TSPmap, a tool making use of traveling salesperson problem solvers in the efficient and accurate construction of high-density genetic linkage maps.

BACKGROUND: Recent advances in nucleic acid sequencing technologies have led to a dramatic increase in the number of markers available to generate genetic linkage maps. This increased marker density can be used to improve genome assemblies as well as add much needed resolution for loci controlling variation in ecologically and agriculturally important traits. However, traditional genetic map construction methods from these large marker datasets can be computationally prohibitive and highly error prone. RESULTS: We present TSPmap, a method which implements both approximate and exact Traveling Salesperson Problem solvers to generate linkage maps. We demonstrate that for datasets with large numbers of genomic markers (e.g. 10,000) and in multiple population types generated from inbred parents, TSPmap can rapidly produce high quality linkage maps with low sensitivity to missing and erroneous genotyping data compared to two other benchmark methods, JoinMap and MSTmap. TSPmap is open source and freely available as an R package. CONCLUSIONS: With the advancement of low cost sequencing technologies, the number of markers used in the generation of genetic maps is expected to continue to rise. TSPmap will be a useful tool to handle such large datasets into the future, quickly producing high quality maps using a large number of genomic markers.

Serum testosterone kinetics after brachytherapy for clinically localized prostate cancer.

PURPOSE: To evaluate temporal changes in testosterone after prostate brachytherapy and investigate the potential impact of these changes on response to treatment. METHODS AND MATERIALS: Between January 2008 and March 2009, 221 consecutive patients underwent Pd-103 brachytherapy without androgen deprivation for clinically localized prostate cancer. Prebrachytherapy prostate-specific antigen (PSA) and serum testosterone were obtained for each patient. Repeat levels were obtained 3 months after brachytherapy and at least every 6 months thereafter. Multiple clinical, treatment, and dosimetric parameters were evaluated to determine an association with temporal testosterone changes. In addition, analysis was conducted to determine if there was an association between testosterone changes and treatment outcomes or the occurrence of a PSA spike. RESULTS: There was no significant difference in serum testosterone over time after implant (p = 0.57). 29% of men experienced an increase ≥ 25%, 23% of men experienced a decrease ≥ 25%, and the remaining 48% of men had no notable change in testosterone over time. There was no difference in testosterone trends between men who received external beam radiotherapy and those who did not (p = 0.12). On multivariate analysis, preimplant testosterone was the only variable that consistently predicted for changes in testosterone over time. Men with higher than average testosterone tended to experience drop in testosterone (p < 0.001), whereas men with average or below average baseline testosterone had no significant change. There was no association between men who experienced PSA spike and testosterone temporal trends (p = 0.50) nor between initial PSA response and testosterone trends (p = 0.21). CONCLUSION: Prostate brachytherapy does not appear to impact serum testosterone over time. Changes in serum testosterone do not appear to be associated with PSA spike phenomena nor with initial PSA response to treatment; therefore, PSA response does not seem related to temporal testosterone changes.

Erectile dysfunction is predictive of all-cause mortality in patients with prostate cancer treated with permanent interstitial brachytherapy.

OBJECTIVE: To evaluate the relationship between pre-treatment erectile function and all-cause mortality in patients with prostate cancer treated with brachytherapy. PATIENTS AND METHODS: In all, 1279 consecutive patients with clinically localized prostate cancer and pre-implant erectile function assessed by the International Index of Erectile Function-6 (IIEF-6) underwent brachytherapy. Potency was defined as an IIEF-6 score of ≥13 without pharmacological or mechanical support. Patients were stratified into IIEF-6-score cohorts (≤12, 13-23 and 24-30). The median follow-up was 5.0 years. RESULTS: The 8-year overall survival (OS) of the study population was 85.1%. The 8-year OS for IIEF-6scores ≤12, 13-23 and 24-30 were 78.0%, 92.8% and 91.4%, respectively (P < 0.001). Cardiovascular events accounted for a significant portion of deaths in each IIEF-6 group. When combined with other risk factors for cardiovascular disease, an IIEF-6 score of ≤12 had an additive effect on all-cause mortality (IIEF-6 score of ≤12 and less than two comorbidities vs two or more comorbidities were 18.2% and 32.1%). CONCLUSIONS: A pre-implant IIEF-6score of ≤12 was associated with a higher incidence of all-cause mortality. Pre-treatment erectile dysfunction is a surrogate for underlying vascular pathology, probably explaining the lower OS in this subset of patients. Aggressive treatment of medical co-morbidity is warranted to impactOS.

