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Purpose: High-dose-rate brachytherapy (HDR-BT) for dose escalation in localized prostate cancer has been established as one standard treatment option. However, long-term results at followup (FU) ≥5 years are usually needed to ensure robustness of reported outcomes. Potential benefit of salvage therapy is, nevertheless, higher when relapse is diagnosed early. This study aimed to solve this dilemma by evaluating the prostate-specific antigen (PSA) nadir for early prediction of long-term biochemical control., Methods and Materials: Combined pelvis-external beam radiation/HDR-BT boost to EQD2 >100 Gy (α/β = 3) was performed in 459 consecutively treated patients. These patients with an FU ≥ 24 months were analyzed and stratified in PSA nadir (nPSA)-groups by PSA nadir within 18 months after radiotherapy (nPSA18). Kaplan-Meier/log-rank tests and Cox-regression models were used to compare the study endpoints., Results: The mean FU was 77 months. A PSA nadir within 18 months (nPSA18) <0.5 ng/mL was achieved in 222 patients with median time to reach nPSA18 of 7 months. The 5-year American Society of Therapeutic Radiology and Oncology (ASTRO) biochemical control (prostate-specific antigen disease-free survival) for the nPSA18 group <0.5 ng/mL was 89% and for the group ≥ 0.5 ng/mL, it was 78.6% (p = 0.011). nPSA18 was an independent predictor of cancer-specific survival, distant metastasis-free survival, and biochemical control (ASTRO) (p = 0.026, p = 0.020, and p = 0.01, respectively)., Conclusions: The present results suggest that the PSA nadir level within 18 months after radiotherapy may serve as an early parameter for long-term biochemical control according to ASTRO definitions following radical dose escalation by HDR-BT for prostate cancer. Excellent outcomes were associated with nPSA18 < 0.5 ng/mL., (Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Dose escalation using high-dose-rate brachytherapy (HDR-BT) is an established treatment method for prostate cancer. First, long-term results were previously published (specific Kiel method). This study aims to evaluate 10-/15-year outcomes of Kiel Protocol 1 (1986-1992)., Methods and Materials: Conformal external beam radiotherapy (EBRT) was delivered to the pelvis (50 Gy per conventional fractionation) along with an HDR boost to the prostate amounting to a combined biologic equivalent dose in 2 Gy per fraction of 117.25 Gy (α/β = 3). The HDR-BT was performed in two fractions of 15 Gy to the peripheral zone of McNeal. The EBRT-clinical target volume covered the full pelvis. The analyzed cohort totaled 122 patients. The reported end points were overall/cancer-specific survival, local recurrence/distant metastasis rates, and biochemical (BC) control rates according to American Society for Therapeutic Radiology and Oncology/Phoenix definitions. All end points were calculated using the Kaplan-Meier method and the log-rank test in univariate analyses., Results: The mean follow-up time was 116.8 months. The 5-, 10-, and 15-year survival rates were 81%, 62.1%, and 45% for overall survival; 92.1%, 83.1%, and 75.3% for cancer-specific survival; 92.5%, 91.4%, and 83.9% for local recurrence-free survival; and 83.8%, 81.2%, and 69.8% for distant metastasis-free survival, respectively. American Society for Therapeutic Radiology and Oncology-defined BC tumor control rates at 5, 10, and 15 years were 81.1%, 74%, and 67.8%, respectively. According to Phoenix, the BC control rates at 5, 10, and 15 years were 77.8%, 69%, and 63.6%, respectively., Conclusions: The long-term results for the combination of HDR-BT and EBRT continue to show excellent results, providing high equivalent dose in 2 Gy per fraction and high disease control rates. These outcomes were reproducible for the extended follow-up period ranging up to 21.9 years., (Copyright © 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze the long-term effect of local dose escalation using conformal hypofractionated high-dose-rate brachytherapy (HDR-BT) boost and pelvic external-beam radiation therapy (EBRT) in hormone-naïve men with localized prostate cancer., Patients and Methods: A total of 579 men were consecutively treated with pelvic EBRT and dose escalating HDR-BT since 1986 in two prospective trials: 378 patients at William Beaumont Hospital (1991-2002), and 201 patients at Kiel University (1986-1999). BT optimization was done modulating both, the dwell times and spatial source positions. A short course of neoadjuvant/concurrent androgen deprivation therapy was given to 222 patients. Hormone-naïve patients only (n = 324) with a follow-up > or = 18 months were analyzed. All patients had at least one poor prognostic factor (stage > or = T2b, Gleason Score > or = 7, pretreatment prostate-specific antigen [PSA] > or = 10 ng/ml): any one factor 122 patients, any two factors 122 patients, and three factors 80 patients. This cohort was stratified by equivalent dose (ED): dose level 1, < or = 