Repeated Previous Transarterial Treatments Negatively Affect Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib

: Background: Transarterial chemoembolisation (TACE) and radioembolisation (TARE) can lead to the deterioration of liver function, especially in cases of a high tumour burden, potentially lessening the beneﬁts of subsequent systemic treatments. We aimed to verify whether a high number of previous transarterial treatments modiﬁed the outcomes of patients who received sorafenib as a frontline systemic treatment. Methods: A retrospective analysis of a large multicenter dataset containing prospectively collected data of sorafenib-treated patients was conducted. Results: Data from 696 patients were analysed, with 139 patients having received >two transarterial procedures before starting sorafenib. A propensity score matched 139 identiﬁed pairs of patients. Having received >two locoregional treatments was independently associated with a shorter survival (hazard ratio 1.325, 95% conﬁdence interval 1.018–1.725, p = 0.039). This pattern was conﬁrmed amongst responders to sorafenib, but not in progressors. A trend toward a higher rate of the permanent discontinuation of sorafenib due to liver failure (18.7 vs. 10.8%, p = 0.089) and a lower rate of eligibility for second-line treatments (24.5 vs. 17.3%, p = 0.184) was observed in patients who had received >two transarterial procedures. Conclusions: Repeated endovascular treatments negatively impacted the survival of HCC patients, especially sorafenib-responders. An early switch to systemic therapies should be considered in cases that are unlikely to respond.


Introduction
Hepatocellular carcinoma (HCC) is a relevant global health problem causing more than 800,000 deaths worldwide every year [1,2].HCC can be treated with different modal-ities, including surgical, percutaneous and systemic therapies, according to the stage of the disease.
While early stages of the disease are preferably treated with surgical or percutaneous therapies, patients in more advanced stages are usually candidates for a combination of different treatments according to their Barcelona Clinic for Liver Cancer (BCLC) stage.Patients in the intermediate stage (BCLC B) are usually treated with transarterial procedures, while patients in the advanced stage (BCLC C) with preserved liver function and an Eastern Cooperative Group Performance Status (ECOG-PS) are better suited for systemic therapies [3].
Among transarterial treatments, transarterial chemoembolisation (TACE) is the most popular option.However, the risk of liver function impairment following TACE is well known [4,5].Transarterial radioembolisation (TARE), also known as selective internal radiotherapy, is another transarterial procedure which gained popularity following promising preliminary results [6].Different from TACE, the efficacy of TARE is based on delivering the cytotoxic radioisotope Yttrium-90 to HCC rather than relying on the ischemic effect of embolisation.Therefore, it has the potential to treat larger tumours, including in neoplastic portal vein invasion [7], which is instead a contraindication to TACE.TARE, however, is not recommended for locally advanced HCC following the failure of three different Phase 3 trials [8][9][10], but it has been used before these results and is currently used in selected cases in the context of a multidisciplinary discussion [11].The potential benefit of TARE should be checked against the risk of radiation-induced liver damage, a condition which could lead to irreversible liver failure [8][9][10] In 2022, the BCLC group updated its recommendations regarding two critical concepts: treatment stage migration and untreatable progression [12].The first concept consists of selecting a treatment reserved for a more advanced stage for patients unsuitable for other recommended therapy.Untreatable progression applies to patients who either do not respond or progress after receiving the initial recommended treatment, but they still fit into the initial BCLC stage: in this scenario, the recommendations warrant considering a therapy destinated initially to a more advanced stage [13].
The low adherence to the guideline recommendations is a known phenomenon in HCC [14].Due to the heterogeneity of the HCC population, multidisciplinary teams might recommend treatments diverging from the guidelines in case of comorbidities, borderline liver functional reserve, local expertise, or patients' preferences.Consequently, patients within the early and intermediate stages might receive multiple locoregional treatments (especially when the tumour burden is relatively low) before a condition of untreatable progression is declared by the tumour boards, leading to the start of systemic treatment.Despite experts considering that delaying the decision to start a systemic therapy in intermediate HCC might have negative prognostic correlates, data supporting this approach are scarce.Therefore, we aimed to verify whether having received repeated transarterial procedures (both TACE and TARE) affected the overall survival (OS) of patients who had received sorafenib as a first-line systemic treatment.

