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Objective: To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage radiotherapy (SRT)., Methods: Patients with rising PSA post-RP+SRT underwent 68 Ga-HBED-iPSMA PET/CT on a single-arm, prospective imaging trial (NCT03204123). Scans were centrally reviewed with pattern-of-failure analysis by involved site. Positive scans were classified using 3 failure categories: pelvic nodal, extra-pelvic nodal or distant non-nodal. Associations with failure categories were analyzed using cumulative incidence and generalized logits regression., Results: We included 133 men who received SRT a median of 20 months post-RP; 56% received SRT to the prostatic fossa alone, while 44% received pelvic SRT. PSMA PET/CT was performed a median of 48 months post-SRT. Overall, 31% of PSMA PET/CT scans were negative, 2% equivocal and 67% had at least 1 positive site. Scan detection was significantly associated with PSA level prior to PSMA PET/CT. Analysis of 89 positive scans demonstrated pelvic nodal (53%) was the most common relapse and fossa relapse was low (9%). Overall, positive scans were pelvic (n = 35, 26%), extra-pelvic nodal (n = 26, 20%) or distant non-nodal failure (n = 28, 21%), and 70% of positive scans were oligorecurrent. We observed similar cumulative incidence for all failure categories and relatively few clinicodemographic associations. Men treated with pelvic SRT had reduced odds of pelvic failure versus exclusive fossa treatment., Conclusion: Pelvic, extra-pelvic nodal, and distant non-nodal failures occur with similar incidence post-SRT. Regional nodal relapse is relatively common, especially with fossa-only SRT. A high oligorecurrence rate suggests a potentially important role for PSMA-guided focal therapies., (Copyright © 2022. Published by Elsevier Inc.)

Objective: To evaluate a multimodal strategy aimed at treating all sites of disease that provides a rapid readout of success or failure in men presenting with non-castrate metastatic prostate cancers that are incurable with single modality therapy., Materials and Methods: Twenty selected men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis were treated using a multimodal approach that included androgen deprivation, radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease or the primary site. Outcomes of each treatment were assessed sequentially. Androgen deprivation was discontinued in responding patients. The primary end point was an undetectable prostate-specific antigen (PSA) after testosterone recovery. The goal was to eliminate all detectable disease., Results: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after androgen deprivation alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval: 3%-38%) achieved the primary end point, which persisted for 5, 6, 27+ , and 46+ months. All patients meeting the primary end point had been classified with M1b disease at presentation., Conclusion: A sequentially applied multimodal treatment strategy can eliminate detectable disease in selected patients with metastatic spread at diagnosis. The end point of undetectable PSA after testosterone recovery should be considered when evaluating new approaches to rapidly set priorities for large-scale testing in early metastatic disease states and to shift the paradigm from palliation to cure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To characterize the impact of androgen-deprivation therapy (ADT) on the incidence of cardiovascular events (CE) in prostate cancer patients treated with radiotherapy (RT)., Materials and Methods: There were 2211 patients with localized prostate cancer treated with RT from 1988 to 2008 at our institution. There were 991 patients (44.8%) who received ADT at the time of RT for a median of 6.1 months. Salvage ADT was initiated prior to CE in 365 men (16.5%) at a median of 5.5 years (range: 0.6 to 18.4 years) after RT and continued for a median of 4.3 years. A nomogram was constructed to predict the 10-year risk of CE "post-RT" (i.e., after RT)., Results: Patients receiving ADT at the time of RT exhibited significantly higher 10-year incidence of CE (19.6%, 95% CI 17.0%-22.6%) than those not receiving ADT (14.3%, 95% CI 12.2%-16.7%, P = .005). On multivariate analysis, both ADT at the time of RT (P = .007) and the time of salvage (P = .0004) were associated with increased CE risk, as were advanced age (P  =  .02), smoking (P  =  .0007), history of diabetes (P  =  .0007), and history of CE before RT (P  <  .0001). A nomogram using patient age, smoking status, history of pre-RT CE, history of diabetes, and ADT use at the time of RT predicted the rate of 10-year CE with a C-index of 0.81 (95% CI, 0.72-0.88)., Conclusion: While ADT is often an essential part of prostate cancer treatment, patients should be counseled regarding increased risks of CE and prophylactic efforts should be considered to mitigate that risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To compare the long-term, prostate-specific antigen relapse-free survival outcome and incidence of toxicity for patients with low-risk prostate cancer who underwent brachytherapy or intensity-modulated radiotherapy (RT)., Methods: A total of 729 consecutive patients underwent brachytherapy (n = 448; prescription dose 144 Gy) or intensity-modulated RT alone (n = 281; prescription dose 81 Gy). The prostate-specific antigen relapse-free survival using the nadir plus 2 ng/mL definition and late toxicity using the National Cancer Institute's Common Terminology Criteria for Adverse Events were determined., Results: The 7-year prostate-specific antigen relapse-free survival rate for the brachytherapy and intensity-modulated RT groups was 95% and 89% for low-risk patients, respectively (P = .004). Cox regression analysis demonstrated that brachytherapy was associated with improved prostate-specific antigen relapse-free survival, even after adjustment for other variables. The incidence of metastatic disease between treatment sessions was low for both treatment groups. Late grade 2 gastrointestinal toxicity was observed in 5.1% and 1.4% of the brachytherapy and intensity-modulated RT groups, respectively (P = .02). No significant differences were seen between treatment groups for late grade 3 or greater rectal complications (brachytherapy 1.1% and intensity-modulated RT 0%; P = .19). Late grade 2 urinary toxicity occurred more often in the brachytherapy group than in the intensity-modulated RT group (15.6% and 4.3%, respectively; P < .0001). No significant differences were seen between the 2 treatment groups for late grade 3 urinary toxicity (brachytherapy 2.2% and intensity-modulated RT 1.4%; P = .62)., Conclusions: Among low-risk prostate cancer patients, the 7-year biochemical tumor control was superior for intraoperatively planned brachytherapy compared with high-dose intensity-modulated RT. Although significant toxicities were minimal for both groups, modest, but significant, increases in grade 2 urinary and rectal symptoms were noted for brachytherapy compared with intensity-modulated RT., (Published by Elsevier Inc.)