94 Gy, n = 58, and dose level 2, > 94 Gy, n = 266, assuming an alpha/beta ratio of 1.2. The ASTRO definition for biochemical failure was used., Results: Mean follow-up was 5.3 years (1.5-13.9 years). For all 324 patients, the 5-year biochemical control (BC) rate was 79%. Cancer-specific survival was 98%, and overall survival 90%. Similar analysis by institution demonstrated no difference in outcomes. For the entire cohort of hormone-naïve men, dose escalation to > 94 Gy resulted in a better 5-year BC of 59% versus 85% (p < 0.001). Discriminating by risk group a striking dose escalation effect was seen in the groups with two or three poor prognostic factors (p = 0.022 and < 0.001, respectively). In the group with only one poor prognostic factor, no statistical difference could be detected questioning the need for ED > 94 Gy., Conclusion: The results demonstrate that conformal HDR-BT is a successful method for delivering very high radiation dose to the prostate. The ability to escalate dose to ED > 94 Gy was reflected in improved long-term outcomes in terms of BC, significantly for those patients with two or three poor prognostic factors reaching BC rates of 85%.

Theoretically, all patients newly diagnosed with prostate cancer are faced with a choice of treatment options: radical prostatectomy or radio therapy. Although these different treatments may have no differences in terms of survival, they may have very different consequences on the subsequent quality of life (QoL). Prerequisite to analyze QoL is a reliable and valid instrument to assess these differences not only in terms of general QoL (EORTC QLQ-C30) but prostate specific symptoms with a prostate specific module as well. Therefore, the aim of this study was a psychometric evaluation (validation) of the prostate-specific module (PSM). Five historical cohort studies were put together for an empirical meta-analysis. The main objective was to analyze the module's psychometric properties. The total sample consisted of 1,185 patients, of whom 950 completed the QoL questionnaires (EORTC QLQ-C30 and a prostate specific module developed by Kuechler et al.). First step of analysis was a principal component analysis that revealed the following scales: urinary problems, incontinence, erectile dysfunction, sexual problems, problems with partner, pain, heat, nutrition, and psychic strain. The module showed good reliability and concurrent validity and very good construct validity, since the module is able to discriminate between different treatment regimes, tumor stages and age. The German PSM is a reliable, valid and applicable tool for QoL in patients with prostate cancer.

Purpose: High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of < or =6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered., Methods and Materials: Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36-50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an alpha /beta of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen > or =10, Gleason score > or =7, or clinical stage > or =T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 x 3 to 15 Gy x 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used., Results: Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5-14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or biochemical control among the three institutions. The corresponding 8-year rates with and without androgen deprivation therapy were biochemical control 85% and 81%; overall survival 83% and 78%; cause-specific survival 89% and 94%; and metastatic rates of 16.6% and 7.3%. A multivariate analysis revealed androgen deprivation therapy did not predict for biochemical failure for either the entire group or the subset of 177 patients harboring all three poor prognostic factors. Moreover, adding androgen deprivation therapy strongly correlated with higher rates of both metastasis (p = 0.09; hazard ratio, 2.08) and cancer-related deaths (p = 0.02, hazard ratio 3.25). These negative results for the most unfavorable group led us to question if androgen deprivation therapy might have a deleterious impact through delay in delivery of the potentially curative radiation or whether there may be a biologic basis by fixing the cycling cells in G0., Conclusions: Accelerated hypofractionated pelvic EBRT integrated with TRUS-guided conformally modulated HDR administered to 1,260 patients in three institutions was an excellent method of delivering very high radiation dose to the prostate in 5 weeks. Similar high overall, cause-specific, and biochemical no evidence of disease survival rates achieved show that prostate HDR can be successfully delivered in academic and community settings. At 8 years, the addition of a course of < or =6 months of neoadjuvant/concurrent androgen deprivation therapy to a very high radiation dose did not confer a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We question the value of a short course of androgen deprivation therapy when used with high-dose radiation.

