Transarterial chemoembolization (TACE) is being widely used as a non-surgical therapy for the simultaneous treatment of chemotherapy and selective ischemia for hepatocellular carcinoma (HCC). On the basis of a higher level of evidence, TACE has been proven to improve the survival rate for patients with intermediate-stage HCC, defined as Barcelona-clinic liver cancer (BCLC) stage B HCC, for which patients are not candidates for curative strategies such as surgical resection, liver transplantation, and local ablative therapies [1-4].

Depending on the nature of the tumor, including size, number, growth pattern, and anatomical location, the treatment response is not always easy to obtain from a single session, showing differences in outcomes between reports [5,6]. Thus, repeated TACEs are often performed to achieve a sufficient outcome. However, the method for predicting “TACE refractoriness” that does not show a therapeutic response even after repeated TACE treatments is still unclear. Enhanced criteria of TACE refractoriness were proposed by Japanese experts, which considered insufficient treatment response, increase in tumor number, new structural invasion or metastasis, and change in tumor markers [7]. In the recent Korean guideline, [8-10] sorafenib treatment was recommended if the stage progressed despite more than three repeated TACE treatments within 6 months.

However, in practice, there are too many heterogeneous situations to select a consistent treatment strategy; therefore, the clinical decision of the primary physician often plays a larger role than the formal guidelines in determining the appropriate time to try or switch to other therapies including radiotherapy, radiofrequency ablation, and sorafenib.

Therefore, we conducted an online survey and summarized the results below to identify the trends in the actual clinical application of TACE and the recognition of TACE refractoriness among the clinicians treating HCC in Korea.

From November 9, 2017 to December 16, 2017, a total of 161 liver cancer clinicians in Korea were enrolled, including 121 gastroenterologists, 15 surgeons, five radiation oncologists, one hematologist, and 19 medical doctors of other fields (Table 1). All participants were working in tertiary medical centers where treatment procedures were performed via an intra-arterial route. Each individual accessed the online survey and selected his/her desired answers among the 17 multiple-choice questions. For 11 of the 17 questions, the participants were allowed to select multiple answers. All participants had worked in their fields for more than 10 years.

To compare practice patterns according to the size of the hospital, participants were divided into two groups: the five highestvolume centers and the lower volume centers. Clinical practice patterns according to the location of the hospitals were also compared by dividing participants into two groups: who were located in metropolitan areas (Seoul and Gyeonggi provinces) that had chance to easily access to the five high-volume centers, and who were located in other provinces.

The General Rules for the Clinical and Pathological Study of Primary liver cancer, developed by the Liver Cancer Study Group of Japan, were used to classify portal vein tumor thrombosis [10]. According to these rules, the definition of Vp3 was the presence of a tumor thrombus in the first branches of the portal vein, and the definition of Vp4 was the presence a tumor thrombus in the main trunk of the portal vein and/or the contra‐lateral portal vein branch to the primarily involved lobe.

Statistical analyses were conducted using the IBM SPSS Statistics software, version 23.0 (IBM Corp., Armonk, NY, USA), and a two-sided P-value of <0.05 was considered significant. The Chisquare test and Fisher’s exact test, as appropriate, were applied to compare qualitative variables.

Baseline information of the participants are summarized in Table 1. Of 128 (79.5%) male and 33 (20.5%) female participants, 42 (26.1%) clinicians were working in the five high-volume centers, and 120 (74.5%) clinicians were working in the medical centers located in Seoul and Gyeonggi provinces.

The effects of TACE on HCC and the changes in survival patterns may vary depending on the patient’s residual liver function and the characteristics of the tumor itself, so it is often necessary to repeatedly perform TACE because a single trial does not obtain sufficient results in many cases [11,12]. It is still controversial whether treatment should be changed during repeated TACE or whether the effect obtained at some time point will help predict a patient’s survival [5,13]. Although the recent HCC guideline by the Korean Liver Cancer Association suggested that progression of the disease after multiple trials of TACE treatment could be regarded as TACE refractoriness [14], there has been no actual definition of TACE refractoriness that can help further establish a treatment plan.

