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1.  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 (%)
2.  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
3.  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
4.  Analysis of prognostic factors in localized high-risk prostate cancer patients treated with HDR brachytherapy, hypofractionated 3D-CRT and neoadjuvant/adjuvant androgen deprivation therapy (trimodality therapy) 
Journal of Radiation Research  2013;55(3):527-532.
Trimodality therapy consisting of high dose rate (HDR) brachytherapy combined with external beam radiation therapy (EBRT), neoadjuvant hormonal therapy (NHT) and adjuvant hormonal therapy (AHT) has been used to treat localized high-risk prostate cancer. In this study, an analysis of patients receiving the trimodality therapy was performed to identify prognostic factors of biochemical relapse-free survival (bRFS). Between May 2005 and November 2008, 123 high-risk prostate cancer patients (D'Amico classification) were treated with NHT prior to HDR brachytherapy combined with hypofractionated EBRT. Among these patients, 121 had completed AHT. The patients were assigned by time to be treated with a low-dose or high-dose arm of HDR brachytherapy with subsequent hypofractionated 3D conformal radiation therapy (3D-CRT). Multivariate analysis was used to determine prognostic factors for bRFS. With a median follow-up of 60 months, the 5-year bRFS for all patients was 84.3% (high-dose arm, 92.9%; low-dose arm, 72.4%, P = 0.047). bRFS in the pre-HDR PSA ≤ 0.1 ng/ml subgroup was significantly improved compared with that in the pre-HDR PSA > 0.1 ng/ml subgroup (88.3% vs 68.2%, P = 0.034). On multivariate analysis, dose of HDR (P = 0.045, HR = 0.25, 95% CI = 0.038–0.97) and pre-HDR PSA level (P = 0.02 HR = 3.2, 95% CI = 1.18–10.16) were significant prognostic factors predicting bRFS. In high-risk prostate cancer patients treated with the trimodality therapy, the dose of HDR and pre-HDR PSA were significant prognostic factors. The pre-HDR PSA ≤ 0.1 subgroup had significantly improved bRFS. Further studies are needed to confirm the relevance of pre-HDR PSA in trimodality therapy.
PMCID: PMC4014157  PMID: 24351458
high-risk prostate cancer; HDR; trimodality therapy; PSA response
5.  Combination external beam radiation and brachytherapy boost with androgen deprivation for treatment of intermediate-risk prostate cancer: long-term results of CALGB 99809 
Cancer  2011;117(24):5579-5588.
Combined transperineal prostate brachytherapy (TPPB) and external beam radiation (EBRT) is widely used for treatment of prostate cancer. Long-term efficacy and toxicity results of a multicenter Phase II trial assessing combination of EBRT and TPPB boost with androgen deprivation therapy (ADT) for intermediate-risk prostate cancer are presented.
Intermediate-risk patients per MSKCC/NCCN criteria received six months of ADT, 45 Gy EBRT to the prostate and seminal vesicles, followed by TPPB with I125(100 Gy) or Pd103(90 Gy). Toxicity was graded using NCI CTC version 2 and RTOG late radiation morbidity scoring systems. Disease free survival (DFS) was defined as time from enrollment to progression (biochemical, local, distant or prostate cancer death). In addition to the protocol definition of biochemical failure (3 consecutive PSA rises >1.0ng/ml after 18 months from treatment start), the 1997 ASTRO consensus and Phoenix definitions were also assessed in defining DFS. The Kaplan-Meier method was used to estimate DFS and overall survival.
61/63 enrolled patients were eligible. Median follow-up was 73 months. Late grade 2 and 3 toxicity, excluding sexual dysfunction, occurred in 20% and 3% of patients. Six year DFS applying the protocol definition, 1997 ASTRO consensus, and Phoenix definitions was 87.1%, 75.1%, and 84.9%. 6 deaths occurred, only one was attributed to prostate cancer. 6 year overall survival was 96.1%.
In a cooperative setting, combination of EBRT and TPPB boost plus ADT resulted in excellent DFS with acceptable late toxicity for patients with intermediate-risk prostate cancer.