The effect of pro-qura case volume on post-implant prostate dosimetry.

PURPOSE: To evaluate the effect of prostate brachytherapy case volume on postimplant dosimetric quality in Pro-Qura proctored programs. METHODS AND MATERIALS: From August 1999 to December 2008, the computed tomography datasets for 6,600 prostate implants performed by 129 brachytherapists were submitted to Pro-Qura for dosimetric analysis. Brachytherapists were divided into three roughly equal-sized terciles based on total case volume. Postimplant computed tomography scans were obtained at a median of 30 days. Excellent target coverage was defined by a V100≥90% and D90≥100% minimum prescribed peripheral dose. To determine if the number of excellent implants improved with increasing case numbers, each brachytherapist's series of implants was bisected into early and late experience by a moveable critical point. RESULTS: For the entire cohort, the mean V100 and D90 were 89.2% and 102.8%, respectively, with 47.7% of the implants scored as excellent. Brachytherapists in the highest-case tercile had a significantly greater fraction of excellent target coverage (57.9%) than did those in the two lower terciles (39.5% and 45.7%, p=0.015). Twenty-one (25.6%) of the 82 brachytherapists with sufficient case volume for dosimetric improvement analyses demonstrated quality improvement over time. Although there was no significant difference between prostate volume and seed strength, the number of seeds used was significantly greater in adequate implants. CONCLUSIONS: The highest-volume brachytherapists were most likely to obtain excellent target coverage. We are encouraged that in general practice, nearly 48% of all implants were scored excellent. It is conceivable that with greater expert third-party involvement, an even greater percentage of cases with excellent target coverage will become reality.

The incidence of transition zone prostate cancer diagnosed by transperineal template-guided mapping biopsy: implications for treatment planning.

OBJECTIVES: To report the incidence of transition zone (TZ) cancer in patients undergoing transperineal template-guided mapping biopsy (TTMB) of the prostate gland. METHODS: Five hundred thirty-nine consecutive patients underwent TTMB by means of an anatomic technique with sampling of 24 defined prostate regions. The position of each biopsy core was recorded in 3 dimensions. For every patient, the location of each positive biopsy core, the number of positive cores, the Gleason score, the percentage involvement of each core, and the presence/absence of perineural invasion was documented. RESULTS: The median volumetric prostate volume was 56.0 cm(3) with an ellipsoid TZ volume of 20.1 cm(3). The median number of TTMB cores was 58 with a median of 11 TZ cores. Two hundred eighty-seven (53.2%) were diagnosed with prostate cancer. TZ cancer was detected in 130 (45.3%) of patients with prostate cancer but only 6 (4.6%) were confined to the TZ. Overall, 38.9% of TZ cores were positive for malignancy. Of the TZ cancers, 37 (28.5%), 64 (49.2%), and 29 (22.3%) were assigned Gleason scores 6, 7, and 8-10. Compared with a standard 12-core biopsy approach, the results of the TZ biopsy upgraded the Gleason score in 24.6% of patients. Only 4 cancers (3.1%) involving the TZ were classified as clinically insignificant. CONCLUSIONS: Although only 4.6% of cancers were confined to the TZ, 45.3% of all prostate cancer patients had TZ involvement.

Postimplant rectal dosimetry is not dependent on 103Pd or 125I seed activity.

