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1.  Distinguishing prostate-specific antigen bounces from biochemical failure after low-dose-rate prostate brachytherapy 
The 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 methods
Five 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.
Thirty-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.
Although 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.
PMCID: PMC4200178  PMID: 25337125
brachytherapy; prostatic neoplasms; prostate-specific antigen; relapse
2.  Prostate-Specific Antigen Bounce Following Stereotactic Body Radiation Therapy for Prostate Cancer 
Introduction: Prostate-specific antigen (PSA) bounce after brachytherapy has been well-documented. This phenomenon has also been identified in patients undergoing stereotactic body radiation therapy (SBRT). While the parameters that predict PSA bounce have been extensively studied in prostate brachytherapy patients, this study is the first to analyze the clinical and pathologic predictors of PSA bounce in prostate SBRT patients.
Materials and Methods: Our institution has maintained a prospective database of patients undergoing SBRT for prostate cancer since 2006. Our study population includes patients between May 2006 and November 2011 who have at least 18 months of follow-up. All patients were treated using the CyberKnife treatment system. The prescription dose was 35–36.25 Gy in five fractions.
Results: One hundred twenty patients were included in our study. Median PSA follow-up was 24 months (range 18–78 months). Thirty-four (28%) patients had a PSA bounce. The median time to PSA bounce was 9 months, and the median bounce size was 0.50 ng/mL. On univariate analysis, only younger age (p = 0.011) was shown to be associated with an increased incidence of PSA bounce. Other patient factors, including race, prostate size, prior treatment by hormones, and family history of prostate cancer, did not predict PSA bounces. None of the tumor characteristics studied, including Gleason score, pre-treatment PSA, T-stage, or risk classification by NCCN guidelines, were associated with increased incidence of PSA bounces. Younger age was the only statistically significant predictor of PSA bounce on multivariate analysis (OR = 0.937, p = 0.009).
Conclusion: PSA bounce, which has been reported after prostate brachytherapy, is also seen in a significant percentage of patients after CyberKnife SBRT. Close observation rather than biopsy can be considered for these patients. Younger age was the only factor that predicted PSA bounce.
PMCID: PMC3904182  PMID: 24478988
PSA; SBRT; SAbR; prostate cancer; CyberKnife
3.  Stereotactic Body Radiation Therapy (SBRT) for clinically localized prostate cancer: the Georgetown University experience 
Stereotactic body radiation therapy (SBRT) delivers fewer high-dose fractions of radiation which may be radiobiologically favorable to conventional low-dose fractions commonly used for prostate cancer radiotherapy. We report our early experience using SBRT for localized prostate cancer.
Patients treated with SBRT from June 2008 to May 2010 at Georgetown University Hospital for localized prostate carcinoma, with or without the use of androgen deprivation therapy (ADT), were included in this retrospective review of data that was prospectively collected in an institutional database. Treatment was delivered using the CyberKnife® with doses of 35 Gy or 36.25 Gy in 5 fractions. Biochemical control was assessed using the Phoenix definition. Toxicities were recorded and scored using the CTCAE v.3. Quality of life was assessed before and after treatment using the Short Form-12 Health Survey (SF-12), the American Urological Association Symptom Score (AUA) and Sexual Health Inventory for Men (SHIM) questionnaires. Late urinary symptom flare was defined as an AUA score ≥ 15 with an increase of ≥ 5 points above baseline six months after the completion of SBRT.
One hundred patients (37 low-, 55 intermediate- and 8 high-risk according to the D’Amico classification) at a median age of 69 years (range, 48–90 years) received SBRT, with 11 patients receiving ADT. The median pre-treatment prostate-specific antigen (PSA) was 6.2 ng/ml (range, 1.9-31.6 ng/ml) and the median follow-up was 2.3 years (range, 1.4-3.5 years). At 2 years, median PSA decreased to 0.49 ng/ml (range, 0.1-1.9 ng/ml). Benign PSA bounce occurred in 31% of patients. There was one biochemical failure in a high-risk patient, yielding a two-year actuarial biochemical relapse free survival of 99%. The 2-year actuarial incidence rates of GI and GU toxicity ≥ grade 2 were 1% and 31%, respectively. A median baseline AUA symptom score of 8 significantly increased to 11 at 1 month (p = 0.001), however returned to baseline at 3 months (p = 0.60). Twenty one percent of patients experienced a late transient urinary symptom flare in the first two years following treatment. Of patients who were sexually potent prior to treatment, 79% maintained potency at 2 years post-treatment.
SBRT for clinically localized prostate cancer was well tolerated, with an early biochemical response similar to other radiation therapy treatments. Benign PSA bounces were common. Late GI and GU toxicity rates were comparable to conventionally fractionated radiation therapy and brachytherapy. Late urinary symptom flares were observed but the majority resolved with conservative management. A high percentage of men who were potent prior to treatment remained potent two years following treatment.
PMCID: PMC3610192  PMID: 23497695
Prostate cancer; SBRT; CyberKnife; SHIM; AUA; SF-12; Quality of life; Common Toxicity Criteria (CTC); Benign PSA bounce; Urinary symptom flare
4.  Minimal percentage of dose received by 90% of the urethra (%UD90) is the most significant predictor of PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer 
BMC Urology  2012;12:28.
To clarify the significant clinicopathological and postdosimetric parameters to predict PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer.