PMCID: PMC3338200  PMID: 22535500
prostate; brachytherapy; radiation; cooperative group trial; hormonal therapy
6.  Predictors of distant metastasis after combined HDR brachytherapy and external beam radiation for prostate cancer 
To determine predictors of distant metastases (DM) in prostate cancer patients treated with high dose rate brachytherapy boost (HDR-B) and external beam radiation therapy (EBRT).
Material and methods
From 1991 to 2002, 768 men with localized prostate cancer were treated with HDR-B and EBRT. The mean EBRT dose was 37.5 Gy (range: 30.6-45 Gy), and the HDR-B was 22 or 24 Gy delivered in 4 fractions. Univariate and multivariate analyses using a Cox proportional hazards model including age at diagnosis, T stage, Gleason score (GS), pretreatment PSA, biologically equivalent dose (BED), and use of androgen deprivation therapy (ADT) was used to determine predictors of developing distant metastases.
The median follow-up time for the entire patient population was 4.2 years (range: 1-11.2 years). Distant metastases were identified in 22/768 (3%) of patients at a median of 4.1 years. PSA failure according to the Phoenix definition developed in 3%, 5%, and 14% of men with low, intermediate, and high risk disease with a median time to failure of 3.8 years. Prostate cancer specific mortality was observed in 2% of cases. T stage, GS, and use of ADT were significantly associated with developing DM on univariate analysis. GS, and use of ADT were the only factors significantly associated with developing DM on multivariate analysis (p < 0.01). Patients who received ADT had significantly higher risk features suggesting patient selection bias for higher DM in this group of patients rather than a negative interaction between HDR-B and EBRT.
In men treated with HDR-B and EBRT, GS is a significant factor on multivariate analysis for developing distant metastasis.
PMCID: PMC3797412  PMID: 24143146
brachytherapy; distant metastases; high-dose-rate; prostate cancer
7.  High-Intensity Focused Ultrasound as Salvage Therapy for Patients With Recurrent Prostate Cancer After Radiotherapy 
Korean Journal of Urology  2014;55(2):91-96.
To evaluate the oncologic outcomes and postoperative complications of high-intensity focused ultrasound (HIFU) as a salvage therapy after external-beam radiotherapy (EBRT) failure in patients with prostate cancer.
Materials and Methods
Between February 2002 and August 2010, we retrospectively reviewed the medical records of all patients who underwent salvage HIFU for transrectal ultrasound-guided, biopsy-proven locally recurred prostate cancer after EBRT failure (by ASTRO definition: prostate-specific antigen [PSA] failure after three consecutive PSA increases after a nadir, with the date of failure as the point halfway between the nadir date and the first increase or any increase great enough to provoke initiation of therapy). All patients underwent prostate magnetic resonance imaging and bone scintigraphy and had no evidence of distant metastasis. Biochemical recurrence (BCR) was defined according to the Stuttgart definition (PSA nadir plus 1.2 ng/mL).
A total of 13 patients with a median age of 68 years (range, 60-76 years) were included. The median pre-EBRT PSA was 21.12 ng/mL, the pre-HIFU PSA was 4.63 ng/mL, and the period of salvage HIFU after EBRT was 32.7 months. The median follow-up after salvage HIFU was 44.5 months. The overall BCR-free rate was 53.8%. In the univariate analysis, predictive factors for BCR after salvage HIFU were higher pre-EBRT PSA (p=0.037), pre-HIFU PSA (p=0.015), and short time to nadir (p=0.036). In the multivariate analysis, there were no significant predictive factors for BCR. The complication rate requiring intervention was 38.5%.
Salvage HIFU for prostate cancer provides effective oncologic outcomes for local recurrence after EBRT failure. However, salvage HIFU had a relatively high rate of complications.
PMCID: PMC3935076  PMID: 24578803
High-intensity focused ultrasound ablation; Prostatic neoplasms; Salvage therapy
8.  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
9.  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
10.  Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years 
Stereotactic body radiotherapy (SBRT) may yield disease control for prostate cancer in a brief, hypofractionated treatment regimen without increasing treatment toxicity. Our report presents a 6-year update from 304 low- (n = 211), intermediate- (n = 81), and high-risk (n = 12) prostate cancer patients who received CyberKnife SBRT.