PURPOSE: In this study, the effect of prostate brachytherapy seed activity on postimplant rectal dosimetry was evaluated in Pro-Qura (Prostate Brachytherapy Quality Assurance; Seattle, WA) proctored, community-based programs. METHODS AND MATERIALS: Twenty-three hundred patients (1563 iodine-125 [(125)I] and 737 palladium-103 [(103)Pd]) from 78 brachytherapists with postimplant rectal dosimetry were identified. Seed activity was stratified into three tertiles for each isotope (≤0.300, 0.301-0.326, and >0.326 mCi/seed for (125)I and ≤1.330, 1.331-1.547, and >1.547 mCi/seed for (103)Pd). Postimplant dosimetry was performed in a standardized fashion. The rectum was contoured by outlining the outer rectal wall. The volume of the rectum receiving 100% of the prescription dose (R(100)) was calculated in cubic centimeters. The prostate V(100) and D(90) volumes were also calculated. RESULTS: The mean prostate volume was 35.8 and 32.3 cm(3) for (125)I and (103)Pd. The median time to postimplant CT was 30 days. For (125)I, the V(100) increased from 91.0% to 93.7% (p=0.012) and the D(90) increased from 105.9% to 108.7% (p<0.001) for the lowest to the highest (125)I seed activities. In contrast, no significant changes in V(100) (p=0.751) or D(90) (p=0.200) were discerned when stratified by seed activity. For both isotopes, there was no correlation between seed activity and R(100), and R(100) was highest for the intermediate seed activities. Overall, the R(100) was lower for (103)Pd vs. (125)I (0.63 vs. 0.82 cm(3), p<0.001). CONCLUSIONS: Within the confines of seed activities used in this study, higher activity seeds did not result in a deleterious effect on rectal dose. Higher activity seeds were associated with improved prostate dosimetry for (125)I, whereas (103)Pd dosimetry was not dependent on seed activity.

The correlation between annular treatment margins and biochemical failure in prostate brachytherapy patients with optimized intraprostatic dosimetry.

PURPOSE: To determine whether periprostatic treatment margins correlate with biochemical control in prostate brachytherapy patients with optimized intraprostatic dosimetry. METHODS AND MATERIALS: Nineteen biochemically failed brachytherapy patients were matched to 74 dosimetric and clinically equivalent nonfailures. The median followup time for the entire study population was 9.4 years. Eligibility requirements included a Day 0 intraprostatic D(90) of 100% or greater and V(100) of 90% or greater, absence of androgen deprivation therapy, and no evidence of distant metastasis in biochemically failed patients. A 5-mm annulus was constructed around the perimeter of each prostate. D(90) and V(100) at the anterior, posterior, superior, inferior, right lateral, and left lateral aspects of the annulus were evaluated for patients with biochemically controlled and failed disease. Biochemical progression-free survival (bPFS) was defined as a prostate-specific antigen level of 0.40ng/mL or less after nadir. D(90) and V(100) parameters were compared between the controlled and failed groups using logistic regression. Predictors of biochemical failure were identified using Cox regression. RESULTS: No statistically significant differences in prostate-specific antigen level, Gleason score, percent positive biopsies, or intraprostatic dosimetry were observed between the controlled and failed patients. The D(90) and V(100) at the anterior, posterior, superior, inferior, right lateral, and left lateral aspects of the annulus were not statistically different between biochemically controlled and failed groups. CONCLUSION: In this study, there was no relationship observed between annular dosimetry and biochemical control. It is unlikely that further radial dose intensification would have altered treatment outcome in this population of patients with optimized intraprostatic dosimetry.

Permanent prostate brachytherapy in prostate glands <20 cm(3).

PURPOSE: To investigate the dosimetry, treatment-related morbidity, and biochemical outcomes for brachytherapy in patients with prostate glands <20 cm(3). METHODS AND MATERIALS: From November 1996 to October 2006, 104 patients with prostate glands <20 cm(3) underwent brachytherapy. Multiple prostate, urethral, and rectal dosimetric parameters were evaluated. Treatment-related urinary and rectal morbidity were assessed from patient questionnaires. Cause-specific survival, biochemical progression-free survival, and overall survival were recorded. RESULTS: The median patient age, follow up, and pre-treatment ultrasound volume was 64 years, 5.0 years and 17.6cm(3), respectively. Median day 0 dosimetry was significant for the following: V100 98.5%, D90 126.1% and R100 <0.5% of prescription dose. The mean urethral and maximum urethral doses were 119.6% and 133.8% of prescription. The median time to International Prostate Symptom Score resolution was 4 months. There were no RTOG grade III or IV rectal complications. The cause-specific survival, biochemical progression-free survival, and overall survival rates were 100%, 92.5%, and 77.8% at 9 years. For biochemically disease-free patients, the median most recent postbrachytherapy PSA value was 0.02 ng/mL. CONCLUSION: Our results demonstrate that brachytherapy for small prostate glands is highly effective, with an acceptable morbidity profile, excellent postimplant dosimetry, acceptable treatment-related morbidity, and favorable biochemical outcomes.

cExternal beam radiation results in minimal changes in post void residual urine volumes during the treatment of clinically localized prostate cancer.

