Safety and efficacy of drug-eluting microspheres chemoembolization under cone beam computed tomography control in patients with early and intermediate stage hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for most primary liver tumours and is the fourth most common cause of cancer-related death in the world.¹ The prognosis of the disease correlates strongly with liver function (defined by Child-Pugh’s class, bilirubin, albumin, clinically relevant portal hypertension, ascites), tumour status (defined by number and size of nodules, presence of vascular invasion, extrahepatic spread) and general tumourrelated health status.² The Barcelona Clinic of Liver Cancer (BCLC) staging system divides patients into five groups to facilitate treatment selection and prognosis prediction.² According to the guidelines of the European Association for the Study of the Liver (EASL) and the European Society of Medical Oncology (ESMO), transarterial chemoembolization (TACE) is the standard treatment for HCC in patients with intermediate-stage disease, i.e., BCLC stage B.^2,3 Furthermore, a clinical situation known as “treatment stage migration” has been introduced since not all patients with early-stage disease can be treated with surgery or ablation but may benefit from TACE.⁴ The intention of treatment stage migration is to offer the next most suitable option within the same stage or the next prognostic stage to patients who do not respond to the recommended treatment or do not qualify for it, thus improving their outcomes.^{4, 5, 6}

The principle of TACE is selective delivery of a high local concentration of a chemotherapeutic drug mixed with embolic material, which results in strong cytotoxic and ischemic effects.² Two techniques are currently recommended: conventional TACE (cTACE) and drug-eluting microsphere transarterial chemoembolization (DEM-TACE).^2,3 Conventional TACE (cTACE) uses a mixture of Lipiodol and chemotherapeutics, while DEM-TACE uses microparticles that can be loaded with a chemotherapeutic drug that is released in the target tissue slowly and in a controlled manner. The most frequently used drug in DEM-TACE is doxorubicin.⁷

Untreated patients with BCLC stage B disease have a median OS of 10 to 16 months after HCC diagnosis.^2,8 The median OS for patients treated with TACE is approximately 20 months after treatment initiation.^5,9 In well-selected patients, median OS can be prolonged to 30–50 months.^2,3 A difference in OS between patients treated with doxorubicin-loaded DEM-TACE and those treated with cTACE has not been observed.^10,11

A further improvement in TACE was the introduction of cone beam CT (CBCT) control during the procedure. CBCT is mounted on a C-arm fluoroscopy unit in the Institute of Radiology suite, allowing enhanced visibility in soft-tissue and vascular procedures. CBCT enables more precise implementation of TACE from planning to microcatheter positioning, which ensures visualization of the tumour-feeding vessels and parenchymal staining during TACE, achieving a detection accuracy significantly superior to that of standard 2D angiography.^12,13

The aim of this single-institution retrospective study was to evaluate the safety and effectiveness of doxorubicin drug-eluting microsphere chemoembolization under CBCT control in patients with early and intermediate stage HCC.

The purpose of this retrospective study was to evaluate the safety and effectiveness of DEM-TACE in patients with early and intermediate stage HCC. TACE is the standard of care for HCC patients with intermediate-stage disease. Moreover, for patients who are ineligible for surgical resection or percutaneous ablation, TACE is also considered a first-line treatment option in the early stage.^16,17 However, intermediate HCC corresponds to a highly heterogeneous group of patients with significant variations in number and size of tumour, patient performance status and liver function, resulting in variable survival rates.¹⁸ The median OS for patients treated with TACE is reported to range from approximately 19 months to 40–50 months in well-selected patients^2,3,9, which is consistent with our results. The median OS in our study was 25.8 months, with a range from 5.6 months to more than 7 years. A multicentric study by Han et al. in 2019 showed a median OS of 19.9 months with a range from 7 months to more than 4 years.¹⁹ A study by Burrel et al. showed that the median OS can be prolonged up to 48.6 months with careful patient selection.⁴ Several prognostic factors, such as Child Pugh class and tumour number, have been linked to higher survival rates and can be used to select ideal candidates for TACE.^19,20 The Child Pugh score is a valuable tool for assessing liver function, and our results support its correlation with survival. However, this score does not consider some events that may indicate end-stage liver disease (e.g., renal failure, spontaneous bacterial peritonitis, hyponatremia, recurrent encephalopathy, and malnutrition) and may be replaced by other selection criteria in the future.¹⁶ Another factor that may lead to better survival rates in some studies is treatment stage migration, as the survival of BCLC-A patients is expected to be better than that of BCLC-B patients.⁶ Treatment stage migration also applies to BCLC stage B. Although most patients achieve an objective response after treatment, they can present with new tumour sites during their follow-up and thus qualify as having disease progression. Intrahepatic treatable progression can be treated with repeat TACE. On the other hand, the untreatable progression may necessitate initiation of systemic therapy. In this study, migration to systemic therapy was recorded in 24 patients.

