Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907).

PURPOSE: This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. METHODS AND MATERIALS: This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. RESULTS: Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P = .65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P = .62) and 1.2 versus 0.6% (P = .62), respectively. CONCLUSIONS: Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.

Long-term oncological and functional outcomes support use of low-dose-rate brachytherapy with or without external beam radiation in young men (≤60 years) with localized prostate cancer.

PURPOSE: To evaluate the oncological and functional outcomes of young men treated with low-dose-rate brachytherapy (BT) for prostate cancer (PCa). MATERIALS AND METHODS: 423 men aged ≤60 years with clinically localized PCa were treated with BT ± external beam radiation. Biochemical failure was defined by Phoenix criteria. Freedom from biochemical failure (FFbF) and cancer-specific survival (CSS) at 10 and 15 years were estimated by the Kaplan-Meier method with the log-rank test to compare outcomes between National Comprehensive Cancer Network risk groups. The Cox proportional hazards model was used to determine significant predictors for FFbF and CSS. RESULTS: Median followup was 9.9 years (range, 5.1-21.7). Median age was 57 years (range, 39-60), and median prostate-specific antigen was 6.1 ng/mL (range, 0.8-71). Overall, 10- and 15-year FFbF rates were 89% and 88%; 10- and 15-year CSS rates were 99% and 98%. Increasing disease risk was associated with lower FFbF and CSS (p < 0.0001). Biologically effective dose (p < 0.0001) and use of external beam radiation (p = 0.005) were significantly associated with higher FFbF. In men potent before BT, 64% (151/237) had preserved erectile function at a median 10.2 years. There was no significant difference between treatment groups with respect to long-term urinary function (p = 0.56). CONCLUSIONS: Younger men treated with BT experience excellent long-term PCa control with low rates of treatment-related toxicity.

Gleason 7 prostate cancer treated with low-dose-rate brachytherapy: lack of impact of primary Gleason pattern on biochemical failure.

UNLABELLED: What's known on the subject? and What does the study add? There appears to be a clear difference in cancer control outcomes for patients with Gleason scores of 3+4 and those with scores of 4+3 after radical prostatectomy. It has been documented that patients with Gleason 4+3 prostate cancer have higher incidences of non-organ-confined disease than those with primary pattern 3. Higher rates of extracapsular extension, seminal vesicle invasion and positive margins have been found to be associated with primary pattern 4 over 3. These higher rates of non-organ-confined disease can lead to increased biochemical failure, which, in turn, can lead to higher mortality rates. This study provides information on the prognostic significance of primary Gleason pattern in the brachytherapy management of prostate cancer. Study Type - Prognosis (case series) Level of Evidence 4. OBJECTIVES: • To report the biochemical outcomes for Gleason 7 prostate cancer treated with brachytherapy. • To analyse the impact of the primary Gleason pattern as well as other disease- and treatment-related factors on outcome. PATIENTS AND METHODS: • A total of 560 patients with Gleason 7 prostate cancer were treated between 1990 and 2008 with brachytherapy, alone or in combination with hormonal therapy and/or external beam radiation therapy. • There were 352 patients with Gleason pattern 3+4 and 208 with Gleason pattern 4+3. • The mean (range) presenting PSA level was 11.2 (1-300) ng/mL, and the median was 7.8 ng/mL. • The presenting clinical stages were T1b in 1%, T1c in 33%, T2a in 16%, T2b in 32%, T2c in 16% and T3 in 2% of patients. RESULTS: • The actuarial freedom from biochemical failure rate at 10 years was 82%. • There was no significant difference between 10-year freedom from biochemical failure rates for patients with Gleason scores of 3+4 (79%) and those with scores of 4+3 (82%). • Biologically effective dose and presenting PSA level were both significant predictors of biochemical failure in multivariate analysis. CONCLUSIONS: • The primary Gleason pattern in Gleason 7 prostate cancer shows no significant effect on biochemical failure when treated with brachytherapy. • These results are different from those found after radical prostatectomy and are probably attributable to the enhanced local control afforded by a brachytherapy approach to this disease subset.

Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial.

BACKGROUND: Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required. METHODS/DESIGN: This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 ((125)I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with (125)I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during (125)I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events. DISCUSSION: To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa. TRIAL REGISTRATION: UMIN000003992.

Impact of hormonal therapy on intermediate risk prostate cancer treated with combination brachytherapy and external beam irradiation.

PURPOSE: We assessed the impact of androgen suppressive therapy on biochemical failure in patients with intermediate risk prostate cancer treated with brachytherapy and external beam irradiation. MATERIALS AND METHODS: From 1994 to 2006, 432 patients with intermediate risk prostate cancer as defined by the National Comprehensive Cancer Network were treated with low dose rate brachytherapy and external beam irradiation with or without 9 months of androgen suppressive therapy. Gleason score was 7 in 76% of cases and prostate specific antigen was 1.4 to 20 ng/ml (median 7.6). Of the patients 350 received androgen suppressive therapy and 82 did not. The biologically effective dose was 142 to 280 Gy2 (median 206). Followup was 23 to 155 months (median 56). RESULTS: The overall 8-year biochemical failure-free rate using the Phoenix definition in patients with vs without androgen suppressive therapy was 92% vs 92% (p = 0.4). The therapy had no significant impact on the biochemical failure-free rate in patients with Gleason score 7 (92% vs 90.5%, p = 0.55), prostate specific antigen 10 to 20 ng/ml (92% vs 100%, p = 0.32), T2b-T2c disease (89.5% vs 97%, p = 0.27) and more than 1 intermediate risk feature (90% vs 100%, p = 0.2). CONCLUSIONS: We addressed the relative importance of radiation dose vs hormonal therapy for intermediate risk prostate cancer. With high biologically effective dose combination treatment androgen suppressive therapy did not have a significant impact on the 8-year biochemical failure-free rate. We question its routine use in this setting.

There is no correlation between erectile dysfunction and dose to penile bulb and neurovascular bundles following real-time low-dose-rate prostate brachytherapy.

PURPOSE: We evaluated the relationship between the onset of erectile dysfunction and dose to the penile bulb and neurovascular bundles (NVBs) after real-time ultrasound-guided prostate brachytherapy. METHODS AND MATERIALS: One hundred forty-seven patients who underwent prostate brachytherapy met the following eligibility criteria: (1) treatment with 125I brachytherapy to a prescribed dose of 160 Gy with or without hormones without supplemental external beam radiation therapy, (2) identification as potent before the time of implantation based on a score of 2 or higher on the physician-assigned Mount Sinai Erectile Function Score and a score of 16 or higher on the abbreviated International Index of Erectile Function patient assessment, and (3) minimum follow-up of 12 months. Median follow-up was 25.7 months (range, 12-47 months). RESULTS: The 3-year actuarial rate of impotence was 23% (34 of 147 patients). An additional 43% of potent patients (49 of 113 patients) were using a potency aid at last follow-up. The penile bulb volume receiving 100% of the prescription dose (V(100)) ranged from 0-0.05 cc (median, 0 cc), with a dose to the hottest 5% (D(5)) range of 12.5-97.9 Gy (median, 40.8 Gy). There was no correlation between penile bulb D(5) or V(100) and postimplantation impotency on actuarial analysis. For the combined right and left NVB structures, V(100) range was 0.3-5.1 cc (median, 1.8 cc), and V(150) range was 0-1.5 cc (median, 0.31 cc). There was no association between NVB V(100) or V(150) and postimplantation impotency on actuarial analysis. CONCLUSION: Penile bulb doses are low after real-time ultrasound-guided prostate brachytherapy. We found no correlation between dose to either the penile bulb or NVBs and the development of postimplantation impotency.

Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes.

