Palliative Androgen Deprivation Therapy Research Articles

Salvage high-intensity focused ultrasound (S-HIFU) for recurrence after primary radiotherapy of prostate cancer

ObjectivesTo evaluate functional and oncological outcomes of salvage high-intensity focal ultrasound (S-HIFU) after external beam radiotherapy (EBRT) failure in prostate cancer (PCa) patients. MethodsThis single-center study included patients who underwent S-HIFU for local recurrence after EBRT between 2006 and 2023. Cancer-specific survival, metastasis-free survival and progression-free survival were illustrated using Kaplan–Meier curves. Disease progression was defined by one of the following criteria: increase of 2ng/mL or more above the PSA nadir, positive post-S-HIFU biopsy or initiation of androgen deprivation therapy (ADT). Multivariable Cox proportional hazards model was used to identify predictors of disease progression after S-HIFU. ResultsA total of 52 S-HIFU sessions for 48 patients were performed. Median time between EBRT and S-HIFU was 6.5 years. Median PSA before S-HIFU was 3.2ng/mL and median PSA nadir after S-HIFU was 0.58ng/mL. A total of 39 (81.3%) complications was recorded, including 3 (6.3%) high grade complications according to the Clavien-Dindo classification. After a median follow-up period of 6 years, 14 (29.2%) patients developed metastatic disease. Eighteen (37.5%) patients had no recurrence, whereas 30 (62.5%) patients received ADT for disease progression. The estimated 5-yr cancer-specific survival (CSS), metastasis-free survival (MFS) and progression-free survival rates (PFSR) were 100%, 79.9% (95% CI 67–92) and 41.2% (95% CI 74–96), respectively. The estimated 10-yr CSS, MFS and PFSR were 80% (95% CI 45–100), 50.7% (95% CI 19.4–82.1) and 14% (95% CI 10.8–45), respectively. The hazard of progression increased with the intermediate (HR 3.8; 95% CI 0.99 to 15; p=0.049) and high pre-EBRT d’Amico-s risk group (HR 4.1; 95% CI 0.98 to 16.2; p=0.050). Also, the time between EBRT and S-HIFU was significantly associated with risk of progression (HR 0.61; 95% CI 0.43 to 0.86; p=0.004). No significant difference linked to the disease progression (DP) risk was found between focal vs whole-gland treatment (p=0.70). ConclusionPhysicians should consider HIFU as a local salvage treatment after failed EBRT, thus avoiding or delaying palliative androgen deprivation therapy. Further studies are needed to improve patient selection for this therapy. Level of evidence4.

Long-term Outcomes and Patient Satisfaction Following Salvage Robot-assisted Radical Prostatectomy: A Modern Perspective

Background and objectiveApproximately two-thirds of men who undergo primary treatment for prostate cancer (PC) will experience biochemical recurrence (BCR). Salvage robot-assisted radical prostatectomy (sRARP) offers curative treatment in this disease setting and men who choose this option may avoid palliative androgen deprivation therapy (ADT). The purpose of this study was to describe long-term outcomes and patient feedback following sRARP. MethodsWe reviewed data for consecutive men with biopsy-proven localized BCR who underwent sRARP and pelvic lymph node dissection at a single tertiary referral center between 2004 and 2021. Perioperative data, Clavien-Dindo complications, and functional outcomes were recorded. The Kaplan-Meier method was used to estimate prostate-specific antigen–free (≥0.2 ng/ml) survival (PSAFS) and metastasis-free survival (MFS). Three Likert-type items (score 1-5) from the validated Surgical Satisfaction Questionnaire-8 were distributed to patients postoperatively. Key findings and limitationsWe included 78 men, of whom 72 (92%) had undergone primary radiotherapy and six (8%) had received primary prostate ablation. Median follow-up was 10.1 yr (interquartile range 5.8–12.4). Final pathology identified ≥pT3N0M0 in 35 patients (45%) and positive margins in 23 (29%). The overall complication rate was 50%. Of the 26 (33%) major (grade ≥III) complications, anastomotic stricture (32%) was most common. The estimated 3-, 5-, and 10-yr survival rates were 85.6% and 80.2%, 83.5% for PSAFS (n = 11), and 74.1%, 83.5%, and 70.5% for MFS (n = 23), respectively. At last follow-up, postoperative ADT had been administered to 17 patients (22%), and 39 men (50%) remained alive a decade after sRARP. Continence and potency were maintained in 33/62 (53%) and 1/16 (6%) patients, respectively. Thirty-five respondents (45%) reported median questionnaire scores (≥4) in favor of sRARP. Limitations include the small single-center series and a single query point for patient feedback. Conclusions and clinical implicationsLong-term outcomes of sRARP suggest that the technical challenges and morbidity of the procedure are qualified by patient feedback and the opportunity to evade the morbidity and mortality of biochemically recurrent PC. Patient summaryWe reviewed the cancer outcomes and side effects of robot-assisted surgical removal of the prostate after treatment failure with radiation or ablation for prostate cancer. We found that this type of treatment has substantial risks and long-term side effects, but the surgery provides an opportunity to cure prostate cancer and/or avoid the consequences of indefinite hormonal treatment. Overall, most men who underwent this surgery were not disappointed with their decision despite the higher risks and consequences.

