Treated Prostate Cancer Patients Research Articles

Do all prostate cancer patients want, and experience shared decision making prior to curative treatment?

In comparable men with non-metastatic prostate cancer, radical prostatectomy (RP), radiotherapy (RAD) and active surveillance (AS) are treatment options with similar survival rates, but different side-effects. Healthcare professionals consider pretreatment shared decision making (SDM) to be an essential part of medical care, though the patients' view about SDM is less known. In this article, we explore prostate cancer (PCa) patients' SDM wish (SDMwish), and experiences (SDMexp). Material and methods: This is a registry-based survey performed by the Cancer Registry of Norway (2017-2019). One year after diagnosis, 5,063 curatively treated PCa patients responded to questions about their pre-treatment wish and experience regarding SDM. Multivariable analyses identified factors associated with SDM. Statistical significance level: p < 0.05. Results: Overall, 78% of the patients wished to be involved in SDM and 83% of these had experienced SDM. SDMwish and SDMexp was significantly associated with decreasing age, increasing education, and living with a partner. Compared with the RP group, the probability of SDMwish and SDMexp was reduced by about 40% in the RAD and the AS groups. Conclusion: Three of four curatively treated PCa wanted to participate in SDM, and this wish was met in four of five men. Younger PCa patients with higher education in a relationship, and opting for RP, wanted an active role in SDM, and experienced being involved. Effective SDM requires the responsible physicians' attention to the individual patients' characteristics and needs.

Development and validation of a nomogram to predict cancer-specific survival in nonsurgically treated elderly patients with prostate cancer

Prostate Cancer (PC) is the most common male nonskin tumour in the world, and most diagnosed patients are over 65 years old. The main treatment for PC includes surgical treatment and nonsurgical treatment. Currently, for nonsurgically treated elderly patients, few studies have evaluated their prognostic factors. Our aim was to construct a nomogram that could predict cancer-specific survival (CSS) in nonsurgically treated elderly PC patients to assess their prognosis-related independent risk factors. Patient information was obtained from the Surveillance, Epidemiology and End Results (SEER) database, and our target population was nonsurgically treated PC patients who were over 65 years old. Independent risk factors were determined using both univariate and multivariate Cox regression models. A nomogram was built using a multivariate Cox regression model. The accuracy and discrimination of the prediction model were tested using the consistency index (C-index), the area under the subject operating characteristic curve (AUC), and the calibration curve. Decision curve analysis (DCA) was used to examine the potential clinical value of this model. A total of 87,831 elderly PC patients with nonsurgical treatment in 2010–2018 were included in the study and were randomly assigned to the training set (N = 61,595) and the validation set (N = 26,236). Univariate and multivariate Cox regression model analyses showed that age, race, marital status, TNM stage, chemotherapy, radiotherapy modality, PSA and GS were independent risk factors for predicting CSS in nonsurgically treated elderly PC patients. The C-index of the training set and the validation set was 0.894 (95% CI 0.888–0.900) and 0.897 (95% CI 0.887–0.907), respectively, indicating the good discrimination ability of the nomogram. The AUC and the calibration curves also show good accuracy and discriminability. We developed a new nomogram to predict CSS in elderly PC patients with nonsurgical treatment. The model is internally validated with good accuracy and reliability, as well as potential clinical value, and can be used for clinical aid in decision-making.

Machine Parameter Optimization of a Clinical Linear Accelerator Using Deep Reinforcement Learning for Automatic Generation of Deliverable Prostate VMAT Plans

Reinforcement learning (RL) is an artificial intelligence (AI) approach involving learning through trial and error which has demonstrated performance exceeding humans and existing algorithms in multiple domains. We hypothesized that machine parameter optimization using RL will produce deliverable treatment plans faster and with superior dosimetry compared to conventional inverse optimization, which was tested in the setting of VMAT for localized prostate cancer. We included 151 previously treated prostate cancer patients, separated into training (n = 116) and testing (n = 35) cohorts. We used a policy gradient RL approach, where contours, dose distribution and machine parameters for the current control point are taken as input by a 3D convolutional neural network (CNN) and continuous machine parameters for the next control point are predicted, allowing the CNN to directly control the linear accelerator (Linac) model. Training was initialized using a subset of 20 training cases with plans produced in our clinical treatment planning system (TPS) prescribed 60 Gy in 20 fractions (denoted Training-TPS), but continued for all 116 training cases through trial and error-based RL. Following training, RL VMAT was applied to the initialization subset of 20 training cases (Training-RL) and 35 test cases (Test-RL), comparing resultant dosimetry. Training was conducted for 10 days using 4 GPUs generating 22,000 plans for exploration, enabling dosimetric improvements compared to the TPS-based plans and generalization to all 116 training cases. Following training, mean ± SD RL execution time for automatic plan generation was 2.9 ± 0.6 seconds. Automatic gradient descent-based parameter rescaling was applied to enable quantitative comparison with the TPS-based plans, and final dose metrics are provided in Table 1. Overall dosimetry was comparable between the TPS and RL approaches in the training and test sets, although PTV coverage and maximum dose did not meet objectives in several RL-based plans. To our knowledge, this is the first demonstration of direct RL-based control of a 3D Linac model. Initial performance is promising, demonstrating model convergence in the training set with a small number of existing plans required for initialization. However, limitations exist in model generalizability which are under continued investigation through approaches made possible through RL including data augmentation.

