Risk of severe late toxicity after radiotherapy following radical prostatectomy - a nationwide study.

OBJECTIVE: To estimate the long-term risks of severe late toxicities for radiation therapy (RT) following radical prostatectomy (RP) in an unselected nationwide cohort, as severe side-effects are rare but may occur years later. PATIENTS AND METHODS: The study population comprised all men undergoing RP between 1997 and 2016 in the Prostate Cancer database Sweden (PCBaSe) (n = 40 962). By (1:2) matching, two cohorts were created: 2789 men exposed to postoperative RT and 5578 unexposed men with comparable age, comorbidities, and year of surgery. Cumulative incidences and rate ratios were calculated for the following outcomes: symptoms and interventions of the urinary or intestinal tract demanding inpatient care, secondary malignancies, and non-prostate cancer mortality. RESULTS: The largest differences were seen for late toxicities affecting the urinary tract. The 10-year cumulative incidences among those exposed to postoperative RT vs the RP-only group were: 17.8% vs 10.5% for procedures of the urinary tract (difference 7.3%, 95% confidence interval [CI] 4.4 to 10.3; relative risk [RR] 1.74, 95% CI 1.47 to 2.05); 6.0% vs 1.2% for haematuria (difference 4.8%, 95% CI 3.1 to 6.5; RR 6.50, 95% CI 4.31 to 10.10); and 2.4% vs 1.1% for bladder cancer (difference 1.4%, 95% CI 0.4 to 2.3; RR 2.71, 95% CI 1.72 to 4.33). The groups were similar regarding intestinal toxicity, other secondary malignancies, and non-prostate cancer mortality. Adjustments for preoperative tumour risk factors did not importantly affect the rate ratios. CONCLUSION: Severe late toxicity after postoperative RT following RP predominately affects the bladder and can appear many years after RT.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer (HYPO-RT-PC): patient-reported quality-of-life outcomes of a randomised, controlled, non-inferiority, phase 3 trial.

BACKGROUND: The HYPO-RT-PC trial compared conventionally fractionated radiotherapy with ultra-hypofractionated radiotherapy in patients with localised prostate cancer. Ultra-hypofractionation was non-inferior to conventional fractionation regarding 5-year failure-free survival and toxicity. We aimed to assess whether patient-reported quality of life (QOL) differs between conventional fractionation and ultra-hypofractionation up to 6 years after treatment in the HYPO-RT-PC trial. METHODS: HYPO-RT-PC is a multicentre, open-label, randomised, controlled, non-inferiority, phase 3 trial done in 12 centres (seven university hospitals and five county hospitals) in Sweden and Denmark. Inclusion criteria were histologically verified intermediate-to-high-risk prostate cancer (defined as T1c-T3a with one or two of the following risk factors: stage T3a; Gleason score ≥7; and prostate-specific antigen 10-20 ng/mL with no evidence of lymph node involvement or distant metastases), age up to 75 years, and WHO performance status 0-2. Participants were randomly assigned (1:1) to conventional fractionation (78·0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) via a minimisation algorithm with stratification by trial centre, T-stage, Gleason score, and prostate-specific antigen. QOL was measured using the validated Prostate Cancer Symptom Scale (PCSS) and European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline, the end of radiotherapy, months 3, 6, 12, and 24 after radiotherapy, every other year thereafter up to 10 years, and at 15 years. The primary endpoint (failure-free survival) has been reported elsewhere. Here we report QOL, a secondary endpoint analysed in the per-protocol population, up to 6 years after radiotherapy. The HYPO-RT-PC trial is registered with the ISRCTN registry, ISRCTN45905321. FINDINGS: Between July 1, 2005, and Nov 4, 2015, 1200 patients were enrolled and 1180 were randomly assigned (conventional fractionation n=591, ultra-hypofractionation n=589); 1165 patients (conventional fractionation n=582, ultra-hypofractionation n=583) were included in this QOL analysis. 158 (71%) of 223 patients in the conventional fractionation group and 146 (66%) of 220 in the ultra-hypofractionation group completed questionnaires at 6 years. The median follow-up was 48 months (IQR 25-72). In seven of ten bowel symptoms or problems the proportion of patients with clinically relevant deteriorations at the end of radiotherapy was significantly higher in the ultra-hypofractionation group than in the conventional fractionation group (stool frequency [p<0·0001], rush to toilet [p=0·0013], flatulence [p=0·0013], bowel cramp [p<0·0001], mucus [p=0·0014], blood in stool [p<0·0001], and limitation in daily activity [p=0·0014]). There were no statistically significant differences in the proportions of patients with clinically relevant acute urinary symptoms or problems (total 14 items) and sexual functioning between the two treatment groups at end of radiotherapy. Thereafter, there were no clinically relevant differences in urinary, bowel, or sexual functioning between the groups. At the 6-year follow-up there was no difference in the incidence of clinically relevant deterioration between the groups for overall urinary bother (43 [33%] of 132 for conventional fractionation vs 33 [28%] of 120 for ultra-hypofractionation; mean difference 5·1% [95% CI -4·4 to 14·6]; p=0·38), overall bowel bother (43 [33%] of 129 vs 34 [28%] of 123; 5·7% [-3·8 to 15·2]; p=0·33), overall sexual bother (75 [60%] of 126 vs 59 [50%] of 117; 9·1% [-1·4 to 19·6]; p=0·15), or global health/QOL (56 [42%] of 134 vs 46 [37%] of 125; 5·0% [-5·0 to 15·0]; p=0·41). INTERPRETATION: Although acute toxicity was higher for ultra-hypofractionation than conventional fractionation, this long-term patient-reported QOL analysis shows that ultra-hypofractionation was as well tolerated as conventional fractionation up to 6 years after completion of treatment. These findings support the use of ultra-hypofractionation radiotherapy for intermediate-to-high-risk prostate cancer. FUNDING: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.

