Introduction
Hepatocellular carcinoma (HCC) is a prevalent malignancy, ranking as the sixth most frequently diagnosed cancer and the third leading cause of cancer-related mortality globally [
1,
2]. The burden of HCC is particularly high in Asia, where approximately 72% of all HCC cases are reported, with China alone accounting for more than 50% [
3]. Unfortunately, most patients are diagnosed at advanced stages when curative surgery is not feasible, resulting in a discouraging 5-year survival rate ranging from 10 to 18% [
4,
5].
First-line systemic therapies for unresectable advanced HCC currently include tyrosine kinase inhibitors (TKIs), such as sorafenib (SHARP) [
6] and lenvatinib (REFLECT) [
7]. Recently, the Food and Drug Administration (FDA) approved a combination of atezolizumab and bevacizumab for patients with unresectable or metastatic HCC who had not undergone prior systemic therapy, based on the phase III IMbrave150 trial [
8]. Subsequently, this is recommended as the preferred first-line approach by various guidelines owing to its remarkable efficacy. However, the latest updated findings from IMbrave150 have revealed limited benefits for high-risk patients, characterized by Vp4, bile duct invasion, and/or tumor occupancy ≥ 50% (TO ≥ 50%) of the liver, with a median overall survival (OS) of 7.6 months [
9,
10]. Unfortunately, patients with major portal vein tumor thrombosis (PVTT) (Vp3 and Vp4) treated with sorafenib experienced a disappointingly short median survival of only 3.1–6.0 months [
11,
12]. Notably, high-risk patients were not included in the REFLECT trial. Outcome data of high-risk patients are limited because of their extremely poor prognosis, resulting in often being excluded from previous trials. Consequently, there is an unmet need for effective interventions for high-risk patients.
Recently, a few combination immunotherapy approaches, such as lenvatinib plus pembrolizumab (KEYNOTE-524) [
13] and camrelizumab plus apatinib (CARES-310) [
14], have emerged as first-line treatment options for patients with HCC. Although the phase III LEAP-002 trial, which evaluated the combination of lenvatinib and pembrolizumab, did not achieve its intended primary endpoint it should be noted that this treatment regimen exhibited superior OS compared to lenvatinib alone (21.2 vs.19.0 months, hazards ratio [HR] = 0.84; 95% confidence interval [CI]: 0.708–0.997,
p = 0.0227). These combination therapies have demonstrated promising anti-tumor activity and displayed acceptable safety profiles when used in treatment-naïve patients with unresectable HCC [
15]. These findings emphasize the importance of further investigation into the synergy between TKIs and immune checkpoint inhibitors (ICIs).
Hepatic arterial infusion chemotherapy (HAIC), a therapeutic approach employed for primary and metastatic hepatic malignant tumors, enables the targeted delivery of a potent dosage of drugs directly to liver tumors [
16‐
19]. This localized administration results in a significant local anti-tumor effect. Recent investigations have focused on the use of HAIC as a stand-alone treatment or in combination with sorafenib for advanced HCC, with notable findings being favorable outcomes in terms of both response rate and survival outcomes [
16,
18,
20].
Considering the different anti-malignant mechanisms of TKIs, PD-1 inhibitors, and HAIC, combining these three modalities may show potential synergistic effects and promising preliminary efficacy in advanced HCC. This study aimed to retrospectively investigate the effectiveness and safety of combining lenvatinib with PD-1 inhibitors and HAIC as a first-line treatment for high-risk patients with advanced HCC.
Discussion
Owing to the insidious onset of HCC, most patients are diagnosed at advanced stages, wherein a high tumor burden and PVTT often manifest as prevalent features. In China, patients with high-risk HCC tumor thrombi in the main portal vein trunk or those with a significant tumor burden, particularly those with tumors occupying more than 50% of the liver, are commonly encountered [
3]. Unfortunately, these patients have a remarkably unfavorable prognosis [
21,
22].
