The ART of decision making: Retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma

How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma

BackgroundThe pathologic responses to transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) are heterogeneous and result in disparate outcomes. The study aimed to establish and validate an effective nomogram for predicting pathologic complete response (PCR) after TACE.MethodsWe analyzed the clinicopathologic characteristics of HCC patients undergoing hepatectomy following TACE. Variables with statistical significance in a multivariate logistic regression analysis were incorporated in the nomogram.ResultsWe detected PCR in 64 (50.4%) patients in the training cohort and 18 (37.5%) patients in the validation cohort. Univariable and multivariable logistic regression revealed that hepatitis B virus (HBV) DNA load (P=0.031), α-fetoprotein (AFP, P=0.040), maximum tumor diameter (P=0.003), preoperative TACE session (P=0.026), and modified Response Evaluation Criteria in Solid Tumors (mRECIST) complete response (P=0.030) were identified as significant predictors of PCR. Incorporating these 5 factors, a nomogram was developed which attained concordance indexes of 0.80 [95% confidence interval (CI): 0.72–0.87] and 0.82 (95% CI: 0.68–0.95) for predicting PCR in the training and validation cohorts, respectively.ConclusionsThe easy-to-use nomogram achieved a good post-TACE prediction of PCR in HCC patients. Using the model, patients who would benefit most from TACE could be identified, and the subsequent appropriate procedures could be guided accordingly.

New Developments in the Treatment of Hepatocellular Carcinoma: The Concept of Adjuvant and Neoadjuvant Chemotherapy

INTRODUCTION:Patients with unresectable hepatocellular carcinoma treated with conventional transarterial chemoembolization (cTACE) have heterogeneous tumor burden and liver function. Therefore, the selection of patients for repeated cTACE is challenging owing to different outcomes. This study aimed to establish a decision-making scoring system for repeated cTACE to guide further treatment.METHODS:All patients with hepatocellular carcinoma who underwent cTACE between 2008 and 2019 were included and randomly assigned into training (n = 324) and validation (n = 162) cohorts. Tumor Size, number of Masses, Albumin-bilirubin score, baseline Alpha-fetoprotein level, and Response to initial cTACE session were selected to generate a “SMAART” score in the training cohort. Patients were stratified according to the SMAART score: low risk, 0–2; medium risk, 3–4; and high risk, 5–8. Prediction error curves based on the integrated Brier score and the Harrell C-index validated the SMAART scores and compared them with the Assessment for Retreatment with Transarterial chemoembolization (ART) score.RESULTS:The low-risk group had the longest median overall survival of 39.0 months, followed by the medium-risk and high-risk groups of 21.2 months and 10.5 months, respectively, with significant differences (P < 0.001). The validation cohort had similar results. The high-risk group had 63.1% TACE refractory cases. The Harrell C-indexes were 0.562 and 0.665 and the integrated Brier scores were 0.176 and 0.154 for ART and SMAART scores, respectively.DISCUSSION:The SMAART score can aid clinicians in selecting appropriate candidates for subsequent cTACE. A SMAART score of ≥5 after the first cTACE session identified patients with poor prognosis who may not benefit from additional cTACE sessions.

Objectives: To develop and validate a predictive model for early refractoriness of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).Methods: In this multicenter retrospective study, a total of 204 consecutive patients who initially underwent TACE were included. Early TACE refractoriness was defined as patients presented with TACE refractoriness after initial two consecutive TACE procedures. Of all patients, 147 patients (approximately 70%) were assigned to a training set, and the remaining 57 patients (approximately 30%) were assigned to a validation set. Predictive model was established using forward stepwise logistic regression and nomogram. Based on factors selected by logistic regression, a one-to-one propensity score matching (PSM) was conducted to compare progression-free survival (PFS) between patients who were present or absent of early TACE refractoriness. PFS curve was estimated by Kaplan-Meier method and compared by log-rank test.Results: Logistic regression revealed that bilobar tumor distribution (p = 0.002), more than three tumors (p = 0.005) and beyond up-to-seven criteria (p = 0.001) were significantly related to early TACE refractoriness. The discriminative abilities, as determined by the area under the receiver operating characteristic (ROC) curve, were 0.788 in the training cohort and 0.706 in the validation cohort. After PSM, the result showed that patients who were absent of early TACE refractoriness had a significantly higher PFS rate than those of patients who were present (p < 0.001).Conclusion: This study presents a predictive model with moderate accuracy to identify patients with high risk of early TACE refractoriness, and patients with early TACE refractoriness may have a poor prognosis.

