The Christie School of Oncology: Christie Research Publications Repository
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FLASH-induced DNA damage reduction measured in vitro correlates with effective oxygen depletion determined in silico: further support for oxygen depletion contributing to FLASH's reduced damage burden in vitro
No full textOBJECTIVES: FLASH irradiation demonstrates notable normal-tissue protective effects, including reduced damage in vitro. Radiochemical mechanisms proposed include radical-radical recombination and transient oxygen depletion (TOD), but the relative contributions remain unclear. This study compares FLASH-mediated DNA damage reduction in vitro with oxygen depletion for FLASH radiotherapy modelled in silico, to (i) investigate the contribution of TOD towards the reduced damage burden in vitro, and (ii) evaluate its contribution to the broader FLASH effect in vivo. METHODS: An in silico model was used to identify and compare the parameter space for FLASH-induced oxygen depletion in an in-vitro setup with experimental DNA damage reduction data, previously determined using the alkaline comet assay ex vivo. RESULTS: Correlation analysis revealed a strong relationship between model-predicted oxygen depletion and experimentally-observed DNA damage reduction (Spearman's = 0.87, P = 2 × 10-6; Pearson's = 0.85, P = 4 × 10-6). CONCLUSIONS: Findings support a significant role for TOD in the FLASH-induced reduction in damage in vitro at low oxygen tensions. However, parameter spaces identified, for both oxygen depletion in silico and DNA damage reduction in vitro, suggest that TOD may only partially contribute to the wider-ranging FLASH sparing effects in vivo. Further work is required to clarify this. ADVANCES IN KNOWLEDGE: Findings support TOD as a key mechanism for the reduced damage burden of FLASH in vitro. However, further work is required to demarcate the sparing effects of FLASH in vivo
Standard versus reduced-dose chemoradiotherapy in anal cancer (PLATO-ACT4): short-term results of a phase 2 randomised controlled trial
No full textBACKGROUND: Localised squamous cell carcinoma of the anus is treated with radical chemoradiotherapy. Cure rates are high, but treatment can result in substantial acute and long-term morbidity. We aimed to assess whether lower dose chemoradiotherapy maintains high local control rates in patients with early-stage disease, with the secondary aim of reducing toxicity. METHODS: ACT4 is a phase 2, prospective, multicentre, open-label, two-arm non-comparative, randomised, controlled trial, investigating reduced-dose intensity-modulated radiotherapy (rd-IMRT: 41·4 Gy in 23 fractions) in patients with early-stage anal cancer; T1-2 (≤4 cm) N0-NxM0. Eligible patients were at least 16 years of age, with an Eastern Cooperative Oncology Group performance status of 0-1. The primary outcome is 3-year loco-regional failure rates. Patients were randomly assigned 1:2 (with stratification by T stage, N stage, gender, HIV status, and randomising site) to standard-dose IMRT (sd-IMRT: 50·4 Gy in 28 fractions) or rd-IMRT with concurrent mitomycin and capecitabine chemotherapy. Here, we report the pre-planned, modified intention-to-treat analysis of secondary endpoints 6 months after treatment end-complete clinical response, compliance, patient-reported outcomes (EORTC QLQ-C30 and ANL27), and safety data. The trial is registered at the ISRCTN registry (ISRCTN88455282) and is ongoing but no longer recruiting. FINDINGS: 163 patients were recruited from 28 UK tertiary centres between April 24, 2017, and Dec 1, 2020. 160 patients were included in the primary analysis (sd-IMRT n=55; dr-IMRT n=105). Data on ethnicity were not collected. The median patient age was 66 years (IQR 58-72 years); 117 (73%) were female and 43 (27%) male; and 129 (94%) of 138 evaluable samples were p16 positive. Complete clinical responses at 6 months were 87% (46 of 53) for sd-IMRT and 92% (89 of 97) for rd-IMRT. Radiotherapy interruptions of 3 days or more occurred in 14 (26%) of 55 patients in sd-IMRT and 16 (15%) of 105 patients in rd-IMRT. Chemotherapy modifications occurred in 27 (49%) of 55 patients in sd-IMRT and 39 (37%) of 105 patients in rd-IMRT. Grade 3 or worse acute toxicity was reported in 25 (46%) of 55 patients in sd-IMRT and 37 (35%) of 105 patients in rd-IMRT. The most common grade 3 or worse adverse events were radiation dermatitis (seven [13%] of 55 in sd-IMRT and ten [10%] of 105 in rd-IMRT), and diarrhoea (four [7%] of 55 in sd-IMRT and nine [9%] of 105 in rd-IMRT). Serious adverse events occurred in eight (15%) of 55 patients in sd-IMRT and ten (10%) of 105 patients in rd-IMRT. Patient-reported outcomes for most issues deteriorated at the end of treatment and resolved to baseline by 6 weeks in both groups. Poorer sexual function for men and women was observed at 6 months following sd-IMRT. INTERPRETATION: Good 6-month complete clinical responses rates were seen in both groups. Early results suggest rd-IMRT is well tolerated with oncological outcomes maintained. 3-year locoregional failure rates are awaited. FUNDING: Cancer Research UK and Stand Up to Cancer
Real-world outcomes of second-line carboplatin plus pemetrexed after first-line osimertinib in EGFR-mutant advanced NSCLC: An international multicentre cohort study