BACKGROUND: To evaluate the impact of external beam radiation therapy (XRT) on weekly ultrasound determined post-void residual (PVR) urine volumes in patients with prostate cancer. METHODS: 125 patients received XRT for clinically localized prostate cancer. XRT was delivered to the prostate only (n = 66) or if the risk of lymph node involvement was greater than 10% to the whole pelvis followed by a prostate boost (n = 59). All patients were irradiated in the prone position in a custom hip-fix mobilization device with an empty bladder and rectum. PVR was obtained at baseline and weekly. Multiple clinical and treatment parameters were evaluated as predictors for weekly PVR changes. RESULTS: The mean patient age was 73.9 years with a mean pre-treatment prostate volume of 53.3 cc, a mean IPSS of 11.3 and a mean baseline PVR of 57.6 cc. During treatment, PVR decreased from baseline in both cohorts with the absolute difference within the limits of accuracy of the bladder scanner. Alpha-blockers did not predict for a lower PVR during treatment. There was no significant difference in mean PVR urine volumes or differences from baseline in either the prostate only or pelvic radiation groups (p = 0.664 and p = 0.458, respectively). Patients with a larger baseline PVR (>40 cc) had a greater reduction in PVR, although the greatest reduction was seen between weeks one and three. Patients with a small PVR (<40 cc) had no demonstrable change throughout treatment. CONCLUSION: Prostate XRT results in clinically insignificant changes in weekly PVR volumes, suggesting that radiation induced bladder irritation does not substantially influence bladder residual urine volumes.

Prebiopsy PSA velocity not reliable predictor of prostate cancer diagnosis, Gleason score, tumor location, or cancer volume after TTMB.

OBJECTIVES: To evaluate the effect of prostate-specific antigen (PSA) velocity (PSAV) on prostate cancer diagnosis, Gleason score, tumor location, and cancer volume in men undergoing transperineal template-guided mapping biopsy (TTMB). PSAV has been associated with greater Gleason scores and greater prostate cancer-specific mortality. METHODS: From January 2005 through September 2007, 217 patients underwent TTMB. The inclusion criteria included a persistently elevated PSA level and/or diagnosis of atypical small acinar proliferation or high-grade prostatic intraepithelial neoplasia on previous biopsy. The prostate gland was arbitrarily divided into 24 regions, and a median of 58 cores were obtained per patient. The patients were divided into 3 velocity cohorts according to the following changes in PSA level in the year before biopsy: < or =0.0, 0.1-1.9, and > or =2.0 ng/mL. The PSAV was evaluated as a predictor for prostate cancer diagnosis, Gleason score, tumor volume, and cancer location. RESULTS: The mean patient age was 64.2 years, with a mean prebiopsy PSA level of 8.5 ng/mL. Prostate cancer was diagnosed in 97 patients (44.7%). The study population had undergone an average of 1.8 +/- 1.0 biopsies before TTMB. PSAV did not predict for prostate cancer diagnosis (P = .84), Gleason score (P = .78), the percentage of positive cores (P = .37), or tumor location. CONCLUSIONS: Among patients with persistently elevated PSA levels despite previously negative biopsy findings, PSAV did not reliably predict for a diagnosis of prostate cancer nor did it correlate with prostate cancer grade, volume, or location using TTMB.

Pretreatment serum testosterone and androgen deprivation: effect on disease recurrence and overall survival in prostate cancer patients treated with brachytherapy.

