The Christie School of Oncology: Christie Research Publications Repository
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Camidanlumab tesirine for relapsed or refractory classic hodgkin lymphoma: a phase 2 study
No full textOutcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL following brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received ≥3 prior lines of systemic therapy (or ≥2 if ineligible for hematopoietic stem cell transplant). Patients received 45 μg/kg Cami (intravenously, once every 3 weeks [Q3W]) in cycles 1 to 2, followed by 30 μg/kg IV Q3W for ≤1 year. The primary endpoint was overall response rate (ORR) per 2014 Lugano Classification. Secondary endpoints included complete response rate (CRR), progression-free survival (PFS), and overall survival (OS). In total, 117 patients were enrolled with a median age of 37.0 (range, 19, 87) years. The ORR was 70.1% (95% CI, 60.9, 78.2) with a CRR of 33.3% (24.9, 42.6). The median PFS was 9.13 (95% CI, 5.3, 15.0) months; median OS was not reached. Thirty-three (28.2%) patients discontinued treatment because of treatment-emergent adverse events; the most common reasons were skin and subcutaneous tissue disorders (10 [8.5%] patients), infections and infestations (5 [4.3%]), and nervous systems disorders (5 [4.3%]). Guillain-Barré- or polyradiculopathy-type events occurred in 8 (6.8%) patients. Cami was efficacious in this heavily pretreated population; however, the efficacy was overshadowed by substantial issues with the safety profile. NCT04052997
IPEM code of practice for proton therapy dosimetry based on the NPL primary standard proton calorimeter calibration service
No full textInternationally, reference dosimetry for clinical proton beams largely follows the guidelines published by the International Atomic Energy Agency (IAEA TRS-398 Rev. 1 (2024). This approach yields a relative standard uncertainty of 1.7% (k= 1) on the absorbed dose to water determined under reference conditions. The new IPEM code of practice presented here, enables the relative standard uncertainty on the absorbed dose to water measured under reference conditions to be reduced to 1.0% (k= 1). This improvement is based on the absorbed dose to water calibration service for proton beams provided by the National Physical Laboratory (NPL), the UK's primary standards laboratory. This significantly reduced uncertainty is achieved through the use of a primary standard level graphite calorimeter to derive absorbed dose to water directly in the clinical department's beam. This eliminates the need for beam quality correction factors (kQ,Q0) as required by the IAEA TRS-398 approach. The portable primary standard level graphite calorimeter, developed over a number of years at the NPL, is sufficiently robust to be useable in the proton beams of clinical facilities both in the UK and overseas. The new code of practice involves performing reference dosimetry measurements directly traceable to the primary standard level graphite calorimeter in a clinical proton beam. Calibration of an ionisation chamber is performed in the centre of a standard test volume (STV) of dose, defined here to be a 10 × 10 × 10 cm volume in water, centred at a depth of 15 cm. Further STVs at reduced and increased depths are also utilised. The designated ionisation chambers are Roos-type plane-parallel chambers. This article provides all the necessary background material, formalism, and specifications of reference conditions required to implement reference dosimetry according to this new code of practice. The Annexes provide a detailed review of ion recombination and how this should be assessed (Annex A1) and detailed work instructions for creating and delivering the STVs (Annex A2)
VAV2 drives EGFR-mediated rac1 responses in prostate cancer
No full textThe small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of Rac1 results in impaired proliferation and migration of prostate cancer cells. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix regulation. Combined expression profiling and unbiased RNAi screening of Rac1 guanine nucleotide exchange factors identified VAV2 as the foremost mediator EGF-induced GTP loading onto Rac1 in prostate cancer cells. Depletion of VAV2 from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. IHC assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression. IMPLICATIONS: This study highlights the central role of VAV2 in prostate cancer cell proliferation and migration, as well as its potential prognostic value in disease progression
The 2024 state of science report from the European organisation for research and treatment of cancer's radiation oncology scientific council
