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.
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.
HIFU; prostate cancer; PSA
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.
Prostate cancer; Brachytherapy; PSA bounce; Post-dosimetry; UD90 (%)
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.
prostate cancer; monotherapy; sector analysis
The nadir prostate-specific antigen (PSA) at 1 year (nPSA12) was investigated as an early estimate of biochemical and clinical outcome after radiotherapy (RT) alone for localized prostate cancer.
From May 1989 to November 1999, 1000 men received 3D conformal RT alone (median, 76 Gy) with minimum and median follow-up periods of 26 and 58 months, respectively, from the end of treatment. The calculation of PSA doubling time (PSADT) was possible in 657 patients. Multivariate analyses (MVAs) via Cox proportional hazards regression were used to determine the association of nPSA12 to biochemical failure (BF; ASTRO definition), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality (OM). Dichotomization of nPSA12 was optimized by evaluating the sequential model likelihood ratio and P-values.
In MVA, nPSA12 as a continuous variable was independent of RT dose, T-stage, Gleason score, pretreatment initial PSA, age, and PSADT in predicting for BF, DM, CSM, and OM. Dichotomized nPSA12 (≤2 versus >2 ng/mL) was independently related to DM and CSM. Kaplan-Meier 10-year DM rates for nPSA12 ≤2 versus >2 ng/mL were 4% versus 19% (P < .0001).
nPSA12 is a strong independent predictor of outcome after RTalone for prostate cancer and should be useful in identifying patients at high risk for progression to metastasis and death.
prostate cancer; prostate-specific antigen nadir; 3D conformal radiotherapy; distant metastasis; cause-specific mortality
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.
Prostate cancer; androgen deprivation therapy; hormone-sensitive metastatic prostate cancer; PSA kinetics; Time to PSA nadir
To examine the rates of long-term biochemical recurrence-free survival (BRFS) with respect to isotope in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) and brachytherapy.
A total of 242 consecutive patients with intermediate-risk prostate cancer were treated with iodine-125 (125I) or palladium-103 (103Pd) implants after EBRT (range 45.0–50.4 Gy) from 1996 to 2002. Of the 242 patients, 119 (49.2%) were treated with 125I and 123 (50.8%) with 103Pd. Multivariate Cox regression analysis was used to analyze BRFS, defined according to the Phoenix definition (prostate-specific antigen nadir plus 2 ng/mL) with respect to Gleason score, stage, pretreatment prostate-specific antigen level, and source selection. Late genitourinary/gastrointestinal toxicities were assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale.
At a median follow-up of 10 years, the BRFS rate was 77.3%. A statistically significant difference was found in the 10-year BRFS rate between the 125I- and 103Pd-treated groups (82.7% and 70.6%, respectively; P = .001). The addition of hormonal therapy did not improve the 10-year BRFS rate (77.6%) compared with RT alone (77.1%; P = .22). However, a statistically significant difference in the BRFS rate was found with the addition of hormonal therapy to 103Pd, improving the 10-year BRFS rate for (73.8%) compared with 103Pd alone (69.1%; P = .008). On multivariate analysis, isotope type (103Pd vs 125I), pretreatment prostate-specific antigen level > 10 ng/mL, and greater tumor stage increased the risk of recurrence by 2.6-fold (P = .007), 5.9-fold (P < .0001), and 1.7-fold (P = .14), respectively.
125I renders a superior rate of BRFS compared with 103Pd when used with EBRT. Hormonal therapy does not provide additional benefit in patients with intermediate-risk prostate cancer treated with a combination of EBRT and brachytherapy, except for the addition of hormonal therapy to 103Pd.
To report the toxicity and long-term outcomes of dose-escalated intensity-modulated radiation therapy (IMRT) for patients with localised prostate cancer.
Methods and Materials
From 2001 to 2005, a total of 125 patients with histologically confirmed T1-3N0M0 prostate cancer were treated with IMRT to 74Gy at the Austin Health Radiation Oncology Centre. The median follow-up was 5.5 years (range 0.5–8.9 years). Biochemical prostate specific antigen (bPSA) failure was defined according to the Phoenix consensus definition (absolute nadir + 2ng/mL). Toxicity was scored according to the RTOG/EORTC criteria. Kaplan-Meier analysis was used to calculate toxicity rates, as well as the risks of bPSA failure, distant metastases, disease-specific and overall survival, at 5 and 8-years post treatment.