Validation of automated post-adjustments of HDR prostate brachytherapy treatment plans by quantitative measures and oncologist observer study

PURPOSEThe aim was to evaluate a postprocessing optimization algorithm's ability to improve the spatial properties of a clinical treatment plan while preserving the target coverage and the dose to the organs at risk. The goal was to obtain a more homogenous treatment plan, minimizing the need for manual adjustments after inverse treatment planning. MATERIALS AND METHODSThe study included 25 previously treated prostate cancer patients. The treatment plans were evaluated on dose-volume histogram parameters established clinical and quantitative measures of the high dose volumes. The volumes of the four largest hot spots were compared and complemented with a human observer study with visual grading by eight oncologists. Statistical analysis was done using ordinal logistic regression. Weighted kappa and Fleiss’ kappa were used to evaluate intra- and interobserver reliability. RESULTSThe quantitative analysis showed that there was no change in planning target volume (PTV) coverage and dose to the rectum. There were significant improvements for the adjusted treatment plan in: V150% and V200% for PTV, dose to urethra, conformal index, and dose nonhomogeneity ratio. The three largest hot spots for the adjusted treatment plan were significantly smaller compared to the clinical treatment plan. The observers preferred the adjusted treatment plan in 132 cases and the clinical in 83 cases. The observers preferred the adjusted treatment plan on homogeneity and organs at risk but preferred the clinical plan on PTV coverage. CONCLUSIONSQuantitative analysis showed that the postadjustment optimization tool could improve the spatial properties of the treatment plans while maintaining the target coverage.

Increased cytokine gene expression and cognition risk associated with androgen deprivation therapy.

BackgroundAndrogen deprivation therapy (ADT) is a standard treatment modality for locally advanced, high‐risk, and metastatic hormone‐sensitive prostate cancer. Long‐term ADT treatment likely develops side‐effects that include changes in cognition or onset of dementia. However, the molecular understanding of this effect remains elusive. We attempt to establish a link between ADT and changes in cognitive function using patient databases and bioinformatics analyses.MethodsGene expression profiling was performed using RNA sequencing data from Alzheimer patient cohort and compared with the data from advanced‐stage prostate cancer patients receiving neoadjuvant antiandrogen therapy. Differentially expressed genes (DEGs) were analyzed using the Ingenuity knowledge database.ResultsA total of 1952 DEGs in the Alzheimer patient cohort and 101 DEGs were identified in ADT treated prostate cancer patients. Comparing both data sets provided a subset of 33 commonly expressed genes involving cytokine‐cytokine signaling with an over representation of cytokine‐cytokine receptor interaction, inflammatory cytokines, signaling by interleukins together with alterations in the circulating lymphocyte repertoire, adaptive immune responses, regulation of cytokine production, and changes in T‐cell subsets. Additionally, lipopolysaccharide, tumor necrosis factor, and toll‐like receptors were identified as upstream transcriptional regulators of these pathways. The most commonly expressed genes viz. IL‐17A, CCL2, IL‐10, IL‐6, IL‐1RN, LIF/LIFR were further validated by quantitative RT‐PCR exhibited higher expression in antiandrogen treated neuronal, glial, and androgen‐responsive prostate cancer cells, compared to no‐androgen antagonist treatment.ConclusionsOur findings suggest that changes in cytokine signaling under the influence of ADT in prostate cancer patients may be linked with cognitive impairment presenting new avenues for diagnostic and therapeutic development in combating brain deficits.

Evaluation of the representativeness ofthe German Oncology Dynamics dataset.