Study Design
A retrospective analysis of prospectively collected data from the ARchives of Patients with hEpatocellular carcinoma treated with Sorafenib (ARPES) database was conducted.The ARPES database contains data from different Italian Centres (IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna; Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola; Degli Infermi Faenza Hospital; Ospedale Cardarelli, Napoli; Ospedale Papa Giovanni XXIII, Bergamo; Azienda Ospedaliero-Universitaria Pisana, Pisa; Centro Clinico e Ricerche Humanitas, Milano).This study included consecutive patients who received the first dose of sorafenib between January 2010 and December 2019.Data were collected individually from every centre.Starting from January 2010, co-investigators from every centre updated a shared electronic registry every 3 to 6 months.
To guarantee an adequate observation time after the start of the systemic treatment, the time for the last follow-up visit was fixed on 31 July 2022.We consider the data analysis to be retrospective in nature because we analyzed the number of transarterial procedures that the patients received before starting sorafenib, while the observation of each patient began with the first administration of sorafenib.

Sorafenib Management
Sorafenib was prescribed for HCC in the advanced (BCLC-C) or intermediate stage (BCLC-B) when not amenable to locoregional treatments.The starting dose was 800 mg (two 200 mg tablets twice a day) according to the manufacturer's instructions.Downdosing (including temporary suspension, interruption or dose reductions) was admitted to deal with non-tolerable adverse effects.
Sorafenib was continued until (i) clinical and radiologic progression, according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) [15]; patients stopped sorafenib in case of radiological progression; (ii) the non-tolerable toxicity from sorafenib; and (iii) the worsening of hepatic function, which excluded the possibility of receiving sorafenib safely.

Number of Previous Transarterial Procedures
Data regarding previous locoregional treatments were obtained from the ARPES database (including specific procedures and the number of treatments).Transarterial procedures included both TACE and TARE.Patients were categorised as having received zero to two or >two transarterial procedures before receiving sorafenib.An indication for performing transarterial procedures had been provided after an assessment from local multidisciplinary tumour boards, according to the comorbidities, performance status, liver function and tumor load As a rule of thumb, patients received an indication for TACE when all the following conditions were satisfied: (1) unresectable disease, not amenable to other curative procedures, including percutaneous treatments; (2) acceptable residual liver function (up to Child-Pugh B7); and (3) fairly high likelihood of achieving a complete response on all treated nodules without inducing irreversible liver failure preventing subsequent systemic treatments.Generally speaking, patients with more than six nodules or with nodules >6 cm were not considered candidates for TACE.At the same time, no more than three nodules were treated during each procedure.All TACE procedures were performed using superselective techniques.TARE was considered a therapeutic option for patients with a disease not amenable to curative procedures, a unilobar extension and a maximum tumour diameter up to 8 cm.Macrovascular invasion was generally considered as a contraindication to TACE, while portal vein VP1-VP2-VP3 thrombosis (i.e., up to the right/left portal branch homolateral to the lesions) was permitted for TARE.Extrahepatic disease or tumour thrombus in the main portal trunk or in the portal branch contralateral to the lesions were considered contraindications to transarterial treatments.

Transarterial Procedures Performed after the Start of Sorafenib
The policies of the participating centres did not contemplate locoregional treatments following the start of sorafenib as a routine practice.The choice to start sorafenib was in fact taken for patients deemed not amenable to these treatments.
Locoregional treatments while receiving sorafenib were performed only in selected cases, and this choice was always based upon a multidisciplinary evaluation.For example, these cases included patients with a deep and prolonged response (to achieve a complete response) or with a slow progression on a limited number of lesions, with the main bulk of HCC stable for a long time.
These situations accounted for seven patients in the whole study population, two and five of which belonging the groups who had received >two and ≤two transarterial procedures, respectively.Considering the small number of these cases and the limited impact on the prognosis, these cases maintained their original allocation to the respective study group.

Subgroup Analyses
A specific subgroup analysis was designed, distinguishing patients whose imaging response was progressive disease from those who achieved disease control (defined as either complete response, partial response or stable disease) according to the mRECIST criteria.This choice was made to better capture the potential effects of receiving multiple TACE procedures in the long term, as non-responders were far more likely to die from a rapidly progressing HCC than from liver failure.Similar subgroup analyses have been used to investigate the survival correlates of the improved management of sorafenib over time and other effects that might impact the long-term survival of sorafenib-treated patients [16,17].