All patients completed radiotherapy without any treatment breaks. The 8-year risks of ≥ Grade 2 genitourinary (GU) and gastrointestinal (GI) toxicity were 6.4% and 5.8% respectively, and the 8-year risks of ≥ Grade 3 GU and GI toxicity were both < 0.05%. The 5 and 8-year freedom from bPSA failure were 76% and 58% respectively. Disease-specific survival at 5 and 8 years were 95% and 91%, respectively, and overall survival at 5 and 8 years were 90% and 71%, respectively.
These results confirm existing international data regarding the safety and efficacy of dose-escalated intensity-modulated radiation therapy for localised prostate cancer within an Australian setting.
dose escalation; IMRT; late effects; prostate cancer; toxicity; radiation
To quantify the impact of radiotherapy (RT) dose escalation on the timing of biochemical failure (BF) and distant metastasis (DM) for prostate cancer treated with RT alone.
Methods and Materials
A total of 667 men with clinically localized intermediate and high risk prostate cancer treated with 3D-conformal RT alone were retrospectively analyzed. The interval hazard rates of DM and biochemical failure (BF), using ASTRO and Phoenix (Nadir+2) definitions, were determined. Median follow-up was 77 months.
Multivariate analysis showed that increasing RT dose was independently associated with decreased ASTRO BF (P<.0001), Nadir+2 BF (P=.001), and DM (P=.006). The preponderance (85%) of ASTRO BF occurred at ≤4 years after RT, while Nadir+2 BF was more evenly spread over years 1-10, with 55% BF in ≤4 years. RT dose escalation caused a shift in the BF from earlier to later years. The interval hazard function for DM appeared to be biphasic (early and late peaks) overall and for the <74 Gy group. In patients receiving ≥74 Gy, there was a reduction in the risk of DM in both the early and late waves, although the late wave appears reduced to a greater degree.
The ASTRO definition of BF systematically underestimates late BF due to backdating. RT dose escalation diminished and delayed BF; the delay suggests that there may still be local persistence in some patients. For DM, higher RT dose reduced both the early and late waves, suggesting that persistence of local disease contributes to both.
Prostate cancer; Radiotherapy dose; Hazard function; Biochemical failure; Distant metastasis
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.
prostatic neoplasms; brachytherapy; magnetic resonance imaging
To report the clinical outcome of high dose rate brachytherapy as sole treatment for clinically localised prostate cancer.
Between March 2004 and January 2008, a total of 351 consecutive patients with clinically localised prostate cancer were treated with transrectal ultrasound guided high dose rate brachytherapy. The prescribed dose was 38.0 Gy in four fractions (two implants of two fractions each of 9.5 Gy with an interval of 14 days between the implants) delivered to an intraoperative transrectal ultrasound real-time defined planning treatment volume. Biochemical failure was defined according to the Phoenix Consensus and toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 3.
The median follow-up time was 59.3 months. The 36 and 60 month biochemical control and metastasis-free survival rates were respectively 98%, 94% and 99%, 98%. Toxicity was scored per event with 4.8% acute Grade 3 genitourinary and no acute Grade 3 gastrointestinal toxicity. Late Grade 3 genitourinary and gastrointestinal toxicity were respectively 3.4% and 1.4%. No instances of Grade 4 or greater acute or late adverse events were reported.
Our results confirm high dose rate brachytherapy as safe and effective monotherapy for clinically organ-confined prostate cancer.
Prostate cancer; Brachytherapy; High dose rate; Iridium; Monotherapy
To evaluate prognostic factors in salvage radiotherapy (RT) for patients with pre-RT prostate-specific antigen (PSA) < 1.0 ng/ml.
Between January 2000 and December 2009, 102 patients underwent salvage RT for biochemical failure after radical prostatectomy (RP). Re-failure of PSA after salvage RT was defined as a serum PSA value of 0.2 ng/ml or more above the postradiotherapy nadir followed by another higher value, a continued rise in serum PSA despite salvage RT, or initiation of systemic therapy after completion of salvage RT. Biochemical relapse-free survival (bRFS) was estimated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model.
