Testosterone recovery after androgen deprivation therapy in localised prostate cancer: Long-term data from two randomised trials.

BACKGROUND AND PURPOSE: To determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT). MATERIALS AND METHODS: In 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly. T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed. RESULTS: Overall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery. CONCLUSIONS: Testosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials.

PURPOSE: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

SARS-CoV-2 mRNA vaccine-induced immune responses in rheumatoid arthritis.

Our objective was to characterize T and B cell responses to vaccination with SARS-CoV-2 antigens in immunocompromised rheumatoid arthritis (RA) patients. In 22 RA patients, clinical and biological variables were analyzed before and 4 weeks after each of 3 messenger RNA (mRNA) vaccine doses and compared with unmatched healthy individuals. Sequentially sampled peripheral blood mononuclear cells and sera were collected to determine immune profiles and to analyze the T cell response to a spike peptide pool and B cell specificity to the receptor-binding domain (RBD). Anti-spike antibodies were detectable in 6 of 22 RA patients after 1 dose of vaccine with increasing titers after each booster dose, although the overall response was lower compared with that in healthy control individuals. Responding patients after the first dose were more likely to have RA antibodies and a higher baseline proportion of circulating follicular B cells. In RA patients, the mRNA vaccine elicited a robust CD4+ T response to a spike peptide pool following the first and second doses. Consistent with the serologies, RBD-specific B cells exhibited a modest increase after the first dose and the second dose resulted in marked increases only in a fraction of the RA patients to both ancestral and omicron RBD. Our results highlight the importance of multidose COVID-19 vaccination in RA patients to develop a protective humoral response. However, these patients rapidly develop specific T CD4+ responses, despite delayed B cell responses.

Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials.

PURPOSE: The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS: Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality. RESULTS: Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION: ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

Mindfulness-based stress reduction to improve depression, pain and high patient global assessment in controlled rheumatoid arthritis.

Objective: The aim was to improve distressing patient-reported outcomes (PROs) that persisted in RA patients with clinically controlled inflammation (controlled RA). Methods: In a pragmatic pilot study, we offered mindfulness-based stress reduction (MBSR), a group intervention, to controlled RA patients who had high (≥16) Centre for Evaluation Studies depression (CES-D) scores and/or patient general assessment of disease activity (PGA) at least 2/10 larger than evaluator general assessment (EGA) (PGA-EGA: Delta). Evaluations before, 6 and 12 months after MBSR included CES-D, PGA, modified HAQ, simple disease activity index (SDAI), anxiety (general anxiety disorder 7; GAD-7), coping strategies (coping with health injuries and problems; CHIP), sleep disturbance and pain. Facilitators and obstacles to recruitment and participation were identified. A subset of patients was interviewed for qualitative analysis of their experience. Results: Out of 306 screened patients, 65 were referred, 39 (60%) agreed and 28 (43%) completed MBSR. Anticipated burden, timing and frequency of group meetings, commuting issues, age extremes and co-morbidities were barriers to participation. Up to 12 months after MBSR, anxiety, depression, emotion-oriented coping, sleep and function significantly improved. Nonetheless, no significant impact was observed on pain, PGA, Delta or SDAI. The interviews revealed that benefits, including integration of effective coping strategies, were maintained. Conclusion: We addressed MBSR feasibility issues and selection of outcomes in controlled RA patients with distressing PROs. For patients who chose to participate in MBSR, lasting benefits were evident for anxiety, depression, sleep and function. Larger studies are required to evaluate the weaker impact of MBSR on RA-related pain and PGA.

Women's preferences for water immersion during labor and birth: Results from a discrete choice experiment.