Cell-by-cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression.

The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR-dependent and AR-independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell-by-cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone-naïve and hormone-treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in >99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR-) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N- and C-terminal antibodies yielded similar results. The combination of %AR- cancer cells, %AR- fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR- cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR- cells with disease progression and palliative ADT.

SPARKLE: a new spark in treating oligorecurrent prostate cancer: adding systemic treatment to stereotactic body radiotherapy or metastasectomy: key to long-lasting event-free survival?

BackgroundMetastasis-directed therapy (MDT) significantly delays the initiation of palliative androgen deprivation therapy (pADT) in patients with oligorecurrent prostate cancer (PCa) with a positive impact on patient’s quality of life. However, it remains unclear whether the addition of ADT improves polymetastatic free survival (PMFS) and metastatic castration refractory PCa-free survival (mCRPC-FS) and how long concomitant hormone therapy should be given. A significant overall survival (OS) benefit was shown when an androgen receptor targeted agent (ARTA) was added to pADT in patients with metastatic hormone sensitive PCa (HSPC). However, whether the addition of and ARTA to MDT in the treatment of oligorecurrent PCa results in better PMFS and mCRPC-FS has not been proven yet.Methods & designPatients diagnosed with oligorecurrent HSPC (defined as a maximum of 5 extracranial metastases on PSMA PET-CT) will be randomized in a 1:1:1 allocation ratio between arm A: MDT alone, arm B: MDT with 1 month ADT, or arm C: MDT with 6 months ADT together with ARTA (enzalutamide 4 × 40 mg daily) for 6 months. Patients will be stratified by PSA doubling time (≤ 3 vs. > 3 months), number of metastases (1 vs. > 1) and initial localization of metastases (M1a vs. M1b and/or M1c). The primary endpoint is PMFS, and the secondary endpoints include mCRPC-FS, biochemical relapse-free survival (bRFS), clinical progression free survival (cPFS), cancer specific survival (CSS), overall survival (OS), quality of life (QOL) and toxicity.DiscussionThis is the first prospective multicentre randomized phase III trial that investigates whether the addition of short-term ADT during 1 month or short-term ADT during 6 months together with an ARTA to MDT significantly prolongs PMFS and/or mCRPC-FS.Trial registrationClinicalTrials.gov Identifier: NCT05352178, registered April 28, 2022.

174TiP SPARKLE: A new spark in treating oligorecurrent prostate cancer: Adding systemic treatment to stereotactic body radiotherapy or metastasectomy: Key to long-lasting event-free survival?

Metastasis-directed therapy (MDT), performed by either metastasectomy or stereotactic body radiation therapy (SBRT) significantly delays the initiation of palliative androgen deprivation therapy (pADT) in patients with oligorecurrent prostate cancer (PCa). This delay positively impacts patient’s quality of life. For this approach, however, it remains unclear whether adding a certain period of ADT improves polymetastatic disease-free survival (PM-DFS) and castration refractory PCa-free survival (CRPC-FS).