The median follow-up period was 44 months (range, 11-103 months). Forty-three patients experienced PSA re-failure after salvage RT. The 4-year bRFS was 50.9% (95% confidence interval [95% CI]: 39.4-62.5%). In the log-rank test, pT3-4 (p < 0.001) and preoperative PSA (p = 0.037) were selected as significant factors. In multivariate analysis, only pT3-4 was a prognostic factor (hazard ratio: 3.512 [95% CI: 1.535-8.037], p = 0.001). The 4-year bRFS rates for pT1-2 and pT3-4 were 79.2% (95% CI: 66.0-92.3%) and 31.7% (95% CI: 17.0-46.4%), respectively.
In patients who have received salvage RT after RP with PSA < 1.0 ng/ml, pT stage and preoperative PSA were prognostic factors of bRFS. In particular, pT3-4 had a high risk for biochemical recurrence after salvage RT.
Prostate cancer; Radiotherapy; Radical Prostatectomy; PSA; Pathological tumor stage
To evaluate the efficacy of hypofractionated radiotherapy (HyRT) with or without image guided radiotherapy (IGRT) in intermediate risk prostate cancer.
105 patients were treated with HyRT, 43,8 Gy and 54,75 Gy were delivered to the seminal vescicles and to the prostate, respectively; 3,65 Gy/fraction three times weekly. All patients underwent 9 months hormonal therapy. Patient position was verified with daily kV cone beam CT in 69 patients (IGRT group). Acute and late toxicities were evaluated according to RTOG scale. Biochemical relapse was defined using PSA nadir + 2 ng/mL. The data were prospectively collected and retrospectively analyzed to evaluate the efficacy of IGRT.
After a median follow-up of 31 months the actuarial 3-year bNED was 93,7%. During RT, 10.5% and 7.6% of patients developed ≥Grade 2 rectal and urinary toxicities, respectively. The cumulative incidence of ≥Grade 2 late rectal and urinary toxicities at 3 years were 6,9%, and 10,8%, respectively. The incidence of ≥Grade 2 late rectal toxicities was significant reduced in the IGRT group (1,6% vs. 14,5%, p=0,021). Two patients developed Grade 3 urethral obstruction and one patient developed grade 3 rectal bleeding.
HyRT represents a well-tolerated treatment able to achieve a high bNED. The use of daily IGRT is beneficial for reducing the incidence of late toxicities.
Intermediate-risk prostate cancer; Hypofractionated radiotherapy; IGRT; 3D-CRT
Prostate cancer is the most common tumor in men. The most commonly used diagnostic and tumor recurrence marker is Prostate Specific Antigen (PSA). After surgical removal or radiation treatment, PSA levels drop (PSA nadir) and subsequent elevated or increased PSA levels are indicative of recurrent disease (PSA recurrence). For clinical follow-up and local care PSA nadir and recurrence is often hand calculated for patients, which can result in the application of heterogeneous criteria. For large datasets of prostate cancer patients used in clinical studies PSA measurements are used as surrogate measures of disease progression. In these datasets a method to measure PSA recurrence is needed for the subsequent analysis of outcomes data and as such need to be applied in a uniform and reproducible manner. This method needs to be simple and reproducible, and based on known aspects of PSA biology.
We have created a simple Perl-based algorithm for the calculation of post-treatment PSA outcomes results based on the initial PSA and multiple PSA values obtained after treatment. The algorithm tracks the post-surgical PSA nadir and if present, subsequent PSA recurrence. Times to PSA recurrence or recurrence free intervals are supplied in months.
Use of the algorithm is demonstrated with a sample dataset from prostate cancer patients. The results are compared with hand-annotated PSA recurrence analysis. The strengths and limitations are discussed.
The use of this simple PSA algorithm allows for the standardized analysis of PSA recurrence in large datasets of patients who have undergone treatment for prostate cancer. The script is freely available, and easily modifiable for desired user parameters and improvements.
To evaluate the influence of prostate-specific antigen (PSA) kinetics following maximal androgen blockade (MAB) on disease progression and cancer-specific survival in patients with metastatic, hormone-sensitive prostate cancer.
