Publications by authors named "Michelle Braccioforte"

38 Publications

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

JAMA Netw Open 2021 Jul 1;4(7):e2115312. Epub 2021 Jul 1.

Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown.

Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment.

Design, Setting, And Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020.

Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT).

Main Outcomes And Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models.

Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001).

Conclusions And Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251338PMC
July 2021

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

Eur Urol 2021 Aug 10;80(2):142-146. Epub 2021 May 10.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2021.04.035DOI Listing
August 2021

Long-term outcomes of a prospective randomized trial of Cs/I permanent prostate brachytherapy.

Brachytherapy 2021 Jan-Feb;20(1):38-43. Epub 2020 Oct 12.

Department of Radiation Oncology, Perelman Center for Advanced Medicine, University of Pennsylvania Philadelphia, PA. Electronic address:

Purpose: Iodine-125 (I) is the most commonly used isotope for prostate brachytherapy (BT). Cesium-131 (Cs) has a higher dose rate and shorter dose delivery time resulting in decreased duration of acute urinary morbidity. Long-term data suggest excellent oncologic outcomes; it is not known how outcomes compare. A prospective randomized trial comparing the two isotopes was initiated.

Materials And Methods: Patients with low- or intermediate-risk disease were treated with a BT in a single outpatient facility. Prescription dose was 144 Gy for I and 115 Gy for Cs. Androgen deprivation or supplemental EBRT was not allowed. The primary study objective was comparison of the mean EPIC Urinary Domain Score. Secondary objective was biochemical relapse-free survival (BRFS) comparison. Time-to-event for all outcomes of interest was measured from implant date.

Results: One hundred forty men were enrolled; 81.4% were low-risk and 18.6% were intermediate-risk. The median followup was 97 months. Urinary and sexual health-related quality of life did not differ between isotopes at any recorded time point. At 2 months after implantation, bowel health-related quality of life was worse with I; however, this difference was lost at subsequent time points. The 9-year BRFS was 87.2% and 84.0% for the I and Cs group, respectively (p = 0.897). There was no statistically significant difference in BRFS based on initial T stage, PSA, or Gleason score.

Conclusions: Short- and long-term urinary, sexual, and bowel quality of life, as well as long-term biochemical control were comparable between I and Cs. This report therefore supports the continued use of Cs as an effective and comparable alternative isotope.
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http://dx.doi.org/10.1016/j.brachy.2020.07.005DOI Listing
October 2020

Long-term biochemical outcomes using cesium-131 in prostate brachytherapy.

Brachytherapy 2019 Nov - Dec;18(6):800-805. Epub 2019 Aug 16.

Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD. Electronic address:

Purpose: Long-term outcomes reveal equivalent biochemical outcomes with low-dose-rate (LDR) brachytherapy (BT) compared with radical prostatectomy and external-beam radiotherapy for the management of prostate cancer. Iodine-125, the most commonly used isotope, may be associated with long-term urinary consequences. Cesium-131 (Cs) has a higher dose rate and shorter dose delivery time, predicting a shorter duration of urinary morbidity. We report our institution's high-volume experience and the most mature data to date on outcomes with Cs prostate BT.

Methods And Materials: 571 men (median age: 65.38 years) with low (55%)-, intermediate (36%)-, and high-risk disease (9%) received monobrachytherapy, dual-modality, or trimodality using Cs at a single institution. Risk groups were defined according to the National Comprehensive Cancer Network definition. Median prescription dose for definitive LDR-BT and LDR-BT boost was 115 Gy and 70 Gy, respectively. Median initial PSA was 6.1 ng/mL (IQR: 4.6-8.7).

Results: Median followup time was 5 years. 5/7-year overall survival for low-, intermediate-, and high-risk patients was 96.9%/96/9%, 92.8%/89.7%, and 95.8%/87.1%, respectively (p = 0.02). 5/7-year freedom from biochemical failure for low-, intermediate-, and high-risk patients was 98.5%/96.3%, 94.1%/86.4%, and 93.2%/74.5%, respectively (p < 0.01). 5/7-year prostate cancer -specific survival was 100%/100%, 99.3%/99.3%, and 98.0%/98.0% for low-, intermediate-, and high-risk patients, respectively (p < 0.01).

Conclusions: Cs is a viable alternative isotope for prostate brachytherapy for organ-confined disease. Long-term biochemical control and survival outcomes are excellent and on par with those attained with the use of I or Pd. This report therefore supports the continued use of Cs as an effective and comparable alternative isotope.
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http://dx.doi.org/10.1016/j.brachy.2019.07.002DOI Listing
April 2020

Surgery vs Radiotherapy in the Management of Biopsy Gleason Score 9-10 Prostate Cancer and the Risk of Mortality.

JAMA Oncol 2019 02;5(2):213-220

Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: It is unknown how treatment with radical prostatectomy (RP) and adjuvant external beam radiotherapy (EBRT), androgen deprivation therapy (ADT), or both (termed MaxRP) compares with treatment with EBRT, brachytherapy, and ADT (termed MaxRT).

Objective: To investigate whether treatment of Gleason score 9-10 prostate cancer with MaxRP vs MaxRT was associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) risk.

Design, Setting, And Participants: The study cohort comprised 639 men with clinical T1-4,N0M0 biopsy Gleason score 9-10 prostate cancer. Between February 6, 1992, and April 26, 2013, a total of 80 men were consecutively treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were consecutively treated with RP and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. Follow-up started on the day of prostate EBRT or RP and concluded on October 27, 2017.

Exposures: Of the 559 men managed with RP and pelvic lymph node dissection, 88 (15.7%) received adjuvant EBRT, 49 (8.8%) received ADT, and 50 (8.9%) received both.

Main Outcomes And Measures: Treatment propensity score-adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index.

Results: The cohort included 639 men, with a mean (SD) age of 65.83 (6.52) years. After median follow-ups of 5.51 years (interquartile range, 2.19-6.95 years) among 80 men treated with MaxRT and 4.78 years (interquartile range, 4.01-6.05 years) among 559 men treated with RP-containing treatments, 161 men had died, 106 (65.8%) from prostate cancer. There was no significant difference in the risk of PCSM (adjusted hazard ratio, 1.33; 95% CI, 0.49-3.64; P = .58) and ACM (adjusted hazard ratio, 0.80; 95% CI, 0.36-1.81; P = .60) when comparing men who underwent MaxRP vs MaxRT, with plausibility indexes for equivalence of 76.75% for the end point of the risk of PCSM and 77.97% for the end point of the risk of ACM. Plausibility indexes for all other treatment comparisons were less than 63%.

Conclusions And Relevance: Results of this study suggest that it is plausible that treatment with MaxRP or MaxRT for men with biopsy Gleason score 9-10 prostate cancer can lead to equivalent risk of PCSM and ACM.
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http://dx.doi.org/10.1001/jamaoncol.2018.4836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439553PMC
February 2019

Long-term outcomes analysis of low-dose-rate brachytherapy in clinically T3 high-risk prostate cancer.