Objectives: To evaluate the use of real-time kilovoltage cone-beam computed tomography (CBCT) during prostate brachytherapy for intraoperative dosimetric assessment and correcting deficient dose regions., Methods: A total of 20 patients were evaluated intraoperatively with a mobile CBCT unit immediately after implantation while still anesthetized. The source detector system was enclosed in a circular CT-like geometry with a bore that accommodates patients in the lithotomy position. After seed deposition, the CBCT scans were obtained. The dosimetry was evaluated and compared with the standard postimplantation CT-based assessment. In 8 patients, the deposited seeds were localized in the intraoperative CBCT frame of reference and registered to the intraoperative transrectal ultrasound images. With this information, a second intraoperative plan was generated to ascertain whether additional seeds were needed to achieve the planned prescription dose. The final dosimetry was compared with the postimplantation scan assessment., Results: The mean differences between the dosimetric parameters from the intraoperative CBCT and postimplant CT scans were < .5% for percentage of volume receiving 100% of the prescription dose, minimal dose received by 90% of the prostate, and percentage of volume receiving 150% of the prescription dose. The minimal dose received by 5% (maximal dose) of the urethra differed by 8% on average and for the rectum an average difference of approximately 18% was observed. After fusion of the implanted seed coordinates from the intraoperative CBCT scans to the intraoperative transrectal ultrasound images, the dosimetric outcomes were not significantly different from the postimplantation CT dosimetric results., Conclusions: Intraoperative CT-based dosimetric evaluation of prostate permanent seed implantation before anesthesia reversal is feasible and might avert misadministration of dose delivery. The dosimetric measurements using the intraoperative CBCT scans were dependable and correlated well with the postimplant diagnostic CT findings., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objectives: It is unclear whether postoperative salvage radiation therapy (SRT) and early adjuvant radiotherapy (ART) after radical prostatectomy lead to equivalent long-term tumor control. We studied a group of patients undergoing ART by comparing them with a matched control group undergoing SRT after biochemical failure., Methods: Using a multi-institutional database of 2299 patients, 449 patients with pT3-4N0 disease were eligible for inclusion, including 211 patients receiving ART and 238 patients receiving SRT. Patients were matched in a 1:1 ratio according to preoperative prostate-specific antigen Gleason score, seminal vesicle invasion, surgical margin status, and follow-up from date of surgery., Results: A total of 192 patients were matched (96:96). The median follow-up was 94 months from surgery and 73 months from RT completion. There was a significant reduction in biochemical failure with ART compared with SRT. The 5-year freedom from biochemical failure (FFBF) from surgery was 75% after ART, compared with 66% for SRT (hazard ratio [HR] = 1.6, P = .049). The 5-year FFBF from the end of RT was 73% after ART, compared with 50% after SRT (HR = 2.3, log rank [LR] P = .0007). From the end of RT, SRT and Gleason score >or=8 were independent predictors of diminished FFBF. From the date of surgery, Gleason score >or=8 was a significant predictor of FFBF., Conclusions: Early ART for pT3-4N0 prostate cancer significantly reduces the risk of long-term biochemical progression after radical prostatectomy compared with SRT. Gleason score >or=8 was the only factor on multivariate analysis associated with metastasic progression.