No full textBACKGROUND: First-line osimertinib is one of the standards of care for EGFR-mutant advanced non-small cell lung cancer (NSCLC), but most patients eventually progress. After progression, carboplatin plus pemetrexed remains the most widely used second-line therapy, yet robust real-world data in this setting are scarce. METHODS: We conducted a retrospective multicentre cohort study from four European countries in patients with EGFR-mutant advanced NSCLC who received second-line carboplatin plus pemetrexed following osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), safety, and exploratory analyses of associations between baseline factors and outcomes. RESULTS: We identified a total of 252 patients. Median PFS and OS were 5.3 months (95 % CI 4.7-5.9) and 9.6 months (95 % CI 8.2-11.1), respectively. The ORR was 40.7 %, with grade ≥ 3 adverse events reported in 19.3 % of patients. ECOG ≥ 2 and liver metastases independently predicted worse OS; ECOG ≥ 2 and a history of smoking were associated with shorter PFS. Early progression on osimertinib (<18 months) correlated with shorter OS (8.3 vs 14.7 months; HR 1.66, P = 0.005). Neither the timing between osimertinib discontinuation and chemotherapy initiation nor EGFR mutation subtype influenced efficacy. CONCLUSIONS: In real-world European practice, second-line carboplatin plus pemetrexed provides modest benefit post-osimertinib, with outcomes strongly influenced by ECOG status, metastatic burden, and prior osimertinib duration. Despite a clinically diverse cohort, outcomes were consistent with historical reports. These data help define benchmarks for future trials and underscore the need for personalised sequencing strategies, particularly in high-risk subgroups
Localised non-small cell lung cancer: patient characteristics and radical radiotherapy outcomes according to KRAS mutation status
No full textAnalysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification
No full textClinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification
Sotorasib versus docetaxel for previously treated KRAS G12C-mutated non-small-cell lung cancer: a plain language summary
No full textPatients' treatment experiences and involvement in treatment decision-making in metastatic colorectal cancer: Results of a patient survey in Europe and Canada
No full textNY-ESO-1 targeting in non-small cell lung cancer: promise and challenges of letetresgene autoleucel
No full textThe use of radiotherapy in the cure of different cancers - further results from the FORTY (favourable outcomes from radiotherapy) project
No full textAIMS: Overall, almost 40% of patients surviving 5 years are estimated to have received radiotherapy (RT). The utilisation of RT for individual tumour types in 5-year survivors was examined. MATERIALS AND METHODS: Patient-level data on RT utilisation in cancer patients in England were analysed. Patient, tumour, and treatment event data were obtained for the 5-year period 2009-2013, together with 5-year individual patient survival (to 2018 ie pre Covid-19 pandemic). All tumour sites (excluding C44) and ages were included. 5-year survivors (n = 537,970) were divided into 22 tumour sites, plus a category of 'Other' (5% of patients) where tumour site was unknown, leaving 508,753 with known tumour site diagnosis. RESULTS: Overall cancer-specific 5-year survival was 52%. Of the 5-year survivors with definite tumour site diagnosis, 200,269 (39%) received RT. Breast cancer accounted for 50% of RT patients, prostate 24%. 75% of breast cancer 5-year survivors received RT, 65% of head and neck patients, 49% of rectum, 49% of central nervous system (CNS), and 43% of prostate patients. 25% of lymphoma 5-year survivors received RT. Only 29% of lung cancer 5-year survivors received RT. In 6 tumour sites (pancreas, leukaemia, kidney, colon, ovary, and melanoma), <5% of patients (n = 3981, 2%) received RT. Excluding these, 50% of 5-year survivors received RT. CONCLUSIONS: RT contributes significantly to 5-year survival. RT was delivered to 50% of 5-year survivors in tumour sites where RT is utilised for ≥5% of patients. Including the additional tumour sites where RT is used rarely, RT was delivered to almost 40% of patients. We recommend that this exercise is repeated regularly. This 50% figure emphasises the importance of RT. It is critical for service planning and public health messaging. It should be noted for the development of the new cancer plan
Impact of prostate radiotherapy on survival outcomes in patients with metastatic castration-sensitive prostate cancer: a meta-analysis of randomized phase 3 clinical trials
No full textBACKGROUND AND OBJECTIVE: Despite advancements in systemic therapy for metastatic castration-sensitive prostate cancer (mCSPC), the survival benefits of radiotherapy (RT) remain uncertain. This meta-analysis evaluates whether addition of RT to the standard of care (SOC) improves radiographic progression-free (rPFS) and overall (OS) survival, with a focus on systemic therapy intensification. METHODS: A targeted review of three phase 3 trials (HORRAD, STAMPEDE, and PEACE-1) was conducted to assess the role of prostate RT in mCSPC. Two reviewers evaluated study quality, and a meta-analysis using a random-effect model (Review Manager v5.3) analyzed rPFS and OS as the primary outcomes (hazard ratio [HR] with 95% confidence interval [CI]). Subgroup analyses focused on low-volume disease as per the CHAARTED criteria, with heterogeneity assessed via I(2) and significance set at p < 0.05. KEY FINDINGS AND LIMITATIONS: This meta-analysis of 3665 patients from HORRAD, STAMPEDE, and PEACE-1 found that addition of RT to SOC did not improve rPFS or OS in the overall mCSPC population. However, in low-volume disease, RT with SOC and abiraterone acetate (AA) improved rPFS significantly (HR = 0.65, 95% CI: 0.45-0.93; p = 0.02) without an OS benefit. Limitations include pooled data, patient heterogeneity, and variations in treatments and follow-up. CONCLUSIONS AND CLINICAL IMPLICATIONS: Prostate RT does not improve rPFS or OS in the overall mCSPC population, but offers a significant rPFS benefit in low-volume disease when combined with SOC and AA. Although no OS improvement was observed, the synergy between AA and RT underscores the value of RT for carefully selected patients. Further prospective studies are needed to refine treatment strategies and improve outcomes