Salvage Involved-Field and Extended-Field Radiation Therapy in Positron Emission Tomography–Positive Nodal Recurrent Prostate Cancer: Outcomes and Patterns of Failure

PurposeThe optimal salvage pelvic treatment for nodal recurrences in prostate cancer is not yet clearly defined. We aimed to compare outcomes of salvage involved-field radiation therapy (s-IFRT) and salvage extended-field radiation therapy (s-EFRT) for positron emission tomography/computed tomography–positive nodal-recurrent prostate cancer and to analyze patterns of progressions after salvage nodal radiation therapy. Methods and MaterialsPatients with 18F-fluorocholine or 68Ga prostate-specific membrane antigen ligand positron emission tomography/computed tomography–positive nodal-recurrent prostate cancer and treated with s-IFRT or s-EFRT were retrospectively selected. Time to biochemical failure, time to palliative androgen deprivation therapy (ADT), and distant metastasis–free survival were analyzed. ResultsBetween 2009 and 2019, 86 patients were treated with salvage nodal radiation therapy: 38 with s-IFRT and 48 with s-EFRT. After a median follow-up of 41.9 months (5.4-122.1 months), 47 patients presented a further relapse: 31 after s-IFRT and 16 after s-EFRT, with only 1 in-field relapse. The median time to palliative ADT was 24.8 months (95% confidence interval [CI], 13.3-93.5 months) in the s-IFRT group and not yet reached (95% CI, 40.3 months to not yet reached) in the s-EFRT group (P = .010). The 3-year biochemical failure–free rate was 70.2% (95% CI, 51.5%-82.9%) with s-IFRT and 73.9% (95% CI, 55.4%-85.7%) with s-EFRT (P = .657). The 3-year distant metastasis–free survival was 74.1% (95% CI, 56.0%-85.7%) with s-IFRT and 82.0% (95% CI, 63.0%-91.8%) with s-EFRT (P = .338). Conclusionss-EFRT and s-IFRT for positron emission tomography–positive nodal-recurrent prostate cancer provide excellent local control. Time to palliative ADT was longer following s-EFRT than following s-IFRT.

68Ga-PSMA-PET/CT-based radiosurgery and stereotactic body radiotherapy for oligometastatic prostate cancer.

Androgen deprivation therapy (ADT) remains the standard therapy for patients with oligometastatic prostate cancer (OMPC). Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT)-based stereotactic body radiotherapy (SBRT) is emerging as an alternative option to postpone starting ADT and its associated side effects including the development of drug resistance. The aim of this study was to determine progression free-survival (PFS) and treatment failure free-survival (TFFS) after PSMA-PET/CT-based SBRT in OMPC patients. The efficacy and safety of single fraction radiosurgery (SFRS) and ADT delay were investigated. Patients with ≤5 metastases from OMPC, with/without ADT treated with PSMA-PET/CT-based SBRT were retrospectively analyzed. PFS and TFFS were primary endpoints. Secondary endpoints were local control (LC), overall survival (OS) and ADT-free survival (ADTFS). Fifty patients with a total of 75 metastases detected by PSMA-PET/CT were analyzed. At the time of SBRT, 70% of patients were castration-sensitive. Overall, 80% of metastases were treated with SFRS (median dose 20 Gy, range: 16-25). After median follow-up of 34 months (range: 5-70) median PFS and TFFS were 12 months (range: 2-63) and 14 months (range: 2-70), respectively. Thirty-two (64%) patients had repeat oligometastatic disease. Twenty-four (48%) patients with progression underwent second SBRT course. Two-year LC after SFRS was 96%. Grade 1 and 2 toxicity occurred in 3 (6%) and 1 (2%) patients, respectively. ADTFS and OS rates at 2-years were 60.5% and 100%, respectively. In multivariate analysis, TFFS significantly improved in patients with time to first metastasis (TTM) >36 months (p = 0.01) and PSA before SBRT ≤1 ng/ml (p = 0.03). For patients with OMPC, SBRT might be used as an alternative to ADT. This way, the start/escalation of palliative ADT and its side effects can be deferred. Metastases treated with PSMA-PET/CT-based SFRS reached excellent LC with minimal toxicity. Low PSA levels and longer TTM predict elongated TFFS.

Oncological Outcomes of Metastasis-Directed Therapy in Oligorecurrent Prostate Cancer Patients Following Radical Prostatectomy.

Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ≤5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan–Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27–70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58–164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103–132). In total, 314 MDTs were performed and 25 patients (13%) received ≥3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials.