The median PSA at presentation was 5.8 ng/ml. Fifty-seven patients received neoadjuvant hormonal therapy for up to one year. The first 50 patients received a total dose of 35 Gy in 5 fractions of 7 Gy. The subsequent 254 patients received a total dose of 36.25 Gy in 5 fractions of 7.25 Gy. Toxicity was assessed with the Expanded Prostate Cancer Index Composite questionnaire and the Radiation Therapy Oncology Group urinary and rectal toxicity scale. Biochemical failure was assessed using the nadir + 2 definition.
No patients experienced Grade III or IV acute complications. Fewer than 5% of patients experienced any acute Grade II urinary or rectal toxicities. Late urinary Grade II complications were observed in 4% of patients treated to 35 Gy and 9% of patients treated to 36.25 Gy. Five (2%) late Grade III urinary toxicities occurred in patients who were treated with 36.25 Gy. Late Grade II rectal complications were observed in 2% of patients treated to 35 Gy and 5% of patients treated to 36.25 Gy. Bowel and urinary quality of life (QOL) scores initially decreased, but later returned to baseline values. An overall decrease of 20% in the sexual QOL score was observed. QOL in each domain was not differentially affected by dose. For patients that were potent prior to treatment, 75% stated that they remained sexually potent. Actuarial 5-year biochemical recurrence-free survival was 97% for low-risk, 90.7% for intermediate-risk, and 74.1% for high-risk patients. PSA fell to a median of 0.12 ng/ml at 5 years; dose did not influence median PSA levels.
In this large series with long-term follow-up, we found excellent biochemical control rates and low and acceptable toxicity, outcomes consistent with those reported for from high dose rate brachytherapy (HDR BT). Provided that measures are taken to account for prostate motion, SBRT’s distinct advantages over HDR BT include its noninvasiveness and delivery to patients without anesthesia or hospitalization.
PMCID: PMC3674983  PMID: 23668632
Prostate; Stereotactic body radiotherapy; CyberKnife
11.  Focal cryosurgical ablation of the prostate: a single institute’s perspective 
BMC Urology  2013;13:2.
With the stage migration of prostate cancer witnessed in the late 1990’s and early 2000’s along with the persistent morbidities associated with prostatectomy and radiation therapy, the concept of focal prostate cancer treatment remains quite attractive. Herein we evaluate the tolerability and non-oncologic outcomes of a highly select cohort of men that underwent focal cryoablation of the prostate for the treatment of localized prostate cancer.
Pre-operatively, erectile function was assessed by SHIM questionnaire while voiding symptoms were assessed by AUA symptom score. Twenty-six highly select patients (23 low-risk prostate cancer and 3 intermediate-risk prostate cancer) with documented minimal disease on saturation prostate biopsy underwent focal cryoablation of the prostate (24 hemi-ablation and 2 subtotal ablation). Subsequently, serum PSAs were obtained every 3 months for 2 years and then every 6 months thereafter. PSA failure was defined as an increase of 0.50 ng/ml over nadir. Mean follow-up was 19.1 months. Subjective assessment of erectile function and voiding was assessed post-operatively at each visit.
Based on our PSA failure definition, 11.5% (3 patients) of the cohort experienced biochemical failure. In two of the three patients, localized disease was detected on subsequent transrectal ultrasound guided biopsy. These two patients went on to have favorable PSA nadirs after undergoing conventional definitive therapy (one patient had external beam radiation and one patient had whole gland cryoablation). Within the study cohort, 27% (7 patients) reported new post-operative erectile dysfunction requiring therapy while no patients reported new post-operative urinary incontinence or worsening of voiding symptoms.
These preliminary results add to the expanding body of literature that the minimally invasive focal cryosurgical ablation of the prostate is a safe procedure with few side effects. The true extent of cancer control remains in question, but in highly select patients, favorable PSA kinetics have been demonstrated. If confirmed by further studies with long-term follow-up, this treatment approach could have a profound effect on prostate cancer management.