To evaluate the representativeness of the German Oncology Dynamics (OD) dataset by comparing its projected patient population structure with that outlined in published epidemiological literature. The OD is an international cross-sectional semi-retrospective survey collecting anonymized patient cases from a representative panel of physicians via a web-based questionnaire; the cases are quality-checked and projected to the drug-treated prevalence using physician workload information. The present study verifies the OD 2018 projected patient proportions by indication and sex against prevalence figures in IARC's Globocan and the Cancer in Germany report by the Robert Koch Institute. Additionally, age group and metastasis presence distributions in gonadotropin-releasing hormone analog (GnRHa)-treated prostate cancer patients are compared with the findings of a registry-based study: Retrospective Analysis of Patients with Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes by Hupe et al. [3]. The OD demonstrated a cancer type distribution similar to the comparator sources. Cancer-specific sex distribution differences could be attributed to real-world diagnosis and treatment patterns. The age group distributions of GnRH-treated prostate cancer patients did not differ significantly between the OD and the Hupe et al. [3] study according to confidence interval comparisons and a Kolmogorov-Smirnov test. Projected patient distributions for the OD Germany were similar to those documented in the published literature. The dissimilarities can be attributed to the low drug-treated prevalence of some cancer types and sex-specific diagnosis timeline differences. Further investigations are needed to verify the reliability of histological biomarker data as well as patient demographics in other countries.

The Impact of the Ongoing COVID-19 Epidemic on the Increasing Risk of Adverse Pathology in Prostate Cancer Patients Undergoing Radical Prostatectomy.

We aimed to assess whether the ongoing course of the COVID-19 epidemic has been associated with an increased risk of adverse pathology (AP) findings in prostate cancer (PC) patients treated with radical prostatectomy (RP). We performed a retrospective data analysis which included 408 consecutive, non-metastatic, previously untreated PC patients who underwent RP in our institution between March 2020 and September 2021. Patients were divided into two equally numbered groups in regard to the median surgery date (Early Epidemic [EE] and Late Epidemic [LE]) and compared. Adverse pathology was defined as either grade group (GG) ≥ 4, pT ≥ 3a or pN+ at RP. Patients in the LE group demonstrated significantly higher rates of AP than in the EE group (61 vs. 43% overall and 50 vs. 27% in preoperative non-high-risk subgroup, both p < 0.001), mainly due to higher rates of upgrading. On multivariable analysis, consecutive epidemic week (odds ratio: 1.02, 95% confidence interval: 1.00–1.03, p = 0.009) as well as biopsy GG ≥ 2 and a larger prostate volume (mL) were associated with AP in non-high-risk patients. The study serves as a warning call for increased awareness of risk underassessment in contemporarily treated PC patients.

Preliminary Evaluation of 68Ga-P16-093, a PET Radiotracer Targeting Prostate-Specific Membrane Antigen in Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a promising molecular target for imaging of prostate adenocarcinoma. 68Ga-P16-093, a small molecule PSMA ligand, previously showed equivalent diagnostic performance compared to 68Ga-PSMA-11 PET/CT in a pilot study of prostate cancer patients with biochemical recurrence (BCR). We performed a pilot study for further characterization of 68Ga-P16-093 including comparison to conventional imaging. Patients were enrolled into two cohorts. The biodistribution cohort included 8 treated prostate cancer patients without recurrence, who underwent 6 whole body PET/CT scans with urine sampling for dosimetry using OLINDA/EXM. The dynamic cohort included 15 patients with BCR and 2 patients with primary prostate cancer. Two patients with renal cell carcinoma were also enrolled for exploratory use. A dynamic PET/CT was followed by 2 whole body scans for imaging protocol optimization based on bootstrapped replicates. 68Ga-P16-093 PET/CT was compared for diagnostic performance against available 18F-fluciclovine PET/CT, 99mTc-MDP scintigraphy, diagnostic CT, and MRI. 68Ga-P16-093 deposited similar effective dose (0.024mSv/MBq) and lower urinary bladder dose (0.064mSv/MBq) compared to 68Ga-PSMA-11. The kidneys were the critical organ (0.290mSv/MBq). While higher injected activities were preferable, lower injected activities at 74-111MBq (2-3mCi) yielded 80% retention in signal-to-noise ratio. The optimal injection-to-scan interval was 60min, with acceptable delay up to 90min. 68Ga-P16-093 PET/CT showed superior diagnostic performance over conventional imaging with overall patient-level lesion detection rate of 71%, leading to a change in management in 42% of the patients. Based on its favorable imaging characteristics and diagnostic performance in prostate cancer, 68Ga-P16-093 PET/CT merits further investigation in larger clinical studies.

CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that voltage gated calcium channel (VGCC) expression is increased in cancer, particularly CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients. This was corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models, which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. Expression was found to be of a shortened 170kDa CaV1.3 isoform associated with plasma and intracellular membranes, which failed to induce calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This mechanism was found to promote the proliferation and survival of ADT resistant CRPC cells. Overall, this study demonstrates for the first time in PCa that under ADT specific CaV1.3 isoforms promote an upregulation of SOCE which contributes to treatment resistance and CRPC biology. Thus, this novel oncochannel represents a target for therapeutic development to improve PCa patient outcomes.

Prostate Cancer–specific Survival After Radical Prostatectomy Is Improved Among Metformin Users but Not Among Other Antidiabetic Drug Users

BackgroundMetformin has been linked to improved survival among diabetic prostate cancer (PCa) patients, while hyperinsulinemia and insulin usage has been related to worse prognosis. ObjectiveTo evaluate the association of metformin and other antidiabetic drugs with PCa death and androgen deprivation therapy (ADT). Design, setting, and participantsThe study cohort included 14424 men who underwent radical prostatectomy in Finland during 1995–2013. Cases were identified, and clinical data were collected from patient files and national registries using personal identification numbers. InterventionInformation on the use of each antidiabetic drug during 1995–2014 was collected from prescription registry of the Social Insurance Institution of Finland. Outcome measurements and statistical analysisThe risks of PCa death and initiation of ADT were analyzed by antidiabetic drug use with the Cox regression method. Each antidiabetic drug group was analyzed separately to model simultaneous usage. Pre- and postdiagnostic uses were analyzed separately. Results and limitationsPrediagnostic use of antidiabetic drugs in general had no association with the risk of PCa death. Prediagnostic use of metformin was related to a reduced risk of ADT initiation (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59–0.96), while high-dose insulin users had an increased risk. Overall, antidiabetic drug use after PCa diagnosis was associated with an elevated risk of PCa death. Only postdiagnostic metformin use was associated with reduced risks of PCa death (HR 0.47, 95% CI 0.30–0.76) and ADT initiation compared with nonusers. Study limitations are missing information on glycemic control, smoking, living or exercise habits, prostate-specific antigen, and Gleason score. ConclusionsAmong surgically treated PCa patients, use of metformin was associated with improved disease-specific survival, while insulin and insulin secretagogues were associated with poor survival. Metformin might be a favorable diabetes treatment among men with PCa. Patient summaryIn this Finnish nationwide study, we found that the risks of prostate cancer death and cancer progression are lowered among metformin users, but not among other antidiabetic drug users. Metformin might be a favorable treatment choice for diabetes in men with prostate cancer.

Dosimetric Uncertainties in Dominant Intraprostatic Lesion Simultaneous Boost Using Intensity Modulated Proton Therapy

PurposeWhile intensity modulated proton therapy can deliver simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL) with high precision, it is sensitive to anatomic changes. We investigated the dosimetric effects from these changes based on pretreatment cone-beam computed tomographic (CBCT) images and identified the most important factors using a multilayer perceptron neural network (MLPNN). Methods and MaterialsDILs were contoured based on coregistered multiparametric magnetic resonance images for 25 previously treated prostate cancer patients. SIB plans were created with (1) prostate clinical target volume − V70 Gy = 98%; (2) DIL − V98 Gy > 95%; and (3) all organs at risk within clinical constraints. SIB plans were applied to daily CBCT-based deformed planning computed tomography (CT). DIL − V98 Gy, bladder/rectum maximum dose (Dmax) and volume changes, femur shifts, and the distance from DIL to organs at risk in both planning computed tomograms and CBCT were calculated. Wilcoxon signed-ranks tests were used to compare the changes. MLPNNs were used to model the change in ΔDIL − V98 Gy > 10% and bladder/rectum Dmax > 80 Gy, and the relative importance factors for the model were provided. The performances of the models were evaluated with receiver operating characteristic curves. ResultsComparing initial plan to the average from evaluation plans, respectively, DIL − V98 Gy was 89.3% ± 19.9% versus 86.2% ± 21.3% (P = .151); bladder Dmax 71.9 ± 0.6 Gy versus 74.5 ± 2.9 Gy (P < .001); and rectum Dmax 70.1 ± 2.4 Gy versus 74.9 ± 9.1Gy (P = .007). Bladder and rectal volumes were 99.6% ± 39.5% and 112.8% ± 27.2%, respectively, of their initial volume. The femur shift was 3.16 ± 2.52 mm. In the modeling of ΔDIL V98 Gy > 10%, DIL to rectum distance changes, DIL to bladder distance changes, and rectum volume changes ratio are the 3 most important factors. The areas under the receiver operating characteristic curves were 0.89, 1.00, and 0.99 for the modeling of ΔDIL − V98 Gy > 10%, and bladder and rectum Dmax > 80 Gy, respectively. ConclusionsDosimetric changes in DIL SIB with intensity modulated proton therapy can be modeled and classified based on anatomic changes on pretreatment images by an MLPNN.