PEACE V \u2013 Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases (STORM): a study protocol for a randomized controlled phase II trial

BackgroundPelvic nodal recurrences are being increasingly diagnosed with the introduction of new molecular imaging techniques, like choline and PSMA PET-CT, in the restaging of recurrent prostate cancer (PCa). At this moment, there are no specific treatment recommendations for patients with limited nodal recurrences and different locoregional treatment approaches are currently being used, mostly by means of metastasis-directed therapies (MDT): salvage lymph node dissection (sLND) or stereotactic body radiotherapy (SBRT). Since the majority of patients treated with MDT relapse within 2 years in adjacent lymph node regions, with an estimated median time to progression of 12–18 months, combining MDT with whole pelvic radiotherapy (WPRT) may improve oncological outcomes in these patients. The aim of this prospective multicentre randomized controlled phase II trial is to assess the impact of the addition of WPRT to MDT and short-term androgen deprivation therapy (ADT) on metastasis-free survival (MFS) in the setting of oligorecurrent pelvic nodal recurrence.Methods & designPatients diagnosed with PET-detected pelvic nodal oligorecurrence (≤5 nodes) following radical local treatment for PCa, will be randomized in a 1:1 ratio between arm A: MDT and 6 months of ADT, or arm B: WPRT added to MDT and 6 months of ADT. Patients will be stratified by type of PET-tracer (choline, FACBC or PSMA) and by type of MDT (sLND or SBRT). The primary endpoint is MFS and the secondary endpoints include clinical and biochemical progression-free survival (PFS), prostate cancer specific survival, quality of life (QoL), toxicity and time to castration-resistant prostate cancer (CRPC) and to palliative ADT. Estimated study completion: December 31, 2023.DiscussionThis is the first prospective multicentre randomized phase II trial assessing the potential of combined WPRT and MDT as compared to MDT alone on MFS for patients with nodal oligorecurrent PCa.Trial registrationClinicalTrials.gov Identifier: NCT03569241, registered June 14, 2018, ;Identifier on Swiss National Clinical Trials Portal (SNCTP): SNCTP000002947, registered June 14, 2018.

A Review of Stereotactic Body Radiation Therapy in the Management of Oligometastatic Prostate Cancer.

Management strategies such as surgery and systemic therapy (androgen-deprivation therapy and chemotherapy) are considered a standard of care for patients with oligometastatic prostate cancer and have shown some positive results in many patients. However, they are often accompanied by side-effects that can negatively affect patients. The aim of this study is to review the potential of stereotactic body radiation therapy (SBRT) in the management of oligometastatic prostate cancer and to compare treatment outcomes with SBRT to those under standard of care management regarding progression-free survival (PFS), androgen-deprivation therapy (ADT)-free survival and local control rate (LCR) as well as a comparison of toxicity profiles. MEDLINE (PubMed), EMBASE, and Clinicaltrials.gov databases were searched to identify prospective randomised controlled trials as well as retrospective studies investigating SBRT and standard of care management for oligometastatic prostate cancer. Data on treatment outcomes and toxicity profiles were extracted. A total of 18 studies were included: 14 reported on the use of SBRT and four reported on the use of standard of care management. For SBRT, median PFS was 7.36-24 months. Median ADT-free survival was 12.3-39.7 months. The LCR varied, with some reports of 100% at 6 months and others of 92% at 5 years. No significant grade 3 toxicity was reported, with only five grade 3 events reported in two studies. For standard of care management, most of the studies reported 3-year PFS of 46.9-58.6%, with one study reporting a median PFS of 38.6 months. No standard of care study reported on LCR and ADT-free survival. Although different toxicity grading systems were used depending on the treatment modality, there were some reports of grade 3 events using standard of care management. SBRT appears to be a safe and effective modality for treating oligometastatic prostate cancer, having the potential to defer palliative ADT. Although LCR is excellent compared to conventional therapies, the PFS rate is reportedly inferior to standard of care therapies. No significant grade 3 toxicity was observed with SBRT.