Purpose: To develop and validate a random forest (RF) based predictive model of early refractoriness to transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC).Methods: A total of 227 patients with unresectable HCC who initially treated with TACE from three independent institutions were retrospectively included. Following a random split, 158 patients (70%) were assigned to a training cohort and the remaining 69 patients (30%) were assigned to a validation cohort. The process of variables selection was based on the importance variable scores generated by RF algorithm. A RF predictive model incorporating the selected variables was developed, and five-fold cross-validation was performed. The discrimination and calibration of the RF model were measured by a receiver operating characteristic (ROC) curve and the Hosmer-Lemeshow test.Results: The potential variables selected by RF algorithm for developing predictive model of early TACE refractoriness included patients' age, number of tumors, tumor distribution, platelet count (PLT), and neutrophil-to-lymphocyte ratio (NLR). The results showed that the RF predictive model had good discrimination ability, with an area under curve (AUC) of 0.863 in the training cohort and 0.767 in the validation cohort, respectively. In Hosmer-Lemeshow test, the RF model had a satisfactory calibration with P values of 0.538 and 0.068 in training cohort and validation cohort, respectively.Conclusion: The RF algorithm-based model has a good predictive performance in the prediction of early TACE refractoriness, which may easily be deployed in clinical routine and help to determine the optimal patient of care.

Chemoembolization and Radioembolization for Hepatocellular Carcinoma

We read with interest the letter of Kudo et al. from one of the large Japanese series of patients undergoing transarterial chemoembolization (TACE), who tried to validate the Assessment for Retreatment (ART) score1 in their patient sample. When the authors applied the same selection criteria to their 513 patients treated with >2 TACE procedures, only 49 patients were eligible for ART score-based analysis for having received two TACE procedures within 90 days (all others had longer intervals between TACE sessions) and the ART score was not able to differentiate between two prognostic groups. Looking at the two ART score groups in the Japanese patient sample more closely, it is quite obvious that the Japanese low ART score group was very similar to our own European cohort (median survival 22.4 versus 23.7/27.6 months), while the big difference was in the high ART score group between Kudo et al.'s and our cohorts (median survival 16.5 versus 6.6/8.1 months). In trying to understand this, one would have to take a closer look at the patient characteristics in both cohorts. First of all, the ART score does yield two groups with different survival in the Japanese patients as well, but the difference is much less pronounced than in the European patients and did not reach statistical significance. This could well be due to the small patient number in this analysis, which was only performed in 44 of the 49 patients (see fig. 1 of Kudo et al.). Regarding the overall small sample size (n = 49), the unexplained exclusion of 10% of patients may have had a significant impact on survival analysis. Besides that, and as pointed out by the authors, there are obvious differences in the patient and procedural characteristics between European and Japanese centers. In particular, Japanese patients usually present with smaller tumors due to nationwide screening programs and the TACE procedure is often carried out more meticulously than in European centers, allowing for less frequent TACE procedures and supposedly longer survival in patients undergoing TACE in Japan.2 This could potentially introduce a special selection bias, as indicated by the fact that less than 10% of Kudo et al.'s cohort was eligible for ART score calculation compared to almost 90% in the Austrian cohorts. But for a universally applicable score, these differences should be taken care of by diverting a different fraction of patients into the appropriate prognostic group. Surprisingly, this was not the case as much as we would expect: despite presumably smaller tumors and a more selective TACE procedure, still 27.3% of the Japanese patients retreated with TACE within 3 months presented with a high ART score before TACE 2, not so different from the 38% in the Austrian cohort. Considering that overall survival in TACE patients seems to be longer in Japan compared to Europe,2 it is not so much the longer survival in the Japanese high ART score group but the surprisingly low survival in the Japanese low ART score group that is hard to explain. Since we do not have any data on the BCLC-staging, Child-Pugh scores, which type of Child-Pugh score was applied, the differences in etiology of liver disease, the reason for performing a second TACE within 3 months, causes of death, total number of TACE cycles applied, etc., in the Japanese patients, it is impossible to reach any firm conclusions from the data presented by Kudo et al. In particular, BCLC-stage A could be much more prevalent in Japan, where cadaveric liver transplantation is very rare and living donors will likely not be able to fill in the demand, leaving more BCLC-A patients for TACE compared to Europe. With such a small patient number, it is conceivable that there was a significant imbalance between baseline variables in the Japanese cohort, e.g., BCLC-stage A in high ART score versus B in low ART score, which would have a major impact on survival. Likewise, a higher number of patients with a more marginal liver function or a significantly higher tumor burden in the low ART score group could explain the comparatively low survival, the atypical need for an early second TACE, and the less pronounced survival difference in the Japanese cohorts. We would definitely be very interested in seeing a well-matched complete effort to validate the ART score in Asian patients as well as in conducting a well-matched comparative analysis between Asian and Western patients, which could help to even better establish the universal applicability of the ART score as a selection tool for repeat TACE. Markus Peck-Radosavljevic, M.D. Wolfgang Sieghart, M.D. Florian Hucke, M.D. for the Vienna HCC Study Group Department of Internal Medicine III Division of Gastroenterology and Hepatology Medical University of Vienna Vienna, Austria