Purpose: Feasibility of combined fractionated intensity modulated brachytherapy (IMBT) and external beam radiotherapy (EBRT) as well as the effect of local dose escalation was investigated in a non-randomized retrospective observation trial for histologically-proven macroscopic local recurrences of prostate cancer after radical prostatectomy., Methods and Materials: Thirty-five patients with transrectal ultrasound (TRUS) detectable tumors were treated. Applied dose per IMBT fraction was 15 Gy, prescribed on the target (TRUS visible tumor) surface. For the first 21 patients, two fractions of IMBT were delivered in 2 weeks interval, complementary to 30 Gy EBRT to the small pelvis. Further, as second step of dose escalation, 14 patients were treated with 2 x 15 Gy IMBT combined with 40 Gy EBRT. The total treatment time was 4 and 5 weeks, respectively., Results: PSA was decreased in 34 out of 35 patients post-therapeutically. After a mean follow-up of 27 months, 32 out of 35 patients are alive. However, in 67% of the patients, we observed postimplant PSA elevation with or without detectable local and/or systemic progress. The mean duration of biochemical non-evidence of disease (bNED) after radiation was 12 months for all patients (31% in the 30 Gy group and 42% in the 40 Gy group). No RTOG/EORTC grade III or IV side effects were registered during/after radiotherapy., Conclusion: Combined EBRT and IMBT-boost of TRUS detectable recurrences of prostate cancer after radical prostatectomy seems to be a feasible method of salvage treatment. These early results need to be confirmed by further prospective randomized trials and by longer follow-up in all dose groups.

Purpose: To report long-term outcomes in terms of health-related quality of life (HRQoL) and survival of a dose-escalating radiotherapy protocol and to validate a new disease-specific HRQoL instrument., Patients and Methods: 189 consecutive men with prostate cancer were analyzed; 127 patients had T1-2 (1% T1, 66% T2) and 62 patients (33%) T3 tumors. The pelvic lymphatics were treated to a dose of 50 Gy by external-beam irradiation. The prostate dose was limited to 40 Gy using compensators. The prostate was treated to the total nominal dose of 70 Gy using high-dose-rate (HDR) brachytherapy. The fraction dose was 15 Gy in the McNeal zone (planning target volume [PTV] 1), while 8-9 Gy were applied in the entire prostate (PTV 2). The HRQoL of the 145 long-term survivors was assessed using the EORTC QLQ-C30 and a new prostate-specific instrument (PSM-G 1.0). The reliability of the instruments used and HRQoL scale scores were calculated. Uni-/multivariate analyses of variance were performed., Results: At a mean follow-up of 6.5 years 86.3% of the patients were disease-free, and 78% were biochemically controlled. The mean Cronbach's alpha-values were 0.81 for the QLQ-C30, and 0.74 for the prostate-specific module. Univariate analyses of variance by T-stage, grading, prostata-specific antigen (PSA) status after therapy and adjuvant androgen suppression (AS) revealed that PSA elevation after irradiation and AS were associated with significantly diminished HRQoL. In multivariate analyses AS significantly lowered the HRQoL without survival benefit., Conclusion: The described radiotherapy regimen represents a curative and well-tolerated treatment for localized prostate cancer. The HRQoL assessment with both instruments used was reliable. Adjuvant AS and PSA elevation were associated with diminished HRQoL.

