The Christie School of Oncology: Christie Research Publications Repository
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A Systematic Review of Global Pathways for, and Barriers and Enablers to, Clinical Academic Training in Radiation Oncology
No full textDefactinib with avutometinib in patients with solid tumors: the phase 1 FRAME trial
No full textUse of signal transduction inhibitors as single agents to treat cancer leads to resistance because of the plasticity of intracellular signaling, and combination therapy can overcome this. We describe the first-in-human trial of avutometinib (RAF-MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors. The trial met its primary endpoint and recommended a phase 2 dose and schedule. The recommended phase 2 dose and schedule for a 28-day cycle was determined to be avutometinib 3.2 mg once a day, twice weekly (Monday and Thursday or Tuesday and Friday), and defactinib 200 mg twice a day, seven days a week. Both drugs were administered orally on a 3 weeks 'on' and 1 week 'off' basis. The pharmacokinetics and pharmacodynamics were consistent with previous reports of avutometinib and defactinib used as single agents. Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4-63.1) and a median progression-free survival of 20.1 months (95% confidence interval 11.2-43.9) in patients with low-grade serous ovarian cancer. This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820
Identifying the optimal time point for adaptive re-planning in prostate cancer radiotherapy to minimise rectal toxicity using normal tissue imaging biomarkers
No full textBACKGROUND AND PURPOSE: Adaptive radiotherapy (ART) in prostate cancer (PCa), although not yet standard practice, is typically triggered by inter-fractional anatomical changes that emerge progressively during treatment. This study investigates whether radiomics extracted before and during treatment can identify the optimal time point for re-planning, with the goal of reducing late rectal bleeding. MATERIALS AND METHODS: This study included 187 PCa patients from the single-centre, prospectively collected VoxTox dataset (UK-CRN-ID-13716), treated with image-guided radiotherapy using TomoTherapy and daily MVCT. Patients received either 74 Gy in 37 fractions (N = 110) or 60 Gy in 20 fractions (N = 77). Radiomic features were extracted from pre-treatment planning CTs and daily MVCTs. Grade ≥ 1 rectal bleeding was assessed at 2 years post-treatment using CTCAE v4.03. Two analysis strategies were employed: a separate analysis, where weekly features were evaluated independently; and a cumulative analysis, which progressively incorporated features from previous weeks. Logistic regression models with elastic net penalty were trained and evaluated using AUC. RESULTS: In both groups, week 1 provided the highest standalone predictive performance (test AUC = 0.766 for 74 Gy; 0.734 for 60 Gy). In the cumulative analysis, week 3 was optimal for the 74 Gy group (test AUC = 0.767), balancing performance and timing. For the 60 Gy group, week 1 remained optimal but suffered from reduced generalisability (test AUC = 0.643). CONCLUSIONS: Radiomic analysis of daily imaging can support early, proactive ART in PCa, offering a personalised strategy to reduce late rectal bleeding beyond conventional anatomy-based approaches
Retrospective review of patient factors impacting free-breathing respiratory motion magnitude for MR-guided radiotherapy
No full textPatient factors may influence motion management strategy selection for abdominal stereotactic ablative radiotherapy (SABR). This retrospective evaluation investigated the impact of body mass index (BMI), sex, and cirrhosis in 16 patients imaged with cine-magnetic resonance imaging (MRI) on a 1.5 T magnetic resonance linear accelerator (MR Linac). Male patients, those with cirrhosis, and higher BMI tended to exhibit greater motion magnitude, although this was not statistically significant, suggesting that these patients should be prioritised for motion management strategies. Further investigation in larger cohorts is warranted to confirm these trends and guide personalised motion management in abdominal radiotherapy
Systematic review of facial deformation following paediatric head-and-neck radiotherapy: a call or standardised outcomes and dose-response evidence
No full textBleximenib in combination with intensive chemotherapy: A phase 1b study in newly diagnosed Acute Myeloid Leukemia with KMT2A or NPM1 alterations
No full textA Response to the Letter to the Editor: 'Durable Benefit Beyond Response: Reinterpreting Amivantamab Efficacy in METex14 NSCLC Subgroups'
No full textHead and neck and skin (HNS) GEC-ESTRO and BRAPHYQS working groups joint critical review of the use of rhenium-188 in dermato-oncology
No full textNon-melanoma skin cancers are increasing globally, prompting the need for innovative, non-invasive treatment approaches. Radioactive rhenium ((188)Re) paste has emerged as an open-source radiation-based modality in dermato-oncology, offering a novel alternative to conventional radiotherapy and brachytherapy. In this review, a systematic literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar for studies published over the past 20 years. Data were extracted from case series, pilot studies, and clinical trials, with particular emphasis on response rates, dosimetric parameters, and treatment-associated toxicity. Findings from approximately 240 patients demonstrated complete response rates ranging from 86 % to 100 % after one or two treatment applications, while dosimetric analyses revealed a rapid dose fall-off that effectively confines the therapeutic effect to a tissue depth of 2-3 mm, with most adverse effects being mild and transient. Notably, (188)Re differs from conventional brachytherapy (specifically high-dose-rate modality) due to its open-source application and unique dosimetric profile. The use of (188)Re in clinical practice mandates a highly specialized, multidisciplinary team, including radiation oncologists, nuclear medicine specialists, and experienced medical physicists, and strict quality assurance protocols, thereby limiting its application to carefully selected cases. Although (188)Re therapy offers a promising alternative for the treatment of superficial skin cancers, its distinct clinical and dosimetric characteristics warrant further randomized studies with extended follow-up to validate its efficacy and refine patient selection criteria under rigorous multidisciplinary oversight
A single centre experience of patients with rare cancers referred for early phase clinical trials
No full textBACKGROUND: Cancers affecting < 6/100,000/year are classified as rare, but they account for up to 25% of all cancers and are associated with worse 5-year survival than common cancers. Early-phase clinical trials (EPCTs) may represent a viable treatment option for patients with rare cancers as they have evolved significantly with novel designs and the increasing use of precision medicine. METHODS: A retrospective study of patients with rare cancers referred to a large EPCT team at a UK specialist centre over 5 years (2016-2020) was conducted. Patient demographics, medical and oncological history, genomic variants, EPCT participation, responses and survival outcomes were analysed. RESULTS: In total, 240 patients with rare cancers were included. The mean age at diagnosis was 51.7 years (range 16-84), 54.2% of the patients were female. The most frequent rare cancers originated from the digestive system (27.1%), female genital tract (20%) and head and neck (H + N) (18.3%). Molecular profiling was offered to 45.5% of the population, median number of gene alterations was 3 per patient (range 1-20) while actionable gene alterations were reported in 60.2% (n = 50) of those with identified gene aberrations. Fifty-one patients participated in EPCTs, with 39.2% achieving SD and 11.8% PR. Median PFS for trial participants was three months (95% CI 1.12 - 4.88) while median OS in the trial patients was 16 months (95% CI 9.10 - 22.90) compared to 7 months for non-trial participants (95% CI 5.50 - 8.51). Finally, poor Royal Marsden Hospital (RMH) prognostic score (2-3) was correlated with worse survival when controlling for age and sex (HR 1.714, 95% CI 1.19 - 2.46, p = 0.004). CONCLUSIONS: Participation of patients with rare cancers in EPCTs may be associated with a survival benefit and lead to the development of new treatments for these patients. Moreover, expanded use of precision medicine is paramount as it can inform targeted treatment selection in this heterogenous group