BACKGROUND: Hypofractionated radiotherapy for prostate cancer has gained increased attention due to its proposed high radiation-fraction sensitivity. Recent reports from studies comparing moderately hypofractionated and conventionally fractionated radiotherapy support the clinical use of moderate hypofractionation. To date, there are no published randomised studies on ultra-hypofractionated radiotherapy. Here, we report the outcomes of the Scandinavian HYPO-RT-PC phase 3 trial with the aim to show non-inferiority of ultra-hypofractionation compared with conventional fractionation. METHODS: In this open-label, randomised, phase 3 non-inferiority trial done in 12 centres in Sweden and Denmark, we recruited men up to 75 years of age with intermediate-to-high-risk prostate cancer and a WHO performance status between 0 and 2. Patients were randomly assigned to ultra-hypofractionation (42·7 Gy in seven fractions, 3 days per week for 2·5 weeks) or conventional fractionated radiotherapy (78·0 Gy in 39 fractions, 5 days per week for 8 weeks). No androgen deprivation therapy was allowed. The primary endpoint was time to biochemical or clinical failure, analysed in the per-protocol population. The prespecified non-inferiority margin was 4% at 5 years, corresponding to a critical hazard ratio (HR) limit of 1·338. Physician-recorded toxicity was measured according to the Radiation Therapy Oncology Group (RTOG) morbidity scale and patient-reported outcome measurements with the Prostate Cancer Symptom Scale (PCSS) questionnaire. This trial is registered with the ISRCTN registry, number ISRCTN45905321. FINDINGS: Between July 1, 2005, and Nov 4, 2015, 1200 patients were randomly assigned to conventional fractionation (n=602) or ultra-hypofractionation (n=598), of whom 1180 (591 conventional fractionation and 589 ultra-hypofractionation) constituted the per-protocol population. 1054 (89%) participants were intermediate risk and 126 (11%) were high risk. Median follow-up time was 5·0 years (IQR 3·1-7·0). The estimated failure-free survival at 5 years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1·002 (95% CI 0·758-1·325; log-rank p=0·99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0·057). There were no significant differences in grade 2 or worse urinary or bowel late toxicity between the two treatment groups at any point after radiotherapy, except for an increase in urinary toxicity in the ultra-hypofractionation group compared to the conventional fractionation group at 1-year follow-up (32 [6%] of 528 patients vs 13 [2%] of 529 patients; (p=0·0037). We observed no differences between groups in frequencies at 5 years of RTOG grade 2 or worse urinary toxicity (11 [5%] of 243 patients for the ultra-hypofractionation group vs 12 [5%] of 249 for the conventional fractionation group; p=1·00) and bowel toxicity (three [1%] of 244 patients vs nine [4%] of 249 patients; p=0·14). Patient-reported outcomes revealed significantly higher levels of acute urinary and bowel symptoms in the ultra-hypofractionation group compared with the conventional fractionation group but no significant increases in late symptoms were found, except for increased urinary symptoms at 1-year follow-up, consistent with the physician-evaluated toxicity. INTERPRETATION: Ultra-hypofractionated radiotherapy is non-inferior to conventionally fractionated radiotherapy for intermediate-to-high risk prostate cancer regarding failure-free survival. Early side-effects are more pronounced with ultra-hypofractionation compared with conventional fractionation whereas late toxicity is similar in both treatment groups. The results support the use of ultra-hypofractionation for radiotherapy of prostate cancer. FUNDING: The Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council.

