The Christie School of Oncology: Christie Research Publications Repository
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Hydroxychloroquine in combination with platinum doublet chemotherapy as first-line treatment for extensive-stage small cell lung cancer (Study 15): a randomised phase II multicentre trial
No full textBACKGROUND: Most patients with small-cell lung cancer (SCLC) present with extensive-stage (ES) disease and have a poor prognosis despite achieving high initial response rates to platinum-based doublet chemotherapy. This study evaluated whether adding hydroxychloroquine (HCQ) to chemotherapy could improve outcomes. METHODS: This was a randomised multicentre phase II trial. Eligible patients had untreated ES-SCLC, a performance status 0-2 and measurable disease. Patients were randomly assigned (1:1 ratio) to HCQ (400 mg orally twice daily) plus carboplatin-gemcitabine or carboplatin-etoposide alone. Chemotherapy was administered for up to six cycles, with HCQ given concurrently and then as single agent for up to 30 months. Primary endpoint was PFS, aiming for a hazard ratio (HR) of 0.70. RESULTS: 72 patients were randomised (36 HCQ+chemotherapy and 36 chemotherapy alone). Median HCQ treatment duration was 4.4 months. HCQ did not improve PFS (HR 1·12 95 %CI 0·69-1.84; p = 0·64), with a median of 5.7 months (HCQ+chemotherapy) versus 6.2 months (chemotherapy). The corresponding median OS were 8.9 and 10.2 months (HR 0.83, 95 %CI 0.48-1.45, p = 0.52). Fewer patients in the HCQ arm completed four cycles of chemotherapy due to adverse events (64 % vs. 81 %). Grade ≥ 3 adverse events were higher in the HCQ+chemotherapy arm (83.3 % vs. 27.8 %), primarily anaemia, neutropenia, and thrombocytopenia, partly due to the initially higher gemcitabine dose used CONCLUSIONS: Combining HCQ with platinum doublet chemotherapy did not improve PFS or OS outcomes for ES-SCLC, resulting in more patients stopping chemotherapy due to increased adverse events. When considered alongside other randomised studies of HCQ in cancer, the evidence collectively indicates a limited role for HCQ as a therapeutic option
A hypoxia-based prognostic Bayesian network for high-risk prostate cancer patients treated with radiotherapy
No full textChromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
No full textChromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q ('chr. 21amp') in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target
A novel multimodality anthropomorphic phantom enhances compliance with quality assurance guidelines for magnetic resonance imaging in radiotherapy
No full textBACKGROUND AND PURPOSE: The use of magnetic resonance imaging (MRI) for radiotherapy (RT) simulation has grown, prompting quality assurance (QA) guidelines by the Institute of Physics and Engineering in Medicine (IPEM) and the American Association of Physicists in Medicine (AAPM). This study compares a novel multimodality anthropomorphic phantom to an American College of Radiology (ACR) phantom for a subset of these MRI-specific QA tests in RT. MATERIALS AND METHODS: A novel 3D-printed multimodality head-and-neck anthropomorphic phantom was compared to an ACR large MRI phantom. IPEM and AAPM-recommended QA tests were conducted, including informatics/connectivity/data transfer, MRI-CT registration, end-to-end QA, and signal-to-noise ratio (SNR)/percentage integral uniformity (PIU) assessments using RT accessories. RESULTS: Both phantoms were suitable for informatics/connectivity/data transfer. In MRI-CT registration, no errors were found; the ACR phantom offered more quantitative landmarks, while the anthropomorphic phantom provided limited structures. Both phantoms achieved target registration errors (TREs) below 0.97 mm and dice similarity coefficient (DSC) values above 0.9, meeting guidelines. For end-to-end QA, the anthropomorphic phantom facilitated dose measurements of 1.994 Gy versus a calculated 2.01 Gy (-0.8 %). SNR and PIU assessments showed higher values in radiology setups compared to RT setups for both phantoms. CONCLUSIONS: Multimodality anthropomorphic phantoms compatible with dosimetric equipment allow realistic end-to-end QA, unlike the ACR phantom. While the ACR phantom is suitable for informatics and MRI-CT registration, anthropomorphic phantoms better represent clinical scenarios. For comprehensive QA, both ACR and anthropomorphic phantoms are required. Additionally, large field-of-view (FOV) phantoms are crucial for evaluating large FOV MRI distortions
Daratumumab for PRCA after HCT: study and practical considerations from the EBMT transplant complications working party