Purpose: The aim of this study is to analyze, during the prostate-specific antigen (PSA) era, the long-term outcome of patients treated with conformal high-dose-rate (HDR) brachytherapy boost to the prostate with or without androgen deprivation therapy (ADT) when patients are stratified by risk factors for failure., Methods and Materials: Between 1986 and 2000, 611 patients were treated for clinically localized prostate cancer in three prospective trials of external beam radiation therapy (EBRT) and dose-escalating HDR brachytherapy (BT) boost. There were 104 patients treated at Seattle, 198 at Kiel University, and 309 at William Beaumont Hospital. Of the 611 patients, 177 received a short course of neoadjuvant/concurrent ADT. The patients were divided into three risk groups. Group I, comprised of 46 patients, had stage < or =T2a, Gleason score (GS) < or = 6, and initial PSA (iPSA) < or = 10 ng/mL. Group II comprised 188 patients with stage > or =T2b, GS > or = 7, and iPSA > or = 10, with any one factor higher. Group III included 359 patients with any two risk factors higher. The American Society for Therapeutic Radiology and Oncology definition for biochemical failure was used., Results: The mean follow-up was 5 years (range, 0.2-15.3). For the 611 patients, the 5-year and 10-year biochemical control (BC) rates were 77% and 73%, disease-free survival (DFS) was 67% and 49%, and cause-specific survival (CSS) was 96% and 92%, respectively. BC at 5 years for Group I patients was 96%, for Group II 88%, and for Group III patients 69%. CSS at 5 years was 100% in Group I, 99% in Group II, and 95% in Group III patients. In univariate and multiple regression analyses for BC, risk group, stage, iPSA, and GS were significant in predicting failure. However, age, follow-up interval, and ADT did not., Conclusions: EBRT with HDR-BT produced excellent long-term outcomes in terms of BC, DFS, and CSS in patients with prostate cancer even for those at highest risk. Conformal HDR-BT is both a precise dose delivery system and an effective treatment for both favorable and unfavorable prostate cancer. The addition of a short course of neoadjuvant/concurrent ADT failed to improve outcome. The results were similar at all three institutions, giving credence to the reproducibility of the brachytherapy treatment.

Purpose: We examined the survival impact of a course of 6 months or less of adjuvant/concurrent androgen deprivation in patients with unfavorable prostate cancer treated to high radiation doses with external beam (EBRT) and a high dose rate (HDR) brachytherapy boost., Materials and Methods: Between 1986 and 2000, 507 patients were treated with pelvic EBRT (46 Gy) with HDR prostate brachytherapy as a boost. The biological equivalent EBRT dose was between 90 and 130 Gy. At Kiel University and at William Beaumont Hospital 198 and 309 patients were treated. Patient eligibility was pretreatment prostate specific antigen 10 ng/ml or greater, Gleason score 7 or greater, or clinical stage T2b or greater. The brachytherapy dose was escalated from 5.5 x 3 to 15 x 2 Gy. Patients were divided between 177 receiving and 330 not receiving androgen suppression therapy (AST). AST was given for a mean of 6 months. The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used., Results: Mean patient age was 68 years. Mean followup was 4.8 years (range 0.7 to 15.3), that is 4.5 years for AST and 4.9 for radiation alone. Five-year actuarial rates for biochemical control were 74% and 76%, for overall survival they were 81% and 87%, and for disease-free survival they were 67% and 66%, while cause specific survival with and without AST was 90% and 98%, and the 5-year metastatic rates were 10.7% and 6.9%, respectively. On multivariate analysis AST did not improve biochemical control., Conclusions: Pelvic EBRT interdigitated with a transrectal ultrasound guided HDR boost is an excellent method of delivering a high radiation dose to the prostate without rendering the patient radioactive. This trial showed high overall, cause specific and no biochemical evidence of disease survival. For this unfavorable group of patients the addition of a course of 6 months or less of neoadjuvant/concurrent AST to a high radiation dose did not appear to confer a 5-year therapeutic advantage. However, it added side effects and the significant cost of hormones.