Brachytherapy 2018 Nov - Dec;17(6):882-887. Epub 2018 Aug 22.

Prostate Cancer Foundation of Chicago, Westmont, IL.

Purpose: The available data demonstrating that superiority of LDR brachytherapy (LDR-BT) boost in high-risk prostate cancer patients under represents patients with extracapsular extension (T3a) and/or seminal vesicle invasion (T3b) have been limited. We report long-term clinical outcomes data for patients with cT3a/b disease receiving LDR-BT.

Methods And Materials: Ninety-nine men (median age: 69.4 years) with cT3a/bN0M0 high-risk prostate adenocarcinoma received definitive LDR-BT or LDR-BT boost after external beam radiation therapy (EBRT) at a single institution between 1998 and 2007. About 86% of patients received androgen deprivation therapy. Freedom from biochemical failure (FFBF), prostate cancer-specific survival (PCSS), and overall survival (OS) was calculated using the Kaplan-Meier method with the Phoenix definition used as definition of failure. Cox regression analysis was used to compare outcomes between clinical stage, initial PSA, Gleason Score, and percent core positive rate.

Results: With a median followup of 7 years, 7-year rate of FFBF, PCSS, and OS for the entire cohort was 65.2% (±5.6%), 90.1% (±3.6%), and 77.9% (±4.7%), respectively. LDR-BT boost patients achieved a 7-year FFBF rate of 73.5 (±6.5%). No significant difference in outcomes was present between T3a or T3b disease, Gleason score, iPSA stratification and percent core positive rates.

Conclusions: LDR-BT, primarily as a boost in conjunction with ADT and EBRT, is not only feasible, but also highly effective in men with cT3a and cT3b high-risk prostate cancer resulting in excellent biochemical control and survival outcomes. LDR-BT boost implantation of patients should be strongly considered for cT3 patients given the merits of trimodality care.
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http://dx.doi.org/10.1016/j.brachy.2018.07.001DOI Listing
April 2019

Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer.

Urol Oncol 2018 04 21;36(4):157.e15-157.e20. Epub 2017 Dec 21.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Purpose/objective(s): Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset.

Materials/methods: We identified 3,723 patients with intermediate risk prostate cancer treated with BT between 1997 and 2013, including 1,989 and 1,734 patients with FIR and UIR disease, respectively. For the FIR cohort, Fine and Gray's competing risks regression model was used to evaluate whether there was a difference in prostate cancer specific mortality (PCSM) between BT vs. BT + supplemental therapy (ADT, EBRT, or both). For the UIR cohort, this regression model was used to evaluate whether supplemental ADT, EBRT, or both decreased PCSM beyond BT alone. Both regression models were adjusted for clinical and treatment-related factors.

Results: The median follow-up periods were 7.7 years (interquartile range: 5.4-10.5) for the FIR cohort and 7.8 years (interquartile range: 5.3-10.6) for the UIR cohort. For the FIR cohort, there was no difference in PCSM between BT monotherapy vs. BT + supplemental therapy (adjusted hazard ratio [AHR] = 1.70; 95% CI: 0.46-6.29; P = 0.43). For the UIR cohort, supplemental EBRT (AHR = 2.66; 95% CI: 1.12-6.34; P = 0.03), ADT (AHR = 0.96; 95% CI: 0.38-2.43; P = 0.93), or both (AHR = 1.46; 95% CI: 0.42-5.01; P = 0.55) were not associated with improved PCSM compared with BT alone.

Conclusion: In our analysis, supplemental therapies did not offer an improvement in PCSM compared with BT alone for FIR or UIR prostate cancers. Further prospective clinical trials are required to determine whether BT monotherapy may be sufficient for a subset of patients with UIR disease.
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http://dx.doi.org/10.1016/j.urolonc.2017.11.022DOI Listing
April 2018

Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the Risk of Prostate Cancer-Specific Mortality Stratified by the Extent of Competing Mortality.

Int J Radiat Oncol Biol Phys 2016 11 22;96(4):778-784. Epub 2016 Aug 22.

Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is the standard of care for men with intermediate- and high-risk prostate cancer (PC). However, whether competing mortality (CM) affects the ability of ADT to improve, survival remains unanswered.

Methods And Materials: We calculated a CM risk score using a Fine-Gray semiparametric model that included age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for nonmetastatic PC. Fine and Gray competing risk regression analysis was used to assess whether ADT reduced the risk of PC-specific mortality for men with a low versus a high risk of CM among the 4550 patients within the intermediate- and high-risk cohort after adjustment for established PC prognostic factors, year of treatment, site, and ADT propensity score.

Results: After a median follow-up of 8.4 years, 1065 men had died, 89 (8.36%) of PC. Among the men with a low CM score, ADT use was associated with a significant reduction in the risk of PC-specific mortality (adjusted hazard ratio 0.35, 95% confidence interval 0.14-0.87, P=.02) but was not for men with high CM (adjusted hazard ratio 1.33, 95% confidence interval 0.77-2.30, P=.30).

Conclusions: Adding ADT to high-dose RT appears to be associated with decreased PC-specific mortality risk in men with a low but not a high CM score. These data should serve to heighten awareness about the importance of considering competing risks when determining whether to add ADT to RT for older men with intermediate- or high-risk PC.
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http://dx.doi.org/10.1016/j.ijrobp.2016.08.014DOI Listing
November 2016

Race and mortality risk after radiation therapy in men treated with or without androgen-suppression therapy for favorable-risk prostate cancer.

Cancer 2016 Dec 4;122(23):3608-3614. Epub 2016 Aug 4.

Department of Radiation Oncology, Brigham and Women's Hospital-Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: African American (AA) men are more likely than non-AA men to have a comorbid illness that could interact with androgen-deprivation therapy (ADT) and shorten survival. This study assessed the impact that race had on the risk of all-cause mortality (ACM) and other-cause mortality (OCM) among men definitively treated for favorable-risk prostate cancer (PC).

Methods: Between 1997 and 2013, 7252 men with low-risk or favorable intermediate-risk PC were treated with brachytherapy with neoadjuvant ADT (n = 1501) or without neoadjuvant ADT (n = 5751) for a 4-month median duration. Cox and Fine-Gray multivariate regressions were used to analyze whether the risk of ACM and OCM increased among AA men versus non-AA men receiving ADT; adjustments were made for the age at brachytherapy, year of brachytherapy, cardiometabolic comorbidity status, risk group, and ADT treatment propensity score.