PURPOSE: To investigate the biochemical control rate in patients undergoing permanent prostate brachytherapy as a function of the biologically effective dose (BED) and risk group. METHODS AND MATERIALS: Six centers provided data on 3,928 permanent brachytherapy patients with postimplant dosimetry results. The mean prostate-specific antigen level was 8.9 ng/mL. (125)I was used in 2,293 (58%), (103)Pd in 1,635, and supplemental external beam radiotherapy in 882 (22.5%) patients. The patients were stratified into low- (n = 2,188), intermediate- (n = 1,188), and high- (n = 552) risk groups and into three BED groups of < 140 Gy (n = 524), 140-200 Gy (n = 2284), and >200 Gy (n = 1,115). Freedom from biochemical disease progression (biochemical freedom from failure [bFFF]) was determined using the American Society for Therapeutic Radiology Oncology and Phoenix definitions and calculated using the Kaplan-Meier method, with factors compared using the log-rank test. RESULTS: The 10-year prostate-specific antigen bFFF rate for the American Society for Therapeutic Radiology Oncology and Phoenix definitions was 79.2% and 70%, respectively. The corresponding bFFF rates for the low-, intermediate-, and high-risk groups was 84.1% and 78.1%, 76.8% and 63.6%, and 64.4% and 58.2%, respectively (p < 0.0001). The corresponding bFFF rate for the three BED groups was 56.1% and 41.4%, 80% and 77.9%, and 91.1% and 82.9% (p < 0.0001). The corresponding bFFF rate for the low-risk patients by dose group was 69.8% and 49.8%, 86% and 85.2%, and 88.1% and 88.3% for the low-, intermediate, and high-dose group, respectively (p <0.0001). The corresponding bFFF rate for the intermediate-risk patients by dose group was 52.9% and 23.1%, 74.1% and 77.7%, and 94.3% and 88.8% for the low-, intermediate-, and high-dose group, respectively (p < 0.0001). The corresponding bFFF rate for high-risk patients by dose group was 19.2% and 41.7%, 61.8% and 53.2%, and 90% and 69.6% for the low-, intermediate-, and high-dose group, respectively (p < 0.0001). CONCLUSIONS: These data suggest that permanent brachytherapy dose prescriptions can be customized to risk status. In low-risk patients, achieving a BED of >or=140 Gy might be adequate for prostate-specific antigen control. However, high-risk disease might require a BED dose of >or=200 Gy.

Urinary symptom flare after brachytherapy for prostate cancer is associated with erectile dysfunction and more urinary symptoms before implantation.

OBJECTIVE: To examine the relationship of 'symptom flare' with sexual function and lower urinary tract symptoms (LUTS) before brachytherapy, as we noted that after brachytherapy for prostate cancer, some patients had recurrent LUTS after an asymptomatic period; this secondary exacerbation of symptoms ('symptom flare') occurred at approximately 2 years after implantation and was transient in most patients. PATIENTS AND METHODS: In all, 854 patients with organ-confined prostate carcinoma had transrectal ultrasonography-guided transperineal 125I interstitial brachytherapy of the prostate gland between June 1991 and September 2002, and were considered candidates for this study. Detailed information on urinary function was self-administered and prospectively collected before treatment and at intervals using the International Prostate Symptom Score (IPSS). Sexual function was evaluated with the Sexual Health Inventory for Men (SHIM), a five-question, self-administered diagnostic test that can help to indicate the presence or absence of erectile dysfunction (ED). We used previously established criteria to estimate the risk of prostate-specific antigen (PSA) failure by dividing the men into three risk groups, i.e. low-risk, with a PSA level of < or = 10 ng/mL, stage < or = T2a, Gleason < or = 6; medium-risk, with a PSA level of < or = 15 ng/mL, Gleason 7 or stage T2b; and high-risk, with a PSA level of > 15 ng/mL, stage > T2b, or Gleason > or = 8. RESULTS: There was a significant association of flare with ED; men with flare reported significantly more ED than men without (P = 0.020). Men with high-risk disease reported more ED because they received more intensive treatment (hormones and increased radiation dose) than men with medium- or low-risk disease. To correct for this confounding factor, multivariate linear regression was used; the regression was significant overall (P < 0.001), and the effects of risk group (P < 0.001) and flare (P < 0.026) on SHIM score were significant and independent of each other. Flare was also significantly associated with a higher pre-implant IPSS; the probability of flare was 62% for a pre-implant IPSS of zero, to 94% for an IPSS of 30. CONCLUSIONS: Radiation reaction and radiation sensitivity contribute to ED and greater LUTS in men who have had brachytherapy for prostate cancer. This contribution is evident, e.g. in men with ataxia-telangiectasia (ATM) gene mutations. Sequence variants in the ATM gene, particularly those that encode for an amino-acid substitution, are associated with adverse radiotherapy responses among patients treated with 125I prostate brachytherapy. Our finding of the association of urinary symptom flare with ED suggests it would be worthwhile to determine whether sildenafil is as effective in men with flare, and if not, whether higher sildenafil doses would be of value. Alternatively, alpha1-selective adrenoceptor-blocking agents, e.g. terazosin, combined with sildenafil, might be of benefit. Also, patients with a high IPSS before brachytherapy can be warned that they have a greater risk of flare and ED.

