William S. Rilling, MD, FSIR
Professor of Radiology and Surgery
Vice Chair of Clinical Affairs
Medical College of Wisconsin
Milwaukee, Wisconsin
wrilling@mcw.edu

Teik Choon See, MBBCh, BAO, FRCS, FRCR, FBIR
Consultant Interventional Radiologist
Cambridge University Hospitals
NHS Foundation Trust
Cambridge, United Kingdom
teikchoon.see1@nhs.net

What are the most significant voids in current guidance for hepatocellular carcinoma (HCC) interventions?

Dr. Rilling: The field of HCC treatment is evolving very rapidly, and as such, it is very difficult for guidelines to stay current. For example, it has been announced that IMBRAVE 050 (adjuvant atezolizumab/bevacizumab after curative resection or ablation) has met its primary endpoint. This will be a very complex treatment algorithm to integrate into clinical practice for many reasons, and none of the guidelines have addressed this due to the timing of the trial.

Dr. See: Despite the advances in knowledge and technology, management of intermediate HCC remains a huge challenge. Although the majority of patients will undergo locoregional therapy, the precise treatment regimen, whether alone or in combination, is variable. This, along with patient and tumor factors, inevitably results in variable outcomes and a lack of improved survival benefits over the years.

Multiple staging systems are used in studies evaluating HCC treatments, with Barcelona Clinic Liver Cancer (BCLC) staging widely used. What are your initial impressions of the recently updated BCLC staging and any potential implications for future trial designs?

Dr. Rilling: The recent update to the BCLC HCC guidelines brings some welcome changes. Radioembolization is included as a recommended treatment for early stage HCC based on the LEGACY data. This marks the first time radioembolization has been included in these guidelines.

The division of the intermediate-stage (BCLC B) group into three subcategories is another important change. The group with single tumors who may be downstaged to curative-intent treatment is distinctly different from the other two groups. Patients with bilobar disease may be considered for combination therapy with both liver-directed therapy and systemic therapy. This is an area of active investigation where more trials are needed. Future trial designs will likely focus on these BCLC B subgroups and optimizing care across this heterogeneous group.

Dr. See: The updated BCLC guidelines are a further step forward in optimizing HCC management. It stratifies prognosis by integrating albumin-bilirubin score and alpha fetoprotein for additional granularity, particularly for BCLC stage B. It also incorporates recent evidence on transarterial radioembolization (TARE) in BCLC stage 0 and A and implemented trial evidence on systemic therapies in BCLC stage C. The guidelines also introduced the concept of treatment stage migration and untreatable progression, which are both well recognized in the real world.

Interestingly, the guidelines do not include TARE in BCLC stage B. Stereotactic ablative radiotherapy, which is endorsed in other guidelines, has no role in the updated guidelines. Each stage of the disease and patient characteristics feed into the most appropriate single treatment, with no flexibility of combination therapies.

The updated guidelines provide opportunities for future trial designs, with opportunities to stratify the patient groups, standardize treatment selections, and adopt real-life clinical decision-making, all of which will consolidate further evidence.

What are your thoughts on the need and/or potential for more uniform data collection in trials involving HCC intervention?

Dr. See: It is certainly essential to aim for more homogeneous and collaborative data collection in HCC trials to consolidate the current evidence. The wide variabilities of subject cohorts, treatment strategies, and data interpretation inevitably open to potential bias. It can therefore be very difficult to reproduce the results, however valid they may be, even with similar objectives and methodologies.

Which applications outside of HCC do you think hold the most promise for transarterial chemoembolization (TACE)?

Dr. Rilling: In my opinion, TACE remains a very important therapy in patients with neuroendocrine liver metastases. The role of TACE versus bland embolization may come into focus as the RETNET trial has completed enrollment and we await the results of this important trial. Peptide receptor radionuclide therapy has been an important advance in treating neuroendocrine tumors, but TACE probably has higher response rates in the liver and may be underutilized currently in patients with liver-only or liver-dominant metastases.

I think it’s exciting to consider some of the potential extrahepatic applications of TACE. There are some interesting preliminary data on the use of TACE and targeted arterial chemotherapy infusion in head and neck cancer. These patients sometimes have few therapeutic options beyond platinum-based chemotherapy and radiation. Another area of investigation is the use of TACE in musculoskeletal tumors. For example, there are some interesting preliminary data for TACE in desmoid tumors that fail conventional therapy.

Dr. See: The application of TACE is wide ranging. Its therapeutic potential in colorectal liver metastases (CLRM) is encouraging. However, the heterogeneity of patient populations in the studies involving TACE in CLRM means its role has not been fully integrated in the management of CLRM in many regions. TACE has also been used in other hepatic metastases (eg, breast cancer, neuroendocrine tumors, ocular melanoma, sarcoma). In general, its applications in such settings are usually in patients who have failed second-line chemotherapy, and hence, survival benefits are difficult to establish. Ongoing trials are therefore required.

What would you most like to see in a next-generation chemoembolization platform, whether in the drug, material, or delivery facets?

Dr. Rilling: We are currently facing huge barriers to further investment and development of TACE because of the challenging and often unclear regulatory pathway for approval of drug/device combination platforms. I believe this is the number one cause for relative lack of progress in TACE over the last 10 years despite many promising early trials in multiple disease states.