We studied 200 consecutive patients who received LDR-brachytherapy between July 2004 and November 2008. Of them, 137 patients did not receive neoadjuvant or adjuvant androgen deprivation therapy. One hundred and forty-two patients were treated with LDR-brachytherapy alone, and 58 were treated with LDR-brachytherapy in combination with external beam radiation therapy. The cut-off value of PSA bounce was 0.1 ng/mL. The incidence, time, height, and duration of PSA bounce were investigated. Clinicopathological and postdosimetric parameters were evaluated to elucidate independent factors to predict PSA bounce in hormone-naïve patients who underwent LDR-brachytherapy alone.
Fifty patients (25%) showed PSA bounce and 10 patients (5%) showed PSA failure. The median time, height, and duration of PSA bounce were 17 months, 0.29 ng/mL, and 7.0 months, respectively. In 103 hormone-naïve patients treated with LDR-brachytherapy alone, and univariate Cox proportional regression hazard model indicated that age and minimal percentage of the dose received by 30% and 90% of the urethra were independent predictors of PSA bounce. With a multivariate Cox proportional regression hazard model, minimal percentage of the dose received by 90% of the urethra was the most significant parameter of PSA bounce.
Minimal percentage of the dose received by 90% of the urethra was the most significant predictor of PSA bounce in hormone-naïve patients treated with LDR-brachytherapy alone.
PMCID: PMC3487947  PMID: 22974428
Prostate cancer; Brachytherapy; PSA bounce; Post-dosimetry; UD90 (%)
5.  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 
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.
PMCID: PMC1564026  PMID: 16914054
6.  Prostate-specific antigen bounce predicts for a favorable prognosis following brachytherapy: a meta-analysis 
Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone.
Material and methods
We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non-bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test).
The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p < 0.001).
Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect.
PMCID: PMC3899636  PMID: 24474969
brachytherapy; prostate cancer; PSA bounce
7.  Rapid Increase of the Serum PSA Level in Response to High-Intensity Focused Ultrasound Therapy may be a Potential Indicator of Biochemical Recurrence of Low- and Intermediate-Risk Prostate Cancer 
To determine the incidence and magnitude of the rapid increase in the serum PSA (riPSA) level after high-intensity focused ultrasound (HIFU) therapy for prostate cancer, and its correlation with clinical factors.
A total of 176 patients with localized prostate cancer underwent HIFU therapy. Serum riPSA was determined on the basis of the same criteria as those for “PSA bounce”, ie, an increase of ≥0.2 ng/ml with a spontaneous return to the prebounce level or lower. Patients were stratified according to neoadjuvant PSA level, T stage, risk group, age, Gleason score, pretreatment PSA level, post-treatment PSA nadir, and number of HIFU sessions.
riPSA was seen in 53% of patients during a median follow-up period of 43 months. A PSA nadir was achieved within 3 months for 85.1% of the treatments. In all cases, onset of riPSA was seen two days after HIFU therapy, and the median magnitude was 23.69 ng/ml. A magnitude of >2 ng/ml was seen in 89.4% of cases. Univariate analysis revealed that patients with riPSA were associated with usage of hormonal therapy and the post-treatment PSA nadir level. Multivariate Cox regression analysis revealed that riPSA and the number of HIFU sessions were predictors of biochemical recurrence. A significant statistical association was found between the presence of riPSA and the risk of biochemical failure only in the low- and intermediate-risk group.
Patients treated with HIFU who experience post-treatment riPSA may have an increased risk of biochemical recurrence, especially in non-high-risk patients.
PMCID: PMC3095026  PMID: 21603245
HIFU; prostate cancer; PSA
8.  Virtual HDR CyberKnife SBRT for Localized Prostatic Carcinoma: 5-Year Disease-Free Survival and Toxicity Observations 
Frontiers in Oncology  2014;4:321.
Purpose: Prostate stereotactic body radiotherapy (SBRT) may substantially recapitulate the dose distribution of high-dose-rate (HDR) brachytherapy, representing an externally delivered “Virtual HDR” treatment method. Herein, we present 5-year outcomes from a cohort of consecutively treated virtual HDR SBRT prostate cancer patients.
Methods: Seventy-nine patients were treated from 2006 to 2009, 40 low-risk, and 39 intermediate-risk, under IRB-approved clinical trial, to 38 Gy in four fractions. The planning target volume (PTV) included prostate plus a 2-mm volume expansion in all directions, with selective use of a 5-mm prostate-to-PTV expansion and proximal seminal vesicle coverage in intermediate-risk patients, to better cover potential extraprostatic disease; rectal PTV margin reduced to zero in all cases. The prescription dose covered >95% of the PTV (V100 ≥95%), with a minimum 150% PTV dose escalation to create “HDR-like” PTV dose distribution.
Results: Median pre-SBRT PSA level of 5.6 ng/mL decreased to 0.05 ng/mL 5 years out and 0.02 ng/mL 6 years out. At least one PSA bounce was seen in 55 patients (70%) but only 3 of them subsequently relapsed, biochemical-relapse-free survival was 100 and 92% for low-risk and intermediate-risk patients, respectively, by ASTRO definition (98 and 92% by Phoenix definition). Local relapse did not occur, distant metastasis-free survival was 100 and 95% by risk-group, and disease-specific survival was 100%. Acute and late grade 2 GU toxicity incidence was 10 and 9%, respectively; with 6% late grade 3 GU toxicity. Acute urinary retention did not occur. Acute and late grade 2 GI toxicity was 0 and 1%, respectively, with no grade 3 or higher toxicity. Of patient’s potent pre-SBRT, 65% remained so at 5 years.