PMCID: PMC3585847  PMID: 23311921
Prostate cancer; Therapy; Focal; Cryoablation
12.  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
13.  Efficacy and Safety of High-Dose-Rate Brachytherapy of Single Implant with Two Fractions Combined with External Beam Radiotherapy for Hormone-Naïve Localized Prostate Cancer 
Cancers  2011;3(3):3585-3600.
The purpose of this study was to evaluate the efficacy and safety of high-dose-rate (HDR) brachytherapy of a single implant with two fractions plus external beam radiotherapy (EBRT) for hormone-naïve prostate cancer in comparison with radical prostatectomy. Of 150 patients with localized prostate cancer (T1c–T2c), 59 underwent HDR brachytherapy plus EBRT, and 91 received radical prostatectomy. The median follow-up of patients was 62 months for HDR brachytherapy plus EBRT, and 64 months for radical prostatectomy. In patient backgrounds between the two cohorts, the frequency of T2b plus T2c was greater in HDR brachytherapy cohort than in prostatectomy cohort (27% versus 12%, p = 0.029). Patients in HDR brachytherapy cohort first underwent 3D conformal RT with four beams to the prostate to an isocentric dose of 50 Gy in 25 fractions and then, a total of 15–18 Gy in two fractions at least 5 hours apart. We prescribed 9 Gy/fraction for target (prostate gland plus 3 mm lateral outside margin and seminal vesicle) using CT image method for radiation planning. The total biochemical failure-free control rates (BF-FCR) at 3 and 5 years for the HDR brachytherapy cohort, and for the prostatectomy cohort were 92% and 85%, and 72% and 72%, respectively (significant difference, p = 0.0012). The 3-and 5-year BF-FCR in the HDR brachytherapy cohort and in the prostatectomy cohort by risk group was 100 and 100%, and 80 and 80%, respectively, for the low-risk group (p = 0.1418); 92 and 92%, 73 and 73%, respectively, for the intermediate-risk group (p = 0.0492); and 94 and 72%, 45 and 45%, respectively, for the high-risk group (p = 0.0073). After HDR brachytherapy plus EBRT, no patient experienced Grade 2 or greater genitourinay toxicity. The rate of late Grade 1 and 2 GI toxicity was 6% (n = 4). No patient experienced Grade 3 GI toxicity. HDR brachytherapy plus EBRT is useful for treating patients with hormone-naïve localized prostate cancer, and has low GU and GI toxicities.
PMCID: PMC3759211  PMID: 24212968
prostate cancer; high dose rate brachytherapy; external beam radiation therapy; radical prostatectomy
14.  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
15.  Permanent 125I-seed prostate brachytherapy: early prostate specific antigen value as a predictor of PSA bounce occurrence 
To evaluate predictive factors for PSA bounce after 125I permanent seed prostate brachytherapy and identify criteria that distinguish between benign bounces and biochemical relapses.
Materials and methods
Men treated with exclusive permanent 125I seed brachytherapy from November 1999, with at least a 36 months follow-up were included. Bounce was defined as an increase ≥ 0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Biochemical failure (BF) was defined using the criteria of the Phoenix conference: nadir +2 ng/ml.
198 men were included. After a median follow-up of 63.9 months, 21 patients experienced a BF, and 35.9% had at least one bounce which occurred after a median period of 17 months after implantation (4-50). Bounce amplitude was 0.6 ng/ml (0.2-5.1), and duration was 13.6 months (4.0-44.9). In 12.5%, bounce magnitude exceeded the threshold defining BF. Age at the time of treatment and high PSA level assessed at 6 weeks were significantly correlated with bounce but not with BF. Bounce patients had a higher BF free survival than the others (100% versus 92%, p = 0,007). In case of PSA increase, PSA doubling time and velocity were not significantly different between bounce and BF patients. Bounces occurred significantly earlier than relapses and than nadir + 0.2 ng/ml in BF patients (17 vs 27.8 months, p < 0.0001).