Higher OS may be related to the high objective response rates achievable with TACE, which is supported by the fact that an objective response to treatment measured by mRECIST correlates with prolonged OS.^21,22 According to the European Association for the Study of the Liver mRECIST represents the gold standard for radiologically evaluating tumour response during HCC locoregional treatment.² Previously used EASL criteria express the change in the two dimensions of hyperenhancing tumour and therefore also reflect the extent of necrosis caused by the treatment. mRECIST criteria adopted a single long-axis measurement and are simplified objective measure of treatment response, especially with the use of superselective approach where little or no viable tumour is expected. An objective response to TACE is achieved in approximately 50% of patients, with the lowest rate reported to be approximately 16% and the highest reported to be approximately 85.6%.^16,17,23 A prospective, randomized phase II study comparing doxorubicin-loaded DEM-TACE with cTACE showed higher objective response rates in the doxorubicin-loaded DEM-TACE group – 51.6% vs. 43.5%, respectively.¹¹ In a study by Suk et al. assessing CBCT after doxorubicin-loaded DEM-TACE, an objective response was achieved in 85.6% of patients (63.8% complete response, 21.8% partial response).²³ Our results exceed those of the above studies, showing a 91% rate of an objective response defined according to the mRECIST.

The benefits of CBCT for intra-arterial liver procedures are now well established and documented. The detection accuracy of CBCT for HCC lesions is equivalent to those of multidetector CT and MRI and superior to that of angiography. CBCT is the most accurate imaging technique to identify tumour-feeding arteries and can be used to rule out nontarget embolization of nontumour-feeding extrahepatic arteries. These advantages of CBCT can result in better treatment efficacy of DEM-TACE and other intra-arterial therapies.¹³

DEM-TACE has been demonstrated to result in fewer complications than cTACE.²⁴ In a systematic review of cTACE by Lencioni et al., 274 articles with a total of 34,137 patients were analyzed and adverse events were observed in 15,351 patients in a total of 217 selected studies.⁹ The most common procedure-related complication was PES, with the incidence of 47.7%. Other studies describe an even higher incidence of PES, with an estimated rate of 48%.⁹ According to the CIRSE guidelines, PES by itself is considered an expected outcome of the procedure rather than a complication.^14,25 Procedural complications, including intraprocedural small arterial branch rupture, hematoma at the puncture site, cerebellar stroke and radial artery thrombosis following a transradial approach, occurred in 1.1% of our cases. Eosophageal variceal bleeding was managed with endoscopic variceal banding. To our knowledge there is no known mechanism through which TACE could facilitate variceal bleeding. Since the bleeding occurred only once in otherwise large cohort of patients with high risk for variceal bleeding, we believe that this was probably a coincidental event. Other complications are all recognized although extremely rare following TACE procedures and all of them were one-time events.^{26, 27, 28} Intraprocedural small arterial branch rupture was managed with endovascular coil embolization and this complication didn’t prolong the patient’s hospital stay. Ischemic stroke is an extremely rare, but recognized event.²⁷ A recent literature review describes twelve cases in patients undergoing DEB-TACE or cTACE with mechanisms including intrahepatic arteriovenous shunts, hepatopulmonary shunts and intracardiac shunts. The presence of arteriovenous shunting to hepatic or pulmonary veins is routinely checked for at intraprocedural angiography and is a well-known contraindication to performing TACE, while checking for intracardiac shunts is not routinely performed in these patients. The patient in our cohort had a cerebellar stroke, which occurred after the procedure being performed via the right internal mamarian artery. Due to the cerebellar location, we hypothesize this non-target embolization was the result of the reflux of the embolic agent into the vertebral artery. In our patient the symptoms of ischemic insult resolved spontaneously, and no specific treatment was applied. Thrombosis of the radial artery was a result of transradial approach in a patient with a severe stenosis of iliac arteries preventing transfemoral approach. Radial artery occlusion is not a TACE specific complication and it occurs in 1 – 10% of patients following transradial interventions with lower numbers of complications occurring in experienced centers.²⁶ Our patient was managed conservatively while hospitalized but was then lost to angiological follow-up.

Our study has some limitations. This was a retrospective study including only a limited number of patients and no control group. A standard treatment methodology and patient selection criteria for TACE are lacking due to the heterogeneity of the HCC patient population with BCLC stages A and B. Therefore, patient selection should be carefully considered to achieve the best outcomes. Subsequent studies should include a larger group of patients. Other medical centres should also be included since the results of this single-centre study may not be applicable to other centres and geographic regions. Furthermore, although four interventional radiologists performed DEM-TACE according to uniform protocols, minor variations, such as in catheterization selectivity, were inevitable. Finally, the treatment effect of DEM-TACE may also be significantly influenced by multimodality treatment; thus, the long-term outcomes might not be representative.

In conclusion, DEM-TACE under CBCT control in patients with early and intermediate stage HCC is a safe and effective method of care. The results of this study are consistent with that in our study from 2016, confirming that proper patient selection, routine utilization of CBCT control for superselective TACE guidance, regular treatment response evaluation and liver function tests, together with retreatment “on demand” results in high objective tumour response and survival rates.