MRI-Guided Ultrafocal Salvage High-Dose-Rate Brachytherapy for Localized Radiorecurrent Prostate Cancer: Updated Results of 50 Patients

Most patients with local prostate cancer recurrence after radiation therapy undergo palliative androgen deprivation therapy because whole-gland salvage treatments have a high risk of severe toxicity. Focal treatment reduces this risk while offering a second opportunity for cure. We report updated outcomes of ultrafocal salvage high-dose-rate brachytherapy (HDR-BT). Prospectively collected data from the first 50 treated patients were analyzed. Disease status was assessed by 3T multiparametric magnetic resonance imaging (MRI), 18F-Choline or 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography, and systematic or tumor-targeted biopsies. Ultrafocal salvage HDR-BT (1 × 19 Gy) was performed by implanting the clinical target volume (CTV: gross tumor volume + 5 mm margin) under fused transrectal ultrasound/MRI guidance. Follow-up included toxicity grading (using Common Terminology Criteria for Adverse Events 4.0), quality of life assessment, and prostate-specific antigen (PSA) testing. Median follow-up was 31 months. Median CTV D95% was 18.8 Gy. We observed 2% grade 3 genitourinary toxicity, no grade 3 gastrointestinal toxicity, and 22% newly developed grade 3 erectile dysfunction. Five of 13 patients (38%) with self-reported pretreatment potency (International Index of Erectile Function >17) remained potent. Clinically relevant quality of life deterioration was reported for only 6 of 31 items and was not statistically significant. Biochemical failure (nadir + 2) occurred in 26 patients. Among intraprostatic recurrences, 73% were in field. After 2.5 years, biochemical disease-free survival was 51% (95% confidence interval, 37%-69%), metastases-free survival was 75% (64%-89%), androgen deprivation therapy-free survival was 90% (82%-99%), and overall survival was 98% (94%-100%). Presalvage PSA, CTV size, and stage ≥T3 were significantly associated with biochemical failure. Higher-risk patients (stage ≥T3, PSA ≥10, or PSA double time ≤9 months) had 25% biochemical disease-free survival at 2.5 years versus 71% for lower-risk patients. At this early stage, MRI-guided ultrafocal HDR-BT seems to be a safesalvage treatment option, with acceptable biochemical control in a well-selected group of patients and potential for effectively postponing androgen deprivation therapy.

Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients.

Androgen deprivation therapy (ADT) is first‐line palliative treatment in androgen receptor‐positive (AR+) salivary duct carcinoma (SDC), and response rates are 17.6–50.0%. We investigated potential primary ADT resistance mechanisms for their predictive value of clinical benefit from ADT in a cohort of recurrent/metastatic SDC patients receiving palliative ADT (n = 30). We examined mRNA expression of androgen receptor (AR), AR splice variant‐7, intratumoral androgen synthesis enzyme‐encoding genes AKR1C3, CYP17A1, SRD5A1 and SRD5A2, AR protein expression, ERBB2 (HER2) gene amplification and DNA mutations in driver genes. Furthermore, functional AR pathway activity was determined using a previously reported Bayesian model which infers pathway activity from AR target gene expression levels. SRD5A1 expression levels and AR pathway activity scores were significantly higher in patients with clinical benefit from ADT compared to those without benefit. Survival analysis showed a trend toward a longer median progression‐free survival for patients with high SRD5A1 expression levels and high AR pathway activity scores. The AR pathway activity analysis, and not SRD5A1 expression, also showed a trend toward better disease‐free survival in an independent cohort of locally advanced SDC patients receiving adjuvant ADT (n = 14) after surgical tumor resection, and in most cases a neck dissection (13/14 patients) and postoperative radiotherapy (13/14 patients). In conclusion, we are the first to describe that AR pathway activity may predict clinical benefit from ADT in SDC patients, but validation in a prospective study is needed.

Prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT)-guided stereotactic ablative body radiotherapy for oligometastatic prostate cancer: a single-institution experience and review of the published literature.