PURPOSE: Low testosterone has been implicated as a possible adverse prognostic factor in patients with newly diagnosed prostate cancer. We evaluated the impact of pretreatment serum testosterone on survival after prostate brachytherapy. METHODS AND MATERIALS: From October 2001 to November 2004, 619 patients underwent brachytherapy and 546 had a pretreatment serum testosterone level measured. Pretreatment serum testosterone levels were assigned by the following criteria: below-normal (n = 105), low normal (n = 246), mid normal (n = 132), high normal (n = 50), and above normal (n = 13). Median follow-up was 5.2 years. Cause of death was determined for each deceased patient. RESULTS: Six-year biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS) were 97.7%, 99.8%, and 89.2%. When comparing patients with low or low normal testosterone with those with average or higher testosterone, there was no significant difference in bPFS (97.6% vs. 98.4%; p = 0.72), CSS (99.8% vs. 100%; p = 0.72), or OS (88.9% vs. 90.8%; p = 0.73). Among patients with average and higher pretreatment testosterone, there was no significant difference in outcomes when comparing patients who did and did not receive androgen deprivation therapy (ADT). For patients with low or low normal testosterone levels, there was no significant difference in bPFS or CSS when comparing patients who did and did not receive ADT. However, there was a trend toward lower OS in patients with baseline lower testosterone levels who also received ADT (83.9% vs. 91.3%, p = 0.075). CONCLUSIONS: Low pretreatment testosterone levels alone did not affect disease recurrence or OS. Patients with baseline low testosterone who also were treated with ADT had a trend toward decreased OS.

Prostate cancer control and survival in Vietnam veterans exposed to Agent Orange.

BACKGROUND: In this study, we evaluated the impact of Agent Orange exposure on survival in Vietnam Veterans undergoing prostate brachytherapy. METHODS AND MATERIAL: From May 1995 to January 2005, 81 Vietnam veterans (29 with Agent Orange exposure and 52 without) and 433 nonveterans of comparable age (mean age, 58 years) underwent prostate brachytherapy. The mean follow-up was 5.0 years. Biochemical progression-free survival (bPFS) was defined as a prostate-specific antigen (PSA)< or =0.40ng/mL after nadir. Patients with metastatic prostate cancer or hormone refractory disease without obvious metastases who died of any cause were classified as died of prostate cancer. All other deaths were attributed to the immediate cause of death. Multiple parameters were evaluated for impact on survival. RESULTS: At 9 years, Agent Orange-exposed men were least likely to remain biochemically controlled (89.5%, 100%, and 97.2% in Agent Orange-exposed, nonexposed veterans, and nonveterans, respectively, p=0.012). No significant differences in cause-specific (CSS) (p=0.832) or overall survival (OS) (p=0.363) were discerned. In multivariate analysis, CSS was best predicted by Gleason Score and day 0 D(90), whereas Gleason Score, % positive biopsies, and D(90) predicted for bPFS. None of the evaluated parameters predicted for OS, however, a trend was identified for better OS in younger patients and those with a higher D(90). In addition, Agent Orange exposure did not predict for any of the survival parameters. To date, 22 patients have died (metastatic prostate cancer two, second malignancies nine, cardiovascular disease eight, trauma two, and pulmonary one). CONCLUSIONS: In this cohort of prostate brachytherapy patients, Agent Orange exposure did not statistically impact survival in multivariate analysis.

Analysis of the Pro-Qura Database: rectal dose, implant quality, and brachytherapist's experience.

PURPOSE: This study analyzed rectal dosimetry outcomes of Pro-Qura proctored implants to assess the achievability of proposed rectal dose constraints in the setting of standardized pre- and postimplant dosimetry in community-based brachytherapy programs. METHODS AND MATERIALS: From August 2005 to July 2007, 713 postimplant CT scans were evaluated from 26 brachytherapists actively participating in Pro-Qura. Postimplant dosimetry was performed in a standardized fashion. The entirety of the rectal wall was contoured and evaluated for dose. Rectal dose was defined in terms of the volume of the rectum receiving 100% of the prescription dose (R(100)). Criteria for implant adequacy for both (103)Pd and (125)I included a prostate the percentage of the prostate volume covered by the prescription dose (V(100))>80%, a prostate the maximum dose covering 90% of the prostate volume (D(90)) of 90-140%, and an R(100)<1.0cm(3) for early (Day 0-7) dosimetry and <1.3cm(3) for late (Day 20-45) dosimetry. RESULTS: Mean prostatic volume was 35.1cm(3). The mean time from implant to CT scan was 29.9 days (range, 0-45 days). The respective mean overall prostate V(100) and D(90) were 89% and 101%, respectively, and remained consistent for sequence groups 1 through 6. Overall, the mean R(100) was 0.97+/-1.04cm(3). The R(100) was 1.15cm(3) for sequence Group 1 and with each subsequent sequence group decreased with a nadir of 0.83cm(3) in sequence Group 6 (p=0.22). Rectal dosimetry was deemed inadequate in 39% of Group 1 implants but only 22% in Group 6 (p=0.016). The reduced rectal doses did not impact prostate gland coverage. CONCLUSIONS: Using standardized dosimetry, R(100) improved with increasing brachytherapist's experience, reaching a plateau after approximately 20 patients.

