Royal Marsden NHS Foundation Trust

In the PACE-B study, a nonrandomized comparison of toxicity outcomes between stereotactic body radiation therapy (SBRT) platforms revealed fewer urinary side effects with CyberKnife (CK) compared with conventional linac (CL) SBRT. This analysis compares baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts in PACE-B, aiming to provide insight into possible reasons for differing toxicity outcomes between the platforms. Dosimetric parameters for the surrogate urethra (SU), contoured urethra, bladder, bladder trigone (BT), and rectum were extracted from available computed tomography planning scans of PACE-B SBRT patients. The SU and BT were retrospectively delineated. Dose levels analyzed included maximum point dose (Dmax), D2, D50, and D95, where D(n) represents the dose (Gy) to (n)% of the structure. Baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts were compared using Mann-Whitney U tests, t tests, and χ2 tests. Of the 414 patients who received SBRT, 169 (41%) were treated with CK-SBRT and 245 (59%) with CL-SBRT, with dosimetric parameters available for 94% of patients (390/414). There was a nonstatistically significant trend toward more low-risk prostate cancer in the CK-SBRT cohort (12% vs 6% P = .02 [nonsignificant]). Margins were similar between platforms, except posteriorly, where CK-SBRT had smaller margins. CK-SBRT plans had significantly higher median SU Dmax (45.9 Gy vs 42.8 Gy, P < .0001), D2%, and D50% compared with CL-SBRT plans. Additionally, CK-SBRT plans had significantly higher median BT Dmax (43.4 Gy vs 41.6 Gy, P < .0001), D2%, and D95%, as well as higher median bladder Dmax, D50%, and D95%. CK-SBRT plans had lower median rectal D2% (35.5 Gy vs 36.0 Gy, P < .0001) but higher rectal D50% and D95%. Although the CK-SBRT cohort showed lower urinary toxicity, the planned doses to urinary substructures were actually higher, likely due to heterogeneous dose planning. Factors like intrafraction tracking or other confounding variables may explain the differences in toxicity outcomes between the treatment platforms.

Amivantamab is an EGFR-MET bispecific antibody approved as an intravenous formulation for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Intravenous delivery is frequently associated with infusion-related reaction (IRRs), which require adopting slow infusion rates and splitting the first dose over 2 days. The PALOMA study assessed the safety and feasibility of subcutaneous amivantamab administration and identified the formulation and recommended phase II doses (RP2Ds) for multiple dosing schedules. PALOMA is a phase Ib dose-escalation study in 158 participants with advanced solid malignancies. Primary objectives included pharmacokinetics, safety, and determining RP2Ds for every-2-week (Q2W), every-3-week (Q3W), and every-4-week (Q4W) administration. The safety profile of subcutaneous amivantamab was largely consistent with intravenous monotherapy; most common toxicities reflected on-target EGFR/MET inhibition. Subcutaneous amivantamab resulted in meaningfully shorter administration time (≤ 10 minutes vs. 2.3 hours for intravenous beyond cycle 3) and lower incidence and severity of IRRs versus historical intravenous data, which eliminates the need for split-dose administration. Pharmacokinetic analyses and population pharmacokinetic modeling/simulation were used to estimate subcutaneous amivantamab RP2Ds of 1600 mg (2240 mg, ≥ 80 kg), 2400 mg (3360 mg, ≥ 80 kg), and 3520 mg (4640 mg, ≥ 80 kg) for Q2W, Q3W, and Q4W schedules, respectively. The observed efficacy was consistent with intravenous amivantamab monotherapy. Subcutaneous amivantamab administration substantially reduced IRRs, obviating the need for prolonged infusions and 2-day split-dosing at first administration. The identified RP2Ds for subcutaneous amivantamab are implemented in ongoing studies evaluating amivantamab regimens in NSCLC, colorectal cancer, and head and neck squamous cell carcinoma.