Results: After a median follow-up of 8.04 years, 869 men (12.0%) died: 48 (5.52%) of PC and 821 (94.48%) of other causes. There was a significant association between AA race and an increased risk of both ACM (adjusted hazard ratio [AHR], 1.77; 95% confidence interval [CI], 1.06-2.94; P = .028) and OCM (AHR, 1.86; 95% CI, 1.08-3.19; P = .024) among AA men versus non-AA men who received ADT but not among those who did not receive ADT (AHR for ACM, 1.33; 95% CI, 0.93-1.91; P = .12; AHR for OCM, 1.39; 95% CI, 0.96-2.02; P = .08).

Conclusions: ADT use may shorten survival in AA men with favorable-risk PC; therefore, its reservation for the treatment of higher risk PC, for which level 1 evidence supports its use, should be considered. Cancer 2016;122:3608-14. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30224DOI Listing
December 2016

Influence of Comorbidity on the Risk of Mortality in Men With Unfavorable-Risk Prostate Cancer Undergoing High-Dose Radiation Therapy Alone.

Int J Radiat Oncol Biol Phys 2016 07 11;95(4):1158-67. Epub 2016 Mar 11.

Department of Radiation Oncology, Brigham and Women's Hospital-Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: To explore whether a subgroup of men with unfavorable-risk prostate cancer (PC) exists in whom high-dose radiation therapy (RT) alone is sufficient to avoid excess PC death due to competing risk from cardiometabolic comorbidity.

Methods And Materials: This was a cohort study of 7399 men in whom comorbidity (including congestive heart failure, diabetes mellitus, or myocardial infarction) was assessed and recorded with T1-3NxM0 PC treated with brachytherapy with or without neoadjuvant RT, October 1997 to May 2013 at a single providing institution. Cox and competing risks regression analyses were used to assess whether men with unfavorable-intermediate/high-risk versus favorable-intermediate/low-risk PC were at increased risk of PC-specific, all-cause, or other-cause mortality (PCSM, ACM, OCM), adjusting for number of comorbidities, age at and year of brachytherapy, RT use, and an RT treatment propensity score.

Results: After a median follow-up of 7.7 years, 935 men died: 80 of PC and 855 of other causes. Among men with no comorbidity, PCSM risk (adjusted hazard ratio [AHR] 2.74 [95% confidence interval (CI) 1.49-5.06], P=.001) and ACM risk (AHR 1.30 [95% CI 1.07-1.58], P=.007) were significantly increased in men with unfavorable-intermediate/high-risk PC versus favorable-intermediate/low-risk PC, with no difference in OCM (P=.07). Although PCSM risk was increased in men with 1 comorbidity (AHR 2.87 [95% CI 1.11-7.40], P=.029), ACM risk was not (AHR 1.03 [95% CI 0.78-1.36], P=.84). Neither PCSM risk (AHR 4.39 [95% CI 0.37-51.98], P=.24) or ACM risk (AHR 1.43 [95% CI 0.83-2.45], P=.20) was increased in men with 2 comorbidities.

Conclusions: To minimize death from PC, high-dose RT alone may be sufficient treatment in men with 2 or more cardiometabolic comorbidities and unfavorable-intermediate- and high-risk PC.
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http://dx.doi.org/10.1016/j.ijrobp.2016.03.004DOI Listing
July 2016

Comorbidity and the Receipt of Curative Therapy for Favorable-risk Prostate Cancer Prior to and Following the Publication of PIVOT.

Eur Urol Focus 2018 01 3;4(1):64-67. Epub 2016 Mar 3.

Department of Radiation Oncology, Brigham and Women's Hospital-Dana-Farber Cancer Institute, Boston, MA, USA.

The publication of the randomized Prostate Cancer Intervention Versus Observation Trial (PIVOT) in July 2012, in which men with favorable-risk prostate cancer (PCa) were not found to benefit from radical prostatectomy, had the potential to shift PCa practice patterns. Using a prospectively assembled database of 5398 men with low-risk or favorable intermediate-risk PCa selected for curative treatment with brachytherapy in the years preceding and the year following the publication of PIVOT, we evaluated the odds of receiving curative treatment after adjusting for risk group (favorable intermediate vs low), race (black, Hispanic, or other), number of cardiometabolic comorbidities, and age. Following publication, the receipt of curative treatment was significantly lower (adjusted odds ratio [AOR]: 0.40; 95% confidence interval [CI], 0.16-0.99; p=0.05) among men with at least two cardiometabolic comorbidities, in contrast to the increasing trend (p=0.02) noted prior to PIVOT. Among black men, a subgroup at risk for occult high-grade disease, the odds of receiving curative treatment increased after PIVOT (AOR: 1.55; 95% CI, 1.06-2.26; p=0.02). These observations suggest that PIVOT's publication appropriately contributed to decreasing the use of curative treatment in men unlikely to benefit.

Patient Summary: The Prostate Intervention Versus Observation Trial (PIVOT) showed that radical prostatectomy did not benefit men with favorable-risk prostate cancer. Following the publication of PIVOT, the selection of men with multiple medical issues for curative treatment declined, whereas treatment of men at high risk of having aggressive prostate cancer increased.
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http://dx.doi.org/10.1016/j.euf.2016.02.007DOI Listing
January 2018

Definition and Validation of "Favorable High-Risk Prostate Cancer": Implications for Personalizing Treatment of Radiation-Managed Patients.

Int J Radiat Oncol Biol Phys 2015 Nov 29;93(4):828-35. Epub 2015 Jul 29.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Purpose: To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease.

Methods And Materials: We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer-specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database.

Results: Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268).

Conclusions: Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.
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http://dx.doi.org/10.1016/j.ijrobp.2015.07.2281DOI Listing
November 2015

Gleason Score 3 + 5 or 5 + 3 versus 4 + 4 Prostate Cancer: The Risk of Death.

Eur Urol 2016 06 19;69(6):976-9. Epub 2015 Sep 19.

Department of Radiation Oncology, Brigham and Women's Hospital-Dana Farber Cancer Institute, Boston, MA, USA.

Unlabelled: The International Society of Urological Pathology recommends that Gleason score (GS) 8 prostate cancer (PC) is one prognostic category, yet heterogeneity in cancer control potentially exists amongst men with GS 3+5/5+3 versus GS 4+4 PC. We compared PC-specific mortality (PCSM) and all-cause mortality (ACM) risk among men with GS 3+5/5+3 versus GS 4+4 PC using competing-risks and Cox regression analyses, adjusting for age, known PC prognostic factors, treatment, and a treatment propensity score. Between 1998 and 2012, 462 men with GS 8 PC were treated using brachytherapy with supplemental external-beam radiation therapy and/or androgen deprivation therapy at the Chicago Prostate Cancer Center. After a median follow-up of 7.6 yr, 118 men died, 26 of PC. PCSM (adjusted hazard ratio [AHR] 2.77, 95% confidence interval [CI] 1.13-6.80; p=0.026) and ACM (AHR 1.75, 95% CI 1.06-2.87; p=0.028) were significantly higher for men with GS 3+5/5+3 PC than for men with GS 4+4 PC. Subcategorizing GS 8 into PC with or without grade 5 should be considered as a stratification factor in randomized trials.

