The Christie School of Oncology: Christie Research Publications Repository
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Association between immunotherapy timing and efficacy in non-small cell lung cancer: a comprehensive analysis at a high-volume specialist centre
No full textBACKGROUND: The timing of immune checkpoint inhibitor (ICI) administration may influence clinical outcomes in non-small cell lung cancer (NSCLC) patients. Previous studies have shown varying effects of chronotherapy on survival rates, with some suggesting that a higher percentage of doses administered in the morning improves overall survival (OS) and progression-free survival (PFS). This study aimed to evaluate the impact of the timing of the first dose and the percentage of doses administered in the afternoon on survival outcomes in advanced NSCLC patients, as well as explore seasonal variations. METHODS: We conducted a retrospective cohort study at a tertiary cancer centre of patients diagnosed with NSCLC and programmed cell death ligand 1 (PD-L1) expression ≥50% who received first-line palliative treatment with pembrolizumab or atezolizumab. Patients were categorized based on the timing of their first dose (before or after 14:30) and further stratified by the percentage of doses received after 14:30. To evaluate seasonal variance, patients were also stratified into two groups: those who received their first dose within three months before or after the winter solstice ('Winter group') and those who received it within three months before or after the summer solstice ('Summer group'). Survival analysis was conducted using the Kaplan-Meier method. RESULTS: We identified 349 patients who met the inclusion criteria. There was no significant difference in PFS or OS between patients receiving their first ICI dose before 14:30 (n=188) and those receiving it after 14:30 (n=161). However, a significant difference in OS was observed in patients who received more than 50% of their doses in the afternoon. Seasonal variations in dosing timing did not significantly impact survival outcomes. CONCLUSIONS: Our study suggests that the timing of the first ICI dose does not significantly affect survival outcomes in advanced NSCLC patients. However, patients receiving a higher percentage of their doses in the afternoon may experience poorer OS. Further prospective research is needed to confirm these findings and understand the underlying mechanisms before any changes to clinical practice can be recommended
Cancer-selective targeting of the NF-κB pathway via GADD45β/MKK7 inhibition: Results from the phase I trial of the first-in-class inhibitor, DTP3, in patients with relapsed or refractory multiple myeloma
No full textBladder Preservation Strategies in Muscle-invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group
No full textBACKGROUND AND OBJECTIVE: Patient-centric management necessitates providing care aligned with patients' values, preferences, and expressed needs. Therefore, critical assessment of bladder preservation therapies (BPTs) as alternatives to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) and practical recommendations on the optimal selection of patients for BPTs are needed urgently. METHODS: A global committee of bladder cancer experts was assembled to develop BPT recommendations for MIBC. Working groups reviewed the literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined based on discussions. Final recommendations achieved ≥75% agreement during the meeting, with further refinements through web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS: Patients with newly diagnosed MIBC should be offered evaluation in a multidisciplinary setting for consideration of BPTs. The main alternative to RC is trimodal therapy (TMT), and favorable prognostic factors for TMT include unifocal cT2 stage, lack of hydronephrosis, and no multifocal carcinoma in situ (CIS). Other options should be reserved for very select patients who are ineligible for or who decline TMT or RC after thorough consideration of benefits versus risks. These include partial cystectomy (PC) for urachal adenocarcinoma and PC or radical transurethral resection alone for solitary tumors amenable to resection with adequate margins and without concomitant CIS or histologic subtypes. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance on BPTs for MIBC
Metformin for patients with metastatic prostate cancer starting androgen deprivation therapy: a randomised phase 3 trial of the STAMPEDE platform protocol