According to current clinical guidelines systemic therapy, such as lenvatinib or atezolizumab plus bevacizumab, is recommended as the first-line treatment for HCC. However, it is worth noting that the REFLECT, KEYNOTE-524, and LEAP-002 trials did not include patients with high-risk HCC, thus the safety and efficacy of lenvatinib in these patients are still uncertain [
7,
13]. Additionally, the IMbrave150 study demonstrated that the combination of atezolizumab and bevacizumab provides limited benefit to high-risk patients, with a median OS of 7.6 months [
10]. Consequently, available therapeutic options for patients with HCC with high-risk profiles are currently limited.
Recently, Japanese researchers discovered that lenvatinib has the potential to confer advantageous outcomes in high-risk patients. Estimated mPFS and mOS were 132 days and 229 days, and 101 days and 201 days in patients with TO ≥ 50% and Vp4, respectively [
23]. Another study showed that lenvatinib plus PD-1can contribute to notable improvements in survival outcomes among patients with Vp4 and TO ≥ 50%, with the median OS was 11.39 and 6.1 months, respectively [
24]. These studies demonstrate that lenvatinib is safe, effective, and could be a potential therapeutic approach for high-risk patients with HCC. In 2021, the phase III trial FOHAIC-1 demonstrated the heightened ORR and better survival outcomes of HAIC compared to sorafenib. The subgroup analysis unveiled that HAIC surpassed sorafenib even further in terms of OS and PFS in high-risk patients (10.8 vs. 5.7 months, 7.7 vs. 2.9 months respectively) [
20]. Additionally, another phase II trial exploring the efficacy and safety of lenvatinib, toripalimab, and FOLFOX-HAIC as first-line treatments for advanced high-risk HCC showed promising results. The mPFS and mOS was 10.4 months and 17.4 months, respectively, and the ORR was as high as 66.7% [
25]. These findings suggest that HAIC combined with systemic treatment may has potential synergistic efficacy and may be an alternative therapeutic option for high-risk patients with HCC; however, further studies are required to verify these observations. Hence, we conducted a retrospective study to assess the efficacy and safety of HAIC-LEN-PD1 versus LEN-PD1 as first-line treatment for high-risk patients with HCC.
Our previous single-arm study demonstrated the safety and efficacy of HAIC-LEN-PD1 therapy in high-risk HCC patients. The mPFS was 9.8 months and mOS were 19.3 months. According to the mRECIST, the ORR and DCR were 78.3% and 92.8%, respectively [
26]. In this study, patients who received HAIC-LEN-PD1 achieved significantly better PFS (9.6 vs. 4.9 months) and OS (19.3 vs. 9.8 months) than patients who received lenvatinib and PD-1s. Previous studies have implied that the intrahepatic tumor burden affects survival outcomes in patients with advanced HCC, indicating that debulking of the liver tumor increases patient survival [
27,
28]. Additionally, for patients with advanced HCC, it is crucial to reduce tumor burden and preserve liver function, especially in patients with a high tumor burden. Notably, the HAIC-LEN-PD1 group showed an ORR more than three times higher than that of the LEN-PD1 group (76.7% vs. 23.0%), which would be expected to improve liver function and allow the combined treatment to be continued for a longer time, which could potentially be attributed to the increased PFS and OS.
In our study, we chose HAIC as the locoregional treatment instead of TACE combined with lenvatinib plus PD-1s to rapidly reduce tumor burden. The reasons are as follows: first, in our study the median tumor size was 12.2 cm in the HAIC-LEN-PD1 group, while it has been demonstrated that the rate of complete tumor response was significantly lower in large (> 5 cm) HCCs than small HCCs (25% vs. 64%) [
29]. Additionally, a large number of embolization particles are required to embolize large HCCs, which can increase the risk of deterioration of the hepatic functional reserve, post-embolization syndrome, and non-target embolization [
30,
31]. A recent randomized phase III trial demonstrated the superior efficacy and safety of HAIC to TACE in patients with large unresectable HCC (OS: 23.1 vs.16.1 months). Second, most patients in our study had Vp4, which often leads to portal hypertension, a risk of esophagogastric varix rupture, and poor prognosis due to liver dysfunction. Unfortunately, traditional viewpoint holds that TACE is a relatively contraindication in patients with HCC complicated by Vp4, as it may disrupt the hepatic artery blood supply and lead to ischemia-related post-TACE liver failure. Therefore, almost no effective local treatment could be applied to patients with Vp4 currently [
32]. Recently, several reports have shown that HAIC is an effective treatment for HCC with PVTT, even in patients with Vp4. Based on the aforementioned research, we deemed HAIC a more suitable local treatment option than TACE for patients with high-risk HCC.