BACKGROUND AND AIM: No discrete choice experiment study has been conducted to elicit women's preferences for water immersion during labor and birth. METHODS: An online survey including sociodemographic questions and choice cards was conducted to explore women's preferences (i.e., factors that may influence their decision). Each participant responded to 12 choice cards with 6 attributes/factors (i.e., birth mode, duration of the labor phase, pain sensation, risk of severe perineal tears, risk of death of the newborn, and newborn general condition). Utilities were estimated using logit, latent class, and hierarchical Bayesian analyses. FINDINGS: A total of 1088 subjects completed the survey in 2019. The risk of death of the newborn was given high priority by women in all but one analyses, while the risk of severe perineal tears was always considered the least important attribute. The latent class analysis clearly revealed three classes of women. The largest class including 52.9% of women was interested in water birth if it could reduce pain and would be risk-free for the newborn. The second class included 30.8% of women interested in water immersion but only during the labor phase. Finally, the third class (16.2%) did not want to consider water immersion during labor and birth, regardless of its risks and benefits. Follow-up questions revealed that many women were interested in water birth only if they could be assured that there would be no risk for the newborn. DISCUSSION AND CONCLUSION: This study provided insights in favor of water immersion during labor and birth contingent upon the safety of the procedure for the newborn. STATEMENT OF SIGNIFICANCE: No discrete choice experiment on women's preference for water immersion during childbirth was previously conducted. Six attributes/factors were used for the discrete choice experiment. Water immersion is poorly used in Quebec with only 49 (7.9%) women over 621 with childbirth experience reporting such immersion. A majority of women (70-80%) were in favor of water immersion.

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.

French adaptation and validation of the Panic Disorder Severity Scale-self-report.

BACKGROUND: The aims of this study were to conduct a cross-cultural validation of the Panic Disorder Severity Scale - Self-Report (PDSS-SR) and to examine psychometric properties of the French-Canadian version. METHODS: A sample of 256 adults were included in the validation study based on data from the baseline interview of a clinical trial on transdiagnostic cognitive-behavioral therapy for mixed anxiety disorders. Participants completed the Anxiety and Related Disorders Interview Schedule (ADIS-5), and self-report instruments including the PDSS-SR, Beck Anxiety Inventory (BAI), Mobility Inventory for Agoraphobia (MIA), Sheehan Disability Scale (SDS), Patient Health Questionnaire (PHQ-9), Social Phobia Inventory (SPIN), Insomnia Severity Index (ISI) and Penn State Worry Questionnaire (PSWQ). The cross-cultural adaptation in French of the PDSS-SR included a rigorous back-translation process, with an expert committee review. Sensitivity to change was also examined with a subgroup of patients (n = 72) enrolled in the trial. RESULTS: The French version of the PDSS-SR demonstrated good psychometric properties. The exploratory factor analysis supported a one factor structure with an eigenvalue > 1 that explained 64.9% of the total variability. The confirmatory factor analysis (CFA) corroborated a one-factor model with a good model fit. Internal consistency analysis showed a .91 Cronbach's alpha. The convergent validity was adequate with the ADIS-5 clinical severity ratings for panic disorder (r = .56) and agoraphobia (r = .39), as well as for self-report instruments [BAI (r = .63), MIA (accompanied: r = .50; alone: r = .47) and SDS (r = .37)]. With respect to discriminant validity, lower correlations were found with the SPIN (r = .17), PSWQ (r = .11), ISI (r = .19) and PHQ-9 (r = .28). The optimal threshold for probable diagnosis was 9 for the PDSS-SR and 4 for the very brief 2-item version. The French version showed good sensitivity to change. CONCLUSIONS: The French version of the PDSS-SR has psychometric properties consistent with the original version and constitutes a valid brief scale to assess the severity of panic disorder and change in severity over time, both in research and clinical practice.

Quebec Health-related Quality of Life Population Norms in Adults Using the SF-6Dv2: Decomposition by Sociodemographic Data and Health Problems.