Patient Summary: Long-term success rates for men with Gleason score 8 prostate cancer vary depending on whether the most aggressive type of cancer (grade 5) is present at biopsy.
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http://dx.doi.org/10.1016/j.eururo.2015.08.054DOI Listing
June 2016

Short-course androgen deprivation therapy and the risk of death from high-risk prostate cancer in men undergoing external beam radiation therapy and brachytherapy.

Brachytherapy 2015 Nov-Dec;14(6):781-7. Epub 2015 Sep 9.

Department of Radiation Oncology, Brigham and Women's Hospital-Dana-Farber Cancer Institute, Boston, MA.

Purpose: We estimated the risks of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with high-risk prostate cancer (PC) undergoing external beam radiation therapy and brachytherapy with short-course androgen deprivation therapy (ADT) (median 4 months) as compared with men with more favorable-risk PC undergoing standard of care as per the National Comprehensive Cancer Network guidelines.

Methods And Materials: The prospective study cohort comprised 6595 consecutively treated men with T1-4 N0M0 PC whose treatment included brachytherapy between October 16, 1997, and May 28, 2013. Fine and Gray competing risk regression and Cox regression analyses were used to assess the risks of PCSM and ACM in men with high, unfavorable intermediate, and favorable intermediate risk as compared with low-risk PC.

Results: After median followup of 7.76 years, 820 men died (12.43%): 72 of PC (8.78%). Men with favorable intermediate-risk PC did not have significantly increased PCSM risk as compared with men with low-risk PC (adjusted hazard ratio [AHR], 1.26; 95% confidence interval [CI] 0.56, 2.88; p-Value 0.58), whereas men with high-risk PC (AHR, 3.74; 95% CI 1.12, 12.53; p-Value 0.032) and unfavorable intermediate-risk PC (AHR, 3.10; 95% CI 1.43, 6.72; p-Value 0.004) did. Based on 10-year adjusted point estimates of PCSM and ACM for men with high-risk PC being 6.01% (95% CI 3.79%, 8.94%) and 21.30% (95% CI 17.45%, 25.42%), respectively, PCSM comprised 28% of ACM.

Conclusions: In the setting of external beam radiation therapy and brachytherapy, men with high-risk PC have low absolute adjusted estimates of PCSM (~6%) during the first decade after treatment despite receiving only short-course ADT. Whether long-term ADT can lower PCSM and improve survival in these men requires additional study.
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http://dx.doi.org/10.1016/j.brachy.2015.08.004DOI Listing
July 2016

Risk Group and Death From Prostate Cancer: Implications for Active Surveillance in Men With Favorable Intermediate-Risk Prostate Cancer.

JAMA Oncol 2015 Jun;1(3):334-40

Department of Radiation Oncology, Brigham and Women's Hospital-Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Active surveillance (AS), per the National Comprehensive Cancer Network (NCCN) guidelines, is considered for patients with low-risk prostate cancer (PC) and a life expectancy of at least 10 years. However, given the grade migration following the 2005 International Society of Urologic Pathology consensus conference, AS may be appropriate for men presenting with favorable intermediate-risk PC.

Objective: To estimate and compare the risk of PC-specific mortality (PCSM) and all-cause mortality (ACM) following brachytherapy among men with low and favorable intermediate-risk PC.

Design, Setting, And Participants: Prospective cohort study of 5580 consecutively treated men (median age, 68 years) with localized adenocarcinoma of the prostate treated with brachytherapy at the Prostate Cancer Foundation of Chicago between October 16, 1997, and May 28, 2013.

Intervention: Standard of practice per the NCCN guidelines.

Main Outcomes And Measures: Fine and Gray competing risks regression and Cox regression analyses were used to assess whether the risks of PCSM and ACM, respectively, were increased in men with favorable intermediate-risk vs low-risk PC. Analyses were adjusted for age at brachytherapy, year of treatment, and known PC prognostic factors.

Results: After median follow-up of 7.69 years, 605 men had died (10.84% of total cohort), 34 of PC (5.62% of total deaths). Men with favorable intermediate-risk PC did not have significantly increased risk of PCSM and ACM compared with men with low-risk PC (adjusted hazard ratio [HR], 1.64; 95% CI, 0.76-3.53; P = .21 for PCSM; adjusted HR, 1.11; 95% CI, 0.88-1.39; P = .38 for ACM). Eight-year adjusted point estimates for PCSM were low: 0.48% (95% CI, 0.23%-0.93%) and 0.33% (95% CI, 0.19%-0.56%) for men with favorable intermediate-risk PC and low-risk PC, respectively. The respective estimates for ACM were 10.45% (95% CI, 8.91%-12.12%) and 8.68% (95% CI, 7.80%-9.61%).

Conclusions And Relevance: Men with low-risk PC and favorable intermediate-risk PC have similarly low estimates of PCSM and ACM during the first decade following brachytherapy. While awaiting the results of ProtecT, the randomized trial of AS vs treatment, our results provide evidence to support AS as an initial approach for men with favorable intermediate-risk PC.
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http://dx.doi.org/10.1001/jamaoncol.2014.284DOI Listing
June 2015

Androgen deprivation therapy and the risk of death from prostate cancer among men with favorable or unfavorable intermediate-risk disease.

Cancer 2015 Aug 29;121(16):2713-9. Epub 2015 Apr 29.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts.

Background: Radiotherapy (RT), short-course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate-risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC-specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate-risk PC is unknown. The authors assessed PCSM risk after commonly used treatments.

Methods: The cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate-risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing-risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors.

Results: After a median follow-up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13-0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18-2.57 [P =.56]).

Conclusions: Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.
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http://dx.doi.org/10.1002/cncr.29420DOI Listing
August 2015

Association of androgen-deprivation therapy with excess cardiac-specific mortality in men with prostate cancer.

BJU Int 2015 Sep 29;116(3):358-65. Epub 2014 Oct 29.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Houston, TX, USA.

Objectives: To determine if androgen-deprivation therapy (ADT) is associated with excess cardiac-specific mortality (CSM) in men with prostate cancer and no cardiovascular comorbidity, coronary artery disease risk factors, or congestive heart failure (CHF) or past myocardial infarction (MI).

Patients And Methods: In all, 5077 men (median age 69.5 years) with cT1c-T3N0M0 prostate cancer were treated with brachytherapy with or without neoadjuvant ADT (median duration 4 months) between 1997 and 2006. Fine and Gray competing risks analysis evaluated the association of ADT with CSM, adjusting for age, year of brachytherapy, and ADT treatment propensity score among men in groups defined by cardiac comorbidity.