High PSA value assessed 6 weeks after brachytherapy and young age were significantly associated to a higher risk of bounces but not to BF. Long delays between brachytherapy and PSA increase are more indicative of BF.
PMCID: PMC3342157  PMID: 22449081
Brachytherapy; 125 iodine permanent seeds; Prostate cancer; PSA; Bounce; Biochemical relapse
16.  Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiotherapy for Adenocarcinoma of the Prostate: Preliminary Results of RTOG 0321 
To estimate the rate of late grade 3 or greater genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) following treatment with external beam radiation therapy and prostate high dose rate (HDR) brachytherapy.
Methods and Materials
Each participating institution submitted CT based HDR brachytherapy dosimetry data electronically for credentialing and for each study patient. Patients with locally confined T1c-T3b prostate cancer were eligible for this study. All patients were treated with 45 Gy in 25 fractions from external beam radiotherapy and one HDR implant delivering 19 Gy in 2 fractions. All AEs were graded according to CTCAEv3.0. Late GU/ GI AEs were defined as those occurring more than nine months from the start of the protocol treatment, in patients with at least 18 months of potential follow-up.
A total of 129 patients from 14 institutions were enrolled in this study. 125 patients were eligible and AE data was available for 112 patients. The pretreatment characteristics of the patients were as follows: T1c-T2c 91%, T3a-T3b 9%, PSA ≤ 10 70%, PSA >10-≤20 30%, GS 2-6 10%, GS 7 72%, and GS 8-10 18%. At a median follow-up time of 29.6 months, 3 acute and 4 late grade 3 GU/GI AEs were reported. The estimated rate of late grade 3-5 GU and GI AE at 18 months was 2.56%.
This is the first prospective, multi-institutional trial of CT based HDR brachytherapy and external beam radiotherapy. The technique and doses used in this study resulted in acceptable levels of adverse events.
PMCID: PMC2946454  PMID: 20207506
Prostate cancer; High Dose Rate; Brachytherapy; Prospective multi-institutional clinical trial
17.  The relationship between the biochemical control outcomes and the quality of planning of high-dose rate brachytherapy as a boost to external beam radiotherapy for locally and locally advanced prostate cancer using the RTOG-ASTRO Phoenix definition 
Purpose: To evaluated prognostic factors and impact of the quality of planning of high dose rate brachytherapy (HDR-BT) for patients with local or locally advanced prostate cancer treated with external beam radiotherapy (EBRT) and HDR-BT.
Methods and Materials: Between 1997 and 2005, 209 patients with biopsy proven prostate adenocarcinoma were treated with localized EBRT and HDR-BT at the Department of Radiation-Oncology, Hospital A. C. Camargo, Sao Paulo, Brazil. Patient's age, Gleason score (GS), clinical stage (CS), initial PSA (iPSA), risk group for biochemical failure (GR), doses of EBRT and HDR-BT, use of three-dimensional planning for HDR-BT (3DHDR) and the Biological Effective Dose (BED) were evaluated as prognostic factors for biochemical control (bC).
Results: Median age and median follow-up time were 68 and 5.3 years, respectively. Median EBRT and HDR-BT doses were 45 Gy and 20 Gy. The crude bC at 3.3 year was 94.2%. For the Low, intermediate and high risk patients the bC rates at 3.3 years were 91.5%, 90.2% and 88.5%, respectively. Overall survival (OS) and disease specific survival rates at 3.3 years were 97.8% and 98.4%, respectively. On univariate analysis the prognostic factors related bC were GR (p= 0.040), GS ≤ 6 (p= 0.002), total dose of HDR-BT ≥ 20 Gy (p< 0.001), 3DHDR (p< 0.001), BED-HDR ≥ 99 Gy1.5 (p<0.001) and BED-TT ≥ 185 (p<0.001). On multivariate analysis the statistical significant predictive factors related to bC were RG (p< 0.001), HDR-BT ≥ 20 Gy (p=0.008) and 3DHDR (p<0.001).
