Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Selenium and Vitamin E for Prevention of Non-Muscle-Invasive Bladder Cancer Recurrence and Progression: A Randomized Clinical Trial.

Importance: Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer. Objective: To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC. Design, Setting, and Participants: This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required. Interventions: Oral selenium (200 µg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo. Main Outcome and Measures: Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022). Results: The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment. Conclusions and Relevance: In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required. Trial Registration: isrctn.org Identifier: ISRCTN13889738.

Recruiting women with ductal carcinoma in situ to a randomised controlled trial: lessons from the LORIS study.

BACKGROUND: The LOw RISk DCIS (LORIS) study was set up to compare conventional surgical treatment with active monitoring in women with ductal carcinoma in situ (DCIS). Recruitment to trials with a surveillance arm is known to be challenging, so strategies to maximise patient recruitment, aimed at both patients and recruiting centres, were implemented. METHODS: Women aged ≥ 46 years with a histologically confirmed diagnosis of non-high-grade DCIS were eligible for 1:1 randomisation to either surgery or active monitoring. Prior to randomisation, all eligible women were invited to complete: (1) the Clinical Trials Questionnaire (CTQ) examining reasons for or against participation, and (2) interviews exploring in depth opinions about the study information sheets and film. Women agreeing to randomisation completed validated questionnaires assessing health status, physical and mental health, and anxiety levels. Hospital site staff were invited to communication workshops and refresher site initiation visits to support recruitment. Their perspectives on LORIS recruitment were collected via surveys and interviews. RESULTS: Eighty percent (181/227) of eligible women agreed to be randomised. Over 40% of participants had high anxiety levels at baseline. On the CTQ, the most frequent most important reasons for accepting randomisation were altruism and belief that the trial offered the best treatment, whilst worries about randomisation and the influences of others were the most frequent most important reasons for declining. Most women found the study information provided clear and useful. Communication workshops for site staff improved knowledge and confidence but only about half said they themselves would join LORIS if eligible. The most common recruitment barriers identified by staff were low numbers of eligible patients and patient preference. CONCLUSIONS: Recruitment to LORIS was challenging despite strategies aimed at both patients and site staff. Ensuring that recruiting staff support the study could improve recruitment in similar future trials. TRIAL REGISTRATION: ISRCTN27544579, prospectively registered on 22 May 2014.

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml-1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies.

Correlative studies of the Breast Cancer Index (HOXB13/IL17BR) and ER, PR, AR, AR/ER ratio and Ki67 for prediction of extended endocrine therapy benefit: a Trans-aTTom study.

BACKGROUND: Multiple clinical trials demonstrate consistent but modest benefit of adjuvant extended endocrine therapy (EET) in HR + breast cancer patients. Predictive biomarkers to identify patients that benefit from EET are critical to balance modest reductions in risk against potential side effects of EET. This study compares the performance of the Breast Cancer Index, BCI (HOXB13/IL17BR, H/I), with expression of estrogen (ER), progesterone (PR), and androgen receptors (AR), and Ki67, for prediction of EET benefit. METHODS: Node-positive (N+) patients from the Trans-aTTom study with available tissue specimen and BCI results (N = 789) were included. Expression of ER, PR, AR, and Ki67 was assessed by quantitative immunohistochemistry. BCI (H/I) gene expression analysis was conducted by quantitative RT-PCR. Statistical significance of the treatment by biomarker interaction was evaluated by likelihood ratio tests based on multivariate Cox proportional models, adjusting for age, tumor size, grade, and HER2 status. Pearson's correlation coefficients were calculated to evaluate correlations between BCI (H/I) versus ER, PR, AR, Ki67 and AR/ER ratio. RESULTS: EET benefit, measured by the difference in risk of recurrence between patients treated with tamoxifen for 10 versus 5 years, is significantly associated with increasing values of BCI (H/I) (interaction P = 0.01). In contrast, expression of ER (P = 0.83), PR (P = 0.66), AR (P = 0.78), Ki67 (P = 0.87) and AR/ER ratio (P = 0.84) exhibited no significant relationship with EET benefit. BCI (H/I) showed a very weak negative correlation with ER (r = - 0.18), PR (r = - 0.25), and AR (r = - 0.14) expression, but no correlation with either Ki67 (r = 0.04) or AR/ER ratio (r = 0.02). CONCLUSION: These findings are consistent with the growing body of evidence that BCI (H/I) is significantly predictive of response to EET and outcome. Results from this direct comparison demonstrate that expression of ER, PR, AR, Ki67 or AR/ER ratio are not predictive of benefit from EET. BCI (H/I) is the only clinically validated biomarker that predicts EET benefit.

Cabazitaxel versus docetaxel for treatment of metastatic castrate refractory prostate cancer.