Purpose: The purpose of this study was to identify the factors of pain and pain management after transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). Methods: Participants were 99 inpatients with HCC who underwent TACE at C University in Seoul from May to October 2016. The instruments used in this study were the Numerical Rating Scale (NRS), the Pain Management Index (PMI), and the modified Patient Outcome Questionnaire (American Pain Society). The data were analyzed using SPSS 24.0, specifically descriptive statistics, t-test, ANOVA, and multiple regression. Results: The percentage of patients who experienced pain after TACE was 66.7%. The mean pain score immediately after TACE was 4.43±2.36 and the highest score on average was 6.58±2.32. The pain score was highest at 5.24±5.67 hours after TACE. Significant factors influencing pain after TACE were the extent of embolization and the ECOG (Eastern Cooperative Oncology Group) score, which explained 26% of the variance in pain. PMI scores revealed that 33.3% of the participants were inadequately treated for pain. Conclusion: In order to properly manage pain after TACE, medical staff need accurate understanding of pain and to administer the appropriate dosage of analgesics. The development of pain management protocol for patients who have undergone TACE would help achieve these goals.

Backgrounds/AimsThis study aimed to compare the outcomes of liver resection (LR) and transarterial chemoembolization (TACE) in patients with multinodular hepatocellular carcinoma (HCC) within the Milan criteria who were not eligible for liver transplantation.Methods We retrospectively analyzed 483 patients with multinodular HCC within the Milan criteria, who underwent either LR or TACE as an initial therapy between 2013 and 2022. The overall survival (OS) in the entire population and recurrence-free survival (RFS) in patients who underwent LR and TACE and achieved a complete response were analyzed. Propensity score (PS) matching analysis was also used for a fair comparison of outcomes between the two groups.Results Among the 483 patients, 107 (22.2%) and 376 (77.8%) underwent LR and TACE, respectively. The median size of the largest tumor was 2.0 cm, and 72.3% of the patients had two HCC lesions. The median OS and RFS were significantly longer in the LR group than in the TACE group (P<0.01 for both). In the multivariate analysis, TACE (adjusted hazard ratio [aHR], 1.81 and aHR, 2.41) and large tumor size (aHR, 1.43 and aHR, 1.44) were significantly associated with worse OS and RFS, respectively. The PS-matched analysis also demonstrated that the LR group had significantly longer OS and RFS than the TACE group (PS<0.05).ConclusionsIn this study, LR showed better OS and RFS than TACE in patients with multinodular Barcelona Clinic Liver Cancer stage A HCC. Therefore, LR can be considered an effective treatment option for these patients.