Does prior transurethral resection of prostate compromise brachytherapy quality: a dosimetric analysis.

PURPOSE: To evaluate, in a retrospective review, prostate brachytherapy dosimetry outcomes relative to the transurethral resection of the prostate (TURP) cavity size to address the theoretical concern that an intraprostatic cavity may hinder adequate radioactive source placement. METHODS AND MATERIALS: A total of 73 patients who underwent prostate brachytherapy as part of their treatment of localized prostate cancer had a history of a prior TURP. Of these 73 patients, 37 underwent (125)I implantation, 19 (103)Pd implantation, and 17 partial (103)Pd implantation. The dose was calculated using the dose to 90% of the prostate gland (D(90)) from the 1-month post-implant dosimetric analysis. The doses were normalized relative to 100% of the prescription dose. Archived transrectal ultrasound images were used to determine the maximal length and width of the visible residual TURP cavities. The prolate spheroid or symmetric egg shape was used to calculate each residual cavity volume. The derived volume of the TURP cavity was divided by the measured ultrasound volume of the prostate at brachytherapy, creating a percentage of volume measurement for each prostate. All p values, unless otherwise specified, were generated by comparing patients without a visible TURP defect with the subgroups of patients with a visible defect using the Student t test. RESULTS: A visible residual TURP defect was noted on the operative transrectal ultrasound images of 55 (75%) of the 73 patients with a history of TURP before brachytherapy. The 18 patients without a visible TURP defect had a median D(90) of 96% and were used for subsequent statistical comparison. Thirty-six patients with a TURP defect <10% of the entire prostate volume had a median D(90) of 109% (p = 0.02). Thirteen patients with a TURP defect between 10% and 20% of the prostate volume had a median D(90) of 112% (p = 0.03). Six patients with a TURP defect >20% of the prostate volume had a D(90) of 89% (p = 0.43). CONCLUSION: A visible residual TURP cavity that is assumed to have a prolate spheroid shape and occupy >/=10% of a prostate volume did not appear to be a statistically significant hindrance to proper dosimetric outcome.

Urinary symptom flare following I-125 prostate brachytherapy.