Objectives: To assess cabazitaxel versus docetaxel re-challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy. Patients and Methods: The CANTATA trial was a prospective, two-arm, open-label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0-2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression-free survival (PFS) as defined by either date of pain progression, date of a cancer-related skeletal-related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012-003835-40. Results: Between 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54-76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported. Conclusion: Due to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

TUXEDO: A phase I/II trial of cetuximab with chemoradiotherapy in muscle-invasive bladder cancer.

OBJECTIVE: To assess feasibility and preliminary efficacy of adding cetuximab to standard chemoradiotherapy for muscle-invasive bladder cancer. PATIENTS AND METHODS: TUXEDO was a prospective, single-arm, open-label, phase I/II trial conducted in six UK hospitals. Cetuximab was administered with an initial loading dose of 400mg/m2 on day 1 of week -1, and then 7-weekly doses of 250mg/m2 . Radiotherapy schedule was 64Gy/32F with day 1 mitomycin C (12g/m2 ) and 5-fluorouracil (500mg/m2 /day) over days 1-5 and 22-26. Patients with T2-4aN0M0 urothelial cancer and a performance status (PS) of 0-1 were eligible. Prior neoadjuvant therapy was permitted. The phase I primary outcome was impact on radiotherapy treatment completion and toxicity experienced during treatment. The phase II primary outcome was local control at three-months post-treatment. ISRCTN identifier: 80733590. RESULTS: Between Sept-2012 and Oct-2016, 33 patients were recruited; 7 in phase I, 26 in phase II. Three patients in phase II were subsequently deemed ineligible and received no trial therapy. Eight patients discontinued cetuximab due to adverse effects. Median age of patients was 70.1 years (range 60.6-75.1), 20 were PS 0, 27 male and 26 had already received neoadjuvant chemotherapy. In phase I, all patients completed planned radiotherapy, with no delays or dose reductions. Of the 30 evaluable patients in phase II, 25 had confirmed local control 3-months post treatment (77%, 95% CI: 58-90). During the trial there were 18 serious adverse events. The study was halted due to slow accrual. CONCLUSION: Phase I data demonstrate it is feasible and safe to add cetuximab to chemoradiotherapy. Exploratory analysis of phase II data provides evidence to consider further clinical evaluation of cetuximab in this setting.

A Study of Pazopanib Safety and Efficacy in Patients With Advanced Clear Cell Renal Cell Carcinoma and ECOG Performance Status 2 (Pazo2): An Open label, Multicentre, Single Arm, Phase II Trial.

AIM: Patients with advanced renal cell carcinoma and poor performance status (PS≥2) are often deemed unsuitable for treatment. The Pazo2 trial aimed to assess tolerability and efficacy of pazopanib as first-line treatment in renal cancer patients with ECOG PS2. METHODS: Pazo2 was a prospective, single arm, open label, multicentre, phase II trial, conducted in 26 UK centres. Eligible patients were aged ≥18 years, with advanced or metastatic renal cancer and a clear cell component (aRCC), measurable disease as per RECIST Criteria 1.1, and ECOG PS2. Co-primary outcomes, assessed at 6-months after patients entered the trial, were tolerability, defined as the proportion of patients who did not develop "intolerable" adverse events, and efficacy, defined as the proportion of all patients who were progression-free and alive. RESULTS: Between February 21, 2013 and August 12, 2016, 75 patients were registered. Median age was 68.6 years (IQR 64.6-76.0), 100% ECOG PS2, 62.7% 'poor risk' (International Metastatic Renal-Cell Carcinoma Database Consortium). Of the 65 evaluable patients, 70.8% (95% CI: 58.8, 80.4) did not develop "intolerable" adverse events and 56.9% (95% CI: 44.8, 68.2) were still alive and progression-free 6 months after starting pazopanib. Twenty-seven patients developed serious adverse events deemed to be related to pazopanib. CONCLUSION: These data suggests that pazopanib is tolerated and effective in aRCC patients with PS2 and represents a treatment option for patients who cannot receive or tolerate immune checkpoint inhibitors.

Visualising harms in publications of randomised controlled trials: consensus and recommendations.

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles.

Breast Cancer Index Is a Predictive Biomarker of Treatment Benefit and Outcome from Extended Tamoxifen Therapy: Final Analysis of the Trans-aTTom Study.

