The Clatterbridge Cancer Centre NHS Foundation Trust
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Background Understanding patient and health practitioner perspectives on clinical trials can inform opportunities to enhance trial conduct and design, and therefore patient experience. Patients with haematological cancers have faced additional risk and uncertainty during the pandemic but it is unclear how they and practitioners have experienced cancer trials during this period. In the context of a haemato-oncology trial (PETReA), we compared patient and practitioner views and experiences of PETReA before and during COVID-19. Methods Qualitative study embedded within PETReA. Semi-structured interviews (N=41) with patients and practitioners from 16 NHS sites before (n=17) and during the first wave of COVID-19 (n=24). Analysis drew on the framework approach. Results Practitioners acknowledged the need for the trial to continue during the pandemic but their treatment preferences altered, becoming more pronounced for patients who had a favourable response to induction treatment, while staying unchanged for patients with a less favourable response. Practitioners commented that COVID-19 meant the evidence base for the trial arms was lacking or mixed, but that it likely increased the risks of maintenance treatment for patients with a favourable response to induction treatment. While only one participant interviewed withdrew from PETReA during the pandemic, others said they would consider withdrawing if information that they were at increased risk of severe illness from COVID-19 became available. During COVID-19, patients described less frequent contact with the trial team, which left some feeling less clear about their trial pathway. However, several described having in-depth, collaborative discussions with practitioners about the risks and benefits of randomisation in the context of COVID-19. Patients valued these discussions and were reassured by the emphasis practitioners placed on patients being free to withdraw if circumstances changed, and this helped patients feel comfortable about continuing in PETReA. Conclusions The findings point to ways trial communication can support patients to feel comfortable about continuing in a trial during uncertain times, including adopting a more in-depth, collaborative exploration of the risks and benefits of trial arms with patients and emphasising voluntariness. The results are relevant to trialists recruiting patients who are clinically extremely vulnerable or are at increased risk of poor COVID-19 outcomes despite being vaccinated.
Background: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. Methods: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. Findings: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). Interpretation: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. Funding: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.
Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476 , ISRCTN.com ISRCTN78818544 .
Background The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. Methods This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. Results In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0–1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients ( n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). Conclusion This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.
Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011–2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE’s £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP’s indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup.
Background Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally. Patients and methods A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site. Results A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific. Conclusions This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area.
The diversity of the United Kingdom population and its health care personnel makes it unique for research into evidence-based prostate cancer screening and management strategies. Therefore, ensuring that appropriate systems and services are available to enhance treatment support for men with underlying risk factors should be a priority for health care providers. More efforts are also needed to ensure the representation of men of Black ethnic origin and underserved populations in future prostate cancer research used to inform clinical guidelines.
Purpose of review: The incidence of head and neck cancer (HNC) is increasing globally and changes in treatment mean that patients are living longer with the condition. It is recognised that while there have been improvements at the diagnostic phase of the pathway, follow-up and on-going care can be fragmented and inequitable. Integrated care models (ICMs) are acknowledged as beneficial. The National Health Service in England is moving to a model whereby services are being re-organised to integrated care systems. This paper reviews the literature and discusses potential models of care to enhance speech and language therapy (SLT) provision for patients with HNC in line with the emerging ICS. Recent findings: The COVID-19 pandemic has provided an opportunity to review service provision and SLT teams quickly adapted to offering remote support. Discussions are currently on-going to explore the potential for patient initiated follow-up via the PETNECK 2 trial and the Buurtzorg 'neighbourhood model' holds promise. Summary: ICMs put the patient at the centre of care and have reported benefits for experience of care and clinical outcomes. Navigating organisational structures is complex. The Buurtzorg model provides a practical and theoretical framework to support organisational change.