Although patients treated with HAIC-LEN-PD1 had significantly elevated frequencies of grade 3–4 AEs, which may be due to the direct cytotoxicity to hepatocytes and hematopoietic cells induced by HAIC, these TRAEs were expected to be manageable by symptomatic treatment. Hypothyroidism, the most common immune-related adverse event, occurred in 34.9% of patients. All immune-related AEs disappeared after the participants stopped PD-1s and received hormone therapy. Interestingly, we observed a notable increase in splenic size among some patients compared to baseline during the course of the treatment procedure in the HAIC-LEN-PD1 group. Previous studies have unequivocally illustrated the capacity of oxaliplatin to elicit the onset of sinusoidal obstruction syndrome (SOS), culminating in the manifestation of portal hypertension, fluid retention, and hyperbilirubinemia, ultimately exacerbating the deterioration of hepatic function [
33]. Increased splenicsize can be employed as a discerning biomarker, suggesting vulnerability to oxaliplatin-induced hepatic sinusoidal injury. Several patients in the present study experienced hepatic dysfunction despite effective tumor control. Therefore, in addition to assessing the potential hepatotoxicity of lenvatinib and PD-1s, it is crucial to consider the development of SOS and promptly discontinue oxaliplatin administration if necessary. In our department, for patients with refractory thrombocytopenia or spleen size that increased significantly from baseline, partial splentic embolization was performed; however, but the long-term effects should be considered.
Complications associated with portal hypertension, particularly the presence of varices, especially in Vp4 patients, are very important. In this study, by phone follow-up, 18 patients experienced variceal bleeding, 15 of whom were treated with endoscopic hemostasis, 3 of whom were treated with percutaneous transsplenic varices embolization (PTSVE), and 2 of whom were treated with transjugular intrahepatic portosystemic stent shunts (TIPPs). In addition, patients with HCC complicated by PVTT often have associated hepatopetal portal venous shunting, exacerbating portal hypertension and potentially leading to liver failure and upper gastrointestinal bleeding. HAIC not only delivers a high local drug concentration into liver tumors directly but can also enter PVTT through hepatopetal portal venous shunting, providing an antitumor effect on the thrombus. In our study, many patients experienced PVTT recanalization, which reduced portal pressure to a certain extent and reduced the risk of bleeding from gastric varices and refractory ascites. Moreover, it is also very important for patient education and medication management. In our center, patients are reminded to pay attention to the color of the stool and go to the hospital in a timely manner once hematemesis and melena occur.
This study had some limitations. First, its retrospective design and non-randomized nature rendered it susceptible to potential biases, despite the absence of disparities in baseline characteristics. Second, the follow-up time was relatively short for OS because an insufficient number of OS events were observed, and long-term survival data are still required. Third, it should be noted that the evaluation of adverse events may not be fully comprehensive due to the retrospective nature of the study, despite our careful inspection of medical records.
To the best of our knowledge, this is the first study to demonstrate improved OS and PFS with HAIC-LEN-PD1 combination treatment versus LEN-PD1 in systemic treatment-naïve high-risk patients with HCC. Moreover, the survival benefit was generally consistent across multiple patient subgroups. Our results revealed that combined HAIC-LEN-PD1 therapy is more effective than LEN-PD1 in controlling intrahepatic tumors and prolonging patient survival. In conclusion, HAIC-LEN-PD1 is a safe and effective treatment for high-risk patients with HCC and provides significant improvements in OS, PFS, and ORR compared to LEN-PD1 with tolerable toxicity.
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