Conclusion: Virtual HDR prostate SBRT creates a very low PSA nadir, a high rate of 5-year disease-free survival and an acceptable toxicity incidence, with results closely resembling those reported post-HDR brachytherapy.
PMCID: PMC4241836  PMID: 25505732
CyberKnife; prostate cancer; dosimetry; HDR; brachytherapy; image guided; stereotactic body radiotherapy
9.  A single-center study of 100 consecutive patients with localized prostate cancer treated with stereotactic body radiotherapy 
BMC Urology  2013;13:49.
Radiotherapy is an increasingly preferred treatment option for localized prostate cancer, and stereotactic body radiation therapy (SBRT) a relatively established modality of therapeutic irradiation. The present study analyzes the toxicity and biochemical efficacy of SBRT in 100 consecutive prostate cancer patients treated with CyberKnife Robotic Radiosurgery System.
One hundred patients were treated with SBRT at the Radiation Oncology department of San Bortolo Hospital, Vicenza, Italy. All patients included in this IRB-approved protocol-driven prospective study had biopsy-proven prostate cancer. Risk category was low in 41, intermediate in 42, and high in 17 patients. The patients were treated with CyberKnife-SBRT (CK-SBRT), the prescription dose was 35 Gy in five fractions, corresponding to 92 Gy in 2-Gy fractions (α/β =1.5 Gy); 29 patients also received androgen deprivation therapy (ADT).
Median follow-up was 36 months (range, 6–76 months). Acute Grade 2 genitourinary and gastrointestinal toxicity occurred in respectively 12% and 18% of the patients; there were no Grade 3 or higher acute toxicities. Late Grade 1, 2, and 3 genitourinary toxicities occurred in 4%, 3%, and 1% of the patients, respectively; late Grade 1 gastrointestinal toxicity occurred in two patients and Grade 2 toxicity in one patient; no late gastrointestinal toxicities of grade 3 or 4 were observed. Median PSA nadir was 0.45 ng/ml at 36 months for all patients. In the SBRT-monotherapy group, the median PSA nadir at 36 months was 0.62 ng/ml; in the ADT-SBRT group, it was 0.18 ng/ml. Four patients had clinical recurrence: one local, two lymph nodes, and one to the bone. Ninety-six patients had no evidence of biochemical or clinical recurrence. A benign PSA bounce of median 1.08 ng/ml occurred in 12% of the 71 SBRT monotherapy patients at a mean 23 months (range, 18–30 months).
In this study CK-SBRT has provided promising outcomes in localized prostate cancer with good PSA response, minimal toxicity and patient inconvenience.
PMCID: PMC4016542  PMID: 24134138
10.  Hypofractionated SBRT versus conventionally fractionated EBRT for prostate cancer: comparison of PSA slope and nadir 
Patients with early stage prostate cancer have a variety of curative radiotherapy options, including conventionally-fractionated external beam radiotherapy (CF-EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Although results of CF-EBRT are well known, the use of SBRT for prostate cancer is a more recent development, and long-term follow-up is not yet available. However, rapid post-treatment PSA decline and low PSA nadir have been linked to improved clinical outcomes. The purpose of this study was to compare the PSA kinetics between CF-EBRT and SBRT in newly diagnosed localized prostate cancer.
75 patients with low to low-intermediate risk prostate cancer (T1-T2; GS 3 + 3, PSA < 20 or 3 + 4, PSA < 15) treated without hormones with CF-EBRT (>70.2 Gy, <76 Gy) to the prostate only, were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997–2012). Patients were excluded if they failed therapy by the Phoenix definition or had less than 1 year of follow-up or <3 PSAs. 43 patients who were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. PSA nadir and rate of change in PSA over time (slope) were calculated from the completion of RT to 1, 2 and 3 years post-RT.
The median PSA nadir and slope for CF-EBRT was 1.00, 0.72 and 0.60 ng/ml and -0.09, -0.04, -0.02 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadirs and slopes were 0.70, 0.40, 0.24 ng and -0.09, -0.06, -0.05 ng/ml/month, respectively. The PSA slope for SBRT was greater than CF-EBRT (p < 0.05) at 2 and 3 years following RT, although similar during the first year. Similarly, PSA nadir was significantly lower for SBRT when compared to EBRT for years 2 and 3 (p < 0.005).
Patients treated with SBRT experienced a lower PSA nadir and greater rate of decline in PSA 2 and 3 years following completion of RT than with CF-EBRT, consistent with delivery of a higher bioequivalent dose. Although follow-up for SBRT is limited, the improved PSA kinetics over CF-EBRT are promising for improved biochemical control.
PMCID: PMC3923240  PMID: 24484652
SBRT; Stereotactic body radiotherapy; Prostate; External beam; Conventionally fractionated; Nadir; Kinetics; Slope
11.  Comparison of biochemical failure rates between permanent prostate brachytherapy and radical retropubic prostatectomy as a function of posttherapy PSA nadir plus ‘X’ 
Prostate-specific antigen (PSA) nadir + 2 ng/mL, also known as the Phoenix definition, is the definition most commonly used to establish biochemical failure (BF) after external beam radiotherapy for prostate cancer management. The purpose of this study is to compare BF rates between permanent prostate brachytherapy (PPB) and radical retropubic prostatectomy (RRP) as a function of PSA nadir plus varying values of X and examine the associated implications.