Conclusions: we observed that the bC rates correlates with the generally accepted risk factors described in the literature. Dose escalation, evaluated through the BED, and the quality of planning of HDR-BT are also important predictive factors when treating prostate cancer.
PMCID: PMC2424177  PMID: 18566673
high-dose rate brachytherapy; external beam radiotherapy; prostate cancer; RTOG-ASTRO Phoenix; biochemical failure; biochemical control
18.  Low-dose-rate or high-dose-rate brachytherapy in treatment of prostate cancer – between options 
Permanent low-dose-rate (LDR-BT) and temporary high-dose-rate (HDR-BT) brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never to be conducted comparing these two forms of brachytherapy, a comparative analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. The aim of this paper is to look for possible similarities and differences between both brachytherapy modalities. Indications and contraindications for monotherapy and for brachytherapy as a boost to external beam radiation therapy (EBRT) are presented. It is suggested that each of these techniques has attributes that advocates for one or the other. First, they represent the extreme ends of the spectrum with respect to dose rate and fractionation, and therefore have inherently different radiobiological properties. Low-dose-rate brachytherapy has the great advantage of being practically a one-time procedure, and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity. Low-dose-rate brachytherapy has been a gold standard for prostate brachytherapy in low risk patients since many years. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant long-term data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy.
Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy, using current dose regimens. At present, all available clinical data regarding these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates.
PMCID: PMC3635047  PMID: 23634153
brachytherapy; HDR; LDR; prostate cancer; seeds
19.  Comparison between preoperative and real-time intraoperative planning 125I permanent prostate brachytherapy: long-term clinical biochemical outcome 
The purpose of the study is to evaluate the long-term clinical outcome through biochemical no evidence of disease (bNED) rates among men with low to intermediate risk prostate cancer treated with two different brachytherapy implant techniques: preoperative planning (PP) and real-time planning (IoP).
From June 1998 to July 2011, 1176 men with median age of 67 years and median follow-up of 47 months underwent transperineal ultrasound-guided prostate 125I-brachytherapy using either PP (132) or IoP (1044) for clinical T1c-T2b prostate adenocarcinoma Gleason <8 and prostate-specific antigen (PSA) <20 ng/ml. Men with Gleason 7 received combination of brachytherapy, external beam radiation and 6-month androgen deprivation therapy (ADT). Biological effective dose (BED) was calculated using computerized tomography (CT)-based dosimetry 1-month postimplant. Failure was determined according to the Phoenix definition.
The 5- and 7-year actuarial bNED rate was 95% and 90% respectively. The 7-year actuarial bNED was 67% for the PP group and 95% for the IoP group (P < 0.001). Multivariate Cox regression analyses identified implant technique or BED, ADT and PSA as independent prognostic factors for biochemical failure.
Following our previous published results addressing the limited and disappointing outcomes of PP method when compared to IoP based on CT dosimetry and PSA kinetics, we now confirm the long-term clinical, bNED rates clear cut superiority of IoP implant methodology.
PMCID: PMC3904193  PMID: 24341548
Prostate cancer; Brachytherapy; Implant technique; Biochemical failure
20.  Determinants of change of prostate-specific antigen over time and its association with recurrence following external beam radiation therapy of prostate cancer in 5 large cohorts 
To assess the relationship between prognostic factors, post-radiation prostate-specific antigen (PSA) dynamics, and clinical failure following prostate cancer radiation therapy using contemporary statistical models.
Methods and materials
Data from 4,247 patients with 40,324 PSA measurements treated with external beam radiation monotherapy in five cohorts were analyzed. Temporal change of PSA following treatment completion was described by a specially developed linear mixed model (LMM), including standard prognostic factors. These factors, along with predicted PSA evolution, were incorporated into a Cox model to establish their predictive value for the risk of clinical recurrence over time.
Consistent relationships were found across cohorts. The initial PSA decline after radiation therapy was associated with baseline PSA and T-stage (p<0.001). The long-term PSA rise was associated with baseline PSA, T-stage and Gleason score (p<0.001). The risk of clinical recurrence increased with current level (p<0.001) and current slope of PSA (p<0.001). In a pooled analysis, higher doses of radiation were associated with a lower long-term PSA rise (p<0.001) but not with the risk of recurrence after adjusting for PSA trajectory (p=0.63). Conversely, after adjusting for other factors, increased age at diagnosis was not associated with long-term PSA rise (p=0.85) but directly associated with increased risk of recurrence (p<0.001).