Feasibility of MR-guided ultrahypofractionated radiotherapy in 5, 2 or 1 fractions for prostate cancer

The drive towards hypofractionated prostate radiotherapy is motivated by a low alpha/beta ratio for prostate cancer (1 to 3 Gy) compared to surrounding organs at risk, implying an improved therapeutic ratio with increasing dose per fraction. Early evidence from studies of ultrahypofractionated (UHF) prostate HDR brachytherapy has shown good tolerability in terms of normal tissue toxicities and clinical outcomes similar to conventional fractionation schedules.MR-guided stereotactic body radiotherapy (SBRT) with online plan adaptation and real-time tumour imaging may enable UHF doses to be delivered to the prostate safely, without the invasiveness of brachytherapy. The feasibility of UHF prostate treatment planning for the Unity MR-Linac (MRL, Elekta AB, Stockholm) was investigated for target prescriptions and planning constraints derived from the HDR brachytherapy and SBRT literature.Monaco 5.40 (Elekta) was used to generate MRL step-and-shoot IMRT plans for three dose fractionation protocols (5, 2 and 1 fractions), for ten randomly selected previously treated prostate cancer patients. Of the ten plans per UHF scheme, all clinical goals were met in all cases for 5 fractions, and in six cases for both 2 and 1 fraction schemes. PTV D95% was compromised by up to 6.4% and 3.9% of the associated target dose for 2 and 1 fraction plans respectively. There were two cases of PTV D95% compromise greater than a 5% dose decrease for the 2 fraction plans. The study suggests feasibility of the UHF treatment planning approaches if combined with real-time motion mitigation strategies.

Portuguese version of the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP): psychometric validation and prospective application for early functional outcomes at a single institution

BackgroundThe Expanded Prostate Index Composite for Clinical Practice (EPIC-CP) is a short version of the original EPIC, developed to facilitate the instrument’s use in routine care. This study aimed to validate the EPIC-CP Portuguese version, and evaluate its role in presenting early functional outcomes of surgically treated prostate cancer patients at a Latin American referral center.MethodsThe EPIC-CP was self-administered prospectively and individually by all localized prostate cancer patients, before and after robotic-assisted radical prostatectomy, from March 2017 to June 2018 at a single institution. For validation, we used the Cronbach’s alpha coefficient to evaluate internal consistency. The EPIC-CP domains were compared before surgery, and 6 months and 12 months after surgery. Statistical analyses were performed using the student’s t test, and Wilcoxon and Friedman tests, with p values < 0.05 considered significant.ResultsOne hundred and fifty two patients answered the EPIC-CP. The patients had a median age of 62.7 (± 8.5) years and prostate specific antigen level of 6.3 (± 4.6) ng/ml. The Cronbach’s alpha varied from 0.75 to 0.77 for all domains with good internal consistency, except for the “vitality/hormonal” domain, which had a score of 0.35. The domain evolution for the preoperative and 6-month postoperative groups revealed that the domains related to urinary continence and bowel worsened, and were increased during the first 6 months; however, this variation had no obvious clinical implications, and the irritative symptoms improved. Regarding the sexual domain, the scores worsened, and also increased over the first 6 months. The results of the confirmatory factor analysis were robust, with an explained variance of 0.951 and covariance of 0.929.ConclusionsThe Portuguese version of the EPIC-CP is a reliable and valid questionnaire for postoperative patients, and very useful to improve the knowledge of the early functional outcomes of men treated for prostate cancer.