PURPOSE: The Breast Cancer Index (BCI) HOXB13/IL17BR (H/I) ratio predicts benefit from extended endocrine therapy in hormone receptor-positive (HR+) early-stage breast cancer. Here, we report the final analysis of the Trans-aTTom study examining BCI (H/I)'s predictive performance. EXPERIMENTAL DESIGN: BCI results were available for 2,445 aTTom trial patients. The primary endpoint of recurrence-free interval (RFI) and secondary endpoints of disease-free interval (DFI) and disease-free survival (DFS) were examined using Cox proportional hazards regression and log-rank test. RESULTS: Final analysis of the overall study population (N = 2,445) did not show a significant improvement in RFI with extended tamoxifen [HR, 0.90; 95% confidence interval (CI), 0.69-1.16; P = 0.401]. Both the overall study population and N0 group were underpowered due to the low event rate in the N0 group. In a pre-planned analysis of the N+ subset (N = 789), BCI (H/I)-High patients derived significant benefit from extended tamoxifen (9.7% absolute benefit: HR, 0.33; 95% CI, 0.14-0.75; P = 0.016), whereas BCI (H/I)-Low patients did not (-1.2% absolute benefit; HR, 1.11; 95% CI, 0.76-1.64; P = 0.581). A significant treatment-to-biomarker interaction was demonstrated on the basis of RFI, DFI, and DFS (P = 0.037, 0.040, and 0.025, respectively). BCI (H/I)-High patients remained predictive of benefit from extended tamoxifen in the N+/HER2- subgroup (9.4% absolute benefit: HR, 0.35; 95% CI, 0.15-0.81; P = 0.047). A three-way interaction evaluating BCI (H/I), treatment, and HER2 status was not statistically significant (P = 0.849). CONCLUSIONS: Novel findings demonstrate that BCI (H/I) significantly predicts benefit from extended tamoxifen in HR+ N+ patients with HER2- disease. Moreover, BCI (H/I) demonstrates significant treatment to biomarker interaction across survival outcomes.

Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Comparing an Imaging-guided Pathway with the Standard Pathway for Staging Muscle-invasive Bladder Cancer: Preliminary Data from the BladderPath Study.

Transurethral resection of bladder tumour (TURBT) is central to the diagnosis of muscle-invasive bladder cancer (MIBC). With the oncological safety of TURBT unknown, staging inaccuracies commonplace, and correct treatment of MIBC potentially delayed, multiparametric magnetic resonance imaging (mpMRI) may offer rapid, accurate, and noninvasive diagnosis of MIBC. BladderPath is a randomised trial comparing risk-stratified (5-point Likert scale) image-directed care with TURBT for patients with newly diagnosed BC. To date, we have screened 279 patients and randomised 113. Here we report on the first 100 participants to complete staging: 48 in pathway 1 (TURBT) and 52 in pathway 2 (mpMRI for possible MIBC, Likert 3-5). Fifty of 52 participants designated Likert 1-2 (probable NMIBC) from both pathways were confirmed as having NMIBC (96%). Ten of 11 cases diagnosed as NMIBC by mpMRI have been pathologically confirmed as NMIBC, and 10/15 cases diagnosed as MIBC by mpMRI have been treated as MIBC (5 participants underwent TURBT). The specificity of mpMRI for identification of MIBC remains a limitation. These initial experiences indicate that it is feasible to direct possible MIBC patients to mpMRI for staging instead of TURBT. Furthermore, a 5-point Likert scale accurately identifies patients with low risk of MIBC (Likert 1-2), and flexible cystoscopy biopsies appear sufficient for diagnosing BC. PATIENT SUMMARY: We are conducting a clinical trial to assess whether some bladder tumour surgery can be replaced by magnetic resonance imaging scans to determine the stage of the cancer in patients whose tumours appear to be invasive. Our early data suggest that this approach is feasible. The data also show that using a visual score ('Likert scale') can help to identify bladder tumours that are very unlikely to be invasive, and that taking a biopsy in the outpatient clinic when first inspecting the bladder via a camera (diagnostic flexible cystoscopy) is useful for confirming bladder cancer.

Results of a UK National Cancer Research Institute Phase II study of brentuximab vedotin using a response-adapted design in the first-line treatment of patients with classical Hodgkin lymphoma unsuitable for chemotherapy due to age, frailty or comorbidity (BREVITY).

Standard treatment for classical Hodgkin lymphoma (cHL) is poorly tolerated in older patients and results disappointing. We assessed safety and efficacy of brentuximab vedotin (BV), in previously untreated patients with cHL unfit for standard treatment due to age, frailty or comorbidity. The primary outcome was complete metabolic response (CMR) by positron emission tomography/computed tomography after four BV cycles (PET4). The secondary outcomes included progression-free survival (PFS), overall survival (OS), and toxicity. In all, 35 patients with a median age of 77 years and median total Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score of 6 were evaluable for toxicity and 31 for response. A median of four cycles were given (range one-16). In all, 14 patients required dose reduction due to toxicity and 11 patients stopped treatment due to adverse events (AEs). A total of 716 AEs were reported, of which 626 (88%) were Grade 1/2 and 27 (77%) patients had at least one AE Grade ≥3. At PET4, CMR was 25·8% [95% confidence interval (CI) 13·7-42.2%] and objective response rate 83·9% (95% CI 63·7-90·8%). Median PFS was 7·3 months (95% CI 5·2-9·0), and OS 19·5 months. Our results suggest that BV monotherapy is tolerable but suboptimal in the front-line therapy of elderly or comorbid patients with cHL. Combining BV with other agents may be more effective. Trial Registration: Clinicaltrials.gov identifier: NCT02567851.

Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

Importance: Both α-emitting and ß-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and ß-emitting RIs. Objective: To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with ß-emitting RIs. Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018. Study Selection: Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data. Data Extraction and Synthesis: Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model. Main Outcomes and Measures: Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events. Results: Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the ß-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001). Conclusions and Relevance: In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not ß-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.

Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23-gene panel with utility for non-invasive diagnosis and risk stratification.

OBJECTIVES: To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell-pellet (cp)DNA and cell-free (cf)DNA as part of the development of a non-invasive clinical assay. PATIENTS AND METHODS: A panel of SMs was validated by targeted deep-sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture-based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed. RESULTS: The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A, and NRAS; 93.5-98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture-based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA. CONCLUSIONS: SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23-gene panel shows promise for the non-invasive diagnosis and risk stratification of UBC.

Total Fluid Intake and the Risk of Recurrence in Patients With Non-Muscle Invasive Bladder Cancer: A Prospective Cohort Study.

OBJECTIVES: To investigate the role of fluid intake from beverages before and after a diagnosis of bladder cancer in relation to the risk of developing bladder cancer recurrence. STUDY DESIGN: Prospective cohort study. METHODS: 716 patients with non-muscle invasive bladder cancer (NMIBC), who received transurethral resection of a primary bladder tumour (TURBT) and completed self-administrated questionnaires on usual fluid intake from beverages at time of diagnosis (over the year before diagnosis) and during follow-up (over the year after diagnosis), were included. Multivariable Cox regression was used to calculate hazard ratios and 95% confidence intervals of developing recurrent bladder cancer in relation to the intake of total fluid, total alcohol, and individual beverages. RESULTS: During 2,025 person-years of follow-up, 238 (33%) of the included 716 NMIBC patients developed one or more recurrences of bladder cancer. Total fluid intake before diagnosis was not associated with a first recurrence of bladder cancer when comparing the highest and lowest intake group (HR = 0.98, 95% C.I. 0.70-1.38, p = 0.91). Comparable results were obtained for total fluid intake pre-diagnosis and the risk of developing multiple recurrences of bladder cancer (HR = 1.01, 95% C.I. 0.87-1.19, p = 0.85). A total of 379 of the 716 patients reported on usual fluid intake within 1 year of diagnosis. No significant associations between total fluid intake 1 year after diagnosis and a first recurrence of bladder cancer were found when comparing the highest and lowest intake group (HR = 0.91; 95% C.I. 0.60-1.37, p = 0.65) or with multiple recurrences of bladder cancer (HR = 1.06; 95% C.I. 0.89-1.26, p = 0.54). In addition, total alcohol intake and individual beverages were not associated with bladder cancer recurrence. CONCLUSIONS: The results indicate that an individual's fluid intake from beverages is unlikely to have an important role in bladder cancer recurrence.

The association between smoking cessation before and after diagnosis and non-muscle-invasive bladder cancer recurrence: a prospective cohort study.

BACKGROUND: Smoking is a major risk factor for bladder cancer, but the relationship between smoking cessation after initial treatment and bladder cancer recurrence has been investigated less frequently and not prospectively yet. METHODS: 722 non-muscle-invasive bladder cancer (NMIBC) patients (pTa, pT1, and CIS) from the prospective Bladder Cancer Prognosis Programme (BCPP) cohort, selected in the UK between 2005 and 2011, provided complete data on smoking behavior before and up to 5 years after diagnosis. The impact of smoking behavior on NMIBC recurrence was explored by multivariable Cox regression models investigating time-to-first NMIBC recurrence. RESULTS: Over a median follow-up period of 4.21 years, 403 pathologically confirmed NMIBC recurrences occurred in 210 patients. Only 25 current smokers at diagnosis quit smoking (14%) during follow-up and smoking cessation after diagnosis did not decrease risk of recurrence compared to continuing smokers (p = 0.352). CONCLUSIONS: Although quitting smoking after diagnosis might reduce the risk of recurrence based on retrospective evidence, this is not confirmed in this prospective study because the number of NMIBC patients quitting smoking before their first recurrence was too low. Nevertheless, this indicates an important role for urologists and other health care professionals in promoting smoking cessation in NMIBC.

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study.

INTRODUCTION: There is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown. OBJECTIVE: The role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study. METHODS: 728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake. RESULTS: During 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78-1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90-1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42-1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85-1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence. CONCLUSION: Results from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.