Having said that, continued development is important because TACE remains the worldwide standard of care for major portions of the HCC patient population. Access to and reimbursement for alternative therapies for HCC such as radioembolization remains a challenge. As a result, improvements in TACE could potentially have a very large impact worldwide, especially in countries with resource limitations.

Dr. See: The next-generation chemoembolization platform should embrace evolving technologies. Multifunctional nanoplatform TACE may potentiate controlled drug delivery in response to internal and external stimuli, including temperature, pH, or ultrasonic effect. It could also synergize embolic phenomenon and optimize detection of precision drug delivery in combination with imaging techniques. As we make progress in the understanding of the molecular and genomic aspects of HCC, there is the opportunity to explore the use of tumor-directed delivery of immunotherapy, along with ongoing integration of artificial intelligence along the line of radiomics.

If you could design a sufficiently funded randomized trial or large registry exploring a TACE application, what would the broad strokes of its goals and design be?

Dr. See: I think the role of TACE in downstaging is worth exploring, given its potential impact on patient care. This may involve solitary or multinodular HCCs beyond transplant, resection, or ablation criteria. The goals should include local tumor control, progression-free survival, and overall survival. The impact of local tumor control is critical when aiming for downstaging, and this could be evaluated with TACE alone versus TACE and combination therapy. The combination will require further thought, taking into consideration tumor morphology and patient factors, utilizing the principle of precision approach.

What do you see as the most significant obstacles to wider utility of TACE? What data, breakthrough, or changes in guidance might lead to increased visibility within the larger field of oncology?

Dr. Rilling: In the short to intermediate term, I believe the outcomes of current trials investigating the combination of immunotherapy and TACE have the opportunity to increase visibility and wider utility of TACE. For example, the EMERALD 1 and EMERALD 3 trials have the potential to change care pathways for HCC patients, depending on the results.

Dr. See: TACE is well recognized in the field of oncology, particularly in HCC. I do not think there is a reluctance to utilize TACE widely but in fact quite the opposite—clinical colleagues worldwide are keen to maximize the outcomes of TACE for their patients, for example in local tumor control or potentially downstaging. The confounding factors are the spectrum of TACE technologies and administrations, the heterogeneous patient groups, and the confidence in currently available data. The disparity of TACE trials with systemic therapy trials where a fixed-dose approach and strict inclusion and exclusion criteria are well evident. This has an impact on health economy evaluation and sustainability of the intervention. Large randomized controlled trials with well-defined patient cohorts, stringent criteria, and survival endpoints will no doubt attract recognition and stratification of the treatment algorithm.

In your interactions with HCC patients, what are their most common questions or concerns regarding TACE therapy, and how do you address these?

Dr. Rilling: One of the most common concerns we hear from HCC patients regarding TACE is the fear of “chemotherapy.” Patients associate this word with classic cytotoxic chemotherapy side effects such as hair loss, nausea, and vomiting. We explain that the chemotherapy is trapped in the tumor with very little systemic effect and that the symptoms they experience after treatment will be time limited and are related primarily to an inflammatory response to tumor cell death. The patients are also relieved to understand that they will typically receive one or two treatment sessions with further treatment “on demand” depending on response. We also take the opportunity to explain to patients that current systemic therapy for HCC has evolved rapidly and current regimens are generally well tolerated.

Dr. See: The question of utmost importance for the patient is whether TACE will be effective for them and for how long. My personal experience is that they tend not to be too concerned about side effects or how many times or how long the treatment takes, provided it gives them benefits of tumor control. They also want to know how long they can live with the cancer. These are not easy questions. I usually provide them with an overview of HCC management, including the stage of the disease, recommended treatment strategies, and available evidence on outcomes. I then relate that to their disease status and suitability and remind them that despite having the “same” cancer, each HCC patient is different, and what we are trying to do is to offer the best treatment options for them individually, based on current evidence and innovation.

Dr. Rilling, you had the honor of delivering the Dotter Lecture at the 2023 Society of Interventional Radiology Scientific Sessions, which among other topics focused on growing a research infrastructure to support interventional radiology (IR) therapies, in particular National Institutes of Health trials. What do you see as the extension of this concept with respect to interventional oncology (IO)? How can the IO field expand its reach via research at this level?

Dr. Rilling: I think one of our first priorities needs to be to expand research training in our IR residency programs, not just for the sake of IO but all aspects of IR. We have little to no formal research training integrated into the IR/diagnostic radiology residency currently. Residents who learn about research in their training hopefully are more likely to embrace it as they go forward in their careers. Other specialties have dedicated research time and training built in to their programs, and research is thus more ingrained in their culture. We need our future IR/IO physicians to understand the importance of research as the pathway for progress into improving and expanding patient care in our field. We also need to be able to train more clinician-scientists in IR/IO. Federal funding and training grants are available for this purpose, and clinician-scientists will be best positioned to develop high-quality research labs with sustained federal funding.

Disclosures
Dr. Rilling: Consultant to Varian, Boston Scientific Corporation, Terumo, BD Interventional, and AstraZeneca.
Dr. See: Speakers fees from Boston Scientific Corporation and Sirtex Medical.