Therefore, the survey was conducted to see how medical staff in Korea were actually applying TACE in their work fields. In this survey, tumor number, size, and shape (nodular or infiltrative type) were considered as factors to affect the response to TACE treatment. A short period (about 1–3 months) until the appearance of the new lesions or recurrences, the maximum size of 3–7 cm of local recurrence, and the insufficient necrosis or recurrences after 2–3 times of repeated TACE treatments were considered to be suitable for TACE refractoriness. For multiple local recurrence, participants responded that repeated TACE treatment could be performed. However, for patients with advanced stage or suspected TACE refractoriness, clinicians selected sorafenib and localized radiotherapy more frequently. Radiotherapy was more preferred to be performed by the clinicians in the large medical centers or centers with good accessibility to the larger centers, probably because the high-volume centers had sufficient experience and appropriate facilities to perform radiation therapy.

TACE is useful because it can minimize impairment of hepatic function while improving treatment response and survival rate. However, at a certain point in time, repeated TACE treatments could show refractory patterns that diminish its usefulness and result in necrosis of multifocal lesions, which could lead to aggravation of liver function and worse patient survival [7]. Therefore, it is important to determine a precise definition of TACE refractoriness to maximize the effectiveness of TACE itself and other therapies.

Many efforts have been made to subclassify the intermediate stage or provide prediction models through other scoring systems. Sub-classification by applying the Milan criteria and up to 7 criteria had been proposed, while classifying HCC patients in the intermediate stage into B1, B2, B3, B4, and Quasi-C groups according to basal liver function and the presence of marginal portal thrombus [6]. The HAP score began as a predictive model for the effectiveness of the first TACE by scoring serum albumin, serum total bilirubin, serum alpha-fetoprotein, and maximum tumor size [15]. Moreover, the modified HAP-II scoring system, which additionally evaluated the presence of multiple tumors, showed efficacy in 280 patients with HCC in Korea [16]. The ART score system, including the Child-Pugh score, serum aspartate aminotransperase, and response evaluation after the first TACE [17], has not shown efficacy in other studies of HCC patients with chronic hepatitis C in Japan [18], Italy [19], and France [20] and chronic hepatitis B in Taiwan [21], and it was also ineffective in evaluating the efficacy of repeated drugeluting bead TACE for HCC patients in a Spanish multicenter study [22]. However, combined application of the ART score after classification with the HAP score showed a significant efficacy in predicting TACE refractoriness in a recent multicenter study, and an algorithm for performing repeat TACE in early- and intermediate-stage HCC was suggested, and repeated TACE could be performed for patients with an ART score less than 2.5 after the first TACE [23].

Some recent studies have shown that obtaining a complete response at an earlier time strongly predicted a favorable survival outcome in patients with HCC [13,24,25]. Moreover, BCLC stage, pretreatment alpha-fetoprotein level, and tumor number were also independent risk factors for overall survival along these studies [13,24]. Regarding this, not only the on-treatment response but also baseline tumor characteristics and laboratory data could be used as official predictors for TACE refractoriness in the guideline. Assessing TACE refractoriness as quickly as possible could provide clinicians with the opportunity to make treatment strategies easier (such as localized radiotherapy, TACE, and concurrent therapies) and to increase the effectiveness of these next treatment strategies.

According to the results of this survey, the treatment of HCC favored by participants were not significantly different from the treatments recommended in the BCLC stage or proposed by the various scoring systems or sub-classifications as mentioned above. Of course, the management of HCC is difficult to simply standardize and the clinical judgment of the primary care physician considering individual tumor characteristics, economic situation, and the familial environment is still important, but is difficult without sufficient clinical experience. Therefore, standardization of treatments that many physicians can use is still necessary. There is also a need for experts to continue to discuss the subdivision of guidelines for the treatment of HCC in Korea.