Addition of Y-90 radioembolization increases tumor response and local disease control in hepatocellular carcinoma patients receiving sorafenib

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and in up to 90% of patients, HCC develops in a cirrhotic liver [1]. Approximately 70% of the patients present at stages that preclude potentially curative treatment options [2]. Sorafenib treatment has been shown to improve survival in advanced HCC patients [3, 4]; it has been the standard of care for advanced HCC cases with preserved liver function for over a decade, and with the approval of atezolizumab-bevacizumab combination, it has shifted from first- to second-line [5]. Many non-randomized studies have shown that Yttrium-90 (Y-90) radioembolization (RE) is an effective locoregional treatment option with high tolerability [6‐9]. However, two randomized controlled trials have failed to show a survival benefit of RE compared to sorafenib in the first-line setting [10, 11]. Further on, in the SORAMIC trial (SORAfenib in combination with local MICro-therapy guided by gadolinium-EOB-DTPA–enhanced MRI, EudraCT 2009–012576-27, NCT01126645), the combination of RE with sorafenib showed no improved survival compared to sorafenib monotherapy in the first-line [12].

Nevertheless, during the recruitment period of these three trials, no second-line systemic treatment option was available for patients who progressed under sorafenib treatment. During the last few years, further systemic treatment options have been shown to have a survival benefit [13‐15]. This condition underlines the importance of secondary outcome parameters other than overall survival for HCC patients recruited in these trials, such as progression-free survival (PFS), objective response, and disease control [16]. Due to unique challenges in imaging assessment of HCC, criteria for evaluation of these imaging-based secondary outcome parameters have been developed, and response analysis by mRECIST has been shown to correlate with survival in HCC patients who underwent locoregional therapies, including RE [17, 18]. Furthermore, the correlation between survival and objective response according to mRECIST after sorafenib treatment has been confirmed in the SILIUS trial and in the post-hoc analysis of sorafenib arm of the SORAMIC trial [19, 20].

Additionally, some modern imaging criteria have been described to identify cancer patients who do not benefit from treatment. Early tumor shrinkage (ETS) and depth of response (DpR) have been shown to correlate with treatment outcome in various tumor types [21, 22].

This post-hoc analysis of the SORAMIC trial aimed to compare objective response rates, progression-free survival, and response characteristics of combination and sorafenib arms according to mRECIST and modern response criteria, including ETS and DpR, with independent imaging review.

Our results have shown that the combination of sorafenib with RE resulted in a higher response rate using mRECIST and a deeper and longer response than sorafenib monotherapy. Also, the progression rate was lower and time-to-progression was longer in the combination arm. Addition of RE to sorafenib treatment resulted in improved overall and hepatic PFS.

In addition to two negative trials that compared RE with sorafenib, in the SORAMIC study, the addition of RE to sorafenib has failed to improve overall survival in intermediate-advanced HCC patients compared to sorafenib treatment [12]. However, in the SARAH trial, RE resulted in better response and disease control rates, but not in longer PFS [10]. Also, in the treated population of the SIRveNIB trial, the objective response rate was higher, and PFS was longer in the RE arm [11]. In this substudy of the SORAMIC trial, a higher rate of objective response was seen in the combination arm. Furthermore, the addition of RE resulted in significantly longer PFS. These findings suggest an additive anticancer effect of RE to sorafenib treatment. This was also reflected with a higher rate of complete response in the combination arm (13.7% vs. 3.8%).

In SARAH and SIRveNIB, response assessment was done according to RECIST 1.1. Previous analyses showed a good correlation between RECIST and mRECIST in terms of progression only [24, 25]. Many previous studies have confirmed the better association between treatment outcome and response analysis according to mRECIST in HCC patients who received RE [17, 26, 27]. Recently, two studies, one in the Asian population and another in a Western population (a subanalysis of the sorafenib arm in SORAMIC), have shown that objective response assessment by mRECIST is able to predict survival after sorafenib treatment [19, 20]. Besides these, some additional imaging-based markers have been described for earlier detection of treatment response. ETS has been reported as an early predictor of a better outcome in HCC patients [22], and in our study, ETS was more common in the combination arm.

In addition to overall PFS, hepatic PFS was also shorter in the sorafenib arm. In the sorafenib arm, there were more patients with progression and progression in the liver as the first event. This was also seen in the SARAH trial, and there was a similar trend in SIRveNIB. However, combination therapy resulted in more prominent local disease control in the liver.

