The Christie School of Oncology: Christie Research Publications Repository
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Intra-voxel incoherent motion biomarker repeatability in healthy volunteers and sensitivity to chemoradiotherapy-induced changes in patients with uterine cervical cancer
No full textIntra-voxel incoherent motion (IVIM) biomarkers require validation for translation into clinical practice. This work evaluates repeatability and sensitivity to treatment of IVIM biomarkers in the uterine cervix, and assesses suitability of the IVIM model. Six healthy volunteers underwent two scans to evaluate repeatability. Eight patients with stage IIB-IVA cervical squamous cell carcinoma were scanned pre-treatment, and at weeks 3 and 5 into treatment. IVIM and apparent diffusion coefficient (ADC) model fits were compared using the corrected Akaike information criterion (AIC(c)). Tissue diffusion coefficient, D, perfusion signal fraction, f, and p (IVIM), the fraction of voxels better described by the IVIM model, were measured. ADCs calculated with minimum b-values of 0 (ADC (b) (0)) and 150 s/mm(2) (ADC (b) (150)) were compared with f to assess sensitivity to perfusion. Model preference maps qualitatively reflected physiological characteristics of different tissues. Healthy cervix within-subject coefficients of variation were 8% (D), 15% (f), and 12% (p (IVIM)). Tumour D increased from baseline to week 3 (p = 0.02). Baseline p (IVIM) showed large inter-patient variability (range: 0.13-0.68), which persisted throughout treatment. The difference between ADC (b) (0) and ADC (b) (150) correlated with f (repeated measures correlation coefficient r=0.76, p = 0.002). IVIM biomarkers are repeatable in healthy cervix tissue. Tumour D is sensitive to early therapy-induced changes. The IVIM model is not favoured in all tumour voxels, indicating the presence of heterogeneous tumour microenvironments. ADC calculated using b = 0 s/mm(2) can be influenced by a perfusion-dependent bias. Not all tumour voxels are best described by the IVIM model. ADC in cervical tumours can suffer from perfusion-dependent bias
Molecular targeted maintenance therapy versus standard of care in advanced biliary cancer: an international, randomised, controlled, open-label, phase III umbrella trial (SAFIR-ABC10-Precision Medicine)
No full textBACKGROUND: Advanced biliary tract cancers (ABCs) are a heterogeneous group of rare malignancies of the bile ducts and gall-bladder with a poor prognosis and limited treatment options. Cisplatin-gemcitabine (CISGEM) chemotherapy plus immunotherapy (durvalumab or pembrolizumab) is the current first-line standard of care (1L-SoC). ABCs frequently harbour actionable molecular alterations that suggest a high potential for benefit from molecular targeted therapies (MTTs). However, the assessment of potential first-line MTT treatments is hindered by the scarcity of ABCs harbouring a specific alteration and the time required to carry out tumour molecular profiling. MATERIALS AND METHODS: We detail here the design of SAFIR-ABC10, an international, randomised, phase III umbrella trial comparing the efficacy of sequential matched targeted therapy after four cycles (12 weeks) of 1L-SoC versus continued 1L-SoC in patients with ABC and an actionable molecular alteration [European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) tier I or II]. The primary study endpoint is progression-free survival. Besides initial tumour and circulating DNA next-generation sequencing analysis, sequential blood and tumour sampling will be carried out to identify biomarkers of prognosis, response and acquired resistance. PERSPECTIVES: SAFIR-ABC10 is, to our knowledge, the first randomised, umbrella trial assessing the concept of precision medicine in ABC, the ideal setting for addressing this question with a high rate of targetable alterations
Posterior reversible encephalopathy syndrome (PRES) following fruquintinib in a normotensive patient with metastatic colorectal cancer: a case report
No full textWe report a rare case of posterior reversible encephalopathy syndrome (PRES) following fruquintinib treatment in a 71-year-old female with metastatic colorectal adenocarcinoma harbouring a KRAS G12D mutation. The patient had previously undergone multiple lines of chemotherapy and surgical resections with stable disease before receiving fruquintinib under compassionate access. After two cycles, she developed headaches and acute encephalopathy. MRI confirmed PRES without associated hypertension. Fruquintinib was discontinued, and the patient made a full neurological recovery. This case highlights a rare but significant toxicity of anti-vascular endothelial growth factor (VEGF) therapy in the colorectal cancer setting and underscores the importance of early radiological evaluation in suspected PRES
Efficacy and safety of avutometinib ± defactinib in recurrent low-grade serous ovarian cancer: primary analysis of ENGOT-OV60/GOG-3052/RAMP 201
