On the 100th anniversary of Lipiodol’s introduction as a contrast agent in radiology, research is turning to the role of Lipiodol TACE (cTACE) in combination treatments for Hepatocellular carcinoma. Combining locoregional treatments with immunotherapy shows promise, with ongoing investigations seeking to confirm the efficacy and safety of the modality to help improve patient care and outcomes.
by Dr Ahmed Abdelal and Dr Binta Patel
Hepatocellular carcinoma, or HCC, is the most common type of primary liver cancer and the second most common cause of cancer-related deaths, according to 2018 figures.1 The incidence and mortality of HCC continue to rise, despite the availability of a number of treatments.
The management of liver cancer requires a multidisciplinary approach, and treatment options rest on several factors, such as the stage of liver cancer and the patient’s overall health. Among the multiple staging systems used for liver cancer, including the TNM system, the Barcelona Clinic Liver Cancer (BCLC) system is most commonly applied to help determine appropriate treatment options for patients with primary liver cancer. It is divided into four stages: early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D). The BCLC staging also includes the Child-Pugh score, which measures the severity of liver disease and predicts mortality risk.
Currently, only surgical transplantation, tumour resection, and ablative techniques are considered curative treatments when applied to early-stage HCC.2 For patients with unresectable liver cancer, image-guided locoregional therapies are recommended for BCLC stage A and stage B, while systemic therapy is offered for BCLC stage C.
Although locoregional therapies are noncurative, they aim to preserve liver function, slow tumour progression, prolong overall survival, and provide effective downstaging to allow for curative therapies. These minimally invasive procedures include bland trans-arterial embolisation (TAE), trans-arterial chemoembolisation (TACE), ablative therapy, and trans-arterial radioembolisation (TARE).
We are concerned here with TACE and the potential for combining Lipiodol TACE with immunotherapy to improve patient response and outcomes.
The History of cTACE
Discovered in 1901, Lipiodol was brought to market to expand the therapeutic uses of iodine. When its radiopaque properties were discovered 20 years later, in 1921, it made history as the first iodinated contrast agent, with a mounting list of indications. However, it was not until the 1980s that Lipiodol would reclaim its original purpose as a therapeutic agent, with the discovery of TACE by Professor Toshimitsu Konno and colleagues.
Lipiodol TACE, better known as conventional TACE (cTACE), was recognised due to its unique properties, including radiopacity, strong affinity to tumours, and transient embolisation, and its ability to deliver cytotoxic drugs to tumours.
Conventional TACE is performed by injecting a chemotherapeutic agent (or agents) mixed with ethiodised oil into the tumour-feeding artery, leading to ischemic necrosis of the tumour. The infusion is followed by an embolic agent to decrease washout of the injected chemotherapeutic emulsion concentrated in the tumour. The radiopaque properties of Lipiodol enable the operator to visualise the delivery of the cytotoxic drug to the tumour, in real-time, with fluoroscopy. This allows for safe administration of the drug and for the visualisation of the tumour response during post-TACE CT imaging.
cTACE as a Recommended Treatment for HCC
Mechanistically, like other arterial directed therapies (ADT), TACE is designed to provide treatment with minimal collateral damage to the liver and reduced systemic effect. It has long been the recommended treatment option for intermediate-stage HCC within the BCLC staging system. Current European Association for the Study of Liver (EASL) guidelines, for example, recommend TACE as a first-line therapy for patients with BCLC stage B.
With growing evidence for the significance of TACE in early-stage HCC, the 2022 update of the BCLC staging system expanded its recommendations to include TACE as a treatment option for patients who are not eligible or have failed ablation or surgical resection in early-stage HCC.3
To date, cTACE remains one of the most well-studied trans-arterial therapies for HCC. In fact, all ADT modalities, including DEB-TACE, TARE, and TAE, have become an integral part of HCC management. They are routinely used in clinical practice and clinical studies and should be considered complementary rather than competitive to cTACE.
The Search for New Treatments Continues
Despite achievements with current treatment options, new treatment approaches continue to be investigated in the hope of further improving overall survival rates in patients with unresectable liver cancer. These approaches include the development of new immunotherapies and tyrosine kinase inhibitors (TKIs) and research into combining any number of the current modalities. One such investigation proposes the combination of locoregional therapies and immunotherapy.
