After the disappointment of a few failed randomised controlled trials (RCTs), transarterial radioembolization (TARE) is finally back in the spotlight. And interventional radiologists (IRs) are learning from these past failures to shape the future.
Despite negative results, former trials have taught us that TARE is a highly effective treatment option if some essential rules are respected. Firstly, thoughtful selection of patients, with careful evaluation of the liver function reserve. Secondly, adequate arterial vascularisation, with a preference for no harm caused by prior therapy. The third rule is to carry out personalised dosimetry tailored to the vascular anatomy, tumour type and extension, the patient’s characteristics and the goal of treatment.
Learning from the past, the current decade has finally started with successful trials, showing the efficacy and safety of TARE in primary tumours (such as the DOSISPHERE-01 [Boston Scientific], TRACE and LEGACY [Boston Scientific] trials for hepatocellular carcinoma (HCC) in advanced, intermediate and early stages, respectively) as well as metastatic lesions (such as the EPOCH [Boston Scientific] study in second-line colorectal cancer metastases).
Personalised dosimetry has become a central focus of investigation in an attempt to identify the most adequate administered activity for achieving tumoricidal tumour-absorbed doses without harming the surrounding liver parenchyma. With high tumour-absorbed doses, complete tumour necrosis may be achieved, translating into a durable response, conversion to surgery and ultimately significant survival advantage. However, obtaining a high tumour-absorbed dose implies limited dose to the non-tumoral parenchyma— in other words, a high tumour-to-liver ratio. If all or almost all the activity is concentrated selectively in the tumour cells, there is, potentially, no limit to the radioactivity level we could administer!
But what do IRs have to do with this? There is no doubt that good dosimetry starts with a good angiographic work-up, by understanding anatomy, flow distribution and haemodynamics, so that the tumour can be targeted selectively. Over the years, the preliminary angiographic work-up has adapted to increasingly refined dosimetry calculations. From whole-liver and hemi-liver treatments, in which the main challenge was the identification of extrahepatic vessels, we are moving towards selective and super-selective treatments and, where these are not possible, we are learning how to exploit and modify the arterial flow.
While selectivity can be relativity easy to obtain when dealing with hypervascular lesions, and well demarcated and limited tumour burden, it becomes challenging in patients with infiltrative lesions, hypovascular tumours and multifocal extensive disease. How can we obtain a selective intratumoral concentration of particles in these cases?
Several computational studies have shown that even minimal modifications in injection parameters and position, shape and orientation of the supporting catheters and of the microcatheters may have a meaningful impact on the distribution of flow in the target volume. As an example, when the catheter is close to an arterial bifurcation, a preferential flow into one of the two branches is frequently observed, influenced by the size of the distal vessels, their area of distribution, and the morphology and the orientation of the catheter’s tip. The challenge for the operator is to select the most appropriate position for the catheters and, if needed, exploit specific pre-shaped microcatheters, to obtain a homogeneous flow distribution in the entire target liver volume.
The capacity of the arterial branches to receive the right quantity of spheres is another matter of concern, particularly in tumours with multiple feeding vessels and in pre-treated patients with impaired arterial vascularisation. Minor tumour-feeding vessels may require coil embolization to promote flow redistribution. However, redistribution requires an in-depth knowledge of the possible intra- and extrahepatic arterial connections; it may be tricky and unpredictable, varying by specific vascular anatomy, the tumour type and tumour location. The success of flow redistribution has been reported to be lower in certain conditions, such as when parasitised arteries are embolized proximally, or when it is difficult to predict which vessels are going to be recruited after embolization— in centrally located tumours if unilobar treatment is planned, and in hypervascular bulky lesions. As a result, flow redistribution is now recommended only when strictly needed.
Specific microcatheters, such balloon and anti-reflux microcatheters, have recently become available, and through different mechanisms, they are able to modify the haemodynamics and flow distribution, potentially enhancing the intratumoral uptake and reducing the risk of reflux and non-target embolization. These tools may be of particularly useful for treating hypovascular lesions and multifocal disease. How effective they are for radioembolization is still being investigated.
In conclusion, we have learned over the years that, to be successful, radioembolization requires a high level of expertise—it is a truly multidisciplinary treatment modality. Dosimetry is key to success; yet, personalised dosimetry requires personalised angiographic planning based on flow analyses and where possible, flow modification, to achieve selective tumour uptake.
Irene Bargellini works within the Division of Vascular and Interventional Radiology at Florence University Hospital (Florence, Italy).
Disclosures: Bargellini declared having received an institutional research grant from Boston Scientific; consulting fees from AstraZeneca, EISAI, GE Healthcare, Guerbet, Merck, Sirtex, Terumo; honoraria for lectures from AstraZeneca, Bayer, Boston Scientific, Eisai, Guerbet, Merck, Sirtex, Sobi, Terumo; having been part of the Independent Data Safety Monitoring Board for AstraZeneca.