Prostate cancer in Asia: a collaborative report

published_or_final_versio

Personalised biopsy schedules based on risk of Gleason upgrading for patients with low-risk prostate cancer on active surveillance.

OBJECTIVE: To develop a model and methodology for predicting the risk of Gleason upgrading in patients with prostate cancer on active surveillance (AS) and using the predicted risks to create risk-based personalised biopsy schedules as an alternative to one-size-fits-all schedules (e.g. annually). Furthermore, to assist patients and doctors in making shared decisions on biopsy schedules, by providing them quantitative estimates of the burden and benefit of opting for personalised vs any other schedule in AS. Lastly, to externally validate our model and implement it along with personalised schedules in a ready to use web-application. PATIENTS AND METHODS: Repeat prostate-specific antigen (PSA) measurements, timing and results of previous biopsies, and age at baseline from the world's largest AS study, Prostate Cancer Research International Active Surveillance (PRIAS; 7813 patients, 1134 experienced upgrading). We fitted a Bayesian joint model for time-to-event and longitudinal data to this dataset. We then validated our model externally in the largest six AS cohorts of the Movember Foundation's third Global Action Plan (GAP3) database (>20 000 patients, 27 centres worldwide). Using the model predicted upgrading risks; we scheduled biopsies whenever a patient's upgrading risk was above a certain threshold. To assist patients/doctors in the choice of this threshold, and to compare the resulting personalised schedule with currently practiced schedules, along with the timing and the total number of biopsies (burden) planned, for each schedule we provided them with the time delay expected in detecting upgrading (shorter is better). RESULTS: The cause-specific cumulative upgrading risk at the 5-year follow-up was 35% in PRIAS, and at most 50% in the GAP3 cohorts. In the PRIAS-based model, PSA velocity was a stronger predictor of upgrading (hazard ratio [HR] 2.47, 95% confidence interval [CI] 1.93-2.99) than the PSA level (HR 0.99, 95% CI 0.89-1.11). Our model had a moderate area under the receiver operating characteristic curve (0.6-0.7) in the validation cohorts. The prediction error was moderate (0.1-0.2) in theGAP3 cohorts where the impact of the PSA level and velocity on upgrading risk was similar to PRIAS, but large (0.2-0.3) otherwise. Our model required re-calibration of baseline upgrading risk in the validation cohorts. We implemented the validated models and the methodology for personalised schedules in a web-application (http://tiny.cc/biopsy). CONCLUSIONS: We successfully developed and validated a model for predicting upgrading risk, and providing risk-based personalised biopsy decisions in AS of prostate cancer. Personalised prostate biopsies are a novel alternative to fixed one-size-fits-all schedules, which may help to reduce unnecessary prostate biopsies, while maintaining cancer control. The model and schedules made available via a web-application enable shared decision-making on biopsy schedules by comparing fixed and personalised schedules on total biopsies and expected time delay in detecting upgrading

“Man in the driving seat”:A grounded theory study of the psychosocial experiences of Black African and Black Caribbean men treated for prostate cancer and their partners

Objective: Evidence suggests that treatment side‐effects of prostate cancer (CaP) substantially affect the psychosocial well‐being of affected men and their partners. However, this phenomenon is poorly understood among high risk (1 in 4) Black African (BA)/Black Caribbean (BC) men and their partners, as they are currently under‐represented in global research on CaP survivorship. This study explored the psychosocial experiences of BA/BC men with CaP and their partners in the United Kingdom as they lived through the side effects of CaP treatment within their own sociocultural and marital contexts. Methods: Using constructivist grounded theory methodology, interviews and focus groups were conducted with eligible men (n = 25), partners (n = 11), and health care professionals (HCPs) (n = 11) recruited in England. Data were iteratively analysed using constant comparison following the key stages of initial, focused, and theoretical coding until saturation was achieved. Results: Data analysis culminated in the development of a substantive theory “man in the driving seat,” which describes the experiences of BA/BC men with CaP and their partners within their context. Culturally informed gender roles and identities influenced how men and partners responded and coped with the side effects of CaP treatment. There was a hierarchy of power within the BA/BC relationship, in which men were dominantly positioned as leaders, whilst partners mostly operated from a supportive but “accepting” position. Conclusion: Inclusive and culturally sensitive individual and couple‐focused psychosocial support, which is devoid of stereotyping and recognises the experiences of both BA/BC men and their partners is recommended