No full textPure red cell aplasia (PRCA) is a relevant complication after ABO-mismatched allogeneic hematopoietic cell transplantation (HCT). No standard treatment exists, and practice is heterogenous. In this study, we took advantage of an international collaboration to describe characteristics and outcomes of patients receiving daratumumab for PRCA following first allogeneic HCT. We identified 45 patients meeting these criteria (median patient age, 56 years). The median time from HCT to PRCA was 55 days (IQR, 36-116) and all patients were transfusion-dependent at time of daratumumab start. Daratumumab was first-line treatment in 16 patients (36%), most patients (67%) received daratumumab intravenously, and median time from PRCA diagnosis and daratumumab start was 88 days (IQR, 59-219). Incidence of transfusion independence was 69% (95% confidence interval [CI], 52-80%) at 6 months and 80% (95% CI, 62-90%) at 12 months. Incidences of hemoglobin and reticulocyte recoveries were respectively 56 and 78% at 6 months and 65 and 83% at 12 months. Survival at 12 months was 81%, and of 8 deaths, 7 were GVHD- or infection-related. One death was associated with hemolytic anemia. This is the first international and largest study on the use of daratumumab for PRCA after allogeneic HCT, showing high response rates superior to that reported for other treatments. Seven incidents of severe adverse events (mostly infections) underscore the need for close monitoring, proactive management, and comparative studies to determine the role for daratumumab for PRCA. Last, based on these data and a comprehensive literature review, we provide practical consideration for modern PRCA treatment
Real-world experience of Molecular Tumour Boards for clinical decision-making for cancer patients
No full textMolecular Tumour Boards (MTBs) play a crucial role in interpreting genomic results and providing treatment recommendations. We investigated the real-world impact of MTBs on clinical decision-making by surveying health care professionals (HCPs) across the UK; 44 participants from 11 MTBs took part in the study. 97.7% of respondents felt that MTBs increased awareness of available clinical trials matched to genomic alterations, 84% reported more confidence in interpreting genomic data, and 95.4% valued MTBs as educational. Hurdles to the discussion at MTBs included frequency and capacity of MTBs (ctDNA), sample collection and laboratory turnaround time (Tissue samples). One-third of respondents encountered challenges attending MTBs regularly due to workload. The survey highlighted areas for optimisation, such as meeting efficiency, rapid molecular analysis turnaround time, reliable trial matching tools, and ensuring MTBs are included in HCP's job plans
Neoadjuvant PARP inhibitor scheduling in BRCA1 and BRCA2 related breast cancer: PARTNER, a randomized phase II/III trial
No full textPoly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m(2), weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials
Tarlatamab in small-cell lung cancer after platinum-based chemotherapy
No full textBACKGROUND: Tarlatamab, a bispecific delta-like ligand 3-directed T-cell engager immunotherapy, received accelerated approval for the treatment of patients with previously treated small-cell lung cancer. Whether tarlatamab is more effective than chemotherapy in the treatment of patients whose small-cell lung cancer has progressed during or after initial platinum-based chemotherapy is not known. METHODS: We conducted a multinational, phase 3, open-label trial to compare tarlatamab with chemotherapy as second-line treatment in patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy. Patients were randomly assigned to receive tarlatamab or chemotherapy (topotecan, lurbinectedin, or amrubicin). The primary end point was overall survival. Key secondary end points were investigator-assessed progression-free survival and patient-reported outcomes. Results of the prespecified interim analysis (data-cutoff date, January 29, 2025) are reported. RESULTS: A total of 509 patients were randomly assigned to receive tarlatamab (254 patients) or chemotherapy (255 patients). Treatment with tarlatamab resulted in significantly longer overall survival than chemotherapy (median, 13.6 months [95% confidence interval {CI}, 11.1 to not reached] vs. 8.3 months [95% CI, 7.0 to 10.2]; stratified hazard ratio for death, 0.60; 95% CI, 0.47 to 0.77; P<0.001). Tarlatamab treatment also had a significant benefit with respect to progression-free survival and cancer-related dyspnea and cough as compared with chemotherapy. The incidence of adverse events of grade 3 or higher was lower with tarlatamab than with chemotherapy (54% vs. 80%), as was the incidence of adverse events resulting in treatment discontinuation (5% vs. 12%). CONCLUSIONS: Treatment with tarlatamab led to longer overall survival than chemotherapy among patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy. (Funded by Amgen; DeLLphi-304 ClinicalTrials.gov number, NCT05740566.)