Methods and materials
We retrospectively searched for patients who underwent PPB or RRP at our institution between 1998 and 2004. Only primary patients not receiving androgen-deprivation therapy were included in the study. Three RRP patients were matched to each PPB patient on the basis of prognostic factors. BF rates were estimated for PSA nadirs + different values of X.
A total of 1,164 patients were used for analysis: 873 in the RRP group and 291 in the PPB group. Patients were equally matched by clinical stage, biopsy Gleason sum, primary Gleason grade, and pretherapy PSA value. Median follow-up was 3.1 years for RRP patients and 3.6 years in the PPB group (P = .01). Using PSA nadir + 0.1 ng/mL for the definition of BF, the 5-year BF rate was 16.3% for PPB patients and 13.5% for RRP patients (P = .007), whereas at nadir + 2 ng/mL or greater, the BF rates were less than 3% and were indistinguishable between PPB and RRP patients.
In a cohort of well-matched patients who had prostatectomy or brachytherapy, we examined BF as a function of nadir + X, where X was treated as a continuous variable. As X increases from 0.1 to 2.0 ng/mL, the BF curves converge, and above 2.0 ng/mL they are essentially indistinguishable. The data presented are of interest as BF definitions continue to evolve.
PMCID: PMC4123307  PMID: 25074478
Biochemical failure; Brachytherapy; Prostate cancer; Prostatectomy; PSA
12.  The Price of Bouncing-Back: One Year Mortality and Payments for Acute Stroke Patients with Thirty Day Bounce-Backs 
“Bounce-backs” (movements from less intensive to more intensive care settings) soon after hospital discharge for acute stroke are common, but the long-term costs and mortality consequences associated with bouncing-back remain unknown.
To examine one year mortality and healthcare payments of stroke patients experiencing zero, one and ≥2 bounce-backs within thirty days of discharge.
Retrospective analysis of administrative data
422 hospitals, southern and eastern United States
11,729 Medicare beneficiaries ≥65 years surviving at least thirty days with acute ischemic stroke in 2000
One year mortality and predicted total healthcare payments were calculated using log normal parametric survival analysis and quantile regression, respectively. Models included sociodemographics, prior medical history, stroke severity, length of stay and discharge site.
Crude survival at one year for the zero, one and ≥2 bounce-back groups was 83%, 67% and 55% respectively. As compared to the zero bounce-back group, the one bounce-back group had a 49% decrease (Time Ratio [TR] = 0.51, 95% CI = 0.46, 0.56) and the ≥2 bounce-back group had a 68% decrease in adjusted one year survival time (TR = 0.32, CI = 0.27, 0.38). For both high and low cost patients, adjusted predicted payments increased with each additional bounce-back experienced.
Acute stroke patients experiencing bounce-backs within thirty days have strikingly poorer survival and higher healthcare payments over the subsequent year than their counterparts with no bounce-backs. Bounce-backs may potentially serve as a simple predictor for identifying stroke patients at extremely high risk for poor outcomes.
PMCID: PMC2736069  PMID: 18422948
stroke; patient discharge; survival; health insurance reimbursement; patient readmission
13.  Salvage brachytherapy for seminal vesicle recurrence after initial brachytherapy for prostate cancer: a case report 
BMC Research Notes  2014;7(1):760.
To report the efficacy and safety of salvage brachytherapy for seminal vesicle recurrence after initial brachytherapy in a patient with prostate cancer. As far as we know, this is a first report of salvage brachytherapy for seminal vesicle recurrence in Japan.
Case presentation
A 70-year-old Japanese man with low-risk prostate cancer received low-dose-rate brachytherapy. Forty-two months after the seed implantation, he showed biochemical recurrence based on the nadir + 2 ng/mL definition. The prostate specific antigen (PSA) level was 5.11 ng/mL at 58 months after seed implantation. A saturation biopsy of the prostate showed no recurrence. Systemic screening also showed no distant metastases. However, T2-weighted magnetic resonance imaging (MRI) demonstrated a low intensity area at the base of the right seminal vesicle, which was strongly suggestive of recurrence. Sixty months after the initial therapy, a seminal vesicle biopsy confirmed recurrence with a Gleason score of 4 + 3 before salvage brachytherapy was performed. The prescribed dose was 145 Gy, the same as the dose of the initial therapy. One month later, the PSA level had rapidly declined to 0.898 ng/mL without androgen deprivation therapy. Ten months after the salvage brachytherapy, the PSA level reached 0.078 ng/mL. No adverse events were seen during the follow-up period.
We experienced a patient who was successfully treated with salvage brachytherapy for seminal vesicle recurrence. Salvage brachytherapy is one of the promising therapeutic options for recurrence after initial brachytherapy.
PMCID: PMC4216847  PMID: 25344831
Salvage brachytherapy; Seminal vesicle recurrence; Prostate cancer
14.  Time to failure after definitive therapy for prostate cancer: implications for importance of aggressive local treatment 
To explore patterns of time to failure in men receiving high doses of permanent seed brachytherapy with or without external beam radiation therapy as a function of risk status.
Material and methods
Two thousand two hundred and thirty four patients were treated with prostate brachytherapy with median follow up of 8.0 years. The population was 35% low risk, 49% intermediate risk, and 16% high risk (NCCN). Median day 0 implant D90 was 119% and V100 was 98%. Treatment failure was defined as PSA > 0.40 ng/mL after nadir. Rates of biochemical failure, distant metastases, and prostate cancer death were determined with non-prostate death as a competing risk.