To report the outcomes of stereotactic ablative body radiotherapy (SABR) in men with oligometastatic prostate cancer (PCa) diagnosed on prostate-specific membrane antigen (PSMA)-positron emission tomography/computed tomography (PET/CT), based on a single-institution experience and the published literature. This was a retrospective cohort study of the first 20 consecutive men with oligometastatic PCa, treated with SABR in a single institution, who had biochemical recurrence after previous curative treatment (surgery/radiotherapy), had no evidence of local recurrence, were not on palliative androgen deprivation therapy (ADT), and had PSMA-PET/CT-confirmed oligometastatic disease (≤3 lesions). These men were treated with SABR to a dose of 30Gy in three fractions for bone metastases, and 35-40Gy in five fractions for nodal metastases. The outcomes of interest were: PSA response; local progression-free survival (LPFS); distant progression-free survival (DPFS); and ADT-free survival (ADTFS). A literature review was performed to identify published studies reporting on outcomes of PSMA-PET/CT-guided SABR. In our institutional cohort, 12 men (60%) had a decline in PSA post-SABR. One man had local progression 9.6months post-SABR, with 12-month LPFS of 93%. Ten men had distant progression outside of their SABR treatment field, confirmed on PSMA-PET/CT, with 12-month DPFS of 62%, of whom four were treated with palliative ADT, two received prostate bed radiotherapy for prostate bed progression (confirmed on magnetic resonance imaging), and four received a further course of SABR (of whom one had further progression and was treated with palliative ADT). At last follow-up, six men (one with local progression and five with distant progression) had received palliative ADT. The 12-month ADTFS was 70%. Men with longer intervals between local curative treatment and SABR had better DPFS (P = 0.03) and ADTFS (P = 0.005). Four additional studies reporting on PSMA-PET/CT-guided SABR for oligometastatic PCa were identified and included in the review, giving a total of 346 patients. PSA decline was reported in 60-70% of men post-SABR. The 2-year LPFS, DPFS and ADTFS rates were 76-100%, 27-52%, and 58-62%, respectively. Our results showed that PSMA-PET/CT could have an important role in identifying men with true oligometastatic PCa who would benefit the most from metastases-directed therapy with SABR.

Comparison of Peri-operative and Early Oncological Outcomes of Robot-Assisted vs. Open Salvage Lymph Node Dissection in Recurrent Prostate Cancer.

Introduction: Salvage lymph node dissection (sLND) has been proposed as a treatment option for prostate cancer patients with lymph node (LN) recurrence following radical prostatectomy to delay or avoid palliative androgen deprivation therapy (ADT). Historically sLND has been performed using an open approach, with its associated morbidity. A limited number of studies have reported peri-operative outcomes following robot-assisted sLND. However, a direct comparison with the open approach has hitherto not yet been reported. This study investigates whether robot-assisted sLND is associated with better peri-operative outcomes compared to the open approach. Early oncological outcomes are also compared.Patients and methods: In this retrospective study, clinical data were collected from 60 patients undergoing open sLND between 2010–2016 and 30 patients undergoing robot-assisted sLND between 2016 and 2018 at our tertiary referral center. The primary objective of the study was to compare peri-operative outcomes (length of stay, estimated blood loss, operative time, intra-operative, and postoperative complications) and LN yield between both procedures. As secondary objective early oncological outcome [biochemical recurrence-free survival (BRFS) and clinical recurrence-free survival (CRFS)] was compared. Variables of interest were compared using the chi-squared test (categorical variables), two sample t-test, and Mann-Whitney U-test (continuous variables). To compare BRFS and CRFS, Kaplan-Meier analysis, and log-rank tests were performed.Results: Robotic sLND was associated with reduced blood loss (median 100 vs. 275cc; p < 0.0001) and shorter length of stay (median 2 vs. 7 days; p < 0.0001) compared to open sLND. Moreover, postoperative complications within 30 days after surgery were more prevalent in the open sLND group compared to the robotic group (41.6% vs. 20%, p = 0.04). No significant differences in LN yield (for each sLND template), BRFS, and CRFS were detected between both groups.Conclusion: Robot-assisted sLND is associated with significantly reduced peri-operative morbidity compared to open sLND. No difference in LN yield, BRFS and CRFS was seen between both groups. Modern imaging techniques underestimate the tumor burden and therefore, the surgical sLND template should not be limited to the positive spots on pre-operative imaging.

Intention-to-Treat Analysis of 68Ga-PSMA and 11C-Choline PET/CT Versus CT for Prostate Cancer Recurrence After Surgery.