No full textBACKGROUND: Metformin is a widely used anti-diabetic drug. Several studies have suggested that metformin has anticancer activity in some malignancies, including prostate cancer. Metformin might also mitigate the adverse metabolic effects of androgen-deprivation therapy (ADT). We hypothesised that metformin might improve survival in patients with metastatic hormone-sensitive prostate cancer and reduce metabolic complications associated with ADT. METHODS: The STAMPEDE multi-arm, multi-stage, randomised phase 3 trial recruited patients with high-risk locally advanced or metastatic adenocarcinoma of the prostate staged by conventional imaging with isotope bone and CT scanning. This publication reports findings for the most recent STAMPEDE research question, testing the addition of metformin to standard of care for non-diabetic (glycated haemoglobin [HbA1c] <48 mmol/mol [equivalent to <6·5%]) patients with metastatic disease with adequate renal function (glomerular filtration rate ≥45 ml/min/1·73 m(2)) and WHO performance status 0-2. This trial recruited from 112 hospitals in the UK and Switzerland to the STAMPEDE protocol. Patients were randomly allocated (1:1) to standard of care or standard of care plus metformin 850 mg twice daily. Random assignment was by telephone using minimisation with a random element of 20% (developed and maintained by the MRC Clinical Trials Unit at UCL), stratified for randomising hospital, age (<70 years vs ≥70 years), WHO performance status (0 vs 1 or 2), type of ADT, regular long-term use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs; yes vs no), pelvic nodal status (positive vs negative), planned radiotherapy (yes vs no), and planned docetaxel or androgen receptor pathway inhibitor (ARPI) use (docetaxel vs abiraterone, enzalutamide, or apalutamide vs none). Standard of care comprised ADT with or without radiotherapy and with or without docetaxel or ARPI. The primary outcome measure was overall survival, defined as the time to death from any cause, assessed in the intention-to-treat population. Safety was assessed in patients who started treatment. The trial is registered with ClinicalTrials.gov, NCT00268476 and ISRCTN, ISRCTN78818544. FINDINGS: Between Sep 5, 2016, and Mar 31, 2023, 1874 patients with metastatic disease were randomly allocated to standard of care (n=938) or standard of care plus metformin (n=936). The median patient age was 69 years (IQR 63-73) and the median PSA was 84 ng/mL (24-352). 1758 (94%) of 1874 patients were newly diagnosed with metastatic disease and 116 (6%) were diagnosed with metachronous relapsing disease. 1543 (82%) of 1874 patients received ADT plus docetaxel and 52 (3%) received abiraterone, enzalutamide, or apalutamide. The median time to most recent case report form follow-up was 60 months (IQR 49-72). 473 deaths were reported in the standard of care group; median survival was 61·8 months (IQR 29·7 to not reached). There were 453 deaths in the metformin group; median survival was 67·4 months (32·5 to not reached; HR 0·91, 95% CI 0·80-1·03; p=0·15). Grade 3 or worse adverse events were reported in 487 (52%) of 938 patients in the standard of care group and 523 (57%) of 921 patients in the standard of care plus metformin group. 61 (7%) patients in the standard of care group and 84 (9%) patients in the standard of care plus metformin group reported at least one grade 3 or worse gastrointestinal adverse event; all other body systems showed no difference in grade 3 adverse events. There were six drug-related deaths in the standard of care group and one in the standard of care plus metformin group. INTERPRETATION: We did not find significant evidence of an overall survival benefit of adding metformin to standard of care in the overall population of patients with metastatic hormone-sensitive prostate cancer. The side-effect profile of metformin was as expected and consisted mainly of diarrhoea. Adverse metabolic side-effects of ADT were significantly reduced in the metformin group compared with the standard of care group. FUNDING: Cancer Research UK, Prostate Cancer UK, and UK Research and Innovation Medical Research Council
Nanopore-based consensus sequencing enables accurate multimodal tumor cell-free DNA profiling
No full textShallow genome-wide cell-free DNA sequencing holds great promise for noninvasive cancer monitoring by providing reliable copy number alteration (CNA) and fragmentomic profiles. Single-nucleotide variations (SNVs) are, however, much harder to identify with low sequencing depth due to sequencing errors. Here, we present Nanopore Rolling Circle Amplification (RCA)-enhanced Consensus Sequencing (NanoRCS), which leverages RCA and consensus calling based on genome-wide long-read nanopore sequencing to enable simultaneous multimodal tumor fraction (TF) estimation through SNVs, CNAs, and fragmentomics. The efficacy of NanoRCS is tested on 18 cancer patient samples and seven healthy controls, demonstrating its ability to reliably detect TFs as low as 0.24%. In vitro experiments confirm that SNV measurements are essential for detecting TFs below 3%. NanoRCS provides an opportunity for cost-effective and rapid sample processing, which aligns well with clinical needs, particularly in settings where quick and accurate cancer monitoring is essential for personalized treatment strategies
Efficacy and toxicity of hypofractionated radiation therapy for patients with hematologic malignancies: a COVID-era ILROG collaborative report