For all patients, the 10-year biochemical failure, distant metastases, and cause-specific mortality were 4.4%, 1.4%, and 1.3%, respectively. The biochemical failure rates were 1.3%, 4.8%, and 10.0% for men with low, intermediate, and high risk disease, respectively. Median time to failure was 2.8 years. In men who died from prostate cancer, the median time from treatment failure to death was 4.2 years. Overall, 83% of biochemical failures and 97% of metastases occurred within the first 4 years after treatment.
With the dose escalation achieved by high quality brachytherapy dosimetry, even high-risk prostate cancer patients have excellent long term biochemical outcomes. Treatment failures occur early, and one third become metastatic and progress rapidly to prostate cancer death. The low frequency and pattern of failures suggest the presence of micrometastatic disease prior to treatment is rare, even in high risk patients.
PMCID: PMC3899637  PMID: 24474970
biochemical survival; brachytherapy dose escalation; cause specific survival; metastases free survival; prostate cancer
15.  Time to PSA nadir independently predicts overall survival in metastatic hormone sensitive prostate cancer patients treated with androgen deprivation therapy 
Cancer  2009;115(5):981-987.
The purpose of this study was to evaluate the relationship between the kinetics of PSA decline after androgen deprivation therapy (ADT) initiation and overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (HSPC).
We identified a cohort of metastatic HSPC patients treated with androgen deprivation therapy (ADT) using our institutional database. Patients were included if they had at least 2 serum PSA determinations before nadir PSA and at least one serum PSA value available within 1 month of ADT initiation. Patient characteristics, PSA at ADT initiation, nadir PSA, time to PSA nadir (TTN) and PSA decline (PSAD) in relation to OS were analyzed.
179 patients were identified, with a median follow-up after ADT initiation of 4.0 years. Median OS after ADT initiation was 7.0 years. Median PSA at ADT initiation and PSA nadir were 47 and 0.28 ng/mL, respectively. On univariate analysis: TTN <6 months, a PSAD >52 ng/mL/year, PSA nadir ≥ 0.2 ng/mL, a PSA≥47.2 ng/mL at ADT initiation and Gleason score >7, were associated with a shorter OS. On multivariate analysis, TTN<6 months, Gleason score >7 and a PSA nadir ≥ 0.2 ng/mL independently predicted a shorter OS.
To our knowledge, this is the first report to show that a faster time to reach a PSA nadir post-ADT initiation is associated with shorter survival duration in men with metastatic HSPC. These results need confirmation, but may indicate that a rapid initial response to ADT indicates more aggressive disease.
PMCID: PMC2931827  PMID: 19152438
Prostate cancer; androgen deprivation therapy; hormone-sensitive metastatic prostate cancer; PSA kinetics; Time to PSA nadir
16.  Clinical Significance of Free-to-Total Prostate-Specific Antigen (PSA) Ratio in Advanced Prostate Cancer Patients with PSA Less than 0.1 ng/ml after Hormone Treatment 
Korean Journal of Urology  2012;53(3):149-153.
We analyzed the pattern of change in the free-to-total prostate-specific antigen (f/t PSA) ratio and the progression to castration-resistant prostate cancer (CRPC) in patients with advanced prostate cancer who received hormone treatment and whose PSA nadir was below 0.1 ng/ml.
Materials and Methods
We retrospectively analyzed the medical records of 52 patients with advanced prostate cancer. All patients were treated with maximum androgen blockade (gonadotrophin-releasing hormone agonist and anti-androgen agents). The patients were divided into two groups: those with a nadir f/t PSA ratio above 60% and those with a nadir f/t PSA ratio of 60% or below. Age, initial PSA, clinical stage, lymph node metastasis, bone metastasis, and follow-up data, including PSA, free PSA, and f/t PSA ratio, were collected. The Mann-Whitney U-test, Fisher exact test, chi-square test, Kaplan-Meier survival analysis, and log rank test were used.
There were 24 patients in the group with a nadir f/t PSA ratio above 60% and 28 patients in the group with a nadir f/t PSA ratio of 60% or below. After hormone therapy, the median f/t PSA ratio in each group increased from 37% and 34% at 3 months to 75% and 60% at 6 months, respectively. At 9 months, however, the f/t PSA ratio increased to 80% in the group with a nadir f/t PSA ratio above 60%, whereas it decreased to 31% in the group with a nadir f/t PSA ratio of 60% or below. From 9 to 15 months, the f/t PSA ratio showed a tendency to decrease (75 to 37% and 27 to 20%, respectively). The progression to CRPC was significantly different between the two groups (10 vs. 24).
Progression to CRPC was significantly higher in the group with a lower f/t PSA ratio. Additionally, the pattern of change in the f/t PSA ratio was significantly different after 9 months. Collectively, the f/t PSA ratio can be used as an additional marker for prognosis of hormone treatment.
PMCID: PMC3312061  PMID: 22468208
Hormone replacement therapy; Prostate-specific antigen; Prostatic neoplasms
17.  Obesity, Prostate-Specific Antigen Nadir, and Biochemical Recurrence After Radical Prostatectomy: Biology or Technique? Results from the SEARCH Database 
European urology  2012;62(5):910-916.
Obesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors.
To examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men.
Design, setting, and participants
A retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration–based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo.
All patients underwent RP.
Outcome measurements and statistical analysis
We evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir.
Results and limitations
Mean BMI was 28.5 kg/m2. Higher BMI was associated with higher PSA nadir on both univariable (p = 0.001) and multivariable analyses (p < 0.001). Increased BMI was associated with increased BCR risk (hazard ratio [HR]: 1.06; p = 0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p = 0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir (p = 0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available.
Obese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression.
PMCID: PMC3500618  PMID: 22921964
Prostate cancer; PSA nadir; obesity; radical prostatectomy; biochemical recurrence
18.  Iodine-125 prostate seed brachytherapy in renal transplant recipients: an analysis of oncological outcomes and toxicity profile 
Prostate cancer is among the most common non-cutaneous neoplasms affecting renal transplant recipients (RTRs). Available treatments including radical prostatectomy and external beam radiotherapy carry a risk of damage to the transplanted kidney, ureters, or bladder. We assessed the safety and efficacy of Iodine-125 (125I) prostate seed brachytherapy as an alternative to surgery and radiotherapy in these individuals.
Material and methods
We retrospectively reviewed our brachytherapy database to identify patients with a prior history of renal transplantation, who had undergone seed implantation for localized prostate cancer. Long term PSA control and treatment related toxicity, including graft dysfunction, urinary, rectal, and sexual complications, were assessed and compared with published outcomes for surgery and external beam radiotherapy.
Of 1054 patients treated with permanent seed implantation from 2002-2012, we identified four who had a prior history of renal transplantation. Mean time from renal transplantation to prostate cancer diagnosis was 13 years. Mean follow-up after seed implantation was 44 months (range 12-60 months). All four patients remain free of PSA progression. No peri-operative complications were experienced following seed implantation, and all four patients continued to have normal graft function. Long term urinary and rectal function scores were comparable to reported outcomes for seed brachytherapy in the non-transplant population.
125I prostate seed brachytherapy is associated with high rates of biochemical control and minimal toxicity to the renal graft in RTRs. This treatment should be considered as an alternative to surgery in managing RTRs with localized prostate cancer.
PMCID: PMC4003425  PMID: 24790617
brachytherapy; 125I; prostate cancer; renal transplant; seeds
19.  Factors Associated with Short-Term Bounce-back Admissions Following Emergency Department Discharge 
Annals of emergency medicine  2013;62(2):136-144.e1.
Hospitalizations that occur shortly after emergency department (ED) discharge may reveal opportunities to improve ED or follow-up care. There currently is limited, population-level information about such events. We identified hospital and visit-level predictors of bounce-back admissions, defined as 7-day unscheduled hospital admissions after ED discharge.
Using the California Office of Statewide Health Planning and Development (OSHPD) files, we conducted a retrospective cohort analysis of adult (age≥18 years) ED visits resulting in discharge in 2007. Candidate predictors included index hospital structural characteristics such as ownership, teaching affiliation, trauma status, and index ED size; along with index visit patient characteristics of demographic information, day of service, against medical advice or eloped disposition, insurance, and ED primary discharge diagnosis. We fit a multivariable, hierarchical logistic regression to account for clustering of ED visits by hospitals.
The study cohort contained a total of 5,035,833 visits to 288 facilities in 2007. Bounce-back admission within 7 days occurred in 130,526 (2.6%) visits and was associated with Medicaid (OR 1.42, 95% CI 1.40–1.45) or Medicare insurance (OR 1.53, 95% CI1.50–1.55) and a disposition of leaving against medical advice (AMA) or before the evaluation was complete (OR 1.9, 95% CI 1.89–2.0). The three most common age-adjusted index ED discharge diagnoses associated with a bounce-back admission were chronic renal disease, not end stage (OR 3.3, 95% CI 2.8–3.8), end stage renal disease (OR 2.9, 95% CI 2.4–3.6), and congestive heart failure (OR 2.5, 95% CI 2.3–2.6). Hospital characteristics associated with a higher bounce–back admission rate were for-profit status (OR 1.2, 95% CI 1.1–1.3) and teaching affiliation (OR 1.2, 95% CI 1.0–1.3).
We found 2.6% of discharged patients from California EDs to have a bounce-back admission within 7 days. We identified vulnerable populations, such as the very old and the use of Medicaid Insurance, and chronic or end stage renal disease as being especially at risk. Our findings suggest that quality improvement efforts focus on high-risk individuals and that the disposition plan of patients consider vulnerable populations.
PMCID: PMC3720678  PMID: 23465554
20.  Long-term tumor control after brachytherapy for base-of-prostate cancer 
To evaluate the outcomes of patients presenting with cancer at the base of the prostate after brachytherapy as monotherapy.
Material and methods
We retrospectively reviewed the medical records of all patients who had undergone transperineal ultrasound-guided implantation with 125I or 103Pd seeds as monotherapy between March 1998 and December 2006, at our institution. A minimum follow-up interval of 2 years was required for inclusion in our analysis. Dosimetry was assessed using computed tomography 30 days after the implant. Treatment failure was defined as the appearance of biopsy-proved tumor after seed implantation, radiographic evidence of metastases, receipt of salvage therapy, or elevation of the prostate-specific antigen level beyond the nadir value plus 2 ng/mL.