The value of a bladder-filling protocol for patients with prostate cancer who receive post-operative radiation: results from a prospective clinical trial.

BACKGROUND AND PURPOSE: This study compares two different strategies for maintaining a constant bladder volume during a course of postoperative radiotherapy in prostate cancer. In addition, we studied how changes in bladder filling affect the clinical target volume (CTV) and the coverage hereof. MATERIAL AND METHODS: Twenty-nine patients with PSA-relapse after radical prostatectomy were divided into two groups: voiding and drinking 300 ml 1 hour before treatment (Group 1); and maintained a comfortably filled bladder (Group 2). The bladder volumes were calculated based on the planning CT (pCT) and a weekly Cone Beam CT (CBCT) during the treatment period. Furthermore, the variability of bladder extension was analyzed and correlated to the volume of the bladder covered with the 95% of the dose (V95%,bladder). RESULTS: The estimated median bladder volumes were 120 ml (95% CI: (93, 154)) and 123 ml (95% CI: (98, 155)) in groups 1 and 2, respectively. The intra-individual variation in bladder volume, assessed as the standard deviation, was 64 ml (95% CI: (46, 105)) in Group 1 and 61 (95% CI: (45, 94)) ml in Group 2. Increasing the bladder volume extended the bladder cranially while the caudal extension was almost constant. The correlation between bladder volume and V95%,bladder was 3.5 ml per 100 ml in group 1 and 1.2 ml per 100 ml in group 2 with no significant difference. CONCLUSIONS: The intention to maintain a constant volume for the bladder is not fulfilled with either of the protocols in this study, and changes in bladder volumes does not seem to affect the position, or the coverage of the CTV.

[Treatment of non-metastatic prostate cancer]. / Behandling av icke spridd prostatacancer ­ individuellt val.

There is a long history of curative treatment of prostate cancer. However, as prostate cancer often grows very slowly, and symptoms do not have time to develop during a person's lifetime, a more tentative approach has become more and more common in many cases. This may be through either watchful waiting or active surveillance. In the first case palliative hormonal treatment is given in the case of progression, in the latter curative treatment would be the choice. When treatment is deemed necessary for localized disease, surgery and radiotherapy are considered equivalent in terms of efficacy and overall risk of side effects. For locally advanced disease, radiotherapy is the recommended first-hand choice outside the SPCG 15 study. Focal treatment, which may lead to less side effects than surgery or radiotherapy, is not recommended outside trial settings due to lack of long-term follow-up data.

Patient-reported Side Effects 1 Year After Radical Prostatectomy or Radiotherapy for Prostate Cancer: A Register-based Nationwide Study.

BACKGROUND: Data on functional and psychological side effects following curative treatment for prostate cancer are lacking from large, contemporary, unselected, population-based cohorts. OBJECTIVE: To assess urinary symptoms, bowel disturbances, erectile dysfunction (ED), and quality of life (QoL) 12 mo after robot-assisted radical prostatectomy (RARP) and radiotherapy (RT) using patient-reported outcome measures in the Swedish prostate cancer database. DESIGN, SETTING, AND PARTICIPANTS: This was a nationwide, population-based, cohort study in Sweden of men who underwent primary RARP or RT between January 1, 2018 and December 31, 2020. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Absolute proportions and odds ratios (ORs) were calculated using multivariable logistic regression, with adjustment for clinical characteristics. RESULTS AND LIMITATIONS: A total of 2557 men underwent RARP and 1741 received RT. Men who underwent RT were older (69 vs 65 yr) and had more comorbidities at baseline. After RARP, 13% of men experienced incontinence, compared to 6% after RT. The frequency of urinary bother was similar, at 18% after RARP and 18% after RT. Urgency to defecate was reported by 14% of men after RARP and 34% after RT. At 1 yr, 73% of men had ED after RARP, and 77% after RT. High QoL was reported by 85% of men after RARP and 78% of men after RT. On multivariable regression analysis, RT was associated with lower risks of urinary incontinence (OR 0.25, 95% confidence interval [CI] 0.19-0.33), urinary bother (OR 0.79, 95% CI 0.66-0.95), and ED (OR 0.54, 95% CI 0.46-0.65), but higher risk of bowel symptoms (OR 2.86, 95% CI 2.42-3.39). QoL was higher after RARP than after RT (OR 1.34, 95% CI 1.12-1.61). CONCLUSIONS: Short-term specific side effects after curative treatment for prostate cancer significantly differed between RARP and RT in this large and unselected cohort. Nevertheless, the risk of urinary bother was lower after RT, while higher QoL was common after RARP. PATIENT SUMMARY: In our study of patients treated for prostate cancer, urinary bother and overall quality of life are comparable at 1 year after surgical removal of the prostate in comparison to radiotherapy, despite substantial differences in other side effects.