PURPOSE: Although acute urinary morbidity after prostate brachytherapy has been well-documented, long-term effects have not been fully characterized. We describe a late complication of I-125 prostate brachytherapy we have termed urinary symptom flare. METHODS AND MATERIALS: A total of 172 patients who underwent I-125 prostate brachytherapy between 1991 and 1998 completed a pretreatment and at least four follow-up International Prostate Symptom Score (IPSS) forms. Follow-up visits were made 1 month after implant and at 3- to 6-month intervals thereafter. Follow-up periods ranged from 12 to 106 months (median 41.5 months). The number of IPSS forms per patient ranged from 4 to 17 (median 6). A total of 32.6% of patients received both 3 months of neoadjuvant and 3 months of adjuvant hormonal therapy. Postimplant dosimetry revealed D90 values of 5578-25692 cGy (median 17290 cGy). The peak voiding score, indicating the time of the most severe urinary morbidity after brachytherapy, was defined as the highest rise in IPSS recorded after implantation. The nadir score was the lowest IPSS attained after the peak score, generally indicating a return to the patient's preimplant urinary function. A "flare" was defined as a rise in IPSS from the nadir score of at least five points, denoting a late exacerbation of urinary symptoms. Patients with a transient rise in PSA of 0.1 ng/ml or greater were considered to have a PSA bounce. RESULTS: The mean pretreatment IPSS for the study population was 7.5. The mean peak IPSS was 19.4 and occurred from 0.1 to 25 months (median 1.3 months) after the date of implant. The mean nadir IPSS was 6.7 and occurred from 1.6 to 61.6 months (median 14.3) after brachytherapy. A total of 35.5% of patients (61/172) have experienced a urinary flare of 5 or more points, as measured by the IPSS form. The mean "flare" IPSS was 16.4. The time to develop a flare ranged from 5.8 to 64 months (median 23.9 months). The actuarial risk of developing a flare was 21% by 2 years, 34% by 3 years, 38% by 4 years, and 47% by five years. In 72% of patients (44/61) who developed a flare, the flare subsided to baseline by the next follow-up visit. Of the remaining patients, 3% (2/61) reached a baseline value two follow-up visits later. In 25% of the patients (15/61) who experienced a flare, it occurred during their last follow-up visit. No single factor, including PSA (p = 0.9), stage (p = 0.9), use of hormone therapy (p = 0.9), implanted activity (p = 0.1), ultrasound volume (p = 0.4), dose (p = 0.4), seed number (p = 0.4), or needle number (p = 0.9), had a significant effect on the risk of developing a flare. There was a trend for younger patients (65, p = 0.07) to experience the urinary flare. CONCLUSIONS: Acute symptoms after I-125 prostate brachytherapy appear to peak 1 month after a prostate implant and return to their baseline values at 1 year. A transient late exacerbation of urinary symptoms is common and can occur in up to half of all patients by 5 years. There appears to be no statistically significant association between a late exacerbation in urinary symptoms and clinical or implant parameters.

Role of hormonal therapy in the management of intermediate- to high-risk prostate cancer treated with permanent radioactive seed implantation.

PURPOSE: To study the impact of hormonal therapy (HTx) on intermediate- to high-risk prostate cancer treated with permanent radioactive seed implantation. METHODS AND MATERIALS: Patients with Stage T1b-T3bN0 prostate cancer, and Gleason score > or = 7 or prostate-specific antigen (PSA) level >10 ng/mL were treated with seed implantation with or without HTx. Their disease was defined as intermediate risk (PSA 10-20, Gleason score 7, or Stage T2b) or high risk (two or more intermediate criteria, or PSA >20 ng/mL, Gleason score 8-10, or Stage T2c-T3). The median follow-up for 201 eligible patients was 42 months (range 18-110). Biochemical failure was defined as a rising PSA >1.0 ng/mL. Pretreatment disease characteristics, implant dose, and HTx were evaluated using univariate and multivariate analyses. RESULTS: HTx significantly improved 5-year actuarial freedom from biochemical failure rate, 79% vs. 54% without HTx. In addition, high-dose, PSA < or = 15 ng/mL, intermediate risk, and Stage T2a or lower significantly improved outcome in the univariate analyses. HTx was the most significant predictor of 5-year actuarial freedom from biochemical failure (p <0.0001) in a multivariate analysis. The best outcome was in the intermediate-risk patients treated with a high implant dose and HTx, resulting in a 4-year actuarial freedom from biochemical failure rate of 94%. CONCLUSION: In this retrospective review, HTx improved outcome in intermediate- to high-risk prostate cancer patients treated with brachytherapy. HTx was the most important prognostic factor in the univariate and multivariate analyses.