With a median follow-up interval of 89 months (range 25–128 months), all 52 of the identified patients had no evidence of disease progression or biochemical failure. The mean number of cores sampled at the prostate base was 2.84 (median 2); Gleason scores assigned at central review were 6-8 in all patients. Of the 30 patients (58%) for whom dosimetric data were available at day 30, the median V100 values of the right and left base were 92.0% and 93.5%, respectively, and the median D90 values of the right and left base were 148 Gy and 151 Gy, respectively.
Permanent prostate brachytherapy as monotherapy results in a high probability of disease-free survival for men with cancer at the base of the prostate.
PMCID: PMC3551361  PMID: 23346126
prostate cancer; monotherapy; sector analysis
21.  Outcomes of Gleason Score ≤8 among High Risk Prostate Cancer Treated with 125I Low Dose Rate Brachytherapy Based Multimodal Therapy 
Yonsei Medical Journal  2013;54(5):1207-1213.
To investigate the role of low dose rate (LDR) brachytherapy-based multimodal therapy in high-risk prostate cancer (PCa) and analyze its optimal indications.
Materials and Methods
We reviewed the records of 50 high-risk PCa patients [clinical stage ≥T2c, prostate-specific antigen (PSA) >20 ng/mL, or biopsy Gleason score ≥8] who had undergone 125I LDR brachytherapy since April 2007. We excluded those with a follow-up period <3 years. Biochemical recurrence (BCR) followed the Phoenix definition. BCR-free survival rates were compared between the patients with Gleason score ≥9 and Gleason score ≤8.
The mean initial PSA was 22.1 ng/mL, and mean D90 was 244.3 Gy. During a median follow-up of 39.2 months, biochemical control was obtained in 72% (36/50) of the total patients; The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores ≤8, and 40% for those with Gleason scores ≥9 (p<0.001). In Cox multivariate analysis, only Gleason score ≥9 was observed to be significantly associated with BCR (p=0.021). Acute and late grade ≥3 toxicities were observed in 20% (10/50) and 36% (18/50) patients, respectively.
Our results showed that 125I LDR brachytherapy-based multimodal therapy in high-risk PCa produced encouraging relatively long-term results among the Asian population, especially in patients with Gleason score ≤8. Despite small number of subjects, biopsy Gleason score ≥9 was a significant predictor of BCR among high risk PCa patients after brachytherapy.
PMCID: PMC3743192  PMID: 23918571
Prostate cancer; brachytherapy; high risk group; biochemical recurrence
22.  Ultrasensitive Prostate Specific Antigen Assay Following Laparoscopic Radical Prostatectomy – An Outcome Measure for Defining the Learning Curve 
Radical retropubic prostatectomy (RRP) performed laparoscopically is a popular treatment with curative intent for organ-confined prostate cancer. After surgery, prostate specific antigen (PSA) levels drop to low levels which can be measured with ultrasensitive assays. This has been described in the literature for open RRP but not for laparoscopic RRP. This paper describes PSA changes in the first 300 consecutive patients undergoing non-robotic laparoscopic RRP by a single surgeon.
To use ultrasensitive PSA (uPSA) assays to measure a PSA nadir in patients having laparoscopic radical prostatectomy below levels recorded by standard assays. The aim was to use uPSA nadir at 3 months' post-prostatectomy as an early surrogate end-point of oncological outcome. In so doing, laparoscopic oncological outcomes could then be compared with published results from other open radical prostatectomy series with similar end-points. Furthermore, this end-point could be used in the assessment of the surgeon's learning curve.
Prospective, comprehensive, demographic, clinical, biochemical and operative data were collected from all patients undergoing non-robotic laparoscopic RRP. We present data from the first 300 consecutive patients undergoing laparoscopic RRP by a single surgeon. uPSA was measured every 3 months post surgery.
Median follow-up was 29 months (minimum 3 months). The likelihood of reaching a uPSA of ≤ 0.01 ng/ml at 3 months is 73% for the first 100 patients. This is statistically lower when compared with 83% (P < 0.05) for the second 100 patients and 80% for the third 100 patients (P < 0.05). Overall, 84% of patients with pT2 disease and 66% patients with pT3 disease had a uPSA of ≤ 0.01 ng/ml at 3 months. Pre-operative PSA, PSA density and Gleason score were not correlated with outcome as determined by a uPSA of ≤ 0.01 ng/ml at 3 months. Positive margins correlate with outcome as determined by a uPSA of ≤ 0.01 ng/ml at 3 months but operative time and tumour volume do not (P < 0.05). Attempt at nerve sparing had no adverse effect on achieving a uPSA of ≤ 0.01 ng/ml at 3 months.
uPSA can be used as an early end-point in the analysis of oncological outcomes after radical prostatectomy. It is one of many measures that can be used in calculating a surgeon's learning curve for laparoscopic radical prostatectomy and in bench-marking performance. With experience, a surgeon can achieve in excess of an 80% chance of obtaining a uPSA nadir of ≤ 0.01 ng/ml at 3 months after laparoscopic RRP for a British population. This is equivalent to most published open series.
PMCID: PMC2758435  PMID: 19409146
Laparoscopic radical prostatectomy; Ultrasensitive prostate specific antigen assay; Learning curve
23.  Updated Results of Magnetic Resonance Imaging Guided Partial Prostate Brachytherapy for Favorable Risk Prostate Cancer: Implications for Focal Therapy 
The Journal of urology  2012;188(4):1151-1156.
