Joe M. O'Sullivan

Objective To assess the effects of stereotactic radiotherapy (SRT) for neovascular age related macular degeneration (AMD) beyond the two year primary outcome of the StereoTactic radiotherapy for wet Age-Related macular degeneration (STAR) trial. Design Randomised, double masked, sham controlled, device trial involving preplanned recall from standard care. Setting 30 NHS hospitals in the UK. Participants 411 participants aged at least 50 years with chronic, pretreated, active AMD. Intervention Participants received one-off 16 Gray SRT or sham SRT delivered using a robotically controlled device. After two years of monthly study visits, participants reverted to routine care, with anti-VEGF drug selection and dosing intervals based on local practice, but with masking maintained, and repeat data collection at years 3 and 4 study visits. Main outcome measures The main efficacy outcome at year 4 was the number of anti-VEGF injections, tested for superiority (fewer injections). The other main outcome was visual acuity, tested for non-inferiority (five letter margin). Safety outcomes included adverse events, serious adverse events, and microvascular abnormalities. The same analyses were undertaken at years 2, 3, and 4. A within trial costing analysis was undertaken for participants with four years’ follow-up. Results Of 411 participants (204 (58%) women), 274 were allocated to SRT and 137 to sham SRT. The year 4 intention-to-treat efficacy analysis included 222 (81%) participants in the SRT group and 106 (77%) in the sham SRT group. The SRT group received a mean of 19.1 (standard deviation 10.9) injections over four years versus 21.6 (11.3) with sham SRT, an adjusted decrease of 3.2 injections (95% confidence interval (CI) of difference -5.7 to -0.7). During years 3 and 4, the SRT group received a mean cumulative 8.4 injections versus 8.3 injections in the sham SRT group. The final change in visual acuity in the SRT group was 8.3 letters worse than in the sham group (95% CI of difference -12.7 to -4.0). Adverse event rates were similar between groups, but reading centre-detected microvascular abnormalities occurred in 126/218 SRT treated eyes (58%) and 16/102 (16%) sham SRT treated eyes. Conclusion Although the overall reduction in intravitreal therapy was maintained to year 4, the inferior vision in SRT treated eyes effectively reversed the conclusions of the year 2 primary outcome analysis and no longer supports the use of SRT to treat neovascular AMD. Including standard care, masked, extended follow-up within a clinical trial may provide useful clinical insight. Trial registration ClinicalTrials.gov NCT02243878.

Objective. This study assesses rectum organ at risk contours generated using a commercial deep learning auto-contouring model and compares them to clinician contours using geometry, changes in dosimetry and toxicity modelling. Approach. This retrospective study involved 308 prostate cancer patients who were treated using 3D-conformal radiotherapy. Computed tomography images were input into Limbus Contour (v1.8.0b3) to generate auto-contour structures for each patient. Auto-contours were not edited after their generation. Rectum auto-contours were compared to clinician contours geometrically and dosimetrically. Dice similarity coefficient (DSC), mean Hausdorff distance (HD) and volume difference were assessed. Dose-volume histogram (DVH) constraints (V41% - V100%) were compared, and a Wilcoxon signed-rank test was used to evaluate statistical significance of differences. Toxicity modelling to compare contours was carried out using equivalent uniform dose (EUD) and clinical factors of abdominal surgery and atrial fibrillation. Trained models were tested (80:20) in their prediction of grade 1 and above late rectal bleeding (n_total = 124) using area-under the receiver operating characteristic curve (AUC). Main results. Median DSC (interquartile range (IQR)) was 0.85 (0.09), median HD was 1.38 mm (0.60 mm) and median volume difference was -1.73 cc (14.58 cc). Median DVH differences between contours were found to be small (Significance. Although median DVH metrics were similar, variation for individual patients highlights the importance of clinician review. Rectal bleeding prediction accuracy did not depend on the contour method for this cohort. The auto-contouring model used in this study shows promise in a supervised workflow.

Background: Alkaline phosphatase (ALP) declines and pain responses can occur during radium-223 (²²³Ra) treatment, but their association with treatment outcomes is unclear. Methods: For patients with metastatic castration-resistant prostate cancer treated with ²²³Ra in the REASSURE study, we investigated whether ALP decline (Week 12) and/or pain response (during treatment) are associated with improved overall survival (OS). The Brief Pain Inventory-Short Form (BPI-SF) was used to assess pain at baseline and pain response (in patients with baseline BPI-SF score ≥2). Results: Of 785 patients with baseline and Week 12 ALP measurements, 779 were eligible for the OS analyses. Overall, 80% of patients had an ALP decline. Median OS was longer in patients with than without an ALP decline (18.1 versus 14.2 months; HR 0.74; 95% CI 0.60–0.92). In patients with an ALP decline, there was no clear OS difference between those with versus without a pain response. For patients without ALP decline, median OS was longer in those with versus without a pain response (16.2 versus 10.9 months; HR 0.50; 95% CI 0.32–0.77). Conclusions: Decreases in ALP and/or pain during ²²³Ra treatment are associated with improved OS. This may help support clinical decisions. Clinical trial registration: ClinicalTrials.gov identifier NCT02141438.

Background: Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying. Aim: To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection. Design and setting: Prostate Cancer UK facilitated a RAND/UCLA consensus. Method: Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel. Results: Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk. Conclusion: Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines.

Radium-223 (²²³Ra) and Lutetium-177-labelled-PSMA-617 (¹⁷⁷Lu-PSMA) are currently the only radiopharmaceutical treatments to prolong survival for patients with metastatic-castration-resistant prostate cancer (mCRPC); however, mCRPC remains an aggressive disease. Recent clinical evidence suggests patients with mutations in DNA repair genes associated with homologous recombination have a greater clinical benefit from ²²³Ra. In this study, we aimed to determine the utility of combining DNA damage response (DDR) inhibitors to increase the therapeutic efficacy of X-rays, or ²²³Ra. Radiobiological responses were characterised by in vitro assessment of clonogenic survival, repair of double strand breaks, cell cycle distribution, and apoptosis via PARP-1 cleavage. Here, we show that DDR inhibitors increase the therapeutic efficacy of both radiation qualities examined, which is associated with greater levels of residual DNA damage. Co-treatment of ATM or PARP inhibition with ²²³Ra increased cell cycle arrest in the G2/M phase. In comparison, combined ATR inhibition and radiation qualities caused G2/M checkpoint abrogation. Additionally, greater levels of apoptosis were observed after the combination of DDR inhibitors with ²²³Ra. This study identified the ATR inhibitor as the most synergistic inhibitor for both radiation qualities, supporting further pre-clinical evaluation of DDR inhibitors in combination with ²²³Ra for the treatment of prostate cancer.

Supplementary figure SF1 shows CONSORT diagram of trial profile

Supplementary figure SF4 shows (A) Kaplan-Meier plot to estimate median progression free survival as time from first docetaxel (or trial registration if no docetaxel received) until PSA progression per PCWG. Median progression free survival = 20.5 months. (B) Kaplan Meier plot to estimate median overall survival as time from first docetaxel (or trial registration if no docetaxel received) until death. Median not reached.

Supplementary figure SF3 shows examples of WB-MRI pre and post 6 cycles of radium-223 and pelvic radiotherapy. A and B showing tumour burden reduction in femora, C and D showing tumour burden reduction in lumbosacral spine and E and F showing tumour burden increase in thoracic spine.

Supplementary figure SF2 shows mean EPIC score by domain by timepoint. Error bars = 95% confidence intervals.