Artificial Intelligence-Based Organ Delineation for Radiation Treatment Planning of Prostate Cancer on Computed Tomography.

Purpose: Meticulous manual delineations of the prostate and the surrounding organs at risk are necessary for prostate cancer radiation therapy to avoid side effects to the latter. This process is time consuming and hampered by inter- and intraobserver variability, all of which could be alleviated by artificial intelligence (AI). This study aimed to evaluate the performance of AI compared with manual organ delineations on computed tomography (CT) scans for radiation treatment planning. Methods and Materials: Manual delineations of the prostate, urinary bladder, and rectum of 1530 patients with prostate cancer who received curative radiation therapy from 2006 to 2018 were included. Approximately 50% of those CT scans were used as a training set, 25% as a validation set, and 25% as a test set. Patients with hip prostheses were excluded because of metal artifacts. After training and fine-tuning with the validation set, automated delineations of the prostate and organs at risk were obtained for the test set. Sørensen-Dice similarity coefficient, mean surface distance, and Hausdorff distance were used to evaluate the agreement between the manual and automated delineations. Results: The median Sørensen-Dice similarity coefficient between the manual and AI delineations was 0.82, 0.95, and 0.88 for the prostate, urinary bladder, and rectum, respectively. The median mean surface distance and Hausdorff distance were 1.7 and 9.2 mm for the prostate, 0.7 and 6.7 mm for the urinary bladder, and 1.1 and 13.5 mm for the rectum, respectively. Conclusions: Automated CT-based organ delineation for prostate cancer radiation treatment planning is feasible and shows good agreement with manually performed contouring.

Rate of castration-induced prostate stroma regression is reduced in a mouse model of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the resulting enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity of the epithelial and stromal compartments to androgen withdrawal. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but the stromal compartment contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGFß and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGFß or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

The Swedish national guidelines on prostate cancer, part 1: early detection, diagnostics, staging, patient support and primary management of non-metastatic disease.

OBJECTIVE: There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. METHODS: This is part 1 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. It covers the early detection, diagnostics, staging, patient support and management of the non-metastatic disease. Part 2 covers recurrence after local treatment and management of the metastatic disease. RESULTS: The 2022 Swedish guidelines include several new recommendations: rectal iodine-povidone to reduce post-biopsy infections, external beam radiation with focal boost to the tumour, use of a pre-rectal spacer to reduce rectal side effects after external beam radiotherapy in some expert centres, 6 months' concomitant and adjuvant rather than neoadjuvant and concomitant hormonal treatment together with radiotherapy for unfavourable intermediate and high-risk disease, and adjuvant abiraterone plus prednisolone together with a GnRH agonist for a subgroup of men with very high-risk disease. The Swedish guidelines differ from the European by having more restrictive recommendations regarding genetic testing and pelvic lymph node dissection, the risk group classification, recommending ultra-hypofractionated (7 fractions) external radiotherapy for intermediate and selected high-risk cancers, by not recommending any hormonal treatment together with radiotherapy for favourable intermediate-risk disease, and by recommending bicalutamide monotherapy instead of a GnRH agonist for some patient groups. CONCLUSIONS: The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.

The Swedish national guidelines on prostate cancer, part 2: recurrent, metastatic and castration resistant disease.