Ethics
All patients gave their written informed consent for their data to be included in the prospective observational registry, which had been approved by the local ethics committee (protocol no.098/2014/OSS).
The study was conducted according to the ethical guidelines of the latest Declaration of Helsinki.

Statistical Analyses
Continuous variables are expressed as median and interquartile ranges, and categorical variables are expressed as frequencies.The Mann-Whitney test was used to compare different groups, and the two-tails Fischer test was used for categorical variables.
OS was determined from the first received dose of sorafenib to either death, the last visit or the end of the follow-up period.Survival analysis was performed using the Kaplan-Meier method.
Predictors of survival were identified using a Cox regression analysis.Variables associated with survival at the univariate analysis with a p < 0.10 were included in the multivariate model.p-values < 0.05 were considered to be statistically significant.
Univariable and multivariable analyses were perfomed before and after performing propensity score matching to evaluate the initial differences between treatment groups and better assess the role of potential confounders.
The propensity score is the conditional probability of being treated given a set of observed potential confounders.This way, all the information from a group of potential confounders is summarised into a single balancing score variable.The propensity score assures that the distribution of measured baseline covariates is maintained unchanged between different groups.Propensity scores for having received >two transarterial treatments were calculated by performing non-parsimonious multivariate logistic regression models that included all measured potential predictors for the outcome and transarterial treatments.A comparison between groups (patients who had received ≤two transarterial procedures vs. patients who had received >two treatments) was performed using a propensity score matching.
The median duration of sorafenib treatment was 4.7 months (IQR: 2.3-10.3months), with a median sorafenib dose of 474 mg daily.
One hundred and thirty-nine patients (20.0%) had received more than two intraarterial treatments before starting sorafenib.Amongst the remaining population, 119 patients had received two different transarterial procedures, 147 patients had received one treatment and 291 did not receive any treatment before starting sorafenib (Table 1).Patients who had received >two transarterial procedures were significantly different from the other group in terms of the disease duration and the prevalence of macrovascular invasion.A trend toward a higher age and prevalence of extrahepatic spread was also observed (Table 2).Independent predictors of OS in the whole study included the performance status, macrovascular invasion, AFP > 400 ng/mL, Child-Pugh B status and dermatological adverse events (evaluated as a time-dependent variable) (Table 3).

Propensity Score Analysis
The propensity score matching identified 139 pairs of patients.The post-matching comparison of the baseline characteristics of the study groups revealed no significant differences in the key variables (Table 4).The prevalence of patients who achieved disease control was similar across the study groups (48.2 vs. 49.6%,p = 0.905).The total number of locoregional procedures is reported in Figure 1.The multivariable analysis performed in the matched population showed that Child-Pugh B status, AFP >400 ng/mL, macrovascular invasion, extrahepatic spread and >two transarterial procedures (hazard ratio 1.325, 95% confidence interval 1.018-1.725,p = 0.039) were independent prognostic factors (Tables 4 and 5).A high number of previous transarterial procedures was confirmed as an adverse prognostic factor in the group of patients who had achieved disease control with sorafenib (n = 136, hazard ratio 1.493, 95% confidence interval 1.034-2.156,p = 0.033) but not in patients who had progressive disease as their best radiological response (n = 142, hazard ratio 1.211, 95% confidence interval 0.836-1.753,p = 0.311).The survival curves of patients stratified according to the number of previous transarterial procedures are reported in Figure 2.
When analysing the causes of these differences, we found a trend toward a higher rate of the permanent discontinuation of sorafenib due to liver failure (18.7 vs. 10.8%,p = 0.089) and a lower rate of theoretical eligibility for second-line treatments (defined as ECOG-PS < 2 and Child-Pugh A status at the time of permanent sorafenib discontinuation-24.5 vs. 17.3%, p = 0.184) in patients who had received more than two transarterial procedures compared with the other group.Patients eligible for second-line treatments upon sorafenib failure experienced a longer OS compared to patients who had received sorafenib as the only drug [17.1 (13.5-20.7) vs. 8.9 (7.5-10.3)months, p < 0.001].