Purpose: To study the influence of imaging based nodal staging and local dose escalation by a high-dose-rate brachytherapy (HDR-BT) boost in the treatment of locally confined prostate cancer in terms of prostate specific antigen (PSA) recurrence-free survival (biochemical non-evidence of disease (bNED)), treatment toxicity and prognostic variables., Patients and Methods: The prospectively recorded files of 144 men aged in a median of 68 years with a mean follow-up of 8 years (60-171 months) receiving curatively intended, transrectal ultrasound guided high-dose-rate 192-iridium-brachytherapy (HDR-BT) combined with external beam radiation therapy (EBRT) for locally confined prostate cancer were analyzed. T-stages were defined by digital rectal investigation and transrectal sonography (TRUS), nodal staging was performed with computed tomography(CT)/magnetic resonance imaging (MRI) (UICC/AJCR 1992). Twenty-nine patients (20.1%) had T1b-T2a tumors, and 115 patients had T2b-T3 tumors. Median initial PSA (iPSA) was 12.15 ng x mL(-1) (mean 25.61 ng x mL(-1)). The total planned dose applied by external beam radiation was 50 Gy in the pelvis, and 40 Gy in the prostate by in-field-dose modification by individual compensators. The perineal, TRUS guided HDR-BT was delivered in two fractions of 15 Gy each. The target of BT boost was the peripheral zone of the prostate., Results: The overall survival was 71.5% and that of the disease free survival 82.6%. Freedom from distant metastases in T3 stage was 91.3%, whereas for G3 lesions, it was 88.23%. The bNED rate was 72.9%. Regarding treatment related late toxicity according to the EORTC/RTOG score, we observed grade 1, 2, 3 proctitis in 9.72%, 6.94%, 4.10% as well as grade 1, 2, 3 cystitis in 12.5%, 4.16%, 2.08%, respectively. Grade 4 and 5 proctitis or cystitis were not registered., Conclusion: The minimum 5-year and mean 8-year results confirm that local dose escalation by TRUS guided perineal HDR-BT and complementary external beam radiation of the pelvic lymphatics has curative potential in men with locally confined high-risk prostate cancer, although surgical staging results in the literature suggest a high probabilityof microscopic nodal involvements at the level of 25.61 ng x mL(-1) mean PSA. The influence of additional short-term (< 6 months) hormonal ablation on the treatment results could not be stated.

Purpose: To report the 8-year outcome of local dose escalation using high-dose-rate conformal brachytherapy combined with elective irradiation of the pelvic lymphatics for localized prostate cancer., Methods and Materials: One hundred forty-four consecutively treated men (1986-1992) were recorded prospectively. Twenty-nine (20.14%) patients had T1b-2a tumors, and 115 (79.86%) patients had T2b-3 tumors according to, respectively, American Joint Committee on Cancer/Union Internationale Contre le Cancer 1992. All patients had a negative nodal status, proven by CT or MRI. The mean initial PSA value was 25.61 ng/mL (Initial value for 41.66% of patients was <10 ng/mL, for 21.52% was 10-20 ng/mL, and for 32.63% was >20 ng/mL). The total dose applied by external beam radiotherapy was 50 Gy in the pelvis and 40 Gy in the prostate. The high-dose-rate brachytherapy was delivered in two fractions, which were incorporated into the external beam treatment (after 20-Gy and 40-Gy external beam radiotherapy dose). The dose per fraction was 15 Gy for the PTV1 (peripheral prostate zone) and 9 Gy for the PTV2 (entire prostatic gland). Any patient free of clinical or biochemical evidence of disease was termed bNED. Actuarial rates of outcome were calculated by Kaplan-Meier and compared using the log-rank. Cox regression models were used to establish prognostic factors of the various measures of outcome., Results: The median follow-up was 8 years (range 60-171 months). The overall survival rate was 71.5%, and the disease-free survival rate was 82.6%. The bNED survival rate was 72.9%. Freedom from local recurrence for T3 stage was 91.3%, whereas for G3 lesions it was 88.23%. Freedom from distant recurrence for T3 stage was 82.6% and for G3 lesions 70.59%. Univariate survival analyses revealed that low stage (T1-2), low grade (G1-2), no hormonal therapy, initial PSA value less than 40 ng/mL, and PSA normalization <1.0 ng/mL after irradiation were associated with long survival. In multivariate analyses, initial PSA value, PSA kinetics after radiation therapy, and no adjuvant hormonal treatment were independent prognostic factors. Grade 3 late radiation toxicity (according to RTOG/EORTC scoring scheme) was 2.3% for the genitourinary system in terms of cystitis and 4.10% for the gastrointestinal system in terms of proctitis. Grades 4 and 5 genitourinary/gastrointestinal morbidity was not observed. A history of transurethral resection of the prostate with a median interval of less than 6 months from radiotherapy was associated with a high risk of genitourinary toxicity., Conclusion: The 8-year results confirm the feasibility and effectiveness of combined elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for cure of localized and especially high-risk prostate cancer.