No full textBACKGROUND AND PURPOSE: During the COVID19 pandemic, shorter radiation therapy (RT) courses were needed to minimize patient exposure, ensure staff safety, and conserve healthcare resources. In response, guidelines were published by the International Lymphoma Radiation Oncology Group (ILROG) to guide treatment of hematologic malignancies patients with hypofractionated radiation therapy (hRT) regimens. However, outcomes for these hypofractionated dose/fractionation regimens in terms of efficacy and toxicity are unknown. MATERIALS AND METHODS: In collaboration with ILROG, we performed a retrospective multinational, multicenter study. We included patients treated from 01 January 2020 to 01 September 2020 with hRT given according to the published ILROG guidelines or hRT given at > 3 Gy per fraction. We abstracted patient and treatment data from institutional databases. CTCAE v5.0 was used to grade toxicity. RESULTS: We included 219 patients from 8 different institutions treated with 255 RT courses. Median RT dose was 12 Gy (range 4-39) in a median of 3 fractions (range 1-13). Median follow up was 232 days, with 151 patients (69 %) alive at last follow up. Response within the RT field was assessed in 210 sites, and 127 sites (60 %) had a confirmed complete response. Maximal toxicities (per site) reported were Grade 1 (n = 48), Grade 2 (n = 25), Grade 3 (n = 3) and Grade 4 (n = 1). Grade 3/4 toxicities included dermatitis, pain, and hematologic toxicity. CONCLUSIONS: Treatment of hematologic malignancies patients with hRT was generally well tolerated with few unexpected toxicities. These data provide guidance for emergencies, and hRT may be useful and could be considered even in routine settings, especially for certain patient subgroups
Clinical impact of variations in laboratory measurements of growth hormone and insulin-like growth factor I on the classification of acromegaly disease activity status in the United Kingdom
No full textChallenges Facing Single-Handed Neuro-Oncologists and Smaller Centres in the UK: An Interview-Based Investigation with Proposed Solutions
No full textAIMS: Single-handed oncology practice occurs when only one clinician covers a particular tumour site in a department. There is no quantified evidence about experiences of single-handed practice or its impact in oncology. A team supported by the Tessa Jowell Brain Cancer Mission interviewed 35 neuro-oncologists in the United Kingdom (UK) to better understand the workload, challenges and support networks of single-handed neuro-oncologists compared with those of neuro-oncologists at larger centres. METHODS AND METHODS: Semi-structured virtual interviews were completed: January to May 2024. RESULTS: Thirty-five of 58 neuro-oncologists accepted an invitation to interview. Centres were categorised as those with one neuro-oncologist (single-handed): 7 interviews; two neuro-oncologists (dual-handed): 14 interviews; three or more neuro-oncologists (multihanded): 14 interviews. At the time of the study, there were 129 neuro-oncologists working at 52 centres within 29 multidisciplinary team (MDT) networks. Most neuro-oncologists covered more than one tumour site. Single-handed neuro-oncologists described challenges including access to peer review and cover for leave. Seven of ten neuro-oncologists who had been or currently were single-handed reported a negative impact on wellbeing. Respondents described inequity of access to multidisciplinary services geographically, with neuropsychology and neurology access more difficult in smaller centres. The mean number of clinical trials open at single-handed or dual-handed centres was less than one, compared with five at multi-handed centres. However, excellent collaborative and supportive networks and initiatives at a local, regional, and national level were described. CONCLUSION: Single-handed neuro-oncology practice may impact wellbeing, recruitment and retention. National research initiatives should consider ways to increase support for, and increase access to research in, single- and dual-handed centres
The incidence of breast cancer in ovarian cancer patients with BRCA mutations: a multicentre retrospective cohort study
No full textPhase 1 study of IMCnyeso, a T cell receptor bispecific ImmTAC targeting NY-ESO-1-expressing malignancies
No full textIMCnyeso, an immune mobilizing monoclonal T cell receptor against cancer (ImmTAC) bispecific (New York esophageal squamous cell carcinoma [NY-ESO]×CD3) T cell engager, targets an NY-ESO-1/L-antigen family member-1 isoform A (LAGE-1A) peptide presented by histocompatibility leukocyte antigen (HLA)-A∗02:01. In this phase 1 study, 28 HLA-A∗02:01+ patients with advanced NY-ESO-1/LAGE-1A-positive advanced tumors (n = 28) receive IMCnyeso weekly intravenously (dose range: 3-300 μg; 7 dose-escalation cohorts). The primary objective is to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D); additional objectives include preliminary anti-tumor activity, pharmacokinetics, immunogenicity, and pharmacodynamic changes. The study was terminated before fully enrolling dose escalation, and the MTD was not identified. There are no treatment-related discontinuations or deaths. The most common adverse events are grade 1/2 cytokine release syndrome and associated symptoms. Cytokine induction and transient lymphocyte count decreases are observed at doses 30-300 μg. At these doses, preliminary efficacy includes mixed response (2 patients) and a median overall survival of 12 months. IMCnyeso is well tolerated and, at doses ≥30 μg, induces pharmacodynamic changes consistent with T cell redirection. This study was registered at ClinicalTrials.gov (NCT03515551)