Materials and Methods
One hundred thirty-one patients with metastatic, hormone-sensitive prostate cancer treated with MAB at our institution were included in this study. Patients' characteristics, PSA at MAB initiation, PSA nadir, time to PSA nadir (TTN), and PSA decline were analyzed by using univariate and multivariate analysis.
At a median follow-up of 30 months, 97 patients (74.0%) showed disease progression and 65 patients (49.6%) died. Fifty-nine patients (45.0%) died from prostate cancer. In the univariate analysis, PSA at MAB initiation, PSA nadir, TTN, and PSA decline were significant predictors of progression-free survival. Also, PSA nadir, TTN, and PSA decline were significant predictors of cancer-specific survival. In the multivariate analysis, higher PSA nadir (≥0.2 ng/ml) and shorter TTN (<8 months) were independent predictors of shorter progression-free and cancer-specific survival. In the combined analysis of PSA nadir and TTN, patients with higher PSA nadir and shorter TTN had the worst progression-free survival (hazard ratio [HR], 14.098; p<0.001) and cancer-specific survival (HR, 14.050; p<0.001) compared with those with lower PSA nadir and longer TTN.
Our results suggest that higher PSA nadir level and shorter TTN following MAB are associated with higher risk of disease progression and poorer survival in patients with metastatic, hormone-sensitive prostate cancer. Furthermore, these two variables have a synergistic effect on the outcome.
Prognosis; Prostate-specific antigen; Prostatic neoplasms
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.
Prostate cancer; brachytherapy; high risk group; biochemical recurrence
Radical retropubic prostatectomy is considered by many centres to be the treatment of choice for men aged less than 70 years with localized prostate cancer. A rise in serum prostate-specific antigen after radical prostatectomy occurs in 10–40% of cases. This study evaluates the usefulness of novel ultrasensitive PSA assays in the early detection of biochemical relapse. 200 patients of mean age 61.2 years underwent radical retropubic prostatectomy. Levels ≤ 0.01 ng ml–1 were considered undetectable. Mean pre-operative prostate-specific antigen was 13.3 ng ml–1. Biochemical relapse was defined as 3 consecutive rises. The 2-year biochemical disease-free survival for the 134 patients with evaluable prostate-specific antigen nadir data was 61.1% (95% CI: 51.6–70.6%). Only 2 patients with an undetectable prostate-specific antigen after radical retropubic prostatectomy biochemically relapsed (3%), compared to 47 relapses out of 61 patients (75%) who did not reach this level. Cox multivariate analysis confirms prostate-specific antigen nadir ≤ 0.01 ng ml–1 to be a superb independent variable predicting a favourable biochemical disease-free survival (P < 0.0001). Early diagnosis of biochemical relapse is feasible with sensitive prostate-specific antigen assays. These assays more accurately measure the prostate-specific antigen nadir, which is an excellent predictor of biochemical disease-free survival. Thus, sensitive prostate-specific antigen assays offer accurate prognostic information and expedite decision-making regarding the use of salvage prostate-bed radiotherapy or hormone therapy. © 2000 Cancer Research Campaign http://www.bjcancer.com
prostate cancer; PSA nadir; radical retropubic prostatectomy
The purpose of this study was to determine the risk factors for rectal bleeding after prostate brachytherapy. Between April 2005 and September 2009, 89 patients with T1c-2cN0M0 prostate cancer were treated with permanent I-125 seed implantation alone. The prostate prescription dose was 145 Gy, and the grade of rectal bleeding was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Post-treatment planning was performed with fusion images of computerized tomography and magnetic resonance imaging 4–5 weeks after brachytherapy. Patient characteristics and dosimetric parameters were evaluated to determine risk factors for bleeding. The calculated parameters included the rectal volume in cubic centimeters that received >50–200% of the prescribed dose (RV50–200) and the minimal doses received by 1–30% of the rectal volume (RD1–30). The median follow-up time was 42 months (ranging 18–73 months). Grade 1 rectal bleeding occurred in 24 (27.0%) patients, but no Grade 2 or severe bleeding was observed. Usage of anticoagulants had a significant correlation with the occurrence of bleeding (P = 0.007). The RV100–150 and RD1–10 were significantly higher in patients with rectal bleeding than in those without bleeding. The RV100 was identified as a possible threshold value; the 3-year rectal bleeding rate in patients with an RV100 > 1.0 cm3 was 36%, whereas that with an RV100 ≤ 1.0 cm3 was 14% (P < 0.05). Although no Grade 2 morbidity developed in this study, the RV100 should be kept below 1.0 cm3, especially in additional dose-escalated brachytherapy.
prostate cancer; brachytherapy; rectal bleeding; dose-volume-histogram; anticoagulant
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.