OBJECTIVE: The Short-Form 6-Dimension version 2 (SF-6Dv2) is the newest version of the Short-Form 6-Dimension (SF-6D) that is widely used to calculate quality-adjusted life-years (QALYs). The aim of this study was to produce Quebec population norms from the SF-6Dv2. METHODS: An online survey was conducted in the adult general population. Data was stratified by various sociodemographic characteristics, such as age, sex, body mass index, history of illness, and health problems. RESULTS: A total of 4175 respondents completed the SF-6Dv2. Mean (95% confidence interval) and median (interquartile range) utility scores were 0.692 (0.684-0.700) and 0.780 (0.607-0.866), respectively. Floor and ceiling effect corresponded to 0.05% and 3.1%, respectively. Men, nonsmoker, higher education, and employed people had significantly higher scores, while lower scores were found for those with a history of illness and a lower life satisfaction. Those reporting a health problem presented significant lower mean utility scores ranging from 0.340 (nervous problem) to 0.623 (diabetes) for men and from 0.207 (genitourinary) to 0.578 (diabetes) for women as compared with those without health problem (0.793 for men and 0.750 for women). CONCLUSION: This study is the first to provide utility score norms for SF-6Dv2 in the adult general population of Quebec. It also highlighted significant differences among various health problems that can be used to compare populations in studies that do not have a control group.

High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.

BACKGROUND: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. OBJECTIVE: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. DESIGN, SETTING, AND PARTICIPANTS: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. CONCLUSIONS: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. PATIENT SUMMARY: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

BACKGROUND: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. METHODS: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. FINDINGS: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. INTERPRETATION: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. FUNDING: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Optimizing Treatment in Intermediate-Risk Prostate Cancer: Secondary Analysis of a Randomized Phase 3 Trial.

PURPOSE: To identify patients with intermediate-risk prostate cancer (IRPC) benefiting from de-escalation of androgen deprivation therapy (ADT) and/or dose escalated radiation therapy (DERT), we performed a secondary analysis of a phase 3 trial by measuring biochemical failure (BF), distant metastases, prostate cancer-specific mortality, overall survival (OS), and distant metastases-free survival (DMFS) rates according to prognostic intermediate risk factors (IRF). METHODS AND MATERIALS: The initial trial randomized 600 patients with IRPC to a 3-arm trial with 200 patients per arm, consisting of 6 months of ADT plus 70 Gy radiation therapy (ADT + RT70) versus ADT plus a DERT of 76 Gy (ADT + DERT76) versus DERT of 76 Gy alone (DERT76). We performed an analysis based on IRF: clinical stage, prostate-specific antigen level, Gleason score, percentage of positive biopsy cores (PBC) ≥50%, and Gleason pattern. Patients were allocated to 2 groups: favorable intermediate risk (FIR), defined as patients with only 1 IRF without Gleason pattern 4 + 3 or PBC ≥50%; and unfavorable intermediate risk (UIR), defined as all other patients. BF, distant metastases, prostate cancer-specific mortality, OS, and DMFS were compared between FIR and UIR. RESULTS: The median follow-up was 11.3 years (interquartile range, 10.9-11.7). In the FIR cohort, BF and OS were not significantly different between arms. UIR patients had significantly worse DMFS (hazard ratio [95% confidence interval], 1.61 [1.20-2.15]; P = .026) and OS (1.51 [1.12-2.04]; P = .0495) and a nonsignificant higher cumulative incidence of BF rate (1.55 [0.98-2.47]; P = .08). In UIR patients, a significant improvement in BF was seen in the arms receiving ADT compared to DERT76 alone. On multivariable analysis, Gleason pattern 4 + 3 and prostate-specific antigen >10 ng/mL independently affected BF and OS, regardless of the treatment arm. CONCLUSIONS: In IRPC, therapeutic optimization appears possible. To avoid ADT side effects, DERT76 alone appears sufficient in patients harboring only 1 risk factor without Gleason pattern 4 + 3 and PBC ≥50% (FIR). All other UIR patients seem to benefit from ADT + DERT76.

Predicting SF-6Dv2 utility scores for chronic low back pain using the Oswestry Disability Index and Roland-Morris Disability Questionnaire.