Results: After a median follow-up of 4.8 years, no association was detected between ADT and CSM in men with no cardiac risk factors (1.08% at 5 years for ADT vs 1.27% at 5 years for no ADT, adjusted hazard ratio (AHR) 0.83; 95% confidence interval (CI), 0.39-1.78; P = 0.64; n = 2653) or in men with diabetes mellitus, hypertension, or hypercholesterolaemia (2.09% vs 1.97%, AHR 1.33; 95% CI 0.70-2.53; P = 0.39; n = 2168). However, ADT was associated with significantly increased CSM in men with CHF or MI (AHR 3.28; 95% CI 1.01-10.64; P = 0.048; n = 256). In this subgroup, the 5-year cumulative incidence of CSM was 7.01% (95% CI 2.82-13.82%) for ADT vs 2.01% (95% CI 0.38-6.45%) for no ADT.

Conclusion: ADT was associated with a 5% absolute excess risk of CSM at 5 years in men with CHF or prior MI, suggesting that administering ADT to 20 men in this potentially vulnerable subgroup could result in one cardiac death.
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http://dx.doi.org/10.1111/bju.12905DOI Listing
September 2015

Cardiovascular comorbidity and mortality in men with prostate cancer treated with brachytherapy-based radiation with or without hormonal therapy.

Int J Radiat Oncol Biol Phys 2013 Apr 16;85(5):e209-15. Epub 2013 Jan 16.

Department of Radiation Oncology, MD Anderson Cancer Center Orlando, Orlando, Florida, USA.

Purpose: To assess the impact of coronary artery disease (CAD) risk factors and sequelae on the risk of all-cause mortality (ACM) in men treated for prostate cancer (PC).

Methods And Materials: The study cohort comprised 5077 men with PC consecutively treated with curative intent between 1997 and 2006 at the Chicago Prostate Cancer Center. Cox and Fine and Gray's competing risks regression multivariable analyses were performed, assessing whether cardiovascular comorbidity impacted the risk of ACM and PC-specific mortality, respectively, adjusting for CAD risk factors (diabetes mellitus, hypercholesterolemia, or hypertension) and sequelae (congestive heart failure or myocardial infarction), age, year and type of treatment, and known PC prognostic factors.

Results: When compared with men with no comorbidity there was a significantly increased risk of ACM in men with congestive heart failure or myocardial infarction (adjusted hazard ratio [AHR] 1.96, P<.001) and in men with diabetes mellitus (AHR 1.60, P=.03) and hypertension (AHR 1.25, P=.04). In contrast, men with hypercholesterolemia had a similar risk of ACM (AHR 0.68, P=.17) when compared with men with no comorbidity. Other factors associated with a significantly increased risk of ACM included age (AHR 1.09, P<.001), prostate-specific antigen level (AHR 1.25, P=.008), and Gleason score 8-10 disease (AHR 1.71, P=.003). Cardiovascular comorbidity did not impact the risk of PC-specific mortality.

Conclusions: In addition to age and unfavorable PC prognostic factors, select CAD risk factors and sequelae are associated with an increased risk of ACM in men treated for PC. These comorbidity prognostic factors predict time courses of mortality from competing causes, which may be factored into the decision-making process when considering management options for PC in a given individual.
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http://dx.doi.org/10.1016/j.ijrobp.2012.11.039DOI Listing
April 2013

Neoadjuvant hormonal therapy use and the risk of death in men with prostate cancer treated with brachytherapy who have no or at least a single risk factor for coronary artery disease.

Eur Urol 2014 Jan 7;65(1):177-85. Epub 2012 Sep 7.

Department of Radiation Oncology, M.D. Anderson Cancer Center Orlando, Orlando, FL, USA. Electronic address:

Background: Neoadjuvant hormone therapy (NHT) use is associated with an increased risk of all-cause mortality (ACM) in men with a history of coronary artery disease (CAD)-induced congestive heart failure (CHF) or myocardial infarction (MI). However, its effect in men with no or at least a single risk factor for CAD stratified by prostate cancer (PCa) aggressiveness is unknown.

Objective: To assess whether NHT use affects the risk of ACM in men with low-, intermediate-, and high-risk PCa treated with brachytherapy who have no or at least a single risk factor for CAD.

Design, Setting, And Participants: This retrospective study cohort consisted of 5411 men with low-risk PCa (prostate-specific antigen [PSA] <10 ng/ml, Gleason score 6, and clinical stage T1-T2a); 4365 men with intermediate-risk PCa (PSA 10-20 ng/ml or Gleason score <8 or clinical stage
Interventions: Men were treated with or without a median duration of 4 mo of NHT followed by brachytherapy with or without supplemental external-beam radiation therapy (EBRT).

Outcome Measurements And Statistical Analysis: Cox regression multivariable analyses were performed to assess whether NHT use affected the risk of ACM in men with low-, intermediate-, and high-risk PCa, adjusting for age; year of brachytherapy; supplemental EBRT use; the presence of CAD risk factors; treatment propensity score; and known PCa prognostic factors, including pretreatment PSA level, biopsy Gleason score, and clinical stage.

Results And Limitations: NHT use was associated with a significantly increased risk of ACM in men with low-risk PCa (adjusted hazard ratio [HR]: 1.27; 95% confidence interval [CI], 1.07-1.51; p<0.01) but not in men with intermediate-risk (adjusted HR: 1.13; 95% CI, 0.96-1.35; p=0.15) or high-risk PCa (adjusted HR: 0.86; 95% CI, 0.66-1.13; p=0.28). Using an interaction model for the low-risk group, NHT use was associated with a significantly increased risk of ACM in the subgroup of men with at least a single CAD risk factor (adjusted HR: 1.36; 95% CI, 1.07-1.74; p=0.01) but not for men with no CAD risk factors (adjusted HR: 1.19; 95% CI, 0.95-1.51; p=0.13).

Conclusions: For men with no or at least a single risk factor for CAD, NHT use is associated with an increased risk of ACM in the setting of low-risk but not intermediate- or high-risk PCa. This effect is driven by the subgroup of men with at least a single risk factor for CAD. These results warrant prospective validation given the widespread use of NHT for prostate downsizing prior to brachytherapy.
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http://dx.doi.org/10.1016/j.eururo.2012.08.070DOI Listing
January 2014

The number of high-risk factors and the risk of prostate cancer-specific mortality after brachytherapy: implications for treatment selection.

Int J Radiat Oncol Biol Phys 2012 Apr 31;82(5):e773-9. Epub 2012 Jan 31.

Harvard Radiation Oncology Program, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA.

Purpose: To determine whether an increasing number of high-risk factors is associated with higher prostate cancer-specific mortality (PCSM) among men treated with brachytherapy (BT)-based treatment, and whether supplemental therapy has an impact on this risk.