Denosumab in men receiving androgen-deprivation therapy for prostate cancer.

Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures. At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups. Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.

A microsatellite repeat in PCA3 long non-coding RNA is associated with prostate cancer risk and aggressiveness.

Short tandem repeats (STRs) are repetitive sequences of a polymorphic stretch of two to six nucleotides. We hypothesized that STRs are associated with prostate cancer development and/or progression. We undertook RNA sequencing analysis of prostate tumors and adjacent non-malignant cells to identify polymorphic STRs that are readily expressed in these cells. Most of the expressed STRs in the clinical samples mapped to intronic and intergenic DNA. Our analysis indicated that three of these STRs (TAAA-ACTG2, TTTTG-TRIB1, and TG-PCA3) are polymorphic and differentially expressed in prostate tumors compared to adjacent non-malignant cells. TG-PCA3 STR expression was repressed by the anti-androgen drug enzalutamide in prostate cancer cells. Genetic analysis of prostate cancer patients and healthy controls (N > 2,000) showed a significant association of the most common 11 repeat allele of TG-PCA3 STR with prostate cancer risk (OR = 1.49; 95% CI 1.11-1.99; P = 0.008). A significant association was also observed with aggressive disease (OR = 2.00; 95% CI 1.06-3.76; P = 0.031) and high mortality rates (HR = 3.0; 95% CI 1.03-8.77; P = 0.045). We propose that TG-PCA3 STR has both diagnostic and prognostic potential for prostate cancer. We provided a proof of concept to be applied to other RNA sequencing datasets to identify disease-associated STRs for future clinical exploratory studies

A plasma biomarker panel of four MicroRNAs for the diagnosis of prostate cancer

Prostate cancer is diagnosed in over 1 million men every year globally, yet current diagnostic modalities are inadequate for identification of significant cancer and more reliable early diagnostic biomarkers are necessary for improved clinical management of prostate cancer patients. MicroRNAs (miRNAs) modulate important cellular processes/pathways contributing to cancer and are stably present in body fluids. In this study we profiled 372 cancer-associated miRNAs in plasma collected before (~60% patients) and after/during commencement of treatment (~40% patients), from age-matched prostate cancer patients and healthy controls, and observed elevated levels of 4 miRNAs - miR-4289, miR-326, miR-152-3p and miR-98-5p, which were validated in an independent cohort. The miRNA panel was able to differentiate between prostate cancer patients and controls (AUC = 0.88). Analysis of published miRNA transcriptomic data from clinical samples demonstrated low expression of miR-152-3p in tumour compared to adjacent non-malignant tissues. Overexpression of miR-152-3p increased proliferation and migration of prostate cancer cells, suggesting a role for this miRNA in prostate cancer pathogenesis, a concept that was supported by pathway analysis of predicted miR-152-3p target genes. In summary, a four miRNA panel, including miR-152-3p which likely targets genes with key roles in prostate cancer pathogenesis, has the potential to improve early prostate cancer diagnosis.Farhana Matin, Varinder Jeet, Leire Moya, Luke A. Selth, Suzanne Chambers, Australian Prostate Cancer BioResource, Judith A. Clements and Jyotsna Batr

Initial Experience with Radical Prostatectomy Following Holmium Laser Enucleation of the Prostate