Effects of the time interval between prostate brachytherapy and postimplant dosimetric evaluation in community practice: analysis of the Pro-Qura database.

OBJECTIVE: To evaluate the influence of postimplant dosimetric timing on prostate brachytherapy quality in community practice. MATERIALS AND METHODS: The Pro-Qura database was stratified by multiple time intervals between the implant and postimplant dosimetric analysis. Postimplant dosimetry was performed in a standardized fashion. Criteria for implant adequacy included V(100) >80%, D(90) >90%, and V(150) <60% for I-125 and <75% for Pd-103. Implants with V(100) <80% and D(90) <90% were deemed "too cool." Implants were considered "too hot" if D(90) >140% of prescription dose and/or V(150) >150% for I-125 and >75% for Pd-103. RESULTS: For I-125, the average V(100) and D(90) increased from 88.6% to 89.8%, and 102.8% to 103.1% for day 0 and day 30 dosimetry. For Pd-103 implants the change was more pronounced, with V(100) and D(90) increasing from 81.6% to 87.8% (P < 0.001) and 88.7% to 100.0% (P < 0.001) for day 0, and day 30, respectively. The percentage of implants considered too cool based on a V(100) and D(90) criteria decreased from 18.8% and 26.9% on day 0 to 11.0% and 19.7% on day 30, respectively. Implants determined to be too hot based on a V(150) >60% (I-125)/>75% (Pd-103) or D(90) >140% were 16.4% and 2.2% on day 0 and 16.0% and 0.7% on day 30, respectively. CONCLUSION: In community-based brachytherapy programs, postimplant dosimetry performed at day 30 resulted in a statistically and clinically significant improvement in postimplant dosimetry compared with day 0. The influence of timing is substantially greater for Pd-103 than I-125.

Biochemical and functional outcomes following brachytherapy with or without supplemental therapies in men < or = 50 years of age with clinically organ-confined prostate cancer.

OBJECTIVES: Despite favorable long-term prostate brachytherapy outcomes, there remains a bias to recommend radical prostatectomy for young patients. Herein, we report cause-specific survival, biochemical progression-free survival (bPFS), overall survival and functional outcomes in men < or =50 years of age who underwent brachytherapy with or without supplemental therapies. METHODS: From October 1995 to November 2004, 42 consecutive patients < or =50 years of age underwent permanent interstitial brachytherapy. No patient underwent seminal vesicle biopsy or pathologic lymph node staging. The mean and median follow-up was 5.6 and 5.1 year. bPFS was defined as a prostate-specific antigen < or =0.40 ng/mL after nadir. Functional outcome determinations included urinary, bowel and erectile function evaluations. Multiple clinical, treatment and dosimetric parameters were evaluated for impact on survival. RESULTS: Cause-specific survival, bPFS, and overall survival for the entire cohort were 100%, 97.7%, and 100%, respectively. To date, only one patient has failed biochemically. Median time to International Prostate Symptom Score resolution was 3 months. No patient required a postimplant transurethral resection of the prostate or developed urinary incontinence. Two patients developed bulbomembtranous urethral strictures. The overall potency preservation rate was 75.6% (International Index of Erectile Function-6 >13 without mechanical or pharmacologic support). Bowel habits were reported to be the same or better than prior to treatment in 92.5% patients. No severe rectal complications requiring therapeutic intervention occurred. CONCLUSIONS: Men < or =50 years of age have favorable biochemical and functional outcomes following brachytherapy. Depending on risk group assignment, brachytherapy with or without supplemental therapies should be considered a viable option for all healthy men regardless of age.

Primary causes of death after permanent prostate brachytherapy.