We report updated results of magnetic resonance imaging guided partial prostate brachytherapy and propose a definition of biochemical failure following focal therapy.
Materials and Methods
From 1997 to 2007, 318 men with cT1c, prostate specific antigen less than 15 ng/ml, Gleason 3 + 4 or less prostate cancer received magnetic resonance imaging guided brachytherapy in which only the peripheral zone was targeted. To exclude benign prostate specific antigen increases due to prostatic hyperplasia, we investigated the usefulness of defining prostate specific antigen failure as nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. Cox regression was used to determine the factors associated with prostate specific antigen failure.
Median followup was 5.1 years (maximum 12.1). While 36 patients met the nadir +2 criteria, 16 of 17 biopsy proven local recurrences were among the 26 men who also had a prostate specific antigen velocity greater than 0.75 ng/ml per year (16 of 26 vs 1 of 10, p = 0.008). Using the nadir +2 definition, prostate specific antigen failure-free survival for low risk cases at 5 and 8 years was 95.1% (91.0–97.3) and 80.4% (70.7–87.1), respectively. This rate improved to 95.6% (91.6–97.7) and 90.0% (82.6–94.3) using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year. For intermediate risk cases survival was 73.0% (55.0–84.8) at 5 years and 66.4% (44.8–81.1) at 8 years (the same values as using nadir +2 with prostate specific antigen velocity greater than 0.75 ng/ml per year).
Requiring a prostate specific antigen velocity greater than 0.75 ng/ml per year in addition to nadir +2 appears to better predict clinical failure after therapies that target less than the whole gland. Further followup will determine whether magnetic resonance imaging guided brachytherapy targeting the peripheral zone produces comparable cancer control to whole gland treatment in men with low risk disease. However, at this time it does not appear adequate for men with even favorable intermediate risk disease.
PMCID: PMC3744091  PMID: 22901567
prostatic neoplasms; brachytherapy; magnetic resonance imaging
24.  Local prostate cancer radiotherapy after prostate-specific antigen progression during primary hormonal therapy 
The outcome of patients after radiotherapy (RT) for localized prostate cancer in case of prostate-specific antigen (PSA) progression during primary hormonal therapy (HT) is not well known.
A group of 27 patients presenting with PSA progression during primary HT for local prostate cancer RT was identified among patients who were treated in the years 2000–2004 either using external-beam RT (EBRT; 70.2Gy; n=261) or Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18Gy + 50.4Gy; n=71). The median follow-up period after RT was 68 months.
Median biochemical recurrence free (BRFS), disease specific (DSS) and overall survival (OS) for patients with PSA progression during primary HT was found to be only 21, 54 and 53 months, respectively, with a 6-year BRFS, DSS and OS of 19%, 41% and 26%. There were no significant differences between different RT concepts (6-year OS of 27% after EBRT and 20% after EBRT with HDR-BT).
Considering all 332 patients in multivariate Cox regression analysis, PSA progression during initial HT, Gleason score>6 and patient age were found to be predictive for lower OS (p<0.001). The highest hazard ratio resulted for PSA progression during initial HT (7.2 in comparison to patients without PSA progression during primary HT). PSA progression and a nadir >0.5 ng/ml during initial HT were both significant risk factors for biochemical recurrence.
An unfavourable prognosis after PSA progression during initial HT needs to be considered in the decision process before local prostate radiotherapy. Results from other centres are needed to validate our findings.
PMCID: PMC3551819  PMID: 23227960
Prostate cancer; Radiotherapy; Brachytherapy; Ir-192; Prostate-specific antigen; Hormone therapy
25.  Single session of high-intensity focused ultrasound for localized prostate cancer: treatment outcomes and potential effect as a primary therapy 
World Journal of Urology  2013;32(5):1339-1345.
To investigate the treatment outcomes of a single-session high-intensity focused ultrasound (HIFU) using the Sonablate® for patients with localized prostate cancer.
Biochemical failure was defined according to the Stuttgart definition [a rise of 1.2 ng/ml or more above the nadir prostate-specific antigen (PSA)] and the Phoenix definition (a rise of 2 ng/ml or more above the nadir PSA). Disease-free survival rate was defined using the Phoenix criteria and positive follow-up biopsy.
A total of 171 patients were identified. Fifty-two (30.4 %) patients were identified to be with D’Amico low risk, 47 (27.5 %) with intermediate risk, and 72 (42.1 %) with high risk. In the median follow-up time of 43 months, there was 44 (25.7 %) and 36 (21.1 %) patients experienced biochemical failure for Stuttgart and Phoenix definition with mean (±SD) time to failure of 17.8 ± 2.1 and 19.4 ± 2.3 months, respectively. A total of 44 (25.7 %) patients were diagnosed as disease failure. Cox multivariate analysis revealed PSA nadir level (PSA cutoff = 0.2 ng/ml; HR = 9.472, 95 % CI 4.527–19.820, p < 0.001) and D’amico risk groups [HR = 3.132 (95 % CI 1.251–6.389), p = 0.033] were the predictor for failure in single-session HIFU.
Single-session HIFU treatment using the Sonablate® seems to be potentially curative approach. When treated carefully with neoadjuvant hormonal therapy or preoperative transurethral resection of the prostate, higher-risk disease might be able to choose this minimally invasive procedure as primary therapy.
PMCID: PMC4176571  PMID: 24270943
HIFU; Localized prostate cancer; Single-session treatment; Outcome

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