Prostate cancer; Radiotherapy; Brachytherapy; Ir-192; Prostate-specific antigen; Hormone therapy
We previously showed that prostate-specific antigen (PSA) nadir after radical prostatectomy (RP) significantly predicts biochemical recurrence (BCR). Herein, we sought to explore the effect of including PSA nadir into commonly used models on their accuracy to predict BCR after RP.
This was a retrospective analysis of 943 and 1792 subjects from the Shared Equal Access Regional Cancer Hospital (SEARCH) and Duke Prostate Cancer (DPC) databases, respectively. The discrimination accuracy for BCR of seven previously published models was assessed using concordance index and compared with and without adding PSA nadir level in SEARCH. Using data from SEARCH, we developed a new nomogram incorporating PSA nadir to other known predictors (preoperative PSA, pathological Gleason score, PSA nadir level, surgical findings, prostate weight, body mass index and race) of BCR and externally validated it in the DPC.
In SEARCH, the mean concordance index across all seven nomograms was 0.687. After the inclusion of PSA nadir, the concordance index increased by nearly 7% (mean = 0.753). The concordance index of the new nomogram in SEARCH was 0.779 (bias-corrected = 0.767), which was 5% better than the next best model. In DPC, the new nomogram yielded a concordance index of 0.778.
The addition of postoperative PSA nadir to commonly used nomograms increased their accuracies by nearly 7%. Based upon this, we developed and externally validated a new nomogram, which was well calibrated and highly accurate, and is a potentially valuable tool for patients and physicians to predict BCR after RP.
disease-free survival; nomograms; prostate cancer; prostate-specific antigen; prostatectomy; validation studies
The present study compared the difference between intraoperative transrectal ultrasound (iTRUS)-based prostate volume and preplan computed tomography (CT), preplan magnetic resonance imaging (MRI)-based prostate volume to estimate the number of seeds needed for appropriate dose coverage in permanent brachytherapy for prostate cancer.
Materials and Methods
Between March 2007 and March 2011, among 112 patients who underwent permanent brachytherapy with 125I, 60 image scans of 56 patients who underwent preplan CT (pCT) or preplan MRI (pMRI) within 2 months before brachytherapy were retrospectively reviewed. Twenty-four cases among 30 cases with pCT and 26 cases among 30 cases with pMRI received neoadjuvant hormone therapy (NHT). In 34 cases, NHT started after acquisition of preplan image. The median duration of NHT after preplan image acquisition was 17 and 21 days for cases with pCT and pMRI, respectively. The prostate volume calculated by different modalities was compared. And retrospective planning with iTRUS image was performed to estimate the number of 125I seed required to obtain recommended dose distribution according to prostate volume.
The mean difference in prostate volume was 9.05 mL between the pCT and iTRUS and 6.84 mL between the pMRI and iTRUS. The prostate volume was roughly overestimated by 1.36 times with pCT and by 1.33 times with pMRI. For 34 cases which received NHT after image acquisition, the prostate volume was roughly overestimated by 1.45 times with pCT and by 1.37 times with pMRI. A statistically significant difference was found between preplan image-based volume and iTRUS-based volume (p < 0.001). The median number of wasted seeds is approximately 13, when the pCT or pMRI volume was accepted without modification to assess the required number of seeds for brachytherapy.
pCT-based volume and pMRI-based volume tended to overestimate prostate volume in comparison to iTRUS-based volume. To reduce wasted seeds and cost of the brachytherapy, we should take the volume discrepancy into account when we estimate the number of 125I seeds for permanent brachytherapy.