Discussion
We analysed a large dataset of sorafenib-treated patients to investigate whether a high number of previous transarterial procedures was related with an increased risk of liver function deterioration and a shorter survival.Only a minority of patients had received more than two transarterial procedures before starting sorafenib.A relatively low prevalence of heavily pretreated patients was expected, as the enrolling centres had long-term experience treating HCC.Their multidisciplinary teams were well aware of the disadvantages of performing multiple transarterial procedures in non-responding patients in terms of low efficacy and the risk of worsening hepatic function [18][19][20].
We found differences between patients when categorised according to the number of previous transarterial procedures.Patients who had received >two transarterial procedures had a longer disease duration and a lower prevalence of macrovascular invasion (a relative contraindication to TACE but not TARE).Due to this imbalance, a propensity score matching was necessary to compare the two groups properly.
In the matched population, the independent prognosticators were largely confirmed.Additionally, a higher number of previous locoregional procedures was associated with worse survival.This difference in OS was driven by responders, while patients progressing to sorafenib did not see their survival altered by the number of previous procedures (probably as their risk of death was determined by a rapid neoplastic growth rather than liver function deterioration).In this regard, the trend toward a higher rate of patients permanently discontinuing sorafenib for liver failure in the absence of progression found in highly pretreated patients provides a likely explanation for the OS difference.These results are consistent with our initial hypothesis that multiple transarterial treatments can hamper hepatic function in the long term, potentially compromising the survival benefit warranted by the systemic treatment.
Still, our results should be interpreted with caution due to the limitations of this study.First, our analysis involved only patients that received a systemic treatment during their history of HCC.Consequently, our database can not capture the possible benefit of repeated TACE in patients who will not meet the criteria for untreatable progression (for instance, patients achieving a complete response).On the other hand, patients who developed an irreversible worsening of their liver function after TACE but before starting a systemic treatment are not included in our database equally.At the same time, we were unable to assess whether patients had experienced reversible liver function deterioration after the first TACE, an event with potential prognostic relevance as it suggests a more fragile liver functional reserve [21] Second, patients who underwent conventional TACE or Drug-eluting Beads-TACE were both included.Therefore, a slight heterogeneity due to different centre-specific procedures has to be accounted for [22].Third, even if collected prospectively, our data have been analysed retrospectively; consequently, the risk of bias is reduced sensibly but not eliminated.Finally, the multicenter approach adopted for this study certainly added elements of heterogeneity derived from a possibly different propensity of the single centres to perform transarterial procedures.
Despite these limitations, our study can lead to some speculations.For example, our results were obtained by exploring patients who received sorafenib in a timeframe in which second-line treatments were mainly available in the setting of randomised clinical trials.Different drug combinations have shown superiority over sorafenib in recent times, both in terms of the OS and response rate.These combinations include atezolizumabbevacizumab [23] and tremelimumab-durvalumab [24].It is likely that the benefit of preserving liver function in the long term will be even more significant in this new setting.Lenvatinib did not demonstrate a superiority to sorafenib in terms of OS in its registrative trial [25].Still, its superior response rate [25] paired with very recent data showing an impressive median OS of 19.0 months for lenvatinib monotherapy [26] suggests that our previous consideration might also apply to lenvatinib.Therapeutic sequences, including regorafenib [27] and cabozantinib [28], represent another factor in increasing life expectancy and highlight the importance of preserving liver function.Unresectable HCC patients who could reach a third-line treatment as they maintained a good performance status and liver function had a median cumulative OS of 36 months from the sequence sorafenibregorafenib-cabozantinib [29].

Figure 1 .
Figure 1.Categorisation of patients included in the matched analysis according to the number of previous transarterial procedures.

Figure 2 .
Figure 2. Kaplan-Meyer curves of the overall survival of patients included in the matched analysis, stratified according to their best response to sorafenib as per the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1).(A) Responders; (B) Non-responders.CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease.

Figure 2 .
Figure 2. Kaplan-Meyer curves of the overall survival of patients included in the matched analysis, stratified according to their best response to sorafenib as per the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1).(A) Responders; (B) Non-responders.CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease.

Table 1 .
Detailed report of locoregional therapies performed in the whole study population (n = 696) prior to sorafenib initiation.Patients have been categorised according to the number of transarterial chemoembolisation (TACE) and radioembolisation (TARE) procedures received.Variables are reported as frequencies (percentages).

Table 2 .
Comparison of the characteristics of patients who received up to two and more than two transarterial procedures before starting sorafenib.

Table 3 .
Univariable and multivariable Cox regression of overall survival in the whole study population (n = 696).

Table 5 .
Univariable and multivariable Cox regression of overall survival in the matched study population (n = 278).