2522 Background: Pre-existing autoimmune disease (AID) potentially increases the propensity for the development of immune related adverse events (irAE) in response to oncological immune checkpoint inhibitors (ICIs) is biologically plausible and clinically observed. However, due to consistent clinical trial exclusion of those with pre-existing AID, the impact on the frequency and severity of irAEs is uncertain. Here we analyse this relationship in a large, real-world, UK multi-centre cohort. Methods: A retrospective analysis of 2049 patients treated with ICIs over a two year period was undertaken across 12 National Health Service centres by the UK National Oncology Trainees Collaborative for Healthcare Research (NOTCH). Patients received ICIs as standard of care for malignant melanoma, non-small cell lung cancer and renal cell carcinoma. The presence of pre-existing AIDs was assessed and classified as either autoantibody driven or autoinflammatory then correlated with clinically significant irAEs (i.e. ≥grade 2 or all-grade endocrinopathies). Statistical analyses included T-test, Mann-Whitney and Chi-squared. For overall survival (OS) Kaplan-Meier and log-rank tests were utilised. Results: Pre-existing AID were present in 13% (n = 257) of the overall cohort. Pre-existing endocrinopathies (30%; n = 76) were most common followed by rheumatological AIDs (18%; n = 46). In the pre-existing AID cohort there was a female predominance (48% vs 39%; p = 0.006) but no difference in smoking history (p = 0.074) or ethnicity (p = 0.12). There was no difference in ICI treatment between those with and without pre-existing AID (p = 0.2800). IrAEs occurred in 45% (n = 117) patients with pre-existing AID vs 33% (n = 583) without (p£0.001). The median time to onset of irAEs was similar. IrAEs with an increased incidence in the pre-existing AID cohort were colitis (p = < 0.001), arthralgia (p = 0.008) and dermatological irAEs (p = 0.014). There was no difference in the incidence of irAEs in patients with autoantibody driven vs autoinflammatory pre-existing AID (44.0 % vs 44.8%, p = 0.905). In the overall cohort, those with pre-existing AIDs had a median OS of 20.4 months (95% CI: 19.4-21.7) vs 14.1 months (95% CI: 12.8-16.3) in those without pre-existing AID (p = 0.004). Conclusions: This large multi-centre ICI-treated cohort demonstrates that pre-existing AID is a predisposing factor for the development of irAEs, however the incidence is lower than previously quoted. The pathological basis of pre-existing AID did not differentially affect irAE manifestation. Patients with pre-existing AID had improved OS compared to those without which has not been observed in previously reported studies. ICI treatment should be considered in those with pre-existing AID but further studies are needed to determine how best to optimise outcomes whilst mitigating the impact of irAEs.
9584 Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. > 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p > 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs > 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.
4005 Background: The prognosis for pts with PD-EP-NEC is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy; there is no standard second-line (2L) treatment (area of unmet need). Methods: This was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI (70mg/m ² free base)/5-FU (2400 mg/m ² )/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m ² ), Q21 days (ARM B), as 2L therapy in a planned 102 pts with progressive PD-EP-NEC, aimed at selecting a treatment for continuation to a phase III trial. Pts with histologically-confirmed PD-EP-NEC (Ki-67>20%; Grade 3, WHO 2019), who had prior 1L platinum-based chemotherapy and radiological disease progression or discontinuation of 1L therapy due to intolerance, with an ECOG performance status ≤2 were eligible. Randomisation was stratified by Ki-67, ECOG PS, presence of liver metastases, and response to previous platinum-based therapy. Primary endpoint was 6 month (mo) progression-free survival (PFS) rate; 80% power to demonstrate the one-sided 95% confidence interval (CI) of the 6 mo PFS rate excluded 15%, if the true rate was at least 30%, where 30% was the required level of efficacy; a rate of <15% would give grounds for rejection. Intention was to show that the regimens were sufficiently active, but not to assess superiority of one regimen over the other. Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS), and toxicity. Based on futility analysis, the DSMB recommended closure of recruitment in Dec 21. Results: Of 58 patients in 15 UK centres (Nov 18-Dec 21), 29 in ARM A, 29 in ARM B, 57% were male, median age (range): 63.5 years (22-85), 90% ECOG PS 0/1, 10% PS 2, 90% Ki-67≥55%, 33%/38%/29% small/large cell/unknown morphology, primary site: 69% gastrointestinal, 12% unknown, 9% genitourinary, 5% head & neck, 3% gynae, 2% breast, 60% had liver mets, 91%/7%/2% were resistant/sensitive/intolerant to 1L platinum-based treatment. At a median follow up of 6.6 mo, the primary end-point of 6-mo PFS rate was met in ARM A; ORR, median PFS and OS are also presented (Table). Adverse events ≥ grade 3 occurred in 51.7% and 55.2% in ARM A and B and there were 1 and 6 discontinuations due to toxicity in ARM A and B, respectively. Data cleaning is on-going. Conclusions: nal-IRI/5-FU, but not docetaxel, met the primary endpoint (exceeding the threshold for efficacy), with manageable toxicity, and warrants evaluation in a phase III trial. Clinical trial information: 03837977. [Table: see text]
3512 Background: The OPERA trial was testing the hypothesis that Contact x-ray brachytherapy (CXB) 50 kV boost will increase the rectal preservation rate in early T2-T3ab rectal adenocarcinoma. We present the 3 years clinical results. Methods: Inclusion criteria were: Age > 18 years, PS: 0-1, adenocarcinoma, distal - middle rectum, cT2-T3ab cN0-N1 < 8mm staged using MRI, M0. Stratification: T < vs ≥ 3 cm diameter. Control arm (A) was chemoradiotherapy (CRT) 45Gy/ 5 weeks with concurrent chemotherapy (Capecitabine 825 mg / m ² ) and external beam radiotherapy boost (9Gy/ 5 fr/ 1 week). Experimental arm used the same CRT (Cape 45) but the boost used CXB (90 Gy/ 3 fr/ 4 weeks). CXB was given first (B1) for tumor < 3 cm and after cap 45 (B2) for tumor ≥ 3 cm. Response assessment was made at week 14 after treatment start using palpation, endoscopy and MRI. A new assessment could be made at week 20 and 24 with a second MRI.TME was recommended in case of Partial response, Watch& Wait in case of clinical complete response (cCR). Bowel function measurement used LARS score. Main end- point was: Rate of organ preservation at 3 years. The hypothesis (in 2014) was 20% arm A vs 40% arm B (HR:0.53). Results: Between 5-2015 and 6-2020, 144 patients were included (France 96, UK 44, Switzerland 4). The analysis was made in 01-2022 with a median Follow-up time of 34 months. Treatment compliance was good in ≥ 90% of patients. Table gives main patients characteristics and clinical outcome. At three years the OP rate (Kaplan Meier estimate) was respectively arm A vs B: 60% vs 81% (HR 0.34 [95% CI 0.19 – 0.73]; p= 0.005). At three years OP for group A1 and B1 were: 65% vs 97% (HR 0.081 [95% CI 0.01-0.64]; p= 0.02). Conclusions: A CXB boost, when combined with chemoradiotherapy, increases the rate of organ preservation in early rectal adenocarcinoma. Starting with CXB in T < 3 cm appears as an attractive option. A B A1 (T < 3cm) B1 (T < 3cm) N° patient 71 73 30 32 Median age 68 69 69 70 Gender M/F 45/26 43/30 18/12 18/14 T2/T3 45/26 47/26 25/5 29/3 Distal/middle 53/18 53/20 21/9 27/5 cCR (W 14-24) 61% 90% p < 0.001 70% 94% p = 0.027 TME 26 12 8 1 Death 2 2 1 0 LARS < 30 80% 83% 87% 86%.