PURPOSE: To evaluate the primary causes of death in low-risk (low-risk), intermediate-risk (intermediate-risk), and high-risk (high-risk) patients undergoing permanent prostate brachytherapy with or without supplemental therapies. METHODS AND MATERIALS: From April 1995 through November 2004, a total of 1,354 consecutive patients underwent prostate brachytherapy. All patients underwent brachytherapy >3 years before analysis. Of the patients, 532 (39.3%) received androgen deprivation therapy and 703 (51.9%) received supplemental radiation therapy. The median follow-up was 5.4 years. Multiple parameters were evaluated as predictors of cause-specific, biochemical progression-free, and overall survival. RESULTS: The 10-year cause-specific survival was 97.0% (99.7%, 99.0%, and 90.1% for low-risk, intermediate-risk, and high-risk patients). Overall survival was 76.7% (82.5%, 78.3%, and 67.6% for low-, intermediate-, and high-risk patients, respectively). The cumulative death rate for cardiovascular disease was 11.5% (8.7%, 9.3%, and 19.8% for low-, intermediate-, and high-risk patients). The death rate from second malignancies (nonprostate cancer) was 7.2% and was not substantially different when stratified by risk group. Death from all other causes was 6.5% for the entire cohort but 1.3%, 5.0%, and 10.8% for low-, intermediate-, and high-risk patients. In multivariate analysis, death from prostate cancer was best predicted by Gleason score and risk group, whereas death from cardiovascular disease, nonprostate cancer, and all other causes were most closely related to patient age and tobacco use. CONCLUSIONS: Although cardiovascular mortality was the predominant cause of death, prostate cancer was responsible for approximately 10% of all deaths. In particular, overall survival was poorest in the high-risk group. Although high-risk patients were most likely to die of prostate cancer, the divergence in overall survival between high-risk and lower-risk patients primarily resulted from an excess of cardiovascular deaths. Changes in lifestyle to improve cardiovascular health may improve overall survival in patients with clinically localized prostate cancer.

Prostate brachytherapy in men > or =75 years of age.

PURPOSE: To evaluate cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) in prostate cancer patients aged > or =75 years undergoing brachytherapy with or without supplemental therapies. METHODS AND MATERIALS: Between April 1995 and August 2004, 145 consecutive patients aged > or =75 years underwent permanent prostate brachytherapy. Median follow-up was 5.8 years. Biochemical progression-free survival was defined by a prostate-specific antigen level < or =0.40 ng/mL after nadir. Patients with metastatic prostate cancer or hormone-refractory disease without obvious metastases who died of any cause were classified as dead of prostate cancer. All other deaths were attributed to the immediate cause of death. Multiple clinical, treatment, and dosimetric parameters were evaluated for impact on survival. RESULTS: Nine-year CSS, bPFS, and OS rates for the entire cohort were 99.3%, 97.1%, and 64.5%, respectively. None of the evaluated parameters predicted for CSS, whereas bPFS was most closely predicted by percentage positive biopsies. Overall survival and non-cancer deaths were best predicted by tobacco status. Thirty-seven patients have died, with 83.8% of the deaths due to cardiovascular disease (22 patients) or second malignancies (9 patients). To date, only 1 patient (0.7%) has died of metastatic prostate cancer. CONCLUSIONS: After brachytherapy, high rates of CSS and bPFS are noted in elderly prostate cancer patients. Overall, approximately 65% of patients are alive at 9 years, with survival most closely related to tobacco status. We believe our results support an aggressive locoregional approach in appropriately selected elderly patients.

Role of trospium chloride in brachytherapy-related detrusor overactivity.

OBJECTIVES: After prostate brachytherapy, pronounced urinary irritative symptomatology occurs in a substantial minority of patients. In this study, we evaluated the impact of trospium chloride in prostate brachytherapy patients with symptoms consistent with an overactive bladder (OAB). METHODS: From January 1999 through December 2005, 69 permanent prostate brachytherapy patients were identified who received trospium as first-line treatment for OAB. The median interval from implant to initiation of trospium was 23.4 months. Before trospium, we obtained a postvoid residual urine assessment (PVR) and International Prostate Symptom Score (IPSS) for all patients. IPSS resolution was defined as a return to within 2 points of the pre-brachytherapy value and individual IPSS question resolution was defined by a decrease of at least 1 point. RESULTS: The mean patient age was 66.0 years, with a pre-brachytherapy prostate volume of 31.0 cm(3) and a mean preimplant IPSS of 6.5. At trospium initiation, the mean IPSS was 9.6 with a mean PVR of 12.3 mL. IPSS normalization was documented in 55 (79.7%) patients. Twelve months after trospium initiation, the IPSS had decreased by a mean of 4.3 points with the improvement most pronounced for urgency. After trospium, no clinically significant differences were noted in the mean PVR. Twenty-two patients discontinued trospium as a result of the absence of a clinical response or pharmacologic side effects, or after complete resolution of symptoms. CONCLUSIONS: Nearly 80% of patients with brachytherapy-related detrusor overactivity responded favorably to trospium with improvements in IPSS (especially urgency). This was accomplished with an acceptable morbidity profile.