Biochemical recurrence (BCR) after prostate cancer surgery is common, even after additional salvage radiotherapy. BCR might be explained by target miss. Improved diagnostic accuracy provided by PET could potentially circumvent this therapeutic gap. Therefore, we evaluated consecutive 68Ga-prostate-specific membrane antigen (PSMA) PET/CT, 11C-choline PET/CT, and standard CT imaging in the same patient with regard to TNM-stage migration and accordingly adapted curative radiotherapy options including ablative treatment of oligometastases (n ≤ 5). The cost efficacy of PET- versus CT-based treatment was also calculated. Methods: The prospective register database (064/2013BO1) was retrospectively searched for patients fulfilling the following 3 inclusion criteria: BCR after radical prostatectomy (pT2-pT4 pN0-pN1 cM0, postoperative radiotherapy allowed); 11C-choline PET/CT, 68Ga-PSMA PET/CT, and diagnostic CT performed within 24 h; and available clinical data. Ten treatment routines were defined according to current practice. Furthermore, intention-to-treat and treatment-related costs depending on the shift of TNM stage after imaging were analyzed. Eighty-three patients were eligible (median prostate-specific antigen level, 1.9 ng/mL). Results: Both PET examinations led to concordant results in 72% of patients, whereas the concordance of TNM staging between 68Ga-PSMA PET and diagnostic CT was only 36%. Incorrect staging would lead to "wrong" treatment and therefore to additional costs. A 68Ga-PSMA PET study would be cost-effective if additional costs do not exceed €3,844 ($4,312) (vs. CT). The number needed to image was 2 (for CT) and 4 (for 11C-choline PET) to avoid 1 incorrect treatment. In addition, 68Ga-PSMA PET staging enabled new curative options in half the patients with previous radiotherapy who otherwise receive palliative androgen deprivation therapy. Conclusion:68Ga-PSMA PET/CT is cost-effective in all patients with regard to avoidance of incorrect treatment. It enabled new curative options for patients with previous radiotherapy who are usually treated palliatively. Therefore, 68Ga-PSMA PET/CT staging should become standard for BCR after surgery with or without radiotherapy.

Benefits of Elective Para-Aortic Radiotherapy for pN1 Prostate Cancer Using Arc Therapy (Intensity-Modulated or Volumetric Modulated Arc Therapy): Protocol for a Nonrandomized Phase II Trial.

BackgroundIn patients with prostate cancer (PCa) with histopathologically proven pelvic lymph node (LN) metastasis (pN1) after extended pelvic lymph node dissection (ePLND), multimodality treatment consisting of treatment of the primary tumor and whole pelvic radiotherapy (WPRT) combined with androgen deprivation therapy (ADT) offers promising results, leading to better cause-specific survival rates compared with ADT alone. However, in case more than one pelvic LN is invaded by the tumor, approximately 40% of the patients relapse biochemically and clinically. Clinical relapse is present in the para-aortic LNs (M1a disease) in up to 77% of the relapsing cases.ObjectiveWe hypothesize that, based on the evidence that positive LNs represent the door to hematogenous dissemination, elective para-aortic irradiation will reduce the development of both retroperitoneal nodal (M1a) and distant metastasis (M1b or M1c disease), postpone the need for palliative ADT, and prolong the time to castration-refractory disease.MethodsTo test this hypothesis, we will conduct a prospective, nonrandomized phase II trial to study the efficacy of additional elective para-aortic radiotherapy (PART) in pN1 patients compared with those who were historically treated with adjuvant WPRT alone. We aim to include 137 patients with PCa and presence of pN1 disease after ePLND. With this number of patients, an improvement of 15% in the 5-year clinical relapse-free survival can be detected with a power of 80%.ResultsRecruitment of patients for this trial started in 2017 and will be completed approximately by March 2020.ConclusionsThis is the first phase II trial to investigate the benefits of an elective PART in patients with PCa. The results of this trial will potentially serve as a sound base for a later randomized phase III trial. All participants are given a PART information sheet and required to give written informed consent. Results are expected to be published in a peer-reviewed journal.Trial RegistrationClinicalTrials.gov NCT03079323; https://clinicaltrials.gov/ct2/show/NCT03079323 (Archived by WebCite at http://www.webcitation.org/73ELimv1d)International Registered Report Identifier (IRRID)PRR1-10.2196/11256

Oligometastatic Prostate Cancer.