Background: Generic preference-based measures are used to evaluate disability and health-related quality of life (HRQoL). Objective: To evaluate if Short Form Six-Dimensions (SF-6Dv2) is correlated with specific current questionnaires used in chronic low back pain (CLBP) and if a predictive equation of SF-6Dv2 could be established. Methods: Between October 2018 and January 2019, an online survey on CLBP was conducted. HRQoL was measured with two specific questionnaires, i.e. Oswestry Disability Index (ODI) and Roland-Morris Disability Questionnaire (RMDQ), and with the new version of the SF-6Dv2 as a generic preference-based measure. Results: 402 subjects completed at least two of the three HRQoL questionnaires. Mean (95% confidence interval) of SF-6Dv2, ODI, or RMDQ were, respectively, 0.561 (0.553-0.569), 43.7 (42.1-45.2), and 10.3 (9.8-10.8). SF-6Dv2 was moderately correlated with ODI and RMDQ (r = -0.635 and r = -0.542, p < 0.001). The best model to predict SF-6Dv2 explained 50.6% of variability and included ODI. The correlation between actual and predicted SF-6Dv2 was 0.71. Conclusion: This study demonstrated that SF-6Dv2 was moderately correlated with ODI and RMDQ and that ODI was a better predictor. There was a strong correlation between actual and predicted SF-6Dv2 from multivariate models. These results suggest that the model can be used in similar studies to estimate the SF-6Dv2 when it was not measured.

Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial.

BACKGROUND: The role of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) in intermediate-risk prostate cancer (IRPC) remains controversial, particularly in patients receiving dose-escalated RT (DERT). We compared outcomes between patients with IRPC treated with ADT and two different doses of RT vs. RT alone. METHODS: From December 2000 to September 2010, 600 patients with IRPC were randomised to a three-arm trial consisting of 6 months of ADT plus RT 70 Gy (ADT + RT70) vs. ADT plus a DERT of 76 Gy (ADT + DERT76) vs. DERT of 76 Gy alone (DERT76). Primary end-point was biochemical failure (BF), and secondary end-points were overall survival (OS) and toxicity. RT toxicity was assessed by Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. FINDINGS: With a median follow-up of 11.3 years (interquartile range: 10.9-11.7), patients receiving DERT76 alone, compared with patients receiving ADT + RT70 and ADT + DERT76, had higher rates of BF (32%, 18% and 14%, respectively, p < 0.001), higher rates of prostate cancer progression (12%, 4.5% and 3.3%, respectively, p = 0.001) and more deaths due to prostate cancer (6.5%, 3.0% and 1.5%, respectively, p = 0.03) with no significant difference seen between ADT + RT70 and ADT + DERT76. There was no significant difference in OS between the 3 arms. A higher dose of RT (76 Gy) increased late gastrointestinal (GI) toxicity grade ≥ II compared with lower dose (70 Gy) (16% vs 5.3%, p < 0.001) with no statistical difference for late genitourinary toxicity. INTERPRETATION: In IRPC, the addition of 6 months of ADT to RT70 or DERT76 significantly improves BF and appears to decrease the risk of death from prostate cancer compared with DERT76 alone with no difference in OS. In the setting of IRPC, ADT plus RT 70 Gy yields effective disease control with a better GI toxicity profile. Clinicaltrials.gov#NCT00223145.

Group transdiagnostic cognitive-behavior therapy for anxiety disorders: a pragmatic randomized clinical trial.

BACKGROUND: Transdiagnostic group cognitive-behavioral therapy (tCBT) is a delivery model that could help overcome barriers to large-scale implementation of evidence-based psychotherapy for anxiety disorders. The aim of this study was to assess the effectiveness of combining group tCBT with treatment-as-usual (TAU), compared to TAU, for the treatment of anxiety disorders in community-based mental health care. METHODS: In a multicenter single-blind, two-arm pragmatic superiority randomized trial, we recruited participants aged 18-65 who met DSM-5 criteria for principal diagnoses of generalized anxiety disorder, social anxiety disorder, panic disorder, or agoraphobia. Group tCBT consisted of 12 weekly 2 h sessions. There were no restrictions for TAU. The primary outcome measures were the Beck Anxiety Inventory (BAI) and clinician severity rating from the Anxiety and Related Disorders Interview Schedule for DSM-5 (ADIS-5) for the principal anxiety disorder at post-treatment, with intention-to-treat analysis. RESULTS: A total of 231 participants were randomized to either tCBT + TAU (117) or TAU (114), with outcome data available for, respectively, 95 and 106. Results of the mixed-effects regression models showed superior improvement at post-treatment for participants in tCBT + TAU, compared to TAU, for BAI [p < 0.001; unadjusted post-treatment mean (s.d.): 13.20 (9.13) v. 20.85 (10.96), Cohen's d = 0.76] and ADIS-5 [p < 0.001; 3.27 (2.19) v. 4.93 (2.00), Cohen's d = 0.79]. CONCLUSIONS: Our findings suggest that the addition of group tCBT into usual care can reduce symptom severity in patients with anxiety disorders, and support tCBT dissemination in routine community-based care.