Methods And Materials: We analyzed the cases of 2234 men with localized prostate cancer treated between 1991 and 2007 with low-dose rate BT monotherapy (n = 457) or BT with supplemental external-beam radiotherapy (EBRT, n = 229), androgen suppression therapy (AST, n = 424), or both (n = 1124). All men had at least one high-risk factor (prostate-specific antigen >20 ng/mL, biopsy Gleason score 8-10, or clinical stage ≥T2c). Competing-risks multivariable regressions were performed to determine whether the presence of at least two high-risk factors was associated with an increased risk of PCSM, with adjustment for age, comorbidity, and the type of supplemental treatment.

Results: The median follow-up time was 4.3 years. The number of men with at least two high-risk factors was highest in the group treated with BT, EBRT, and AST (21%), followed by BT plus EBRT or AST (13%), and BT alone (8%) (p(trend) < 0.001). The adjusted hazard ratio (AHR) for PCSM for those with at least two high-risk factors (as compared with one) was 4.8 (95% confidence interval [CI], 2.8-8.0; p < 0.001). The use of both supplemental EBRT and AST was associated with a decreased risk of PCSM (AHR 0.5; 95% CI, 0.2-0.9; p = 0.03) compared with BT alone. When the high-risk factors were analyzed separately, Gleason score 8-10 was most significantly associated with increased PCSM (AHR 6.2; 95% CI, 3.5-11.2; p < 0.001).

Conclusions: Men with high-risk prostate adenocarcinoma treated with BT have decreased PCSM if they receive trimodailty therapy that includes EBRT and AST. This benefit is likely most important in men with multiple determinants of high risk.
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http://dx.doi.org/10.1016/j.ijrobp.2011.11.023DOI Listing
April 2012

Hormonal therapy or external-beam radiation with brachytherapy and the risk of death from prostate cancer in men with intermediate risk prostate cancer.

Clin Genitourin Cancer 2012 Mar 29;10(1):21-5. Epub 2011 Nov 29.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Purpose: To determine whether external-beam radiotherapy (EBRT) improves disease control compared with supplemental androgen suppression therapy (AST) in men with intermediate-risk prostate cancer who are being treated with brachytherapy.

Patients And Methods: A total of 807 men with intermediate-risk prostate cancer (T2bNXM0, Gleason ≤7, prostate-specific antigen [PSA] <20 ng/mL; or cT1c-T2bNXM0, Gleason 7) were consecutively treated with either AST and brachytherapy or EBRT and brachytherapy, between 1997 and 2007, and were followed up until September 21, 2007. A Fine and Gray competing risks multivariable regression model was used to assess whether AST or radiotherapy dose escalation reduced the risk of prostate-cancer-specific mortality (PCSM) when adjusting for age, PSA, Gleason score, and tumor category.

Results: Treatment with brachytherapy and with EBRT was associated with a significant increase in the risk of PCSM compared with brachytherapy and AST (adjusted hazard ratio [HR] 4.027 [95% CI, 1.168-13.89]; P = .027) after adjusting for age and prostate cancer prognostic factors. A Gleason score of 4+3 and increasing PSA were associated with worse PCSM (adjusted HR 8.882 [95% CI, 1.095-72.04]; P = .041; and adjusted HR 8.029 [95% CI, 2.38-28.8]; P = .0014, respectively).

Conclusion: Supplemental AST use compared with EBRT is associated with a lower risk of PCSM in men with intermediate-risk PC undergoing brachytherapy. Prospective validation in a randomized controlled trial is needed.
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http://dx.doi.org/10.1016/j.clgc.2011.10.003DOI Listing
March 2012

Diabetes mellitus, race and the odds of high grade prostate cancer in men treated with radiation therapy.

J Urol 2011 Dec 22;186(6):2233-7. Epub 2011 Oct 22.

Harvard Radiation Oncology Program and Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.

Purpose: Black men present more frequently with high grade prostate cancer and are more likely to have diabetes mellitus. We evaluated whether there is an independent association between diabetes mellitus and the risk of high grade prostate cancer in men diagnosed with prostate cancer and treated with radiation therapy.

Materials And Methods: A polychotomous logistic regression analysis was performed to evaluate whether a diagnosis of diabetes mellitus was associated with the odds of Gleason score 7 or 8-10 prostate cancer in a cohort of 16,286 men, adjusting for black race, advancing age, prostate specific antigen and digital rectal examination findings.

Results: Black men (adjusted OR 1.84, 95% CI 1.08-3.13, p = 0.024) and nonblack men (adjusted OR 1.59, 95% CI 1.33-1.89, p <0.001) with diabetes were more likely to have Gleason score 8-10 vs 6 or less prostate cancer than nondiabetic men. However, this was not true for Gleason score 7 vs 6 or less prostate cancer. Black race was significantly associated with Gleason score 7 vs 6 or less prostate cancer in men without and with diabetes (adjusted OR 1.38, 95% CI 1.17-1.63, p <0.001 and 1.61, 95% CI 1.17-2.21, p = 0.003, respectively). Black race was also associated with Gleason score 8-10 vs 6 or less prostate cancer in men without and with diabetes (adjusted OR 1.36, 95% CI 1.01-1.83, p = 0.04 and 1.58, 95% CI 0.98-2.53, p = 0.06, respectively).

Conclusions: In a cohort of men undergoing radiotherapy for prostate cancer the diagnosis of diabetes mellitus was significantly associated with an increased risk of being diagnosed with Gleason score 8-10 prostate cancer independent of black race.
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http://dx.doi.org/10.1016/j.juro.2011.07.072DOI Listing
December 2011

Type of diabetes mellitus and the odds of Gleason score 8 to 10 prostate cancer.

Int J Radiat Oncol Biol Phys 2012 Mar 21;82(3):e463-7. Epub 2011 Sep 21.

Harvard Radiation Oncology Program, Brigham and Women’s Hospital, Department of Radiation Oncology, Boston, MA 02115, USA.

Purpose: It has been recently shown that diabetes mellitus (DM) is significantly associated with the likelihood of presenting with high-grade prostate cancer (PCa) or Gleason score (GS) 8 to 10; however, whether this association holds for both Type 1 and 2 DM is unknown. In this study we evaluated whether DM Type 1, 2, or both are associated with high-grade PCa after adjusting for known predictors of high-grade disease.

Methods And Materials: Between 1991 and 2010, a total of 15,330 men diagnosed with PCa and treated with radiation therapy were analyzed. A polychotomous logistic regression analysis was performed to evaluate whether Type 1 or 2 DM was associated with odds of GS 7 or GS 8 to 10 compared with 6 or lower PCa, adjusting for African American race, age, prostate-specific antigen (PSA) level, and digital rectal examination findings.