PPS was 7.5 months in the sorafenib arm and 7.9 months in the combination arm and 7.6 months in the study population. During the recruitment of the SORAMIC trial and also the other two trials, no second-line treatment was available. Within recent years, a number of systemic therapies have been shown to be effective in HCC patients in first-line and second-line for patients progressed under sorafenib [5, 13‐15]. PPS in our study was similar to the survival of the placebo arm in the RESORCE trial (7.6 vs. 7.8 months) [13]. PPS was significantly longer in patients with initial disease control in our analysis. It may be speculated that effective second-line therapies could improve the survival in the combination arm, which had higher disease control (79.2% vs. 72.1%). This situation shows that the lack of an efficient therapy after progression might be one of the reasons for missed correlation between better response and longer survival in three RE trials.

Recently, atezolizumab-bevacizumab combination therapy has been shown to improve survival of patients with HCC compared to sorafenib and approved as the first-line therapy [5]. However, sorafenib is still used in the first line in cases where atezolizumab-bevacizumab was not available or contraindicated. Additionally, the efficiency of immune checkpoint inhibitors may be lower in patients with non-alcoholic steatohepatitis or Wnt/ß-catenin mutation [28]. Further on, it has been shown as superior to the atezolizumab-bevacizumab in terms of cost efficiency [29]. Also, updated results of the IMbrave 150 study showed that approximately 70% of the patients who received atezolizumab-bevacizumab within the trial had progression at the date of clinical cutoff [30]. Since this combination has not been shown to deteriorate liver functions, these patients are expected to be available for second-line therapies, and sorafenib is one of the two second-line therapies with lenvatinib [31]. However, best treatment sequence is not clearly defined yet. Our results show that combination of sorafenib and RE in selected cases might improve tumor control in those patients. Additionally, improvements in the RE technique, including better particle distribution via personalized dosimetry, improved the outcomes of RE in patients with HCC [32, 33]. These findings underline the need for re-definition of the exact role of RE in HCC again and ways to improve treatment sequencing after the failure or inefficiency of first-line therapies. Also, therapeutic synergism between radiation and immune checkpoint blockade has been suggested by preclinical studies, and a recent study showed 30.6% objective response according to RECIST after RE followed by nivolumab [34].

Considering the importance of liver function in the outcome of HCC patients, RE-induced liver disease has been described as deterioration in liver function at 4–8 weeks [35], and recent findings suggest RE may cause a delayed subclinical liver damage presenting with liver decompensation at 6 months [36]. Additionally, a sub-analysis of SORAMIC patients has shown that patients who received RE in addition to sorafenib had a higher increase in ALBI scores at 4 and 6 months compared to patients who received only sorafenib [37]. This might be the expense for the increased efficacy of combination therapy and the reason of missing translation of improved tumor control into better survival. Nevertheless, better patient selection and utilization of super-selective application of Y-90, instead of lobar approach, would translate into maintaining the liver function after radioembolization. Additionally, good tumor response might lead to downstaging in some patients and translate into the opportunity for potentially curative treatments including resection or transplantation [38, 39]. Furthermore, RE offers significant increase in metabolic function and size of the contralateral lobe [40]. One interesting finding in our study was lower response rates in Child–Pugh B patients. Only one of 12 Child–Pugh B patients had objective response. Although the exact mechanism behind this situation is not clear, it is probably related to higher treatment tolerability in patients with better liver function. Similar results have also been previously reported in HCC patients who received lenvatinib [41]. In that study, Child–Pugh B patients had lower relative dose intensity, and Child–Pugh class was significantly associated with objective response in multivariable analysis considering also the relative dose intensity. This possible relationship is also supported by the GIDEON study [42]. Despite the consistent overall safety profile across Child–Pugh classes, in Child–Pugh B patients, the median duration of sorafenib treatment was significantly shorter and adverse events leading to permanent discontinuation were more common compared to Child–Pugh A patients. In our study, Child–Pugh B was also associated with shorter PFS in multivariate analysis, similar to previous reports [43, 44].

This study has some limitations. First, only 61.4% of the PP population could be evaluated due to the patients underwent no follow-up imaging or were followed by ultrasound. This resulted in selecting a population with a longer OS compared to the trial population. However, the lack of efficient second-line therapies during the trial period was one of the reasons for a low rate of follow-up cross-sectional imaging. Second, there were minor baseline differences between treatment arms in this substudy, including more extrahepatic disease in the combination arm. But, a subgroup analysis of SORAMIC has shown that except for lung metastasis, the extrahepatic disease did not significantly lower treatment outcome [45]. There were more patients with ALBI grade 2 liver function in the sorafenib arm. However, there was no difference in the overall survival between treatment arms. Despite these limitations, this study comprises a cohort collected prospectively within a multicenter trial and only the patients treated strictly following the study protocol, and it represents the largest cohort in the literature showing the additional effect of RE on tumor response in patients receiving sorafenib.

In conclusion, our study showed that the addition of radioembolization resulted in better and deeper tumor control with improved objective response rates and progression-free survival in HCC patients receiving sorafenib.