Dosimetric comparison of RapidPlan and manually optimised volumetric modulated arc therapy plans in prostate cancer

AbstractPurpose:The aim of this study was to evaluate whether RapidPlan (RP) could generate clinically acceptable prostate volumetric modulated arc therapy (VMAT) plans.Methods:The in-house RP model was used to generate VMAT plans for 50 previously treated prostate cancer patients, with no additional optimisation being performed. The VMAT plans that were generated using the RP model were compared with the patients’ previous, manually optimised clinical plans (MP), none of which had been used for the development of the in-house RP prostate model. Differences between RP and MP in planning target volume (PTV) doses, organs at risk (OAR) sparing, monitor units (MU) and planning time required to produce treatment plans were analysed. Assessment of PTV doses was based on the conformation number (CN), homogeneity index (HI), D2%, D99% and the mean dose of the PTV. The OAR doses evaluated were the rectal V50 Gy, V65 Gy, V70 Gy and the mean dose, the bladder V65 Gy, V70 Gy and the mean dose, and the mean dose to both femurs.Results:D99% and mean dose of the PTV were lower for RP than for MP (p = 0·006 and p = 0·040, respectively).V50 Gy, V65 Gy and the mean dose to rectum were lower in RP than in MP (p &lt; 0·001). V65 Gy, V70 Gy and the mean dose to bladder were lower in RP than in MP (p &lt; 0·001). RP had enhanced the sparing of both femurs (p &lt; 0·001) and significantly reduced the planning time to less than 5% of the time taken with MP. MU in RP was significantly higher than MP by an average of 52·5 MU (p &lt; 0·001) and 46 out of the 50 RP plans were approved by the radiation oncologist.Conclusion:This study has demonstrated that VMAT plans generated using an in-house RP prostate model in a single optimisation for prostate patients were clinically acceptable with comparable or better plan quality compared to MP. RP can add value and improve treatment planning efficiency in a high-throughput radiotherapy department through reduced plan optimisation time while maintaining consistency in the plan quality.

Automatic bi-objective parameter tuning for inverse planning of high-dose-rate prostate brachytherapy

We present an automatic bi-objective parameter-tuning approach for inverse planning methods for high-dose-rate prostate brachytherapy, which aims to overcome the difficult and time-consuming manual parameter tuning that is currently required to obtain patient-specific high-quality treatment plans. We modelled treatment planning as a bi-objective optimization problem, in which dose-volume-based planning criteria related to target coverage are explicitly separated from organ-sparing criteria. When this model is optimized, a large set of high-quality plans with different trade-offs can be obtained. This set can be visualized as an insightful patient-specific trade-off curve. In our parameter-tuning approach, the parameters of inverse planning methods are automatically tuned, aimed to maximize the two objectives of the bi-objective planning model. By generating trade-off curves for different inverse planning methods, their maximally achievable plan quality can be insightfully compared. Automatic parameter tuning furthermore allows to construct standard parameter sets (class solutions) representing different trade-offs in a principled way, which can be directly used in current clinical practice. In this work, we considered the inverse planning methods IPSA and HIPO. Thirty-nine previously treated prostate cancer patients were included. We compared automatic parameter tuning, random parameter sampling, and the maximally achievable plan quality obtained by directly optimizing the bi-objective planning model with the state-of-the-art optimization software GOMEA. We showed that for each patient, a set of plans with a wide range of trade-offs could be obtained using automatic parameter tuning for both IPSA and HIPO. By tuning HIPO, better trade-offs were obtained than by tuning IPSA. For most patients, automatic tuning of HIPO resulted in plans close to the maximally achievable plan quality obtained by optimizing the bi-objective planning model directly. Automatic parameter tuning was shown to improve plan quality significantly compared to random parameter sampling. Finally, from the automatically-tuned plans, three class solutions were successfully constructed representing different trade-offs.

Risk of fall and clinical fracture associated with androgen receptor inhibitors: A systematic review and meta-analysis.