Results: Men with Type 1 DM (adjusted odds ratio [AOR], 2.05; 95% confidence interval [CI], 1.28-3.27; p = 0.003) or Type 2 DM (AOR, 1.58; 95% CI, 1.26-1.99; p < 0.001) were significantly more likely to be diagnosed with GS 8 to 10 PCa compared with nondiabetic men. However this was not true for GS 7, for which these respective results were AOR, 1.30; 95% CI, 0.93-1.82; p = 0.12 and AOR, 1.13; 95% CI, 0.98-1.32; p = 0.10.

Conclusion: Type 1 and 2 DM were associated with a higher odds of being diagnosed with Gleason score 8 to 10 but not 7 PCa. Pending validation, men who are diagnosed with Type I DM with GS 7 or lower should be considered for additional workup to rule out occult high-grade disease.
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http://dx.doi.org/10.1016/j.ijrobp.2011.07.003DOI Listing
March 2012

Influence of androgen deprivation therapy on all-cause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction.

Int J Radiat Oncol Biol Phys 2012 Mar 25;82(4):1411-6. Epub 2011 Jun 25.

Department of Radiation Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Purpose: It is unknown whether the excess risk of all-cause mortality (ACM) observed when androgen deprivation therapy (ADT) is added to radiation for men with prostate cancer and a history of congestive heart failure (CHF) or myocardial infarction (MI) also applies to those with high-risk disease.

Methods And Materials: Of 14,594 men with cT1c-T3aN0M0 prostate cancer treated with brachytherapy-based radiation from 1991 through 2006, 1,378 (9.4%) with a history of CHF or MI comprised the study cohort. Of these, 22.6% received supplemental external beam radiation, and 42.9% received a median of 4 months of neoadjuvant ADT. Median age was 71.8 years. Median follow-up was 4.3 years. Cox multivariable analysis tested for an association between ADT use and ACM within risk groups, after adjusting for treatment factors, prognostic factors, and propensity score for ADT.

Results: ADT was associated with significantly increased ACM (adjusted hazard ratio [AHR] = 1.76; 95% confidence interval [CI], 1.32-2.34; p = 0.0001), with 5-year estimates of 22.71% with ADT and 11.62% without ADT. The impact of ADT on ACM by risk group was as follows: high-risk AHR = 2.57; 95% CI, 1.17-5.67; p = 0.019; intermediate-risk AHR = 1.75; 95% CI, 1.13-2.73; p = 0.012; low-risk AHR = 1.52; 95% CI, 0.96-2.43; p = 0.075).

Conclusions: Among patients with a history of CHF or MI treated with brachytherapy-based radiation, ADT was associated with increased all-cause mortality, even for patients with high-risk disease. Although ADT has been shown in Phase III studies to improve overall survival in high-risk disease, the small subgroup of high-risk patients with a history of CHF or MI, who represented about 9% of the patients, may be harmed by ADT.
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http://dx.doi.org/10.1016/j.ijrobp.2011.04.067DOI Listing
March 2012

Risk of death from prostate cancer after radical prostatectomy or brachytherapy in men with low or intermediate risk disease.

J Urol 2011 Jul 14;186(1):91-6. Epub 2011 May 14.

Harvard Radiation Oncology Program, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: Radical prostatectomy and brachytherapy are widely used treatments for favorable risk prostate cancer. We estimated the risk of prostate cancer specific mortality following radical prostatectomy or brachytherapy in men with low or intermediate risk prostate cancer using prospectively collected data.

Materials And Methods: The study cohort comprised 5,760 men with low risk prostate cancer (prostate specific antigen 10 ng/ml or less, clinical category T1c or 2a and Gleason score 6 or less), and 3,079 with intermediate risk prostate cancer (prostate specific antigen 10 to 20 ng/ml, clinical category T2b or T2c, or Gleason score 7). Competing risks multivariable regression was performed to assess the risk of prostate cancer specific mortality after radical prostatectomy or brachytherapy, adjusting for age, year of treatment, cardiovascular comorbidity and known prostate cancer prognostic factors.

Results: After a median followup of 4.2 years (IQR 2.0-7.4) for low risk and 4.8 years (IQR 2.2-8.1) for intermediate risk men, there was no significant difference in the risk of prostate cancer specific mortality among low risk (adjusted hazard ratio 1.62, 95% CI 0.59-4.45, p = 0.35) or intermediate risk men (AHR 2.30, 95% CI 0.95-5.58, p = 0.07) treated with brachytherapy compared with radical prostatectomy. The only factor associated with an increased risk of prostate cancer specific mortality (AHR 1.05, 95% CI 1.01-1.10, p = 0.03) was increasing age at treatment in intermediate risk men.

Conclusions: The risk of prostate cancer specific mortality in men with low or intermediate risk prostate cancer was not significantly different following radical prostatectomy vs brachytherapy.
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http://dx.doi.org/10.1016/j.juro.2011.03.003DOI Listing
July 2011

Predictors of the use of supplemental androgen suppression therapy and external beam radiation in men with high-risk prostate cancer undergoing brachytherapy in community practice.

Brachytherapy 2011 Sep-Oct;10(5):369-75. Epub 2011 Feb 24.

Harvard Radiation Oncology Program, Boston, MA 02215, USA.

Purpose: We assessed clinical- and practice-related variables associated with the use of trimodality treatment (androgen suppression therapy, external beam radiation therapy, and brachytherapy) in a community-based cohort of men with high-risk prostate cancer.

Methods And Materials: The study cohort was composed of 1342 men with a prostate-specific antigen level >20ng/mL, clinical tumor stage T3 or T4, and/or Gleason score 8-10 disease at two community radiation facilities, Chicago Prostate Cancer Center (Chicago PCC) and 21st Century Oncology (21C). Logistic regression multivariable analysis was performed to identify factors associated with trimodality treatment.

Results: Of 1342 men treated from 1991 to 2005, 650 (48%) received trimodality therapy. Factors associated with trimodality use include younger age (adjusted odds ratio [AOR] 0.95, p<0.0001), increasing prostate-specific antigen (AOR 1.54, p<0.0001), Gleason score 7 (AOR 2.88, p<0.0001), Gleason score 8-10 (AOR 4.28, p<0.0001), clinical category T2 (AOR 1.40, p=0.012), clinical category T3 (AOR 4.84, p<0.0001), and year of brachytherapy (AOR 1.13, p<0.0001). Patients treated at 21C were 4.6 times more likely to receive trimodality therapy (p<0.0001) than Chicago PCC. There was a significant interaction between cardiovascular comorbidity status and site (comorbidity×21C, AOR 1.74, p=0.025), indicating that less healthy patients were more likely to receive trimodality treatment at 21C than healthy patients and vice versa at Chicago PCC.

Conclusions: Younger men and those with more aggressive pretreatment clinical factors were more likely to receive trimodality treatment in this community cohort of men with high-risk prostate cancer. Selection for trimodality use varied significantly by site indicating a need for treatment standardization in the community.
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http://dx.doi.org/10.1016/j.brachy.2011.01.004DOI Listing
January 2012

Risk of all-cause and prostate cancer-specific mortality after brachytherapy in men with small prostate size.