Intermediate-stage hepatocellular carcinoma (HCC) is usually treated with locoregional therapy using transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using β-emitting yttrium-90 integral to the glass matrix of the microspheres is an alternative to TACE. This retrospective case-control study compared the outcomes and safety of TARE versus TACE in patients with unresectable HCC. Patients with unresectable HCC without portal vein thrombosis treated with TARE between 2005 and 2008 (n = 61) were retrospectively frequency-matched by age, sex, and liver dysfunction with TACE-treated patients (n = 55) in the Mayo Clinic Hepatobiliary Neoplasia Registry. Imaging studies were reviewed, and clinical and safety outcomes were abstracted from the medical records. Complete tumor response was more common after TARE (12 %) than after TACE (4 %) (p = 0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the two groups (15.0 months for TARE and 14.4 months for TACE; p = 0.47). Two-year survival rates were 30 % for TARE and 24 % for TACE. TARE patients received fewer treatments (p < 0.001). Fifty-nine (97 %) TARE patients received outpatient treatment. In contrast, 53 (98 %) TACE patients were hospitalized for ≥1 day (p < 0.001). Compared with TACE, TARE was more likely to induce fatigue (p = 0.003) but less likely to cause fever (p = 0.02). There was no significant difference in efficacy between TARE and TACE. TARE patients reported more fatigue but had less fever than TACE patients. Treatment with TARE required less hospitalization than treatment with TACE. These findings require confirmation in randomized trials.

Cytokines play an important role in the development of tumors. The purpose of the present study was to evaluate the mechanisms and cytokine level changes after transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). The Short Time-series Expression Miner (STEM) program was utilized to cluster cytokine expression profiles from the day before TACE to day 21 post-TACE. Based on the identified significant signatures, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed. Cytokines were serially monitored in 60 evaluable patients to identify the results of the STEM program. Examination of the significant signatures identified 6 significant time-varied expression patterns for 507 cytokines (profiles 16, 18, 28, 41, 42 and 43). GO analysis was enriched in ‘cytokine receptor-binding’ and ‘cytokine receptor activity’, and the identified signaling pathways included ‘cytokine-cytokine receptor interaction’ and the ‘JAK-STAT signaling pathway’. Ciliary neurotrophic factor (CNTF) level was increased early after TACE, reaching a peak on day 7 before finally decreasing from day 14 onwards, and was significantly positively correlated with aminotransferase level. Serum levels of pre-TACE IL-10 predicted the local tumor response and overall survival (OS) of the patients, while serum levels of post-TACE IL-1β only indicated the local tumor response of the patient. Overall, the present study identified cytokine time-series expression profiles of patients with HCC undergoing TACE. Early phase increases in CNTF after TACE were associated with post-treatment hepatic injury. IL-1β may reflect an objective response after TACE, while IL-10 may represent a biomarker for OS and the objective response pre-TACE, which may help patients with HCC to benefit from TACE.

