Background: The imbalance of angiogenic regulators in tumors drives tumor angiogenesis and causes the vasculature to develop much differently in tumors than in normal tissue. There are several cancer therapy techniques currently being used and developed that target the tumor vasculature for the treatment of solid tumors. This article reviews the aspects of the tumor vasculature that are relevant to most cancer therapies but particularly to vascular targeting techniques. Materials and methods: We conducted a review of identified experiments in which tumors were transplanted into animals to study the development of the tumor vasculature with tumor growth. Quantitative vasculature morphology data for spontaneous human head and neck cancers are reviewed. Parameters assessed include the highest microvascular density (h-MVD) and the relative vascular volume (RVV). The effects of the vasculature on the tumor microenvironment are discussed, including the distributions of hypoxia and proliferation. Results: Data for the h-MVD and RVV in head and neck cancers are highly varied, partly due to methodological differences. However, it is clear that the cancers are typically more vascularized than the corresponding normal tissue. The commonly observed chronic hypoxia and acute hypoxia in these tumors are due to high intratumor heterogeneity in MVD and lower than normal blood oxygenation levels through the abnormally developed tumor vasculature. Hypoxic regions are associated with decreased cell proliferation. Conclusion: The morphology of the vasculature strongly influences the tumor microenvironment, with important implications for tumor response to medical intervention such as radiotherapy. Quantitative vasculature morphology data herein may be used to inform computational models that simulate the spatial tumor vasculature. Such models may play an important role in exploring and optimizing vascular targeting cancer therapies.

The well-known clinical benefits of proton therapy are achieved through higher target-conformality and normal tissue sparing than conventional radiotherapy. However, there is an increased sensitivity to uncertainties in patient motion/setup, proton range and radiobiological effect. Although recent efforts have mitigated some uncertainties, radiobiological effect remains unresolved due to a lack of clinical data for relevant endpoints. Therefore, RBE optimisations may be currently unsuitable for clinical treatment planning. LET optimisation is a novel method that substitutes RBE with LET, shifting LET hotspots outside critical structures. This review outlines the current status of LET optimisation in proton therapy, highlighting knowledge gaps and possible future research. Following the PRISMA 2020 guidelines, a search of the MEDLINE${}^{\circledR }$ and Scopus databases was performed in July 2023, identifying 70 relevant articles. Generally, LET optimisation methods achieved their treatment objectives; however, clinical benefit is patient-dependent. Inconsistencies in the reported data suggest further testing is required to identify therapeutically favourable methods. We discuss the methods which are suitable for near-future clinical deployment, with fast computation times and compatibility with existing treatment protocols. Although there is some clinical evidence of a correlation between high LET and adverse effects, further developments are needed to inform future patient selection protocols for widespread application of LET optimisation in proton therapy.