No full textPURPOSE: This study evaluated the efficacy and safety of avutometinib (rapidly accelerated fibrosarcoma/mitogen-activated extracellular signal-regulated kinase [MEK] clamp) alone or in combination with defactinib (focal adhesion kinase inhibitor) in patients with recurrent low-grade serous ovarian cancer (LGSOC). METHODS: In this phase II, open-label study, patients with recurrent, measurable LGSOC after ≥1 line of platinum chemotherapy were stratified by tumor Kirsten rat sarcoma virus homolog (KRAS) mutation status and randomly assigned to oral avutometinib 4.0 mg two times per week monotherapy or avutometinib 3.2 mg two times per week in combination with oral defactinib 200 mg two times per day. The combination was selected as the go-forward regimen for expansion. The primary end point was objective response rate (ORR) by blinded independent central review. RESULTS: A total of 115 patients received the go-forward combination regimen. Patients had a median of 3 (range, 1-9) prior lines of therapy, including hormonal (86%), bevacizumab (51%), and MEK inhibitor (22%). Confirmed ORR was 31% (95% CI, 23% to 41%) with a median duration of response of 31.1 months (95% CI, 14.8 to 31.1). ORR was 44% in KRAS-mutant and 17% in KRAS wild-type cohorts. The median progression-free survival was 12.9 months (95% CI, 10.9 to 20.2) overall and 22.0 months (95% CI, 11.1 to 36.6) and 12.8 months (95% CI, 7.4 to 18.4) in KRAS-mutant and wild-type cohorts, respectively. The most frequent grade ≥3 treatment-related adverse events (AEs) were elevated creatine phosphokinase (24%), diarrhea (8%), and anemia (5%). Ten percent of patients discontinued because of AEs. CONCLUSION: The efficacy and safety profile of avutometinib in combination with defactinib support this combination as a potential standard of care for recurrent LGSOC. A randomized phase 3 study of avutometinib and defactinib versus investigator's choice of therapy for women with recurrent LGSOC is currently enrolling (RAMP301; ClinicalTrials.gov identifier: NCT06072781)
Metabolic benefits of adding metformin to androgen deprivation therapy for patients with metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Results from the STAMPEDE metformin trial
No full textComparison of target volume changes in T2W and DWI with ADC and cumulative delivered dose in muscle invasive bladder cancer
No full textRucaparib for maintenance treatment of platinum-sensitive, recurrent ovarian carcinoma: Final results of the phase 3, randomized, placebo-controlled ARIEL3 trial
No full textBACKGROUND: In ARIEL3, rucaparib maintenance significantly improved progression-free survival (PFS; primary endpoint) and long-term follow-up (LTFU) outcomes (including PFS2: time to disease progression on subsequent therapy or death) versus placebo in patients with recurrent, platinum-sensitive ovarian cancer. Here we report the final analysis of overall survival (OS; key secondary endpoint), LTFU outcomes, and safety. METHODS: OS and updated LTFU efficacy outcomes were analyzed (data cutoff date: April 4, 2022) across three nested populations (BRCA-mutated, homologous recombination deficient [HRD], and intention to treat [ITT]). RESULTS: Patients were randomized 2:1 to rucaparib (600 mg BID; n = 375) or placebo (n = 189). Median follow-up was 77.0 months. 168 patients in the placebo arm received subsequent treatment; of these, 77 (46 %) received a poly(ADP-ribose) polymerase inhibitor-containing treatment. Median OS from randomization post chemotherapy for rucaparib vs placebo was 45.9 vs 47.8 months (HR 0.83, 95 % CI 0.58-1.19) for the BRCA-mutated population; no OS benefit was found with rucaparib in the HRD and ITT populations. Median PFS2 for rucaparib vs placebo was 26.1 vs 18.4 months (HR 0.67, 95 % CI 0.48-0.94) for the BRCA-mutated population. Rucaparib numerically improved PFS2 and other LTFU outcomes versus placebo in the HRD and ITT populations. Safety was consistent with prior reports; myelodysplastic syndrome and/or acute myeloid leukemia occurred in 4 % and 3 % of patients in the rucaparib and placebo arms, respectively. CONCLUSIONS: OS was similar between treatment arms. PFS benefit with rucaparib was maintained through the subsequent therapy line. These data support rucaparib as maintenance treatment for recurrent ovarian carcinoma
Repositioning Radiation Oncology at the centre of integrated oncology care: A manifesto of the European Society for Radiotherapy and Oncology (ESTRO)
No full textModern oncology increasingly relies on integrated, multimodality care, yet radiation oncology remains undervalued in strategic frameworks despite its central therapeutic role. This ESTRO manifesto calls for a repositioning of radiation oncology as a core discipline in cancer care, scientifically, clinically, and politically. The field now extends beyond beam delivery to encompass systemic therapy integration, personalised strategies based on biology and imaging, and active participation in clinical decision-making and guideline development. Radiation oncology contributes to treatment sequencing, synergistic combinations, and innovation in areas such as radioligand therapy and artificial intelligence. ESTRO's initiatives, including education, research networks, and oncopolicy engagement, underscore the discipline's broad scope and societal value. Strategic partnerships with Pharma and MedTech, alongside a renewed emphasis on equitable access, are essential to sustaining progress. ESTRO invites all stakeholders to recognise radiation oncology as fundamental to the design, delivery, and evolution of modern cancer therapy