It is unknown whether sorafenib can be combined with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma. This study assesses the safety and tolerability of a continuous regimen of sorafenib combined with TACE. This was an open-label phase I study testing a continuous administration of sorafenib (dose escalation from 200 mg twice daily [bid] to 400 mg bid) starting 7 days prior to TACE with doxorubicin (50 mg). Twenty-one patients were screened and 14 received sorafenib combined with TACE. Because there were no dose-limiting toxicities in the first three patients who received sorafenib at a dose of 200 mg bid, subsequent patients received 400 mg bid. Twenty-seven procedures were performed (median, two per patient) and two local therapy-related severe adverse events occurred. The median duration of sorafenib therapy was 246 days (range, 14-547 days). Sorafenib-related adverse events of grade ≥3 were hand-foot skin reaction (n = 3), weight loss (n = 2), diarrhea (n = 1), abdominal pain (n = 1), and thrombocytopenia (n = 3). After treatment with sorafenib and TACE, there was a significant decrease in the concentration of plasma vascular endothelial growth factor (VEGF) from 93 ng/l to 67 ng/l. Continuous administration of sorafenib at a dose of 400 mg bid combined with TACE was tolerable. The adverse event profile of this regimen was comparable with that of sorafenib monotherapy with the exception of thrombocytopenia, which may be more frequent. There were no increases in the circulating VEGF levels after TACE with this combined regimen. (Swiss Association for the Study of the Liver study number 25; ClinicalTrials.gov trial identifier, NCT00478374).

Background. Thrombocytopenia often makes the introduction of systemic treatment difficult in patients with cirrhosis and hepatocellular carcinoma (HCC). We retrospectively evaluated the long-term effects of partial splenic embolization (PSE) with transarterial chemoembolization (TACE) in patients with HCC patients accompanied by thrombocytopenia. Patients and Methods. Twenty-one patients with HCC complicated by severe thrombocytopenia (platelet count, <5.0 × 104/mm3) were treated with PSE and TACE. Both the safety and platelet-increasing effect was evaluated in these patients. Results. Seventeen of 21 patients (81.0%) showed increased platelet counts to ≥5.0 × 104/mm3. Subsequently, 13 patients (61.9%) successfully received systemic chemotherapy. Platelet counts and serum levels of total bilirubin, as well as neutrophil counts, improved significantly one month after treatment. However, serum levels of albumin and hemoglobin decreased significantly one month after treatment. Severe adverse events, including acute liver failure and portal vein thrombus, were observed in two patients. Conclusion. PSE with selective TACE made it possible for patients with HCC and severe thrombocytopenia to receive systemic chemotherapy. Although PSE with TACE was safe and tolerable for most patients, the extent of PSE with TACE in a wide area of the liver may increase the risk for fatal liver failure.

Background CT-guided high-dose-rate (HDR) brachytherapy (hereafter, HDR brachytherapy) has been shown to be safe and effective for patients with unresectable hepatocellular carcinoma (HCC), but studies comparing this therapy with other local-regional therapies are scarce. Purpose To compare patient outcomes of HDR brachytherapy and transarterial chemoembolization (TACE) in patients with unresectable HCC. Materials and Methods This multi-institutional retrospective study included consecutive treatment-naive adult patients with unresectable HCC who underwent either HDR brachytherapy or TACE between January 2010 and December 2022. Overall survival (OS) and progression-free survival (PFS) were compared between patients matched for clinical and tumor characteristics by propensity score matching. Not all patients who underwent TACE had PFS available; thus, a different set of patients was used for PFS and OS analysis for this treatment. Hazard ratios (HRs) were calculated from Kaplan-Meier survival curves. Results After propensity matching, 150 patients who underwent HDR brachytherapy (median age, 71 years [IQR, 63-77 years]; 117 males) and 150 patients who underwent TACE (OS analysis median age, 70 years [IQR, 63-77 years]; 119 male; PFS analysis median age, 68 years [IQR: 63-76 years]; 119 male) were analyzed. Hazard of death was higher in the TACE versus HDR brachytherapy group (HR, 4.04; P < .001). Median estimated PFS was 32.8 months (95% CI: 12.5, 58.7) in the HDR brachytherapy group and 11.6 months (95% CI: 4.9, 22.7) in the TACE group. Hazard of disease progression was higher in the TACE versus HDR brachytherapy group (HR, 2.23; P < .001). Conclusion In selected treatment-naive patients with unresectable HCC, treatment with CT-guided HDR brachytherapy led to improved OS and PFS compared with TACE. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Chapiro in this issue.