71 Background: Patients treated with androgen receptor inhibitors (ARIs) report a higher incidence of falls; although a potential mechanism of action is unknown. This systematic review evaluates the relative risk (RR) of fall and fracture in prostate cancer (PCa) patients that receive ARIs. Methods: We conducted a comprehensive literature search using Cochrane, Scopus and MedlinePlus databases from inception through August 2019, and evaluated all published prospective phase II, III and IV randomized controlled trials that treated PCa patients with ARIs. Reported fall and fractures as adverse events (AEs) were extracted for analysis. Retrospective, phase I, non-randomized phase II, and studies with control arms that used one of the ARIs were excluded. A mixed effects model was used to estimate effects of ARI on the RR, with the included studies treated as random effects and study arms treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Results: Eleven studies met our inclusion criteria. The total population was 11,382; 6536 were in the ARI arm and 4846 in the control (CTL) arm. Study types were: 8 phase III; 2 phase II; 1 phase IV. Subjects in the ARI arm received enzalutamide, apalutamide or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations while in the CTL arm received placebo, bicalutamide or abiraterone. Treatment duration ranged from 5.4 to 20.5 mo for ARI vs. 5.4 to 18.3 mo for CTL. The reported incidence of fall was 481 (7.4%) in ARI and 201 (4.1%) for CTL. The incidence of fracture was 204 (3.1%) in ARI and 93 (1.9%) in control. The use of ARI was associated with an increased risk: all fall grades (RR 1.83; 95% CI 1.56-2.15; p &lt;0.01); high grade fall (RR 1.69; 95% CI 1.09 – 2.62; p=0.019); all grade fracture (RR 1.56; 95% CI 1.23-1.97; p &lt;0.01) and likely high grade fracture (RR 1.62; 95% CI 0.97 – 2.69; p=0.063). Conclusions: The use of ARI significantly increases falls and fractures in PCa patients as assessed by this meta-analysis study. Further studies would be warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.

Glucuronidation of Abiraterone and Its Pharmacologically Active Metabolites by UGT1A4, Influence of Polymorphic Variants and Their Potential as Inhibitors of Steroid Glucuronidation.

Abiraterone (Abi) acetate (AA) is a prodrug of Abi, a CYP17A1 inhibitor used to treat patients with advanced prostate cancer. Abi is a selective steroidal inhibitor that blocks the biosynthesis of androgens. It undergoes extensive biotransformation by steroid pathways, leading to the formation of pharmacologically active Δ4-Abi (D4A) and 5α-Abi. This study aimed to characterize the glucuronidation pathway of Abi and its two active metabolites. We show that Abi, its metabolites, and another steroidal inhibitor galeterone (Gal) undergo secondary metabolism to form glucuronides (G) in human liver microsomes with minor formation by intestine and kidney microsomal preparations. The potential clinical relevance of this pathway is supported by the detection by liquid chromatography-tandem mass spectrometry of Abi-G, D4A-G, and 5α-Abi-G in patients under AA therapy. A screening of UGT enzymes reveals that UGT1A4 is the main enzyme involved. This is supported by inhibition experiments using a selective UGT1A4 inhibitor hecogenin. A number of common and rare nonsynonymous variants significantly abrogate the UGT1A4-mediated formation of Abi-G, D4A-G, and 5α-Abi-G in vitro. We also identify Gal, Abi, and its metabolites as highly potent inhibitors of steroid inactivation by the UGT pathway with submicromolar inhibitor constant values. They reduce the glucuronidation of both the adrenal precursors and potent androgens in human liver, prostate cancer cells, and by recombinant UGTs involved in their inactivation. In conclusion, tested CYP17A1 inhibitors are metabolized through UGT1A4, and germline variations affecting this metabolic pathway may also influence drug metabolism. SIGNIFICANCE STATEMENT: The antiandrogen abiraterone (Abi) is a selective steroidal inhibitor of the cytochrome P450 17α-hydroxy/17,20-lyase, an enzyme involved in the biosynthesis of androgens. Abi is metabolized to pharmacologically active metabolites by steroidogenic enzymes. We demonstrate that Abi and its metabolites are glucuronidated in the liver and that their glucuronide derivatives are detected at variable levels in circulation of treated prostate cancer patients. UDP-glucuronosyltransferase (UGT)1A4 is the primary enzyme involved, and nonsynonymous germline variations affect this metabolic pathway in vitro, suggesting a potential influence of drug metabolism and action in patients. Their inhibitory effect on drug and steroid glucuronidation raises the possibility that these pharmacological compounds might affect the UGT-associated drug-metabolizing system and pre-receptor control of androgen metabolism in patients.