EQ-5D-5L and SF-6Dv2 utility scores in people living with chronic low back pain: a survey from Quebec.

OBJECTIVE: To describe how chronic low back pain (CLBP) impacts on utility scores and which patients' characteristics most affect these scores in the province of Quebec. SETTINGS: Province of Quebec, Canada. PARTICIPANTS: 569 adult patients with CLBP. METHODS AND OUTCOMES: An online survey on low back pain was conducted between October 2018 and January 2019. The EuroQol Five Dimensions (EQ-5D-5L) and the Short Form Six Dimensions version 2 (SF-6Dv2) are two generic preference-based measures used to evaluate health-related quality of life (HRQoL) and provide quality-adjusted life-year utility values. RESULTS: The number of subjects who agreed to participate was 610, but 41 were excluded because 8 had low back pain for less than 3 months and 33 did not start the survey. A total of 569 subjects were analysed, but only 410 completed the survey up to the EQ-5D-5L or SF-6Dv2 sections. Median (range) of EQ-5D-5L was 0.622 (-0.072 to 0.905), and mean (range) of SF-6Dv2 and EQ-Visual Analogue Scale was 0.561 (0.301-0.829) and 51.0 (0-100), respectively. In all multivariate models, health or life satisfaction increased the health utility score, while pain reduced it. Co-occurring health problems were present for a majority (68%) of participants, mainly fatigue/insomnia (57.4%), musculoskeletal disorder (56.2%) and mental disorder (44%). CONCLUSION: This study provided utility scores with EQ-5D-5L and SF-6Dv2 in patients with CLBP in Quebec, and results were similar to other studies conducted in different settings. These values were well below those reported in the Quebec general population and highlight the association between CLBP and HRQoL.

Impending radiographic erosive progression over the following year in a cohort of consecutive patients with inflammatory polyarthritis: prediction by serum biomarkers.

BACKGROUND/PURPOSE: To evaluate biomarkers as predictors of impending erosion progression. METHODS: Variables were measured at baseline and annually up to 5 years in patients with recent-onset polyarthritis treated to zero swollen joints. Erosive status was defined as ≥5 Units in Sharp/van der Heijde Erosion Score; Rapid Erosive Progression (REP) was defined as an increase ≥5 Units in Erosion Scores between consecutive visits. Generalised estimating equations (GEEs) evaluated the effect on REP of positive anticyclic citrullinated peptides (ACPAs) and/or rheumatoid factor (RF), C-reactive protein ˃8.0 mg/L (High-CRP) and 14-3-3η protein ≥0.50 ng/mL (High-14-3-3η), alone and in combinations. RESULTS: Out of 2155 evaluations in 749 consecutive patients, REP occurred after 186 (8.6%) visits, including 13 (2.2%) in patients recruited since 2010. Only 18/537 (3.4%; 6/411 (1.5%) in non-erosive vs 12/126 (9.5%) in patients already erosive) visits without any positive biomarker were followed by REP; at least one biomarker was positive prior to REP in 168/186 (90.3%) visits. Being positive for all four biomarkers conferred a positive predictive value (PPV) of 30.0% (RR 21.8) in patients non-erosive at the visit versus 35.5% (RR 3.07) in those already erosive. High-14-3-3η increased REP only in visits with High-CRP (eg, RR 2.5 to 3.9 when ACPA also positive) and in patients with non-erosive status (eg, RR from 4.3 to 9.4 when also High-CRP). CONCLUSIONS: Adding High-14-3-3η to positive antibodies and CRP improves prediction of impending REP. Although REP is becoming rarer, signatures of biomarkers might help to adapt treatment strategies in at-risk individuals, even those already erosive.