OBJECTIVE: There is now an unprecedented amount of evidence to consider when revising prostate cancer guidelines. We believe that there is a value in publishing summaries of national clinical guidelines in English for others to read and comment on. METHODS: This is part 2 of a summary of the Swedish prostate cancer guidelines that were published in June 2022. This part covers recurrence after local treatment and management of metastatic and castration resistant disease. Part 1 covers early detection, diagnostics, staging, patient support and management of non-metastatic disease. RESULTS: The 2022 Swedish guidelines include several new recommendations. Among these is a recommendation of a period of observation with repeated PSA tests for patients with approximately 10 years' life expectancy who experience a BCR more than 2-5 years after radical prostatectomy, to allow for estimating the PSA doubling time before deciding whether to give salvage radiotherapy or not. Recent results from the PEACE-1 trial led to the recommendation of triple-treatment with a GnRH agonist, abiraterone plus prednisolone and 6 cycles of docetaxel for patients with high-volume metastatic disease who are fit for chemotherapy. The Swedish guidelines differ from the European ones by having more restrictive recommendations about genetic testing of and high-dose zoledronic acid or denosumab treatment for men with metastatic prostate cancer, and by recommending considering bicalutamide monotherapy for selected patients with low-volume metastatic disease. CONCLUSIONS: The 2022 Swedish prostate cancer guidelines include several new recommendations and some that differ from the European guidelines.

3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs.

PURPOSE: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO2) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO2 and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO2-distribution due to antiangiogenic treatment in combination with radionuclide therapy. METHODS: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10(10) tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were 90Y, 131I, 177Lu, and 211At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO2-distributions: micro1 = 2.483, sigma1 = 0.711; micro2 = 2.946, sigma2 = 0.689; micro3 = 3.689, and sigma3 = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. RESULTS: As tumor pO2 approaches normal tissue levels, the therapeutic effect is improved so that the normal tissue absorbed doses can be decreased by more than 95%, while retaining TCP, in the most favorable scenario and by up to about 80% with oxygen levels previously achieved in vivo, when the least favourable oxygenation case is used as starting point. The major difference occurs in poorly oxygenated cells. This is also where the pO2-dependence of the oxygen enhancement ratio is maximal. CONCLUSIONS: Improved tumor oxygenation together with increased radionuclide uptake show great potential for optimising treatment strategies, leaving room for successive treatments, or lowering absorbed dose to normal tissues, due to increased tumor response. Further studies of the concomitant use of antiangiogenic drugs and radionuclide therapy therefore appear merited.

Dosimetric Analysis of the Short-Ranged Particle Emitter 161Tb for Radionuclide Therapy of Metastatic Prostate Cancer.

The aim of this study was to analyze the required absorbed doses to detectable metastases (Dreq) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4-6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The Dreq was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The Dreq for iodine-131 and yttrium-90 was high (920-3300 Gy). The Dreq for lutetium-177 was between 560 and 780 Gy and considerably lower Dreq were obtained for actinium-225 and terbium-161, with 240-330 Gy and 210-280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands.

A comparison of side-effects and quality-of-life in patients operated on for prostate cancer with and without salvage radiation therapy.

PURPOSE: The extent of late side-effects in prostate cancer patients, after radical prostatectomy (RP = reference group) and salvage radiation therapy (SRT) in a self-reporting perspective (PROM) is still under-reported. We aimed to investigate the rate and severity of side-effects and quality-of-life (QoL) according to PROM. METHODS AND MATERIALS: A PROM survey was administered to a cohort of SRT patients matched to a reference group with median follow-up 10 years after surgery. In total, 740 patients were analyzed. To investigate the association between SRT versus reference group regarding side-effects and QoL, a Poisson regression analysis was conducted and presented as relative risk estimates (RR) together with 95% confidence intervals regarding questions related to urinary, rectal, sexual symptoms and QoL. RESULTS: RRs ranged from of 1.7-6.5 on rectal symptoms and 1.2-1.4 for urinary symptoms. In general health, QoL and sexual function all RRs were below 1.1. With increasing age, higher RRs were seen for urinary leakage and lowered sexual function whereas longer time following irradiation showed higher RRs for rectal symptoms and rectal leakage. Limitations of this study include the cross-sectional design and lack of baseline assessment. CONCLUSIONS: Adding SRT to RP does not seem to result in other than acceptable side-effects in the majority of men receiving SRT when taking a long follow-up time (median 10 years after surgery) into account. However, a subset of men develop severe side-effects where rectal bleeding dominates.