Obesity is not predictive of overall survival following permanent prostate brachytherapy.

PURPOSE: To evaluate the impact of obesity on cause-specific (CSS), biochemical progression-free (bPFS), and overall survival (OS) following prostate brachytherapy. MATERIALS AND METHODS: From April 1995 through March 2003, 1093 consecutive patients underwent brachytherapy for clinical T1b-T3a (2002 AJCC) prostate cancer. The median follow-up was 5.6 years. Evaluated body mass index (BMI) subgroups were < 25 (n = 258), 25.0 to 29.9 (n = 547), 30.0 to 34.9 (n = 214), and > or = 35 (n = 74) kg/m2, respectively. A total of 430 (39.9%) and 589 (53.9%) of the patients received androgen deprivation therapy or supplemental external beam radiation therapy, respectively. Multiple clinical, treatment, and dosimetric parameters were evaluated as predictors of CSS, bPFS, and OS. RESULTS: The 11-year CSS, bPFS, and OS for the entire cohort were 97.5%, 95.6%, and 77.6%, respectively. BMI did not impact CSS or bPFS for any of the BMI cohorts. However, OS was statistically lower in patients with a BMI < 25 kg/m2 (P = 0.014). A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS while percent-positive biopsies, risk group, V100 and hypertension predicted for bPFS. Patient age and tobacco use were the strongest predictors of OS. A total of 128 patients have died with 108 (84.4%) of the deaths the result of cardiovascular/pulmonary disease (73) and second malignancies (35). To date, 12 patients have died of metastatic prostate cancer. CONCLUSION: Obesity did not impact CSS, bPFS, or OS in patients treated with permanent prostate brachytherapy. Cardiovascular or pulmonary disease and second malignancies substantially outweighed prostate cancer as competing causes of death.

Dosimetry of an extracapsular anulus following permanent prostate brachytherapy.

PURPOSE: Recent studies have suggested that extracapsular brachytherapy treatment margins correlate with biochemical control. It is likely that volumetric geographic dosimetric parameters will be more robust than selected radial measurements. Accordingly, we evaluated extracapsular volumetric dosimetric parameters in low-risk patients. MATERIALS AND METHODS: A total of 263 low-risk prostate cancer patients randomized to Pd-103 versus I-125 were implanted with a brachytherapy target volume consisting of the prostate with a 5-mm periprostatic margin. The median follow-up was 4.2 years. All patients were implanted at least 3 years prior to analysis. Within 2 hours of implantation, an axial CT was obtained for postimplant dosimetry. A 5-mm three-dimensional periprostatic anulus was constructed around the prostate and evaluated in its entirety and in 90 degrees segments. Prostate and anular dosimetric parameters consisted of V100/V150/V200 and D90. Biochemical progression-free survival (bPFS) was defined as a PSA < or =0.50 ng/mL after nadir. RESULTS: The Pd-103 and I-125 arms were well-matched in terms of clinical, biochemical, and pathologic presentation. Six-year bPFS was 96.8% versus 99.2% for I-125 versus Pd-103 (P = 0.149). The most recent median posttreatment PSA was <0.04 ng/mL for both isotopes. No significant differences in postoperative anular doses were discerned between bPFS and failed patients. CONCLUSIONS: A postimplant 5-mm, three-dimensional periprostatic anulus provides substantial information regarding dosimetric coverage. However, with a median follow-up of 4.2 years, such volumetric and geographic parameters have not proven useful in predicting biochemical outcome in low-risk patients.