Brachytherapy; Prostate cancer; Prostate volume
Background. Perception remains that brachytherapy-based regimens are inappropriate for patients having increased risk of extracapsular extension (ECE). Methods. 321 consecutive intermediate and high-risk disease patients were treated between 1/92 and 2/97 by one author (M. Dattoli) and stratified by NCCN guidelines. 157 had intermediate-risk; 164 had high-risk disease. All were treated using the combination EBRT/brachytherapy ± hormones. Biochemical failure was defined using PSA >0.2 and nadir +2 at last followup. Nonfailing patients followup was median 10.5 years. Both biochemical data and original biopsy slides were independently rereviewed at an outside institution. Results. Overall actuarial freedom from biochemical progression at 16 years was 82% (89% intermediate, 74% high-risk) with failure predictors: Gleason score (P = .01) and PSA (P = .03). Hormonal therapy did not affect failure rates (P = .14). Conclusion. This study helps to strengthen the rationale for brachytherapy-based regimens as being both durable and desirable treatment options for such patients. Prospective studies are justified to confirm these positive results.
Periprostatic brachytherapy doses impact biochemical control. In this study, we evaluate extracapsular volumetric dosimetry following permanent prostate brachytherapy in patients entered in a multi-institutional community database.
Material and methods
In the database, 4547 patients underwent brachytherapy (3094 – 125I, 1437 – 103Pd and 16 – 131Cs). Using the originally determined prostate volume, a 5 mm, 3-dimensional peri-prostatic anulus was constructed around the prostate (except for a 2 mm posterior margin), and evaluated in its entirety and in 90° segments. Prostate dosimetric parameters consisted of a V100 and D90 while the annular dosimetry was reported as a V100.
The intraprostatic V100 and D90 for 103Pd, and 125I were statistically comparable when stratified by isotope and/or monotherapy vs. boost. The overall mean V100 for the periprostatic annulus was 62.8%. The mean V100 at the base (51.6%) was substantially less than the apex (73.5%) and midgland (65.9%). In addition, for all patients, the anterior V100 (45.7%) was less than the lateral (68.8%) and the posterior (75.0%). The geometric V100 annular differences were consistent when evaluated by isotope. Overall, the V100 was higher in the 125I cohort.
The optimal extracapsular brachytherapy dose and radial extent remains unknown, but will prove increasingly important with reductions and/or elimination of supplemental external beam radiation therapy. The large multi-institutional community database demonstrates periprostatic annular doses that are not as robust as those in selected high volume brachytherapy centers, and may be inadequate for optimal biochemical control following monotherapeutic brachytherapy, especially in higher risk patients.
brachytherapy; dosimetry; prostate cancer; treatment margins
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.
PATIENTS AND METHODS
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.
Laparoscopic radical prostatectomy; Ultrasensitive prostate specific antigen assay; Learning curve
To analyze the correlations among comorbidity and overall survival (OS), biochemical progression-free survival (b-PFS) and toxicity in elderly patients with localized prostate cancer treated with 125I brachytherapy.
Elderly men, aged ≥65 years, with low-intermediate risk prostate cancer, were treated with permanent 125I brachytherapy as monotherapy. Comorbidity data were obtained from medical reports using age-adjusted Charlson comorbidity index (a-CCI). The patients were categorized into two age groups (<75 and ≥75 years old), and two comorbidity score groups (a-CCI ≤3 and >3). Toxicity was scored with Radiation Therapy Oncology Group (RTOG) scale.
From June 2003 to October 2009, a total of 92 elderly patients underwent prostate brachytherapy, including 57 men (62%) with low-risk prostate cancer, and 35 men (38%) with intermediate-risk prostate cancer. The median age of patients was 75 years (range, 65-87 years). Forty-seven patients (51%) had a-CCI ≤3 and 45 patients (49%) a-CCI >3. With a median follow-up period of 56 months (range, 24-103 months), the 5-year actuarial OS and b-PFS were 91.3% and 92.4% respectively, without statistical significance between two Charlson score groups. Toxicity was mild. None of the patients experienced gastrointestinal (GI) toxicity, and only 4 patiens (4%) experienced late genitourinary (GU) grade-3 (G3) toxicity. No correlation between acute GU and GI toxicity and comorbidity was showed (P=0.50 and P=0.70, respectively).
Our data suggest that elderly men with low-intermediate risk prostate cancer and comorbidity can be considered for a radical treatment as 125I low-dose rate brachytherapy.
Prostate cancer; brachytherapy; elderly; comorbidity; toxicity; overall survival; biochemical control