Assessments for arterial toxicity in patients receiving systemic anti-cancer therapies

Rankin, Stephen Henry (2026) Assessments for arterial toxicity in patients receiving systemic anti-cancer therapies. PhD thesis, University of Glasgow.

Abstract

Cardiovascular (CV) toxicity is a recognised complication of numerous anticancer treatment regimens. Many cancer therapies may be associated with arterial injury. The mechanism underlying arterial toxicity from cancer treatment is not well understood and the risk may be underappreciated. Immune checkpoint inhibitors (ICI) are an effective anticancer therapy that may be associated with atherothrombotic events such as myocardial infarction (MI) and ischaemic stroke. It is proposed that ICIs induce T-cell infiltration into plaque leading to inflammatory atheroma and plaque rupture. ICIs are used in combination with vascular endothelial growth factor inhibitors (VEGFI). VEGFI alone are associated with hypertension, heart failure and MI. It is unclear if the combination of drug classes has an additive effect on atherothrombosis and ischaemic events. ICI-associated atherothrombosis is supported by basic science and observational retrospective studies. This association has not been observed in randomised clinical trials. Trial design within oncological studies may not be suitable to adequately capture CV events and trial participants may not be representative of the population seen in clinical practice. The true risk, if any, of ischaemic events with ICI is not yet known.

Inflammation plays a role in the development of numerous CV conditions and may be relevant in arterial toxicity from anticancer treatments. While cardiotoxicity is a well-known side effect of anthracyclines, they are also associated with arterial injury. Inflammation is implicated in development of anthracycline cardiotoxicity but the role of inflammation in anthracycline associated arterial injury is not yet known.

Fluorodeoxyglucose positron emission tomography computed tomography [18F]FDG-PETCT is a metabolic imaging technique used for assessment of arterial inflammation and is a surrogate marker of inflammatory atheroma. Quantitative assessment of arterial uptake is performed using the maximal tissue-to-background ratio (TBRmax). Inflammation assessment should be performed using specific imaging parameters. The European Association of Nuclear Medicine (EANM) provided recommendations on how PET protocols should be performed in 2016. However, these recommendations may be out of date with the advances in PET technology, such as the advent of digital PET scanners. The optimal parameters for assessment of arterial inflammation by contemporary digital PET scanners are not well-defined, nor are methods for comparing one PET-CT protocol to another.

[18F]FDG-PETCT may offer mechanistic insight into the possible association of ICI and ischaemic events. [18F]FDG-PETCT assessment of ICI associated arterial inflammation has been previously assessed in small retrospective studies with conflicting results. There have been no prospective studies. No study has assessed the potential additive effect of VEGFI combined with ICI on arterial inflammation.

Aims
The aims of my thesis were: 1) to assess how trial eligibility criteria and CV adverse event (CVAE) reporting may impair the ability to capture CV safety data in ICI+VEGFI combination therapy trials; 2) to assess whether anthracycline exposure is associated with large artery inflammation, measured by [18F]FDGPETCT, in a retrospective analysis of a cohort of patients with lymphoma; 3) to compare current international recommendations for imaging protocols for arterial assessment by [18F]FDG-PETCT in comparison to a locally optimised protocol; 4) to make a prospective assessment of the effect of ICI on arterial inflammatory activity, and; 5) to compare arterial inflammatory effects in patients receiving ICI+VEGFI versus ICI monotherapy and VEGFI monotherapy.

Methods
A systematic review of randomised controlled trials of combination ICI+VEGFI therapy was performed. I assessed data relating to trial eligibility criteria and CVAE reporting. I subsequently performed a retrospective analysis of clinically indicated [18F]FDG-PETCT scans to compare large artery inflammation before and after completion of anthracycline-based chemotherapy. A locally optimised PET imaging protocol was designed and compared with EANM recommendations for arterial inflammation assessment in order to inform the design of my prospective PET-CT study. Novel metrics to quantifiably compare imaging protocols were used for assessment, such as mean contrast recovery (MCR), coefficient of variation (CoV), and error. A prospective observational study of patients with cancer receiving either VEGFI, ICI or ICI+VEGFI was performed. Arterial inflammation was assessed using [18F]FDG-PETCT before and after 24- weeks of therapy. The primary outcome was the change in TBRmax at 24-weeks from baseline in ICI+VEGFI vs monotherapy. Biomarker analyses were also performed.

Results
In the review of 17 trials with 10,313 participants, there was broad CV eligibility criteria using heterogenous definitions of CV disease. No trial published baseline CV characteristics of participants. Reporting of CVAE was inconsistent and subject to incidence thresholds. No trial reported the absence of CVAEs. In 16 trials, AEs were investigator reported without centralised adjudication.
I observed no change in arterial [18F]FDG uptake in patients with lymphoma treated with anthracycline chemotherapy, compared with pre-treatment scans.
Current international recommendations for arterial inflammation assessment by [18F]FDG-PETCT are not applicable to modern digital PETCT scanners. Fewer reconstruction parameters (iterations and subsets) are required for optimal imaging, than recommended by EANM.
In the first prospective study of ICI and large artery inflammation, 55 patients were enrolled (VEGF: n=15; ICI: n=20; VEGFI+ICI: n=20), mean age was 66±10 years, 29% female. CV risk factors were highly prevalent and comparable in all groups. Compared to pre-treatment, at 24 weeks TBRmax had not increased in any group (baseline vs 24 weeks, VEGFI: 1.72±0.2 vs 1.72+0.2; ICI: 1.71±0.1 vs 1.67±0.1; VEGFI+ICI: 1.74±0.2 vs 1.64±0.2). There was no difference in the change of TBRmax over time between groups (p=0.13). The results were consistent when accounting for potential heterogeneity, including clinical characteristics (such as pre-existing CV disease) and arterial characteristics (such as calcification vs none).

Conclusion
Arterial toxicity from anticancer therapies is poorly understood and limitations within oncological efficacy trials impairs accurate capture and quantification of CV toxicity in ICI+VEGFI regimens. The heterogeneity in defining and reporting CVAE, in a population where prevalence of CV disease is unknown, limits understanding of the incidence and severity of events relating to these combinations. [18F]FDG-PETCT analysis did not reveal an association between anthracycline exposure and large artery inflammation. If anthracyclines are associated with arterial injury, this could occur through a non-inflammatory process. Current international recommendations for assessment of large artery inflammation by [18F]FDG-PETCT are not applicable to modern digital PET scanners but metrics, such as MCR, CoV and error, are valuable methods to quantifiably compare imaging protocols. When assessed in a prospective study, ICI exposure was not associated with large artery inflammation, when assessed by [18F]FDG-PETCT, compared to baseline, when used alone or in combination with VEGFI.
Standardisation within the design and reporting of randomised clinical trials and mechanistic PET research are required to truly elucidate the potential association, between ICIs and atherothrombotic events before risk stratification and therapeutic strategies can be developed.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from Roche Diagnostics.
• Subjects: R Medicine > R Medicine (General); R Medicine > RC Internal medicine
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Lang, Professor Ninian
• Date of Award: 2026
• Depositing User: Theses Team
• Unique ID: glathesis:2026-85731
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 02 Feb 2026 11:41
• Last Modified: 02 Feb 2026 11:44
• URI: https://theses.gla.ac.uk/id/eprint/85731

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