Immunotherapy with ICI for HCC
A rapidly growing area of interest for the treatment of HCC is immunotherapy with immune checkpoint inhibitors (ICI) that target the body’s antibodies to direct an immune response towards the tumour.
HCC that develops in the setting of chronic inflammation has an immunosuppressive microenvironment that makes immunotherapy an attractive treatment option. The challenge with immunotherapy is being able to predict which patients will respond to the therapy due to the heterogeneity of HCC. Several clinical trials have investigated ICI for the treatment of advanced HCC. The response rates to monotherapy ranged from 15 per cent to 23 per cent and increased to approximately 30 per cent after combination treatment.4
The recent success of the IMbrave150 (NCT03434379) trial, which studied the combination of atezolizumab and bevacizumab versus sorafenib alone, has highlighted the potential of immunotherapy in HCC. This phase 3 trial included a total of 501 patients with unresectable HCC and no history of systemic treatment. The results showed overall survival (OS) rate of 67.2 per cent with combination therapy and 54.6 per cent with sorafenib at 12 months. Median progression-free survival (PFS) was longer in patients receiving combination therapy than with sorafenib alone, 6.8 months and 4.3 months respectively.5
TACE and ICI Combination Therapy Investigations
Combination therapy with immunotherapy is therefore a promising strategy to improve tumour response and outcomes for patients with HCC. Hence, the rationale behind combining immunotherapy with locoregional therapies such as TACE, TARE, and ablation.
Locoregional therapies aim to destroy the tumour and induce an inflammatory response by releasing tumour-associated antigens and stimulating an anti-tumour microenvironment. However, this effect alone may not be sufficient to lead to significant lasting tumour regression. If combined with immunotherapy, which aims to stimulate an effective systemic immune response against tumour cells, the effect of the locoregional therapy in patients with HCC may be enhanced. Various combinations of therapy for HCC with these modalities have been studied, with a rising interest in studying the synergistic effects of interventional procedures with ICIs.
A 2017 study by Duffy et al investigated the safety and feasibility of combining tremelimumab, an anti-CTLA-4 ICI, with either TACE, radiofrequency ablation, or chemoablation in 32 patients with HCC. The results showed partial response in 26.3 per cent (5/19) of patients, with median time to tumour progression of 7.4 months and median OS of 12.3 months.6
The results of combining immune checkpoint inhibition with subtotal TACE or ablation in patients with advanced HCC are encouraging and demonstrate the potentially improved efficacy of this kind of combination versus monotherapy alone to improve the management of patients with HCC. Investigations are continuing. Three phase 3 trials are currently underway to investigate the addition of ICI with TACE, in comparison to TACE alone, for patients with intermediate-stage HCC (BCLC stage B):
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- The LEAP-012 trial is testing the addition of lenvatinib and pembrolizumab to TACE (NCT04246177);
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- The EMERALD-1 trial is testing the addition of durvalumab, with or without bevacizumab, to TACE (NCT03778957); and
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- The CheckMate 74W trial is testing the addition of nivolumab, with or without ipilimumab, to TACE (NCT04340193).7
In addition, a phase 2/3 trial is investigating the addition of nivolumab to TACE/TAE (NCT04268888) in the treatment of patients with intermediate-stage HCC.
Conclusion
It will take several years to effectively demonstrate the efficacy and safety of these various new treatment modalities. Guerbet is investigating the association between locoregional treatments, especially cTACE of unresectable HCC, with immunotherapy and will continue to push the research in the fight against HCC.
With 100 years of history, Lipiodol remains at the forefront of research in the management of HCC, reconfirming its place in the therapy arsenal of interventional radiology. [APBN]
About the Authors
Dr Ahmed ABDELAL is Guerbet’s Global Head Medical Affairs Interventional Imaging and North America Head of Medical & Regulatory Affairs. He oversees and directs all medical and regulatory activities for Guerbet’s drug products and medical devices, from development through post-approval.
Dr Binta PATEL is Guerbet’s North America Medical Affairs Manager covering both Diagnostic and Interventional Radiology.