Interest in focal therapy for prostate cancer has recently been renewed owing to downward stage migration, improved biopsy and imaging techniques, and the prevalence of either unifocal cancer or a dominant cancer with secondary tumors of minimal malignant potential. Several techniques have potential for focal ablation of prostate cancer. Cryotherapy has been used for some time as primary therapy for complete ablation of the prostate or local recurrence after radiotherapy. Enthusiasm for cryotherapy as the primary therapy has been tempered by the uncertainty about complete ablation of the cancer, the frequent persistence of measurable prostate-specific antigen levels after the procedure, and a high rate of erectile dysfunction. Studies have reported "focal ablation" of prostate cancer with cryotherapy, targeting 1 side of the gland to eliminate a cancer confined to that side with less risk of urinary or sexual complications. Whether cryotherapy has sufficient power to eradicate focal cancer and can be targeted with sufficient accuracy to avoid damage to surrounding structures remains to be demonstrated in prospective clinical trials. High-intensity focused ultrasound (HIFU) has been used widely in Europe for complete ablation of the prostate, especially in elderly men who are unwilling or unable to undergo radical therapy. For low- or intermediate-risk cancer, the short- and intermediate-term oncologic results have been acceptable but need confirmation in prospective multicenter trials presently underway. Whole gland therapy with transrectal ultrasound guidance has been associated with a high risk of acute urinary symptoms, often requiring transurethral resection before or after HIFU. Adverse effects on erectile function seem likely after a therapy that depends on heat to eradicate the cancer, but erectile function after HIFU has not been adequately documented with patient-reported questionnaires. HIFU holds promise for focal ablation of prostate cancer. As with cryotherapy, focal HIFU should reduce the adverse sexual, urinary, and bowel effects of whole gland ablation. New techniques are being developed to allow HIFU treatment under real-time guidance using magnetic resonance imaging, which could improve the precision and reduce the adverse effects further. Another promising technique, currently in clinical trials, is vascular-targeted photodynamic therapy, which has been used for whole gland ablation of locally recurrent cancer after radiotherapy and, more recently, for focal ablation of previously untreated cancer. In combination with a new, systemically administered photodynamic agent, laser light is delivered through fibers introduced into the prostate under ultrasound guidance. This technique does not heat the prostate but destroys the endothelial cells and cancer by activating the photodynamic agent. Damage to surrounding structures appears to be limited and can be controlled by the duration and intensity of the light. We have reviewed the principles of focal therapy and these new therapeutic modalities.