The average global life expectancy is predicted to increase to approximately 80years by 2040 [1]. Cancer is an ageing-related disease, and its prevalence will also increase with this ageing of the population [2]. This rise in older adults living with cancer will demand innovation in service delivery, multidisciplinary collaboration, and a renewed focus on compassionate, patient-centred care. We are therefore compelled to rethink how we approach cancer diagnosis, treatment, and survivorship. This white paper explores the potential realities and challenges through a multidimensional lens, addressing the intersection of demographic shifts, rapid technological advancements, and the evolving needs of older adults living with cancer. Key areas examined include the integration of precision medicine and digital health tools, the adaptation of healthcare delivery models, and the implications for workforce training and resource allocation. The discussion highlights disparities in care, the importance of personalised interventions, and strategies to enhance quality of life for older adults with cancer. By anticipating these developments, the paper offers critical insights for policymakers (who set the rules and goals and allocate funding), health system leaders (who manage the day-to-day operations), clinicians and allied health professionals (who are patient-facing), and patients and caregivers, aiming to promote equity, innovation, quality and resilience in the care of older adults with cancer as we approach the next decade. The paper seeks to consolidate and clarify the diverse issues and opportunities that will emerge as the global population ages and the burden of cancer among older adults rises. With average life expectancy predicted to approach 80years by 2040, and cancer recognised as a disease closely linked to ageing [3], the paper brings together expert perspectives to provide a sector-wide synthesis of the impending challenges. Its purpose is not to offer a conventional systematic review, but rather to serve as a strategic resource for policymakers, health system leaders, clinicians, allied health professionals, patients, and caregivers, informing the response to demographic shifts, technological advances and evolving patient needs. By consolidating insights on disparities in care, the necessity for personalised interventions, and strategies to enhance quality of life, the paper aims to inform and inspire innovation, equity and resilience in geriatric oncology as we approach the next decade.

Avelumab, pembrolizumab, and enfortumab vedotin (EV) demonstrated efficacy in mUC following platinum-based chemotherapy. However, real-world data in patients with urothelial carcinoma with squamous differentiation (UCSD) are limited. The aim of this study is to assess the real-world clinical outcomes of avelumab, pembrolizumab, or EV in mUCSD patients. The ARON-2EV study is a retrospective, international, multicenter analysis in patients with mUC treated with avelumab, pembrolizumab, or EV across 79 centers in 21 countries. Patients were divided into three cohorts: 1 (avelumab), 2 (pembrolizumab), and 3 (EV). Primary endpoints were overall survival (OS) and time on treatment (ToT). Secondary objectives included evaluating clinical factors associated with outcomes and exploring the impact of UCSD histology on response to therapy. Statistical methods included Kaplan-Meier estimates, log-rank tests, Fisher's exact and chi-square tests, and Pearson's correlation coefficients. A total of 1918 patients, 1696 with advanced pure UC (pUC) and 222 with mUCSD (36 in cohort 1, 111 in cohort 2, and 75 in cohort 3), were included. Median OS was shorter in patients with UCSD compared to patients with pUC histology in the three cohorts (1: 13.0 vs 26.8months, HR 2.66,p = 0.003; 2: 10.2 vs 18.5months, HR 1.52,p = 0.008; and 3: 7.6 vs 13.1months, HR 1.68,p = 0.011). Median ToT was shorter in patients with UCSD compared to patients with pUC histology in cohort 1 (3.5 vs 5.6months, HR 1.57,p = 0.044) and 3 (7.6 vs 13.6months, HR 1.83,p = 0.005) but not in cohort 2 (3.7 vs 4.7months, HR 1.19,p = 0.177). Response to therapy was negatively correlated with UCSD histology in cohorts 2 (correlation coefficient 0.094,p = 0.008) and 3 (correlation coefficient 0.107,p = 0.021), while response to avelumab was not correlated with UCSD (correlation coefficient 0.072,p = 0.263). UCSD is a histology with a poor prognosis and response to treatments compared to pUC. Treatments activity and effectiveness in divergent differentiations should be addressed in dedicated prospective studies. NCT05290038.

Artificial intelligence (AI) promises to enhance breast cancer screening. Here we evaluated Google's mammography AI system (version 1.2) across two phases: a retrospective study using 115,973 mammograms from five National Health Service screening services with 39-month follow-up and prospective noninterventional feasibility deployment at 12 sites (9,266 cases). The primary endpoint was AI sensitivity and specificity versus first reader using a 5% noninferiority margin. The secondary endpoints were performance versus second or consensus readers and breast-level analyses. Retrospectively, AI achieved superior sensitivity (0.541 versus 0.437 for first reader, P < 0.001) and noninferior specificity (0.943 versus 0.952, P < 0.001). Cancer detection rate increased from 7.54 to 9.33 per 1,000 women, with AI detecting 25.0% of interval cancers. Performance was particularly strong for first screens (39.3% fewer recalls, 8.8% higher detection) and invasive cancers. No systematic demographic disparities were observed. Simulated second-reader replacement reduced reading time by 32% while increasing detection by 17.7%. Prospective deployment confirmed technical feasibility but revealed a distribution shift requiring threshold recalibration. Implementation requires adaptive calibration and continuous monitoring to ensure safety and equity.

