAb patients were significantly younger (p < 0.0001), had shorter time to reach the nadir (median 6 vs. 11.5 months, p = 0.001) and had a shorter PSA doubling time (p = 0.05). Men younger than age 70 who trigger nadir +2 PSA failure within 38 months of implant have an 80% likelihood of having PSAb and 20% chance of PSAf. With adequate follow-up, 44% of PSA failures by the Phoenix definition in our cohort were found to be benign PSA bounces. Our study reinforces the need for adequate follow-up when reporting PB PSA outcomes, to ensure accurate estimates of treatment efficacy and to avoid unnecessary secondary interventions.

Stereotactic Body Radiotherapy for Localized Prostate Cancer: Interim Results of a Prospective Phase II Clinical Trial

The radiobiology of prostate cancer favors a hypofractionated dose regimen. We report results of a prospective Phase II clinical trial of stereotactic body radiotherapy (SBRT) for localized prostate cancer. Forty-one low-risk prostate cancer patients with 6 months' minimum follow-up received 36.25 Gy in five fractions of 7.25 Gy with image-guided SBRT alone using the CyberKnife. The early (<3 months) and late (>6 months) urinary and rectal toxicities were assessed using validated quality of life questionnaires (International Prostate Symptom Score, Expanded Prostate Cancer Index Composite) and the Radiation Therapy Oncology Group (RTOG) toxicity criteria. Patterns of prostate-specific antigen (PSA) response are analyzed. The median follow-up was 33 months. There were no RTOG Grade 4 acute or late rectal/urinary complications. There were 2 patients with RTOG Grade 3 late urinary toxicity and none with RTOG Grade 3 rectal complications. A reduced rate of severe rectal toxicities was observed with every-other-day vs. 5 consecutive days treatment regimen (0% vs. 38%, p = 0.0035). A benign PSA bounce (median, 0.4 ng/mL) was observed in 12 patients (29%) occurring at 18 months (median) after treatment. At last follow-up, no patient has had a PSA failure regardless of biochemical failure definition. Of 32 patients with 12 months minimum follow-up, 25 patients (78%) achieved a PSA nadir </=0.4 ng/mL. A PSA decline to progressively lower nadirs up to 3 years after treatment was observed. The early and late toxicity profile and PSA response for prostate SBRT are highly encouraging. Continued accrual and follow-up will be necessary to confirm durable biochemical control rates and low toxicity profiles.

PSA Kinetics and PSA Bounce Following Permanent Seed Prostate Brachytherapy

To report the incidence, timing, and magnitude of the benign prostate-specific antigen (PSA) bounce after 125I prostate brachytherapy and correlate the bounce with clinical and/or dosimetric factors. From March 1999 to August 2003, a total of 292 men received 125I prostate brachytherapy without androgen deprivation or supplemental beam radiotherapy and have PSA follow-up >30 months. Implants were preplanned using transrectal ultrasound (TRUS) and performed under transrectal ultrasound/fluoroscopy guidance using preloaded needles. A PSA bounce is defined as an increase >or=0.2 ng/ml with spontaneous return to prebounce level or lower. Resolved PSA bounces were seen in 40% of men with follow-up >30 months. Median onset was 15 months, and median magnitude was 0.76 ng/ml. Magnitude >2 ng/ml was seen in 15%. The only clinical or dosimetric factor predictive of bounce in multivariate analysis was younger age. Median time to increasing PSA level indicative of failure was 30 months. Benign PSA bounces are common after 125I prostate brachytherapy, especially in younger men. An increase >2 ng/ml above the nadir was seen in 15%. Magnitude of increase does not distinguish bounce from failure. Time to the start of the PSA increase can be helpful, but is not absolute. The PSA bounce does not predict subsequent failure. Caution is advised in interpreting an early increasing PSA level in the first 30 months after 125I brachytherapy in favorable-risk patients.