Second cancers in radically treated Norwegian prostate cancer patients

Introduction: The aim of this registry-based cohort study was to estimate second cancer (SC) risk following radical prostate cancer (PC) treatment and evaluate if the risk was influenced by radiotherapy.Materials and methods: We collected data from the Cancer Registry of Norway on all patients with PC as first cancer diagnosis, from 1997 to 2014. Standardized incidence ratios (SIRs) for SC were calculated by comparing our cohort to the standard male population. Subdistribution hazard ratios were estimated in treatment groups, using patients treated with radical prostatectomy (RP) as reference.Results: We analyzed 24,592 radically treated PC patients. The median follow-up was 7.75 and 6.25 years in the external beam radiotherapy (EBRT) and RP-groups, respectively. SIR for SC was indifferent from the reference population in 24,592 radically treated patients, higher following EBRT, SIR 1.12 (1.07–1.17), and lower following RP, SIR 0.93 (0.87–0.99). EBRT treated patients had higher rectal and urinary bladder cancer incidences, SIR 1.38 (1.16–1.64) and 1.49 (1.31–1.69), respectively. The EBRT patients and the patients treated with radiation after RP (RT after RP) had 38 and 27% higher risk of any SC. We found higher risk of bladder cancer for all treatment groups as compared to RP patients. Only EBRT treated patients showed higher risk of rectal and lung cancer.Discussion/conclusions: In our study, we found that PC patients treated with EBRT had an increased incidence of SC compared to the general population. Patients treated with EBRT and RT after RP were found to have increased risk of SCs, using RP patients as reference. The risks of rectal and urinary bladder cancer in patients receiving EBRT were higher compared to both the general population and to patients treated with radical prostatectomy. The risk of SC should be taken into account when discussing treatment for patients and designing follow-up.

Prostate cancer survival among statin users after prostatectomy in a Finnish nationwide cohort.

Improved prostate cancer (PCa) survival by statin use has been reported among PCa patients managed with radiation or androgen deprivation therapy (ADT), while results are controversial for men managed surgically. We evaluate the association between cholesterol-lowering medication with initiation of ADT and disease-specific death among PCa cases who underwent radical prostatectomy in Finland between 1995 and 2013. The study cohort included 14 424 men with PCa who underwent radical prostatectomy in Finland between 1995 and 2013. Cases were identified from national hospital discharge registry. Clinical data were amended from patient files of the treating hospitals. Information on co-morbidities, additional radiation- or chemotherapy, and causes of deaths were collected from national registries. Personal-level data on medication use during 1995-2014 were gathered from national prescription database. Registry linkages were carried out using personal identification number. Lipid-lowering drugs were categorized into statins and non-statin drugs. Risk of PCa death and initiation of ADT was analyzed using Cox-regression model with adjustment for age, radiation therapy, chemotherapy, co-morbidities and other drug use. Statin use was analyzed as time-dependent variable. Delayed risk associations were evaluated in lag-time analysis. Compared to non-users the risk of PCa death was significantly lower among statin users before PCa diagnosis (HR 0.70, 95%CIs 0.52-0.95). For statin use after PCa diagnosis the risk was lowered in age-adjusted analysis (HR 0.76 95%CIs 0.62-0.93) but not after multivariable-adjustment. Post-diagnostic statin use was associated with improved PCa-specific survival in 1, 3 and 5 years lag-time analyses. The risk reduction was clearest for statin use initiated 5 years earlier (HR 0.71 95%CIs 0.55-0.92). Use of statins both before and after PCa diagnosis was associated with reduced risk of ADT use (HR 0.72 95%CIs 0.65-0.80 and HR 0.73, 95%CI 0.67-0.80, respectively). The risk of ADT decreased by increasing intensity of statin use before diagnosis. Statin use among surgically treated PCa patients has significant association with decreased risk of starting ADT and PCa death. The risk is lowered especially among men with statin use before PCa diagnosis and in men who used statins at high-dose. Our results are hypothesis generating due to retrospective study design.

Prevalence of ERG expression and PTEN loss in a Brazilian prostate cancer cohort.

PTEN is the most commonly inactivated tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes. ERG rearrangement is a genomic alteration frequently found in PCa and its prognostic significance has yielded mixed results. Although the association of PTEN and ERG biomarkers has potential impact on clinical outcomes, studies examining the two genes simultaneously are scarce in Brazilian populations. In this study, we retrospectively examined the relationship between ERG expression and PTEN loss in 119 surgically treated prostate cancer patients from Northeastern Brazil through immunohistochemical analysis. ERG expression was found in 41.0% (48/117) of cases and the loss of PTEN detected in 38.1% (40/105) of samples. ERG-positive cases were significantly associated with lower prostate weight; ERG negatively correlated with Gleason score above 6. The lack of associations for PTEN loss alone in this cohort is counter to the literature, which shows that PTEN loss is usually associated with more aggressive disease. The overlapping of the two biomarkers revealed that samples with positive ERG expression without PTEN loss were associated with lower Gleason and lower Grade group. This study contributes with the discussion about the development of the molecular profiling of prostate cancer. The further development of similar studies could help in stratifying specific risk groups, leading to a more personalized therapeutic decision for prostate cancer treatment.