ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer.

BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

Image-Guided Radiotherapy for Pelvic Cancers: A Review of Current Evidence and Clinical Utilisation.

The meticulous selection and utilisation of image-guided radiotherapy (IGRT) are essential for optimal radiotherapy treatment delivery when using highly conformal treatment techniques in pelvic radiotherapy. Pelvic IGRT has several general IGRT issues to consider (such as choice of match strategy, prioritisation between multiple treatment targets and margin estimates) as well as issues specific to pelvic radiotherapy, in particular large inter-fraction organ variation. A range of interventions, including adaptive treatment strategies, have been developed to address these challenges. This review covers general considerations for the clinical implementation of pelvic IGRT in routine practice and provides an overview of current knowledge regarding pelvic inter-fraction organ motion. Published IGRT evidence for each of the major tumour sites (gynaecological, prostate, bladder, rectal and anal cancer) is summarised, as are state-of-the-art adaptive approaches. General recommendations for the implementation of an institutional pelvic IGRT strategy include. •Ensuring consistency between treatment intent and the IGRT approach utilised. •Ensuring minimum national and international IGRT guidance is followed while considering the benefit of daily volumetric IGRT. •Ensuring the appropriate allied health professionals (namely therapy radiographers/radiation therapists) lead on undertaking IGRT. •Ensuring the IGRT workflow procedure is clear and includes an escalation process for difficult set-ups. •Ensuring a robust IGRT service is in place before implementing advanced adaptive approaches.

Pelvic Organ Motion during Radiotherapy for Cervical Cancer: Understanding Patterns and Recommended Patient Preparation.

AIMS: Minimisation of organ position variation during pelvic radiotherapy is vital for accurate treatment. We analysed bladder and rectal filling during radiotherapy to understand variation reduction methods. MATERIALS AND METHODS: Cone beam computed tomography scans (CBCTs) taken twice weekly during three-dimensional conformal radiotherapy were retrospectively analysed for 10 cervical cancer patients. Bladder and bowel preparation was followed. Two independent clinicians outlined bladder, rectum and the primary clinical target volume (CTV) on each CBCT. Effects of time, chemotherapy and drinking time on bladder and rectal volume were analysed. CTV coverage impact was investigated using fixed effect logistic regression modelling. RESULTS: Ten planning scans and 109 CBCTs were reviewed. The bladder volume was 45-578 cm(3) during radiotherapy and 73-664 cm(3) at planning. The bladder volume increased (4 cm(3)/min) with waiting time, decreased (average 4 cm(3)/day) through treatment and was larger (about 50 cm(3)) after chemotherapy. A bladder volume difference > 130 cm(3) from planning led to the planning target volume (PTV) not covering the CTV. The probability of the PTV covering the CTV for every cm(3) deviation from the planning volume reduced by 1.9%, predominantly affecting the uterus. Planning bladder volumes > 300 cm(3) were not reproducible during treatment. The rectal anterior-posterior diameter correlated with volume. No pattern was displayed through treatment. The probability of the PTV covering the CTV with every mm deviation from the planning anterior-posterior diameter reduced by 5.8%, predominantly affecting the cervix. The risk of the PTV not covering the CTV is higher if the rectum is larger during treatment than planning. As bladder volume decreased rectal anterior-posterior diameter increased. CONCLUSION: Our data suggest an ideal planning bladder volume of 150-300 cm(3), a shorter waiting time on post-chemotherapy days and adequate hydration throughout treatment. Laxatives at planning and throughout treatment may also be beneficial. Even with these measures, regular imaging is vital when implementing advanced radiotherapy techniques for gynaecological cancers.

Intensity-modulated radiotherapy (IMRT) to prostate and pelvic nodes-is pelvic lymph node coverage adequate with fiducial-based image-guided radiotherapy?

OBJECTIVE: There remains concern regarding the use of fiducial-based image-guided radiotherapy (IGRT) in patients with high-risk prostate cancer also undergoing intensity-modulated radiotherapy (IMRT) to pelvic nodes. By a retrospective study, we aim to ascertain the impact of the use of fiducial-based IGRT on lymph node planned target volume (PTV) coverage. METHODS: 30 consecutive IMRT prostate and pelvic node plans were reviewed, and dose was recalculated with 1-mm increment movements in anterior, posterior, superior, inferior, right and left directions up to 10 mm. All patients were treated with a full bladder after drinking 450-750 ml of water and empty rectum with the use of sodium citrate enemas daily. Dose-volume histogram parameters were recorded at each position, specifically nodal PTV V95%, V99% and V100%. A local IGRT database was used to identify the likelihood of a particular bony to fiducial offset in all directions. The combined data were used to calculate the percentage risk of underdosing the lymph node PTV on any given fraction. RESULTS: The likelihood of an offset in the left, right and anterior directions occurring and resulting in a failure to cover the PTV was <0.25%. The likelihood of a posterior offset occurring and resulting in inadequate coverage was slightly higher but remained <1%. CONCLUSION: This study confirms the safety of fiducial-based image-guided IMRT (IG-IMRT) with a strict bowel and bladder protocol, allowing a reduction of the clinical target volume to PTV margin of the prostate volume and consequent reduction in rectal toxicity. ADVANCES IN KNOWLEDGE: This study strengthens the evidence supporting the safe implementation of fiducial-based IG-IMRT treating the prostate and pelvic nodes in high-risk prostate cancer.

Bevacizumab treatment for vestibular schwannomas in neurofibromatosis type two: report of two cases, including responses after prior gamma knife and vascular endothelial growth factor inhibition therapy.

OBJECTIVES: Vestibular schwannomas are the hallmark of neurofibromatosis type two. They are difficult to treat, due to their bilateral presentation and the quest for hearing preservation. Our report describes a new treatment approach in this clinical scenario. CASE REPORT: We report two cases which confirm that bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, causes regression of vestibular schwannomas in patients with a previous history of gamma knife radiosurgery or failed treatment with another form of vascular endothelial growth factor targeted therapy. CONCLUSION: In 2009, Plotkin et al. reported the volumetric response of vestibular schwannomas to bevacizumab treatment, both in untreated patients and in patients previously treated with erlotinib, an epidermal growth factor receptor inhibitor. The presented cases support the use of bevacizumab to treat vestibular schwannomas. Given the extremely slow growth of these tumours, we note the rapidity of volume reduction following bevacizumab therapy.