BACKGROUND: Although an increasing number of prostate cancer (PCa) patients received holmium laser enucleation of the prostate (HoLEP) previously for benign prostatic obstruction (BPO), there is still no evidence regarding the outcomes of radical prostatectomy (RP) in this setting. OBJECTIVE: To assess functional and oncological results of RP in PCa patients who received HoLEP for BPO previously in a contemporary multi-institutional cohort. DESIGN, SETTING, AND PARTICIPANTS: A total of 95 patients who underwent RP between 2011 and 2019 and had a history of HoLEP were identified in two institutions. Functional as well as oncological follow-up was prospectively assessed and retrospectively analyzed. INTERVENTION: RP following HoLEP compared with RP without previous transurethral surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients with complete follow-up data were matched with individuals with no history of BPO surgery using propensity score matching. Complications were assessed using the Clavien-Dindo scale. RESULTS AND LIMITATIONS: The median follow-up was 50.5 mo. We found no significant impact of previous HoLEP on positive surgical margin rate (14.0% [HoLEP] vs 18.8% [no HoLEP], p =  0.06) and biochemical recurrence-free survival (hazard ratio 0.74, 95% confidence interval [CI] 0.32-1.70, p =  0.4). Patients with a history of HoLEP had increased 1-yr urinary incontinence rates after RP. After adjusting for confounders, no significant impact of previous HoLEP was found (odds ratio [OR] 0.87, 95% CI 0.74-1.01; p = 0.07). Previous HoLEP did not hamper 1-yr erectile function recovery (OR 1.22, 95% CI 1.05-1.43; p =  0.01). Limitations include retrospective design and small sample size. CONCLUSIONS: RP after previous HoLEP is surgically feasible, with low complication rates and no negative impact on biochemical recurrence-free survival. However, in a multivariable analysis, we observed significantly worse 1-yr continence rates in patients after previous HoLEP. PATIENT SUMMARY: In the current study, we assessed the oncological and functional outcomes of radical prostatectomy in patients who underwent holmium laser enucleation of the prostate (HoLEP) previously due to prostatic bladder outlet obstruction. A history of HoLEP did not hamper oncological results, 1-yr continence, and erectile function recovery

Statement from the DEGRO working group prostate cancer

Aim: To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer. Methods: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity. Results: Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1 × 10 Gy or 2 × 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1 × 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques. Conclusions: Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered

Best practice in active surveillance for men with prostate cancer: a Prostate Cancer UK consensus statement.

OBJECTIVES:To develop a consensus statement on current best practice of active surveillance (AS) in the UK, informed by patients and clinical experts. SUBJECTS AND METHODS:A consensus statement was drafted on the basis of three sources of data: systematic literature search of national and international guidelines; data arising from a Freedom of Information Act request to UK urology departments regarding their current practice of AS; and survey and interview responses from men with localized prostate cancer regarding their experiences and views of AS. The Prostate Cancer UK Expert Reference Group (ERG) on AS was then convened to discuss and refine the statement. RESULTS:Guidelines and protocols for AS varied significantly in terms of risk stratification, criteria for offering AS, and protocols for AS between and within countries. Patients and healthcare professionals identified clinical, emotional and process needs for AS to be effective. Men with prostate cancer wanted more information and psychological support at the time of discussing AS with the treating team and in the first 2 years of AS, and a named healthcare professional to discuss any questions or concerns they had. The ERG agreed 30 consensus statements regarding best practice for AS. Statements were grouped under headings: 'Inclusion/Exclusion Criteria'; 'AS follow-up protocol' and 'When to stop AS'. CONCLUSION:Significant variation currently exists in the practice of AS in the UK and internationally. Men have clear views on the level of involvement in treatment decisions and support from their treating professionals when receiving AS. The Prostate Cancer UK AS ERG has developed a set of consensus statements for best practice in AS. Evidence for best practice in AS, and the use of multiparametric magnetic resonance imaging in AS, is still evolving, and further studies are needed to determine how to optimize AS outcomes