No full textBACKGROUND: Radiotherapy (RT) is a central pillar of a multimodal cancer treatment approach. The ongoing advances in the fields of RT, imaging technologies, cancer biology, and others yield the potential to refine the use of RT. The European Organisation for Research and Treatment of Cancer (EORTC) hosted a dedicated workshop to identify and prioritize key research questions and to define future RT-based treatment strategies to improve the survival and quality of life of cancer patients. METHODS: An initial call for relevant RT research topics led to the formation of workgroups to develop these into new clinical research proposals and projects. The EORTC Radiation Oncology Scientific Council (ROSC) State of Science workshop was held in Brussels, Belgium, in February 2024, bringing together EORTC members and international stakeholders to connect and work on the proposals. RESULTS: Four topics of interest were identified: I) De-escalation of RT, minimizing toxicity while maintaining patients' quality of life, II) Technology-driven RT utilizing advances in treatment techniques, such as spatially fractionated RT to improve outcomes in patients with bulky disease and localized high tumor burden, III) Biology-driven RT, integrating the rapid advances in cancer biology and functional imaging to guide and personalize RT, and IV) New indications adding value and expanding the use of RT. CONCLUSION: The EORTC ROSC State of Science workshop prioritized clinical questions to be addressed in prospective clinical research projects to advance RT care and improve patient outcomes
Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome
No full textColorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up. Here we studied the TME in three clinical cohorts of metastatic CRC with diverse molecular subtype and treatment history. The MISSONI cohort included cases with microsatellite instability that received immunotherapy (n = 59, 24 months median follow-up). The BRAF cohort included BRAF V600E mutant microsatellite stable (MSS) cancers (n = 141, 24 months median follow-up). The VALENTINO cohort included RAS/RAF WT MSS cases who received chemotherapy and anti-EGFR therapy (n = 175, 32 months median follow-up). Using a Deep learning cell classifier, trained upon >38,000 pathologist annotations, to detect eight cell types within H&E-stained sections of CRC, we quantified the spatial tissue organisation and colocalisation of cell types across these cohorts. We found that the ratio of infiltrating endothelial cells to cancer cells, a possible marker of vascular invasion, was an independent predictor of progression-free survival (PFS) in the BRAF+MISSONI cohort (p = 0.033, HR = 1.44, CI = 1.029-2.01). In the VALENTINO cohort, this pattern was also an independent PFS predictor in TP53 mutant patients (p = 0.009, HR = 0.59, CI = 0.40-0.88). Tumour-infiltrating lymphocytes were an independent predictor of PFS in BRAF+MISSONI (p = 0.016, HR = 0.36, CI = 0.153-0.83). Elevated tumour-infiltrating macrophages were predictive of improved PFS in the MISSONI cohort (p = 0.031). We validated our cell classification using highly multiplexed immunofluorescence for 17 markers applied to the same sections that were analysed by the classifier (n = 26 cases). These findings uncovered important microenvironmental factors that underpin treatment response across and within CRC molecular subtypes, while providing an atlas of the distribution of 180 million cells in 375 clinically annotated CRC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland
Dose-response mapping of bladder and rectum in prostate cancer patients undergoing radiotherapy with and without baseline toxicity correction
No full textBACKGROUND AND PURPOSE: Radiotherapy dose-response maps (DRM) combine dose-surface maps (DSM) and toxicity outcomes to identify high-risk subregions in organ-at-risk. This study assesses the impact of baseline toxicity correction on the identification of high-risk subregions in dose-response modeling for prostate cancer patients undergoing radiotherapy. MATERIALS AND METHODS: The analysis included 1808 datasets, with 589 exclusions before toxicity-specific data removal. Bladder/rectum were automatically segmented on planning computed tomography scans, DSMs unwrapped into 91x90 voxel grids, and converted to equivalent doses in 2 Gy fractions (EQD2; α/β = 1 Gy). Seventeen late toxicities were assessed with two methods: (i) baseline toxicity subtracted from the maximum of 12- and 24-months toxicity scores, dichotomized at grade 1, and (ii) maximum of 12- and 24-months toxicity scores dichotomized at grade 1. DSMs were split accordingly, and voxel-wise t-values computed using Welch's t-equation. Statistically significant voxels were identified via the 95th percentile of maximum of t-value (Tmax) distribution. RESULTS: Event counts with baseline correction were 82/82/286/226 for urinary tract obstruction/retention/urgency/incontinence, respectively; without baseline correction, they were 93/104/465/361. For bladder DSMs, urinary incontinence, obstruction, retention, and urgency had 1143/186, 1768/1848, 516/0, and 33/0 significant voxels without/with baseline correction. For rectum DSMs, urinary incontinence and tract obstruction had 604/0 and 1980/889 significant voxels without/with baseline correction. However, no significant associations between rectal DSMs and rectum-related toxicities were found. CONCLUSIONS: DRM without baseline correction appears more sensitive to high-risk subregions due to higher event counts. Non-linear toxicity grading and multivariable analysis may enhance DRM reliability
The clinical application of in vivo dosimetry for gynaecological brachytherapy: a scoping review