Predicting EQ-5D-5L Utility Scores from the Oswestry Disability Index and Roland-Morris Disability Questionnaire for Low Back Pain.

BACKGROUND: Cost utility analysis is important for measuring the impact of chronic disease and helps clinicians and policymakers in patient management and policy decisions, but generic preference-based measures are not always considered in clinical studies. OBJECTIVE: To evaluate if health-related quality-of-life (HRQoL)-specific questionnaires used in chronic low back pain (CLBP) can predict EQ-5D-5L utility scores. METHODS: The data come from an online survey on low back pain conducted between October 2018 and January 2019. Health utility scores for EuroQol Five Dimensions Five Levels (EQ-5D-5L) were calculated with the recommended model of Xie et al. The EQ-5D-5L health states ranged from -0.148 for the worst (55555) to 0.949 for the best (11111). Univariate and multivariate linear regression were performed to predict EQ-5D-5L with Oswestry Disability Index (ODI), Roland-Morris Disability Questionnaire (RMDQ) and clinical variables. RESULTS: Analyses were performed in 408 subjects who completed the questionnaires EQ-5D-5L, ODI or RMDQ. Median (range) of EQ-5D-5L was 0.622 (-0.072 to 0.905). There was high correlation between EQ-5D-5L and ODI (r=-0.78, p<0.001), while it was moderate with RMDQ (r=-0.62, p<0.001). The multivariate model to predict EQ-5D-5L with ODI explained 67.6% of variability, and the correlation between actual and predicted EQ-5D-5L was 0.82. Principal predictors were ODI, duration of LBP, invalidity, health satisfaction (0-10 cm), life satisfaction (0-10 cm), and intensity of pain today (0-10 cm). CONCLUSION: Data from this study demonstrated that individual correlation between ODI and EQ-5D-5L was high, but moderate with RMDQ. Correlations between actual and predicted EQ-5D-5L from multivariate models were higher and very high. Considering these results, the multivariate model can be used in similar studies for patient with CLBP to estimate the utility scores from the ODI when the EQ-5D-5L was not measured.

Quebec Health-Related Quality-of-Life Population Norms Using the EQ-5D-5L: Decomposition by Sociodemographic Data and Health Problems.

OBJECTIVES: Population norms for the EQ-5D-5L were published in Canada but only for Alberta province. The purpose of this study was to derive Quebec population norms from the EQ-5D-5L. METHODS: The data came from a larger study conducted between September 2016 and March 2018 using elicitation techniques for a quality-adjusted life-year project. The online survey was distributed randomly in the province of Quebec. To best describe the entire population, data were stratified by various sociodemographic characteristics such as age, gender, urban and rural populations, whether disadvantaged or not, immigrant or nonimmigrant, and health problems. RESULTS: A total of 2704 (53.8%) respondents completed the EQ-5D-5L. Mean (95% confidence interval) and median (interquartile range) utility scores were 0.824 (0.818-0.829) and 0.867 (0.802-0.911), respectively. The EQ-VAS scores were estimated at 75.9 (75.2-76.6) and 80 (69-90). Subjects with lower scores were those who had a low or high body mass index; were smokers; were single, divorced, or widowed; had no children; were unemployed or sick; had lower education or lower annual income; and had a family or personal history of serious illness. Immigrants had higher scores. There was no difference in gender and urban or rural population. The score logically decreased with worsening health status, from a mean score of 0.896 (0.884-0.908) to 0.443 (0.384-0.501; P < .0001. Similar results were observed for subjects' satisfaction with their health or life. Subjects with lower scores were less willing to take risks. Subjects who declared they were affected by health problems presented significant lower utility scores, ranging from 0.554 (nervous problem) to 0.750 (cancer), compared with those without health problems (0.871; confidence interval: 0.867-0.876). CONCLUSION: This is the first study to present utility score norms for EQ-5D-5L for the Quebec population. These results will be useful for comparison with quality-adjusted life-year studies to better interpret their results. Moreover, utility norms were provided for 21 health problems, which was rarely done.