Assessing Radiographic Response to 223Ra with an Automated Bone Scan Index in Metastatic Castration-Resistant Prostate Cancer Patients.

For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.

Comparative Effectiveness of Different Radical Radiotherapy Treatment Regimens for Prostate Cancer: A Population-Based Cohort Study.

BACKGROUND: It is unclear which radiotherapy technique and dose fractionation scheme is most effective in decreasing the risk of prostate cancer death. METHODS: We conducted a population-based cohort study among 15 164 men in the Prostate Cancer database Sweden (version 4.0) treated with primary radical radiotherapy for prostate cancer in Sweden from 1998 to 2016. We calculated hazard ratios with 95% confidence intervals (CIs) of the association between the following exposure groups and outcome: conventionally fractionated external beam radiotherapy (EBRT) to 78 Gy (39 × 2 Gy), EBRT combined with high dose-rate brachytherapy (HDR-BT) (25 × 2 Gy + 2 × 10 Gy), conventionally fractionated EBRT to 70 Gy (35 × 2 Gy), and moderately hypofractionated (M-HF) dose-escalated EBRT (29 × 2.5 Gy or 22 × 3 Gy). RESULTS: Of the men, 7296 received conventionally fractionated EBRT to 78 Gy, 4657 EBRT combined with HDR-BT, 1672 conventionally fractionated EBRT to 70 Gy, and 1539 M-HF EBRT. Using EBRT to 78 Gy as the reference, the multivariable hazard ratios (95% CIs) of prostate cancer death was 0.64 (0.53 to 0.78) for EBRT combined with HDR-BT, 1.00 (0.80 to 1.27) for EBRT to 70 Gy, and 1.51 (0.99 to 2.32) for M-HF EBRT. The multivariable hazard ratios (95% CIs) for death from any cause were 0.79 (0.71 to 0.88), 0.99 (0.87 to 1.14), and 1.12 (0.88 to 1.42), respectively. The lower risk of prostate cancer death comparing EBRT combined with HDR-BT with conventionally fractionated EBRT to 78 Gy was more pronounced for men with high-risk or poorly differentiated tumors. CONCLUSIONS: In this study, EBRT combined with HDR-BT was the most effective radiotherapy treatment regimen, especially for poorly differentiated tumors. Randomized trials comparing EBRT combined with HDR-BT with dose-escalated EBRT should be a priority.

High precision transponder localization using a novel electromagnetic positioning system in patients with localized prostate cancer.

BACKGROUND AND PURPOSE: The Micropos 4DRT system is being developed to provide accurate, precise, objective, and continuous target localization during radiotherapy. This study involves the first in vivo use of the system, aiming to evaluate the localization accuracy of this electromagnetic positioning technique compared with radiographic localization and to assess its real-time tracking ability. MATERIAL AND METHODS: An active positioning marker was inserted in the prostatic urethra of 10 patients scheduled to receive radiotherapy for localized prostate cancer. A receiving sensor plate (antennae system) was placed at a known position in the treatment tabletop. Initial in vivo system calibrations were performed in three subjects. Ten additional patients were then enrolled in a study arm that compared radiographic transponder location to radiotransponder location simultaneously acquired by the Micropos 4DRT system. Frontal and side radiographs were taken with the radiopaque transponder located at three different positions within the prostatic urethra. RESULTS: The transponder insertions were all successful and without complications. Comparison of the transponder location as per the Micropos 4DRT system with the radiographic transponder localization showed an average (+/-SD) absolute and relative 3D difference of 2.7+/-1.2 and 1.7+/-1.0mm, respectively. Continuous transponder tracking capability was also demonstrated. CONCLUSIONS: Electromagnetic positioning using the Micropos transponder system is feasible in vivo. Evaluation of this novel non-ionizing localization system, in this study using a transponder positioned in the prostatic urethra, indicates transponder localization accuracy to isocenter comparable with X-ray localization of a radiopaque marker.

Clinical feasibility and positional stability of an implanted wired transmitter in a novel electromagnetic positioning system for prostate cancer radiotherapy.