LMM can be reliably used to construct typical patient PSA profiles following prostate cancer radiation therapy. Pre-treatment factors along with PSA evolution and the associated risk of recurrence provide an efficient and quantitative way to assess impact of risk factors on disease progression.
PMCID: PMC2757130  PMID: 19014779
Prostate cancer; Prostate-specific Antigen; PSA velocity; Radiation therapy; Prognostic calculator
21.  Clinical significance and treatment of biochemical recurrence after definitive therapy for localized prostate cancer 
Surgical oncology  2009;18(3):268-274.
Radical prostatectomy and external beam radiation therapy are the established and definitive interventions for clinically localized prostate cancer. These treatment modalities are yet subject to failure observed first by biochemical recurrence, defined by increases in the serum PSA level. We investigated the significance of biochemical recurrence after definitive therapy and the available salvage therapy options for cancer recurrence.
A literature search was performed in PubMed, and applicable studies addressing biochemical recurrence and salvage options after radical prostatectomy or external beam radiation therapy were reviewed.
After radical prostatectomy, a detectable serum PSA level indicates biochemical recurrence. Whether to administer salvage therapy locally or systemically depends largely on prognostic factors including PSA doubling time, Gleason’s score, pathologic stage, and the time interval between radical prostatectomy and biochemical recurrence. Early initiation of salvage therapy has been shown to significantly impact on cancer outcomes.
After external beam radiation therapy, no single PSA level can define biochemical recurrence. Instead, it has been defined by increases in the PSA level above the nadir. Following radiation therapy, PSA doubling time and Gleason score play important roles in determining the need for local versus systemic salvage therapy.
After the diagnosis of biochemical recurrence, it is critical to perform a timely clinical assessment using the prognostic factors mentioned above. Prompt initiation of salvage therapy may prevent subsequent clinical progression and prostate cancer-specific mortality.
PMCID: PMC3501211  PMID: 19394814
Prostate cancer; Radical prostatectomy; Radiation therapy; Biochemical recurrence; PSA recurrence; Salvage
22.  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
23.  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
24.  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
25.  Brachytherapy in the therapy of prostate cancer – an interesting choice 
Contemporary Oncology  2013;17(5):407-412.
Brachytherapy is a curative alternative to radical prostatectomy or external beam radiation [i.e. 3D conformal external beam radiation therapy (CRT), intensity-modulated radiation therapy (IMRT)] with comparable long-term survival and biochemical control and the most favorable toxicity. HDR brachytherapy (HDR-BT) in treatment of prostate cancer is most frequently used together with external beam radiation therapy (EBRT) as a boost (increasing the treatment dose precisely to the tumor). In the early stages of the disease (low, sometimes intermediate risk group), HDR-BT is more often used as monotherapy. There are no significant differences in treatment results (overall survival rate – OS, local recurrence rate – LC) between radical prostatectomy, EBRT and HDR-BT. Low-dose-rate brachytherapy (LDR-BT) is a radiation method that has been known for several years in treatment of localized prostate cancer. The LDR-BT is applied as a monotherapy and also used along with EBRT as a boost. It is used as a sole radical treatment modality, but not as a palliative treatment. The use of brachytherapy as monotherapy in treatment of prostate cancer enables many patients to keep their sexual functions in order and causes a lower rate of urinary incontinence. Due to progress in medical and technical knowledge in brachytherapy (“real-time” computer planning systems, new radioisotopes and remote afterloading systems), it has been possible to make treatment time significantly shorter in comparison with other methods. This also enables better protection of healthy organs in the pelvis. The aim of this publication is to describe both brachytherapy methods.
PMCID: PMC3934024  PMID: 24596528
HDR brachytherapy; LDR brachytherapy; prostate cancer; seeds

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