The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT. We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m2, every 3 weeks). Co-primary endpoints at 12 months were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; recruitment is complete and follow-up is ongoing. Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI 11 to 28]) of 110 patients in the IMPT group and in three (6% [1 to 17]) of 53 patients in the IMRT group (combined odds ratio 2·80 [97·5% CI 0·75 to 10·4]; p=0·079). Mean UW-QoL physical composite scores at 12 months were 78·3 in the IMPT group versus 77·1 in the IMRT group (difference 1·3 [97·5% CI -3·7 to 6·2]; p=0·56). There were 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [four in the IMPT group and five in the IMRT group] and five study treatment-related [one IMPT vs four IMRT]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates were 94% (99% CI 86-98) in the IMPT group versus 97% (82-100) in the IMRT group (hazard ratio [HR] 2·6 [99% CI 0·3 to 20·3; 95% CI 0·5-12·4]; p=0·24), and overall survival rates were 95% (86 to 98) in the IMPT group versus 95% (81-99) in the IMRT group (HR 1·6 [99% CI 0·3 to 8·8; 95% CI 0·4 to 5·9; p=0·47). IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care. Cancer Research UK.

308 Background: Risk stratification in localised prostate cancer (PCa) based on clinicopathological parameters is inadequate, leading to under- and over-treatment. We used CHHiP trial data to externally validate a previously-developed MMAI prognostic model with potential for cost-effective improved treatment personalisation. Methods: H&amp;E slides from CHHiP translational substudy patients were centrally reviewed by a uro-pathologist between 2013 and 2015, with Gleason grade group (GGG) rescored using contemporary guidelines. GGG was reassigned in 52% of cases. We evaluated the locked ArteraAI prostate MMAI algorithm v1.2 which combines age, T-stage, and PSA with digital prostate biopsy H&amp;E images. Multivariable cox regression analysis of biochemical/clinical recurrence (BCR; trial primary endpoint) and development of distant metastases (DM) were performed with models including age and MMAI as continuous (per 0.1 increase) and categorical (ArteraAI pre-validated 3-tier risk groups) variables. The additional prognostic value of MMAI beyond UK-recommended Cambridge Prognostic Group (CPG) and NCCN risk group models was assessed by change in Concordance Index and Likelihood Ratio Test (LRT). Results: Of 1854 patients with centrally-reviewed pathology, 1797 (97%) had clinical data and H&amp;E with sufficient tumour for MMAI analysis. Median follow up was 14.3 years. Patients were classified as MMAI High (129, 7.2%), Intermediate (885, 49.2%) or Low (783, 43.6%). In univariable analysis, high MMAI score was significantly associated with increased BCR risk, as both a categorical variable (MMAI High risk hazard ratio (HR) = 5.07, 95%CI = 3.77-6.81, p=&lt;0.001, MMAI Intermediate-risk HR = 1.90, 1.52-2.36, p=&lt;0.001), and continuous variable (MMAI raw score HR = 1.55, 1.44-1.67, p=&lt;0.001). MMAI was also significantly associated with DM. Addition of MMAI to CPG and NCCN multivariable models significantly improves discrimination (C-index) and overall fit (change in LRT) for BCR and DM (Table 1). Conclusions: ArteraAI MMAI improves prediction of BCR and DM in CHHiP over standard criteria. This first large-scale external validation in a contemporary UK cohort of localised PCa with rigorously standardized care will inform future prospective trials of MMAI biomarker-guided PCa treatment selection. Endpoint Model C index (MMAI risk group) ΔLRT χ² (p) C index (MMAI raw score) ΔLRT χ² (p) BCR CPG + ageCPG + age + MMAI 0.620.65+0.03 p=&lt;0.001 55.6 p=&lt;0.001 0.620.67+0.05 p=&lt;0.001 67.5 p=&lt;0.001 BCR NCCN + ageNCCN + age + MMAI 0.590.64+0.05 p=&lt;0.001 67.2 p=&lt;0.001 0.590.66+0.07 p=&lt;0.001 80.9 p=&lt;0.001 DM CPG + ageCPG + age + MMAI 0.650.71+0.06 p=0.001 35.3 p=&lt;0.001 0.650.73+0.08p=&lt;0.001 47.0 p=&lt;0.001 DM NCCN + ageNCCN + age + MMAI 0.610.70+0.09 p=&lt;0.001 43.4 p=&lt;0.001 0.610.72+0.11 p=&lt;0.001 55.8 p=&lt;0.001 Total, n=1794. Events BCR, n = 426 (23.7%), DM, n = 121 (6.7%).