Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma – protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial

Introduction The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was ‘Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?’ This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT.Methods and analysis We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress.Ethics and dissemination This study was approved by the Yorkshire and The Humber—Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group.Trial registration number ISRCTN41647111

Tranexamic acid versus placebo to prevent bleeding in patients with haematological malignancies and severe thrombocytopenia (TREATT): a randomised, double-blind, parallel, phase 3 superiority trial

Background: Bleeding is common in patients with haematological malignancies undergoing intensive therapy. We aimed to assess the effect of tranexamic acid on preventing bleeding and the need for platelet transfusions. Methods: TREATT was an international, randomised, double-blind, parallel, phase 3 superiority trial conducted at 27 haematology centres in Australia and the UK. We enrolled adults (aged ≥18 years) receiving intensive chemotherapy or haematopoietic stem-cell transplantation for a haematological malignancy, with a platelet count of 10 × 109 platelets per L or less for 5 days or longer. Patients were randomly assigned (1:1) using block randomisation, stratified by site, to tranexamic acid (1 g every 8 h intravenously or 1·5g every 8 h orally) or placebo when their platelet count was less than 30 × 109 platelets per L. Treatment was continued until platelet recovery or day 30. Prophylactic platelet transfusions were maintained as standard of care. The primary endpoint was the proportion of patients who died or had WHO grade 2 or higher bleeding up to day 30. A modified intention-to-treat population including randomly assigned patients whose platelet count decreased to 30 × 109 platelets per L or less was used for analysis. This trial is registered with ClinicalTrials.gov (NCT03136445), ISRCTN (ISRCTN73545489), and the European Clinical Trials Register (EudraCT 2014-001513-35). Findings: Between June 23, 2015, and Feb 17, 2022, 1736 patients were screened for eligibility, 616 of whom were enrolled and randomly assigned (310 to tranexamic acid and 306 to placebo). 19 participants were excluded from the modified intention-to-treat analysis, leaving 300 participants in the tranexamic acid group and 297 in the placebo group. Participant median age was 58 years (IQR 49–65), 380 (62%) of 616 participants were male, and 235 (38%) were female. The proportion of participants who died or had WHO grade 2 or higher bleeding was 31·7% (90/298 [95% CI 26·6–37·4]) in the tranexamic acid group and 34·2% (98/295 [29·0–40·0]) in the placebo group (hazard ratio 0·92 [95% CI 0·67–1·27]; p=0·62). There were no differences in thrombotic events or veno-occlusive disease. 94 serious adverse events in 77 participants were reported up to day 60 in the tranexamic acid group and 103 events in 82 participants in the placebo group. Interpretation: There is insufficient evidence to support routine use of tranexamic acid to reduce bleeding in patients with haematological malignancies undergoing intensive chemotherapy. Funding: UK National Health Service Blood and Transplant and Australian National Health and Medical Research Council