Established therapeutic approaches for clinically localized prostate cancer include watchful waiting (active surveillance), radical prostatectomy, and radiotherapy. The risk of progression during surveillance is related to the initial cancer stage and grade; reasonable evidence has supported the safety and feasibility, during a period of 5-10 years, of an active surveillance regimen for men with low-risk prostate cancer. The progression rates at >10 years have not yet been studied in modern trials. Patients with low-risk tumor characteristics can be actively monitored without sacrificing the possibility of cure and without being exposed to an undue risk of disease progression, although some patients will not accept the emotional burden of living with an untreated cancer. Focal ablation might be an attractive alternative to active surveillance for some patients with low-risk cancer, if it proves to have minimal adverse effects on their quality of life. Radical prostatectomy is an effective form of therapy for patients with clinically significant prostate cancer; however, outcomes are highly sensitive to variations in surgical technique. Because of the risks of perioperative complications and urinary and sexual dysfunction, which appear to be as great with robotic-assisted prostatectomy as with any other technique, patients with low-risk cancer, especially those >60 years, might be attracted to more conservative alternatives, including active surveillance, radiotherapy, and focal ablation. External beam radiotherapy is an effective, noninvasive form of therapy, but it carries the long-term risks of troublesome bowel and sexual and urinary dysfunction. It might be too aggressive for many low-risk cancers detected in screened populations. For more aggressive cancers, local recurrence after radiotherapy carries substantial morbidity and low rates of long-term cancer control. Brachytherapy, a convenient, effective form of radiotherapy, is targeted at selected patients with clinically confined cancer and a prostate size of <60 g without evidence of extraprostatic extension on imaging. However, excellent outcomes require meticulous technique; acute urinary symptoms are frequent; and the long-term risks of proctitis and erectile dysfunction are comparable to the risks associated with external beam radiotherapy. Androgen-deprivation therapy is not recommended for men with localized prostate cancer who would otherwise be candidates for surgery or radiotherapy, because, even with short-term use, the risk of side effects, including osteopenic fracture and major cardiovascular events, serious. For locally extensive cancer, androgen-deprivation therapy should be used alone only for the relief of local symptoms in men with a life expectancy of <5 years who are not eligible for more aggressive treatment.

Objectives: To update our previously published nomogram predicting for biochemical outcome with 10-year data from a larger cohort of patients treated with three-dimensional conformal radiotherapy (RT) or intensity-modulated RT for localized prostate cancer., Methods: From 1988 to 2004, 2253 patients were treated with three-dimensional conformal RT or intensity-modulated RT for clinical Stage T1-T3 prostate cancer. Prescription doses ranged from 64.8 to 86.4 Gy. The median follow-up time was 7 years. The nomogram was developed using a proportional hazards regression model predicting for the probability of biochemical relapse after RT according to the nadir plus 2 ng/mL definition of prostate-specific antigen (PSA) relapse., Results: The 10-year PSA relapse-free survival rate was 62%. The nomogram incorporated the following variables to predict likelihood of PSA failure after RT: pretreatment PSA level, Gleason score, radiation dose, use of neoadjuvant androgen deprivation, and clinical stage. The concordance index of this long-term nomogram was 0.72., Conclusions: A nomogram predicting the 10-year probability of biochemical control after three-dimensional conformal RT or intensity-modulated RT for prostate cancer was reasonably accurate and discriminating. The nomogram also provided evidence that long-term biochemical control can be achieved after conformal RT for the treatment of localized prostate cancer.

Objectives: To determine whether nadir prostate-specific antigen (PSA) levels within 12 months (nadir PSA12) after completion of radiotherapy (RT) can be used as an early marker of recurrence risk., Methods: A total of 4839 patients were treated with RT and without hormonal therapy from 1986 to 1995 for Stage T1-T2 prostate cancer at nine institutions. Of these 4839 patients, 4833, with a median follow-up of 6.3 years, met the criteria for analysis. The study endpoints included freedom from PSA failure, initiation of androgen deprivation, or documented local or distant failure (PSA-DFS); freedom from clinically apparent distant metastasis (DMFS); and overall survival (OS)., Results: Patients with a nadir PSA12 of 2.0 ng/mL or less had an 8-year PSA-DFS, DMFS, and OS rate of 55%, 95%, and 73%, respectively, compared with 40%, 88%, and 69%, respectively, for patients with a nadir PSA12 of more than 2.0 ng/mL. Multivariate analysis confirmed that a nadir PSA12 of greater than 2 ng/mL was an independent predictor of PSA-DFS, DMFS, and OS. Classification and regression tree analysis identified the nadir PSA12 levels after RT associated with PSA-DFS, DMFS, and OS. Nadir PSA12, combined with the pretreatment PSA level, identified patients at particularly high risk of distant metastasis., Conclusions: The results of this large, multi-institutional study have demonstrated that nadir PSA12 is predictive of clinical outcomes for patients with localized prostate cancer after RT. A high pretreatment PSA level and high nadir PSA12 will identify patients at particularly high risk who might benefit from early adjuvant therapy.