No full textBrachytherapy is a key treatment for gynaecological malignancies, delivering high doses to the tumour volume whilst sparing nearby normal tissues due to its steep dose gradient. Accuracy is imperative as small shifts can lead to clinically significant under- or over-dosing of the target volume or organs at risk (OARs), respectively. Independent verification of dose delivered during brachytherapy is not routinely performed but it is important to identify gross errors and define action thresholds to guide inter-fraction treatment decisions. In vivo dosimetry (IVD) is one strategy for improving accuracy and identifying potential errors. Despite promising phantom work, clinical application of IVD is lacking. A literature search was performed using Medline and EMBASE without date limits and based on the PICO framework to evaluate the clinical application of IVD in gynaecological brachytherapy. After screening of titles and abstracts, full text papers were reviewed and 28 studies were identified. Several dosimeters were utilised and measurements were typically taken from the rectum, bladder, vagina and within interstitial catheters. Significant differences between calculated and measured dose were attributed to geometric shifts. The studies reviewed demonstrated the feasibility of IVD in brachytherapy for dose verification but further work is required before IVD can be used to optimise treatment. The purpose of this scoping review is to investigate the clinical application of IVD in gynaecological brachytherapy, understand its challenges and identify the steps required to facilitate integration into everyday clinical practice
Staged gamma Knife radiosurgery for large brain metastases: local control and the influence of systemic treatment
No full textBACKGROUND AND PURPOSE: Staged Gamma Knife radiosurgery (SGKRS) delivers high-dose radiotherapy to large brain metastases (BM) in two or three fractions with a time interval of several weeks. Various systemic treatments have also demonstrated favorable intracranial responses. Therefore, the outcome of patients undergoing radiosurgery and systemic treatment for large BM is of high interest but unknown. MATERIALS AND METHODS: A retrospective cohort study was conducted on patients with large BM treated with SGKRS without previous local treatment directed to the brain. The primary outcome measure was the probability of intracranial local control at 12 months, calculated by the Kaplan-Meier method. Univariable and multivariable Cox regression analyses were performed to identify variables associated with intracranial local control. RESULTS: 295 patients were included. Intracranial local control probability at 12 months was 83 % and overall survival at 12 months was 39 %. In the multivariable Cox regression analysis, receiving any type of concurrent or adjuvant systemic treatment (adjusted hazard ratio [aHR] 0.30, 95 % confidence interval [CI] 0.15-0.61) and volume reduction between the first and second fraction (aHR 0.99, 95 % CI 0.98-0.998) were significantly associated with better intracranial local control. Larger total volume of all treated BM (aHR 1.02, 95 % CI 1.01-1.04) was significantly associated with worse intracranial local control. The probability of symptomatic cerebral radiation necrosis at 12 months was 26 %. CONCLUSION: SGKRS results in high local control, with further improvement when systemic treatment is administered. However, overall survival remains limited, highlighting the importance of adequate patient selection
First-in-human, phase I/II dose escalation and expansion study of zelenectide pevedotin in patients with advanced solid tumors: results from monotherapy dose escalation
No full textPURPOSEZelenectide pevedotin (BT8009) is a Bicycle Drug Conjugate comprising a highly selective Nectin-4-targeting Bicycle peptide, linked to monomethyl auristatin E. We report monotherapy dose-escalation results from Duravelo-1 (Phase I/II; ClinicalTrials.gov identifier: NCT04561362).METHODSAdults with advanced/metastatic solid tumors associated with Nectin-4 expression received zelenectide pevedotin intravenously at 2.5, 5.0, or 7.5 mg/m2 once weekly on a 28-day cycle; or 7.5 mg/m2 on days 1 and 8 of a 21-day cycle; or 7.5 or 10.0 mg/m2 once every 2 weeks on a 28-day cycle. Primary objectives were to evaluate safety and tolerability; antitumor activity and pharmacokinetic characterization were secondary objectives.RESULTSForty-nine patients, most with urothelial carcinoma (UC; 25 of 49), received three previous lines of therapy (median). Common treatment-related adverse events (TRAEs) included nausea (49% [grade 3/4 2%]), likely because of a lack of prophylactic antiemetics during the dose-limiting toxicity period, and fatigue (39% [grade 3/4 6%]). The most common TRAEs of clinical interest were peripheral neuropathy (33% [grade 3/4 2%]), neutropenia (22% [grade 3/4 16%]), and skin reactions (22% [grade 3/4 2%]). The maximum tolerated dose was 7.5 mg/m2 once every 2 weeks; the recommended phase 2 doses were 5.0 mg/m2 once weekly and 7.5 mg/m2 on days 1 and 8 of a 21-day cycle. Across doses (efficacy-evaluable; all tumor types), the objective response rate (ORR) was 24% and the clinical benefit rate (CBR) was 48% (n = 10 of 42; 95% CI, 12.1 to 39.5); the ORR was 38% and the CBR was 57% for patients with UC (n = 8 of 21; 95% CI, 18.1 to 61.6). The median duration of response and the median follow-up for all patients were 11.1 and 7.4 months, respectively.CONCLUSIONZelenectide pevedotin monotherapy demonstrated a generally well-tolerated safety profile and preliminary efficacy, particularly in UC, supporting investigation of UC and non-UC populations in the expansion phase