Opinion statementThe mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside ‘metastasis-directed therapy’ to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.

Pattern of Progression after Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Nodal Recurrences

AimsTo report the relapse pattern of stereotactic body radiotherapy (SBRT) for oligorecurrent nodal prostate cancer (PCa). Materials and methodsPCa patients with ≤3 lymph nodes (N1/M1a) at the time of recurrence were treated with SBRT. SBRT was defined as a radiotherapy dose of at least 5 Gy per fraction to a biological effective dose of at least 80 Gy to all metastatic sites. Distant progression-free survival was defined as the time interval between the first day of SBRT and appearance of new metastatic lesions, outside the high-dose region. Relapses after SBRT were recorded and compared with the initially treated site. Secondary end points were local control, time to palliative androgen deprivation therapy and toxicity scored using the Common Terminology Criteria for Adverse Events v4.0. ResultsOverall, 89 metastases were treated in 72 patients. The median distant progression-free survival was 21 months (95% confidence interval 16–25 months) with 88% of patients having ≤3 metastases at the time of progression. The median time from first SBRT to the start of palliative androgen deprivation therapy was 44 months (95% confidence interval 17–70 months). Most relapses (68%) occurred in nodal regions. Relapses after pelvic nodal SBRT (n = 36) were located in the pelvis (n = 14), retroperitoneum (n = 1), pelvis and retroperitoneum (n = 8) or in non-nodal regions (n = 13). Relapses after SBRT for extrapelvic nodes (n = 5) were located in the pelvis (n = 1) or the pelvis and retroperitoneum (n = 4). Late grade 1 and 2 toxicity was observed in 17% (n = 12) and 4% of patients (n = 3). ConclusionSBRT for oligometastatic PCa nodal recurrences is safe. Most subsequent relapses are again nodal and oligometastatic.

CAPRA-S predicts outcome for adjuvant and salvage external beam radiotherapy after radical prostatectomy.

We aimed to evaluate the predictive value of the Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) for patients treated with radical prostatectomy followed by subsequent external beam radiotherapy (EBRT). A total of 373 patients treated with EBRT between January 2000 and June 2015 were identified in the institutional database. Followup and complete CAPRA-S score were available for 334 (89.5%) patients. CAPRA-S scores were sorted into previously defined categories of low- (score 0-2), intermediate- (3-5), and high-risk (6-12). Time to biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) >0.20 ng/mL after EBRT. Survival analyses were performed using the Kaplan-Meier method and comparisons were made using the log-rank test. Overall median time from surgery to EBRT was 18 months (interquartile range [IQR] 8-36) and median followup since EBRT was 48 months (IQR 28-78). CAPRA-S predicted time to BCR (<0.001), time to palliative androgen-deprivation therapy (ADT) (p=0.017), and a trend for significantly predicting overall survival (OS, p=0.058). On multivariate analysis, the CAPRA-S was predictive of time to BCR only (low-risk vs. intermediate-risk; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.043-0.48, p=0.001). The last PSA measurement before EBRT as a continuous and grouped variable proved highly significant in predicting all outcomes tested, including OS (p≤0.002). CAPRA-S predicts time to BCR and freedom from palliative ADT, and is borderline significant for OS. Together with the PSA before EBRT, CAPRA-S is a useful, predictive tool. The main limitation of this study is its retrospective design.

'First, do no harm': managing the metabolic impacts of androgen deprivation in men with advanced prostate cancer.

Androgen deprivation therapy (ADT) is a standard systemic treatment for men with prostate cancer. Men on ADT may be elderly and have comorbidities that are exacerbated by ADT, such as cardiovascular disease, diabetes, obesity, sedentary lifestyle and osteoporosis. Studies on managing the impacts of ADT have focused on men with non-metastatic disease, where ADT is given for a limited duration. However, some men with advanced or metastatic prostate cancer will achieve long-term survival with palliative ADT and therefore also risk morbidity from prolonged ADT. Furthermore, ADT is continued during the use of other survival-prolonging therapies for men with advanced disease, and there is a general trend to use ADT earlier in the disease course. As survival improves, management of the metabolic effects of ADT becomes important for maintaining both quality and quantity of life. This review will outline the current data, offer perspectives for management of ADT complications in men with advanced prostate cancer and discuss avenues for further research.