Int J Radiat Oncol Biol Phys 2011 Apr 3;79(5):1318-22. Epub 2010 Jun 3.

Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA 02115, USA.

Background: Brachytherapy for prostate cancer can be technically challenging in men with small prostates (≤20 cc), but it is unknown whether their outcomes are different than those of men with larger prostates.

Methods And Materials: We studied 6,416 men treated with brachytherapy in one of 21 community-based practices. Cox regression and Fine and Gray's regression were used to determine whether volume ≤20 cc was associated with a higher risk of all-cause mortality (ACM) or prostate cancer-specific mortality (PCSM), respectively, after adjustment for other known prognostic factors.

Results: 443 patients (6.9%) had a prostate volume ≤20 cc. After a median follow-up of 2.91 years (interquartile range, 1.06-4.79), volume ≤20 cc was associated with a significantly higher risk of ACM (adjusted hazard ratio = 1.33 [95% CI 1.08-1.65], p = 0.0085) with 3-year estimates of ACM for ≤20 cc vs. >20 cc of 13.0% vs. 6.9% (p = 0.028). Only 23 men (0.36%) have died of prostate cancer, and no difference was seen in PCSM by volume (p = 0.4).

Conclusion: Men with small prostates at the time of implant had a 33% higher risk of ACM, and the underlying cause of this remains uncertain. No increase in PCSM was observed in men with volume ≤20cc, suggesting that a small prostate should not in itself be a contraindication for brachytherapy, but inasmuch as absolute rates of PCSM were small, further follow-up will be needed to confirm this finding.
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http://dx.doi.org/10.1016/j.ijrobp.2010.01.023DOI Listing
April 2011

Luteinizing-hormone releasing hormone therapy and the risk of death from Alzheimer disease.

Alzheimer Dis Assoc Disord 2010 Jan-Mar;24(1):85-9

Department of Radiation Oncology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Boston, MA, USA.

Purpose: We evaluated the risk of death from Alzheimer disease (AD) in men with prostate cancer undergoing treatment with or without a luteinizing-hormone releasing hormone (LHRH) agonist.

Methods: Between 1997 and 2007, 6,647 men were treated with brachytherapy for prostate cancer with (N = 1,700) or without (N = 4,947) LHRH agonist therapy. Competing risks multivariable regression was performed to assess whether the use of a LHRH agonist was associated with the risk of death from AD adjusting for the presence of mild AD and age at presentation and known prostate cancer prognostic factors.

Results: After a median follow-up of 4.1 years, 1.2% (81/6,647) of the study cohort died from AD accounting for 16% (81/506) of all observed mortality. There was a significant reduction in the risk of death from AD in men who were treated with a LHRH agonist for a median of 4.0 months as compared with those who were not [adjusted hazard ratio: 0.45 (95% confidence interval, 0.25-0.83); P = 0.01].

Conclusions: LHRH agonist use as compared with no use in men with prostate cancer was associated with a decreased risk of death from AD.
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http://dx.doi.org/10.1097/wad.0b013e31819cb8f4DOI Listing
June 2010

The use of supplemental external beam radiotherapy in men with low-risk prostate cancer undergoing brachytherapy before and after the 1999 American Brachytherapy Society Guideline statement.

Brachytherapy 2010 Apr-Jun;9(2):145-50

Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.

Purpose: In 1999, the American Brachytherapy Society (ABS) recommended brachy-monotherapy for men with low-risk prostate cancer because of the potential for increased toxicity with combined external beam radiotherapy (EBRT) and brachytherapy without the proof of increased efficacy. We investigated the patterns of care in the community in this patient population before and after the reporting of the ABS guideline.

Methods And Materials: The study cohort consisted of 4943 men (median age, 69.0 years) with low-risk prostate cancer treated with brachytherapy with or without supplemental EBRT from 1991 to 2007 across 21 community radiation oncology centers. Multivariable logistic regression analysis was performed to determine if there was a significant association between the year of brachytherapy, prostate-specific antigen level, clinical tumor (T) category, patient's age, and the use of supplemental EBRT.

Results: Supplemental EBRT was used in 647 men (13%). The EBRT use initially increased until 2001 and then decreased yielding a significant association (adjusted odds ratio [AOR], 0.92; p<0.001) between the EBRT use and the year of brachytherapy using a quadratic formulation. Specifically, EBRT use peaked at 24.6% in 2001 and subsequently declined to 3.3% by 2007. Men with clinical category T2a as compared with T1c disease (AOR, 1.43; p<0.001) were more likely to receive combined modality therapy.

Conclusions: The use of supplemental EBRT in men with low-risk prostate cancer treated with brachytherapy has decreased since 2001. This change in practice patterns suggests gradual adoption of the 1999 ABS practice guidelines.
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http://dx.doi.org/10.1016/j.brachy.2009.08.001DOI Listing
June 2010

Prostate cancer-specific mortality and the extent of therapy in healthy elderly men with high-risk prostate cancer.

Cancer 2010 Jun;116(11):2590-5

Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Background: The risk of prostate cancer-specific mortality (PCSM) in healthy elderly men may depend on extent of treatment. The authors of this report compared the use of brachytherapy alone with combined brachytherapy, external-beam radiation to the prostate and seminal vesicles, and androgen-suppression therapy (CMT) in this population.

Methods: The study cohort comprised 764 men aged > or = 65 years with high-risk prostate cancer (T3 or T4N0M0, prostate-specific antigen >20 ng/mL, and/or Gleason score 8-10) who received either brachytherapy alone (n = 206) or CMT (n = 558) at the Chicago Prostate Cancer Center or at a 21st Century Oncology facility. Men either had no history of myocardial infarction (MI) or had a history of MI treated with a stent or surgical intervention. Fine and Gray regression analysis was used to identify the factors associated with PCSM.

Results: The median patient age was 73 years (interquartile range, 70-77 years). After a median follow-up of 4.9 years, 25 men died of prostate cancer. After adjusting for age and prostate cancer prognostic factors, the risk of PCSM was significantly less (adjusted hazard ratio, 0.29; 95% confidence interval, 0.12-0.68; P = .004) for men who received CMT than for men who received brachytherapy alone. Other factors that were associated significantly with an increased risk of PCSM included a Gleason score of 8 to 10 (P = .017).

Conclusions: Elderly men who had high-risk prostate cancer without cardiovascular disease or with surgically corrected cardiovascular disease had a lower risk of PCSM when they received CMT than when they received brachytherapy alone. These results support aggressive locoregional treatment in healthy elderly men with high-risk prostate cancer.
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http://dx.doi.org/10.1002/cncr.24974DOI Listing
June 2010
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