PURPOSE: Three aspects of the RayPilot real-time tracking system were investigated: (1) feasibility of the transmitter with respect to implantation and explantation procedures, (2) user and patients' experiences and (3) quantification of the transmitter positional stability in relation to fiducial markers. METHODS AND MATERIALS: Ten prostate cancer patients scheduled for radiotherapy received transmitter implantation in the prostate, concomitantly with fiducial markers. Transmitter and marker positions were assessed in 3D by orthogonal kV-imaging at daily treatment setup in eight patients. RESULTS: The transmitter was successfully implanted in all patients. Patients reported mild to moderate discomfort and impact on daily activities due to the implant but overall subjective tolerability was good. One patient had spontaneous explantation of the transmitter after four fractions. One patient had transmitter 3D shifts >9 mm, but also inter-marker shifts >6 mm. The mean inter-marker shift in the remaining patients was <1 mm. In four patients, maximum transmitter 3D shifts were 5-7 mm (mean >2 mm). In three patients, mean transmitter 3D shifts were <2 mm. CONCLUSIONS: Implantation and explantation of the transmitter is generally feasible and safe. Patient tolerability is good overall. However, due to interfractional transmitter positional instability in this cohort, use of the system for real-time tracking should be combined with other daily setup techniques.

The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer.

Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided.

Prostate hyperplasia in a transgenic mouse with prostate-specific expression of prolactin.

Prolactin (PRL) is one of several polypeptide factors known to exert trophic effects on the prostate. We have previously reported a dramatic prostate enlargement with concurrent chronic hyperprolactinemia and elevated serum androgen levels in a PRL transgenic mouse (Mt-PRL) with ubiquitous expression of the transgene. To address the role of local PRL action in the prostate, a new transgenic mouse model (Pb-PRL) was generated using the prostate-specific rat probasin (Pb) minimal promoter to drive expression of the rat PRL gene. Pb-PRL transgenic males developed a significant enlargement of both the dorsolateral and ventral prostate lobes evident from 10 wk of age and increasing with age. Expression of the transgene was restricted to the prostate and detected from 4 wk of age. Low levels of transgenic rat PRL were detectable in the serum of adult Pb-PRL animals. Serum androgen levels were normal. The Pb-PRL prostate displayed significant stromal hyperplasia, ductal dilation, and focal areas of epithelial dysplasia. Quantitative analysis of prostatic tissue cellularity demonstrated a marked increase in the stromal to epithelial ratio in all lobes of Mt-PRL and Pb-PRL transgenic prostates compared with controls. Microdissections demonstrated an increased ductal morphogenesis in dorsolateral and ventral prostate lobes of Mt-PRL prostate vs. Pb-PRL and controls. In conclusion, this study indicates the ability of PRL to promote, directly or indirectly, ductal morphogenesis in the developing prostate and further to induce abnormal growth primarily of the stroma in the adult gland in a setting of normal androgen levels.

Gene expression analysis of prostate hyperplasia in mice overexpressing the prolactin gene specifically in the prostate.

The probasin (Pb)-PRL transgenic mice that overexpress the rat PRL gene specifically in the prostate develop a dramatic enlargement of the prostate gland. The objective of this study was to characterize the molecular mechanisms involved in the prostate hyperplasia seen in the Pb-PRL transgenic mice. cDNA microarray analysis was used to identify differentially expressed transcripts in the hyperplastic prostates of 6-month-old transgenic mice compared with age-matched controls. We report the identification of 266 genes (175 up-regulated and 91 down-regulated) that were differentially expressed in the enlarged transgenic prostates compared with controls. Subsequential real-time RT-PCR was used to verify a set of differentially regulated transcripts. The hyperplastic prostates of Pb-PRL transgenic mice demonstrate a molecular pattern supporting the importance of reduced degree of apoptosis for the development of the phenotype. Immunohistochemical analysis of apoptotic activity using two different markers of apoptosis (single-stranded DNA and activated caspase-3) were performed, and the results showed diminished apoptosis activity in the prostate of Pb-PRL transgenic mice compared with control prostates. The increased stromal/epithelial ratio of the Pb-PRL transgenic prostate together with up-regulation of a significant fraction of genes involved in tissue remodeling activity, including the synthesis and degradation of the extracellular matrix and changes in protease activity, suggest that activation of the stroma is involved in the development of prostate hyperplasia. Overall, the differentially expressed transcripts identified in this study show many molecular similarities between the prostate hyperplasia of PRL-transgenic mice and human prostate pathology, including both benign prostatic hyperplasia and prostate cancer.