TPS9610 Background: Geographical differences in the management of primary UM, surveillance for recurrence, and care of metastatic disease have emerged based upon local expertise, treatment availability and insurance coverage. We have initiated accrual to OMNi (NCT04588662), an ambispective database developed to provide contemporary real-world data of UM, capturing its natural history and serving as a virtual biospecimen repository. The overall objectives of OMNi are to characterize regional/international UM management practice patterns and associated clinical outcomes in an effort to inform best practice recommendations. Methods: OMNi utilizes the Pulse Infoframe Healthie platform, a globally compliant platform which enables the structured collection of data mapped to Observational Medical Outcomes Partnership. The data fields created permit longitudinal capture of data including baseline patient and tumor characteristics, treatment of primary lesion and outcomes, surveillance patterns, time to disease recurrence, treatment of recurrent disease with outcomes, and survival. Inclusion criteria include a diagnosis of uveal melanoma and the ability to provide written informed consent for participation in the prospective registry or an institutional waiver by the IRB/ethics committee for retrospective data collection without written informed consent. We have initiated data collection at 3 US and 3 Australian centers, with 184 patients enrolled to date. Based upon feasibility assessment, we anticipate retrospective data entry for ̃2,000 patients and annual recruitment of ̃700 patients once all centers are active. Data collected in this OMNi collaboration, which will include additional US, UK and Australian sites, will facilitate new insights, hypothesis testing, as well as clinical trial development and conduct, and through a governance structure, will be made accessible for research. The OMNi dataset can serve and aid in interpretation of clinical trial outcomes in the real-world, facilitate cutting-edge research, and accelerate the development of diagnostics and therapeutics. Clinical trial information: NCT04588662.
Aged-related changes in the spine are initiated in the discovertebral complex and will extend to the adjacent vertebral bone marrow, cervical uncovertebral and facet joints and spinal ligaments. These occur in response to a wide range of insults, repetitive low-level mechanical trauma being the most important. Degenerative spinal stenosis represents a significant cause of pain and disability in the elderly population. Age-related changes and disc herniation may narrow the central canal and neuroforamina, causing cord compression and myelopathy, cauda equina compromise or individual radiculopathy. Accurate and comprehensive interpretation of age-related spinal imaging findings can be challenging because often there is poor correlation with symptoms. Imaging may confirm the diagnosis of spinal canal stenosis and identify exactly the affected levels and anatomic structures involved, therefore enabling clinical correlation and treatment planning. Plain film imaging remains the first line technique in the evaluation of spinal degenerative changes, being useful in assessing the morphology and alignment of the vertebrae, including the assessment of instability where needed using flexion and extension lateral radiographs and the degree of disc/facet joint degeneration and reactive osteophytosis. Computer tomography (CT) imaging provides more detailed information on the bony components of the spinal degenerative process but suboptimally assesses protrusive disc disease. CT myelography is an invasive procedure mainly restricted to cases in which MR is contraindicated. Magnetic resonance imaging (MRI) is the preferred imaging technique for spinal pathologies as it can clearly delineate the soft tissue contents of the spinal canal and neuroforamina to define both annuloprotrusive and neural pathology.
Up‐to‐date information on coronavirus disease 2019 (COVID‐19) outcomes and risk factors in haematopoietic cell transplantation (HCT) recipients is required to inform on decisions about cancer treatment and COVID‐19 mitigation strategies. We performed a meta‐analysis to address this knowledge gap. All studies with at least five patients who reported COVID‐19‐related deaths in HCT recipients were included. The primary outcome was COVID‐19‐related death. Secondary outcomes were COVID‐19‐related mechanical ventilation (MV) and intensive care unit (ITU) admission. The cumulative COVID‐19‐related death rate among HCT recipients was 21% (95% confidence interval [CI] 18%–24%), while MV and ITU admission rates were 14% (95% CI 11%–17%) and 18% (95% CI 14%–22%), respectively. Subgroup analysis showed higher death rates in patients who developed COVID‐19 within 12 months of HCT (risk ratio [RR] 1.82, 95% CI 1.09–3.03), within 6 months of receiving immunosuppressant drugs (RR 2.11, 95% CI 1.38–3.20) or in the context of active graft‐versus‐host disease (RR 2.38, 95% CI 1.10–5.16). Our findings support the idea that HCT should remain an integral part of cancer treatment during the COVID‐19 pandemic but also highlight the need to prioritise preventative measures in those patients who are at increased risk of adverse COVID‐19 outcomes.
Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies 1–3 . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity 4,5 , its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T reg ) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T reg cells. Accordingly, in mouse models, PI3Kδi decreased the number of T reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T reg cells, accompanied by expansion of pathogenic T helper 17 (T H 17) and type 17 CD8 ⁺ T (T C 17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.
Objectives Accurate image registration is vital in cervical cancer where changes in both planning target volume (PTV) and organs at risk (OAR) can make decisions regarding image registration complicated. This work aims to determine the impact of a dedicated educational tool compared with experience gained in MR guided radiotherapy (MRgRT). Methods Ten therapeutic radiographers acted as observers and were split into two groups based on previous experience with MRgRT and Monaco treatment planning system. Three CBCT- CT, three MR-CT and two MR-MR registrations were completed per patient by each observer. Observers recorded translations, time to complete image registration and confidence. Data was collected in two phases; prior to and following the introduction of a cervix registration guide. Results No statistically significant differences were noted between imaging modalities. Each group was assessed independently pre and post education, no statistically significant differences were noted in either CBCT-CT or MR-CT imaging. Group one MR-MR imaging showed a statistically significant reduction in inter-observer variability (p=0.04), in group two, the result was not statistically significant (p=0.06). Statistically significant increases in confidence were seen in all three modalities (p≤0.05). Conclusions At our institution radiographers consistently registered images across three different imaging modalities regardless of their previous experience. The implementation of an image registration guide had limited impact on inter and intra-observer variability. Radiographers’ confidence showed statistically significant improvements following the use of the registration manual. Advances in knowledge This work helps evaluate training methods for novel roles that are developing in MRgRT.
Conditioning of the bone marrow prior to haematopoietic stem cell transplant is essential in eradicating the primary cause of disease, facilitating donor cell engraftment and avoiding transplant rejection via immunosuppression. Standard conditioning regimens, typically comprising chemotherapy and/or radiotherapy, have proven successful in bone marrow clearance but are also associated with severe toxicities and high incidence of treatment-related mortality. Antibody-based conditioning is a developing field which, thus far, has largely shown an improved toxicity profile in experimental models and improved transplant outcomes, compared to traditional conditioning. Most antibody-based conditioning therapies involve monoclonal/naked antibodies, such as alemtuzumab for graft-versus-host disease prophylaxis and rituximab for Epstein–Barr virus prophylaxis, which are both in Phase II trials for inclusion in conditioning regimens. Nevertheless, alternative immune-based therapies, including antibody–drug conjugates, radio-labelled antibodies and CAR-T cells, are showing promise in a conditioning setting. Here, we analyse the current status of antibody-based drugs in pre-transplant conditioning regimens and assess their potential in the future of transplant biology.
This chapter focuses on the use of particle radiation for treatment of uveal melanomas (UMs), intraocular metastases, and other diseases of the eye and orbit. Ocular particle beam radiotherapy for UM is associated with excellent local tumor control and eye preservation compared with other eye‐conserving forms of primary treatment. Initial clinical presentation of UM can vary and approximately 33% of patients are asymptomatic at the time of diagnosis. Based on the initial clinical evaluation, patients may then be referred for further care to an ocular oncology center. Eye plan treatment planning software is the commonly used proton ocular radiation therapy planning system worldwide. Particle therapy is well established as a “gold standard” treatment for UMs based on prospective, retrospective, and meta‐analysis data. A thorough ocular examination with appropriate imaging is completed at each ophthalmology visit and patients will follow‐up with a combination of the surgical, radiation, and medical oncologist, as appropriate.
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86 members
Arthur Sun Myint
  • Lead Clinician, Papillon Unit
Chinnamani V Eswar
  • Department of Oncology
Abhishek Mahajan
  • Department of Imaging
David C P Cobben
  • Department of Radiotherapy
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