Objectives: To describe the 5-year outcomes of patients with high-risk localized prostate cancer treated with neoadjuvant estramustine and vinblastine followed by concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT)., Methods: A total of 23 patients completed therapy consisting of two 8-week cycles of vinblastine, weekly as 4 mg/m2, followed by 8 weeks of concomitant chemotherapy and 3D-CRT. Estramustine was given daily at 10 mg/kg in three divided doses. 3D-CRT consisted of a total dose of 7560 cGy., Results: Assessable patients include 9 with Stage T3 or greater tumors and 5 with lymph node metastasis at diagnosis. All patients had a Gleason score 7 or greater. The median follow-up was 60 months. Of the 23 assessable patients, 15 (65%) experienced biochemical relapse by American Society for Therapeutic Radiology Oncology criteria. The median time to prostate-specific antigen relapse was 12 months (range 7 to 16). Five patients (22%) developed metastases. The median time to metastasis had not been reached by last follow-up. Of the 23 assessable patients, 11 (48%) received no additional therapy and had noncastrate testosterone levels. Six patients had no evidence of disease and 9 patients were receiving androgen blockade. Three patients died (one of prostate cancer and two of other diseases)., Conclusions: A substantial proportion of patients with unfavorable-risk localized prostate cancer achieved long-term disease control with estramustine and vinblastine and concurrent 3D-CRT, no significant long-term toxicities were seen and 48% underwent no further therapy after RT. These long-term findings support the continued study of chemotherapy combined with RT as a potential alternative to prolonged androgen deprivation.

Objectives: To determine the efficacy of sildenafil for patients with erectile dysfunction after radiotherapy for localized prostate cancer., Methods: Fifty patients with erectile dysfunction after radiotherapy were treated with sildenafil. Their median age was 68 years (range 54 to 78). All were treated with a three-dimensional conformal external beam radiotherapy approach, and the median dose prescribed to the planning target volume was 75.6 Gy. Patients were initially given 50 mg of sildenafil and instructed to use the medication on at least three occasions. They were then contacted to ascertain the efficacy of and tolerance to the medication., Results: Significant improvement in the firmness of the erection after sildenafil was reported in 37 patients (74%), 2 (4%) had partial improvement, and 11 (22%) had no response. Significant improvement in the durability of the erection was reported in 33 patients (66%), 3 (6%) had partial improvement, and 14 (28%) reported no improvement. Patients with partial or moderate erectile function before using sildenafil were more likely to benefit from the medication compared with those with absent function. Among 29 patients with erections classified as partial after radiotherapy, 26 (90%) had a significant response to the medication. In contrast, only 11 (52%) of 21 with erections classified as flaccid after radiotherapy had a significant response to the medication (P = 0.007)., Conclusions: Sildenafil improved erectile function in greater than two thirds of patients with postradiotherapy impotence. Patients with less severe dysfunction are most likely to benefit from this intervention.

Objectives: To determine the impact of neoadjuvant hormonal therapy (NHT) prior to conformal radiotherapy on the reduction of volume of normal tissue structures exposed to high doses of radiation therapy and to evaluate the overall late toxicity and response to treatment among patients treated with this approach., Methods: Among 214 patients treated with neoadjuvant leuprolide acetate and flutamide for 3 months prior to three-dimensional conformal radiotherapy (3D-CRT), 45 patients were prospectively evaluated with detailed dose-volume histogram (DVH) analyses to determine the extent of improvement of the geometry of the target volume after NHT. All patients underwent simulation and conformal treatment planning before and after NHT, and the pre- and posthormone DVH calculations for all normal tissue structures were compared for each patient. In addition, toxicity and response to therapy were evaluated in the 214 patients treated with this combined approach., Results: In the 45 patients evaluated, the median reduction of the rectal and bladder volumes receiving 95% of the prescription dose (D95) were 18% and 46%, respectively, while 91% showed a reduction of small bowel volume in a range of 27% to 100% of the prehormonal values. Among the entire group of 214 patients treated with NHT and 3D-CRT, no grade 3 or 4 toxicity was observed with a median follow-up of 15 months after 3D-CRT. The 3-year actuarial grade 2 late gastrointestinal and genitourinary toxicity rates were 6% and 18%, respectively., Conclusions: Neoadjuvant hormonal therapy effectively reduces the volume of normal tissue exposed to high radiation doses in the majority of treated patients and decreases the potential morbidity of therapy.