Vessel caliber--a potential MRI biomarker of tumour response in clinical trials

Abstract

Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional contrast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus, the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research.

Trial registration: ClinicalTrials.gov NCT00254943 NCT00662506 NCT00756106.

Figures

Figure 1

Vessel calibres in solid cancers. Conceptual illustration showing key factors for vessel-calibre growth and remodelling within a tumour, including vessel dilatation after stimulation by proangiogenic factors such as VEGF, FGFs, ANG-2 and chemokines, and compression of vessels as a result of solid stress induced by tumour growth. In normal tissues, red vessels indicate oxygen-rich feeding arteries and arterioles, blue vessels are veins carrying deoxygenated blood and the intermediate regions indicate a transient capillary stage. In cancerous tissues, slow blood flow is indicated by reduced colour intensity. Abbreviations: ANG-2, angiopoietin-2; FGFs, fibroblast growth factors; VEGF, vascular endothelial growth factor.

Figure 2

Vessel-calibre MRI. a | Example anatomical CE T1-weighted, FLAIR, macrovessel volume-fraction and microvessel volume-fraction images from MRI assessments of a patient with glioblastoma. Note the sensitivity to high blood-volume fractions in the macrovessel image (total blood volume) compared with the microvessel image. b | Macrovessel and microvessel DSC-MRI in the same patient with glioblastoma, with contrast agent passing through the tissue. Before estimation of perfusion and vessel-calibre MRI parameters, the macrovessel (GE) and microvessel (SE) blood-volume relaxation rate images shown here are computed according to the relative decrease in MRI signal intensity over the course of a sequence of GE MRI and SE MRI images, respectively (images 30–34 in this case), thereby adjusting for baseline intensity values and image sampling time (echo time). The so-called ‘first-pass effect’ denotes the initial and transient passage of a relatively tight bolus of the contrast agent following intravenous administration of the agent and is observed as a peak in the relative relaxation rate signal (peaks for normal tissue approximately at image 32). The contrast agent first-pass effect is particularly dominant in large vessels in the macrovessel images because of high contrast agent concentrations combined with high sensitivity to the magnetic susceptibility effect induced by the agent. After the initial first-pass contrast agent passage, repeated passages of what remains of the circulating and increasingly dispersed contrast agent bolus can be appreciated as smaller and dissipating signal oscillations. c | Macrovessel and microvessel volume fractions are estimated from the area under the GE and SE first-pass curves (top left), respectively. The concept of vessel-calibre MRI stems from the relationship between increased macrovessel volume fractions for increasing vessel calibres, and microvessel volume fractions, which are selectively sensitive to small (radius <10 µm) vessel calibres (bottom left). Mean vessel density maps (Box 1) are thus derived from the quotient of macrovessel and microvessel volume fractions, whereas the vessel-calibre index also accounts for water diffusion and the absolute blood volume fraction. Abbreviations: CE, contrast-enhanced; DSC-MRI, dynamic susceptibility-contrast MRI; FLAIR, fluid-attenuated inversion recovery; GE, gradient-echo; SE, spin-echo.

Figure 3

Vessel-calibre MRI during antiangiogenic therapy. Selected MRI-derived images obtained over the course of a phase II trial of cediranib combined with CRT in adult patients with newly diagnosed glioblastomas. From top to bottom: contrast-enhanced T1-weighted MRI illustrating a permeable tumour vasculature; FLAIR MRI showing the tumour and vasogenic oedema; macrovessel blood-volume fractions; vessel-calibre maps; and volume renderings from 3D anatomical MRI with time-of-flight MRI angiography. Compared with pretreatment baseline images (day −1), cediranib therapy (days 1 and 8) decreased the signal enhancement in the tumour, indicative of reduced permeability of the tumour vasculature, by day 8 (yellow arrow), and oedema was subsequently reduced (yellow arrowhead; day 50). Treatment effects of antiangiogenic and adjuvant combination therapy were also observed after the end of CRT (up to day 400); however, the cancer eventually relapsed and progressed, although this outcome is not clear using standard contrast and FLAIR MRI protocols. Volume fractions and vessel calibres show reductions that are related to the responses observed by conventional contrast-enhanced and FLAIR MRI following therapy (white arrow; day 50), but the vessel-calibre response also reveals unique properties of tissue that do not match the spatial distribution of the volume-fraction map. In contrast to the major vessels identified by standard MRI angiography (bottom panels), the vessel-calibre map depicts changes in the tumour microvasculature that are well below the image resolution achievable using the conventional approach; note the increased vessel calibres in the relapsed tumour region (white arrowhead; day 400), which is not easily appreciated on conventional MRI nor on the volume-fraction map. Abbreviations: CRT, chemoradiation therapy; FLAIR, fluid-attenuated inversion recovery.

Figure 4

Advanced MRI assessments might inform optimal dose scheduling. On the basis of our experience with cediranib,,,, the initial responses, plateaus and reversals in tumour response that are observed using advanced MRI parameters occur at different timepoints after initiation of therapy. In this example model of tumour-vessel architecture, showing a typical vascular-normalization response after cediranib treatment and CRT in patients with newly diagnosed glioblastomas, the perfusion estimate (blood flow) peaks after approximately 1 week of therapy (day 8), whereas the maximum reduction in vessel calibres occurs 1 week later (day 15; note the reduced diameter of the example vessels). These effects are preceded by an early, substantial, and prolonged normalization of the abnormal arterio-venous ratio evident in the model of the baseline data (day 1; arteries/arteriole shown in red, with veins in blue), estimated using vessel architectural imaging. Consistent with the vessel-calibre response, the apparent change in abnormal ΔSO2 levels reaches its minimum at two weeks (day 15; purple colour). After the end of CRT, all of these parameters reverse, thereby indicating an end to the vascular-normalization window. Furthermore, in patients who were deemed unresponsive to therapy, limited evidence of such responses was seen. Collectively, advanced MRI protocols might facilitate the design of improved early-phase trials by informing the optimization of the dosing regimen for antiangiogenic agents and could also potentially support a personalized-medicine approach by enabling therapy to be tailored to individual patients based on parameters indicative of biological and, in particular, vascular responses. In addition, early identification of patients who are unlikely to respond to therapy could help decision making regarding whether therapy should be discontinued, particularly in patients who experience adverse events. Abbreviations: ΔSO2, relative oxygen saturation levels; CRT, chemoradiation therapy.