Subcutaneous or intramuscular interferon-alpha (IFN-α) has been used in combination with intravenous chemotherapy for advanced HCC to enhance antitumor activity [55]. Subcutaneous IFN-α has also been combined with HAIC, resulting in higher ORRs than those achieved with HAIC alone, although the survival benefit of this combination is inconclusive [42,56,57]. However, a randomized Phase 2 trial comparing HAIC with or without IFN-α showed inferior OS for the group treated with the HAIC–IFN-α combination [43]. Because of such inconsistencies between study findings, IFN-α has not been routinely used in combination with HAIC.

HAIC has been combined with sorafenib to leverage the synergistic effects of the combination. A randomized Phase 2 trial was conducted to compare HAIC plus sorafenib with sorafenib alone as a first-line therapy for patients with CP score of up to B7; the trial demonstrated that HAIC plus sorafenib resulted in a higher ORR (21.7% vs. 7.3%) and longer OS (median survival, 10.6 vs. 8.6 months, p = 0.031) [44]. Subsequently, Kudo et al. [45] conducted the SILIUS trial, a multicenter randomized Phase 3 trial comparing frontline use of sorafenib with or without HAIC, and confirmed a higher ORR and longer time to progression (TTP) in the combination group, but the OS were similar between two groups. They also conducted a subgroup analysis and revealed the combination therapy yielded longer OS than sorafenib treatment did in patients with Vp4 PVT. He et al. [47] reported another randomized Phase 3 trial comparing sorafenib with or without HAIC in 2019 in patients with PVT (Vp4: 37%); the results showed that patients treated with the combination therapy exhibited more favorable outcomes, including higher ORRs and longer OS periods (median survival, 13.4 vs. 7.1 months; HR 0.35; p < 0.01). Although these two studies have reported opposite results regarding the effects of first-line HAIC combination, they differed in several aspects. First, they enrolled different patients: all patients enrolled in the study by He et al. had PVT, whereas only 63.2% of those in the study by Kudo et al. had PVT. Hepatitis B virus–related HCC was less prevalent in the study by Kudo et al. (23.4%) than in the study by He et al. (80%). Second, He et al. administered an oxaliplatin-based regimen, modified FOLFOX6, every 3 weeks, which is also a common intravenous chemotherapy regimen for advanced HCC in China; by contrast, the regimen in the SILIUS trial was cisplatin plus 5-fluorouracil (5-FU) every 4 weeks. Because of inherent differences between oxaliplatin and cisplatin, the use of these two platinum-based chemotherapeutic modalities may result in different synergistic effects with sorafenib [58]. Third, He et al. used repeated intra-arterial catheterization, which allows for the adjustment of the microcatheter tip position and the re-embolization of newly developed gastroduodenal collateral arteries. These differences may contribute to the different OS results in these two trials. In summary, HAIC combined with sorafenib could provide favorable ORR and may provide OS benefits. Further research should be conducted to explore the optimal chemotherapeutic agents, protocol procedures, and target patient populations.

Data regarding the combination of HAIC with lenvatinib are limited. A retrospective study of 24 patients treated with HAIC plus standard-dose lenvatinib reported an encouraging ORR of 58% and a disease control rate of 79% [48]. Additional prospective studies of the combination of HAIC and lenvatinib are ongoing.

HAIC combined with radiation therapy (RT) has also been extensively investigated, particularly in subgroups of patients with PVT. Han et al. [51] conducted a small-scale single-arm pilot study of three-dimensional conformal RT followed by HAIC for HCC; they observed an ORR of 45% with manageable adverse events. Investigators from Hiroshima University, Japan, have published a series of retrospective studies comparing HAIC plus RT with HAIC alone, focusing on patients with PVT. Their results revealed impressive ORRs in the HAIC-RT combination arm, but no significant survival benefits were observed [52,53]. Furthermore, Kodama et al. [54] retrospectively reviewed the effects of HAIC plus RT compared with treatment with sorafenib in patients with major PVT (Vp3/4) by using case–control matching analysis. The HAIC-RT combination group demonstrated more favorable clinical outcomes, including OS (median survival, 9.9 vs. 5.3 months, p = 0.002) and progression-free survival (median survival, 3.9 vs. 2.1 months, p = 0.048). The findings of these studies indicate that HAIC plus RT may yield favorable ORRs and survival benefits; nevertheless, evidence from prospective randomized controlled studies is still unavailable.

Immune checkpoint inhibitor–based combinations have changed the treatment paradigm for advanced HCC [59,60] and are likely to remain the cornerstone of systemic treatment in the next few years. The IMbrave150 trial compared treatment with atezolizumab plus bevacizumab and treatment with sorafenib; they reported an impressive ORR of 30% and an unprecedented OS benefit for the combination treatment over sorafenib (median survival, 19.2 vs. 13.4 months, HR 0.66) [60,61]. Several ongoing Phase 3 trials testing immune checkpoint inhibitors in combinations with other immuno-oncology agents or multikinase inhibitors (MKIs) are ongoing.

Chemotherapeutic modalities have been proved to be synergistic with anti-PD1/PD-L1 antibodies in several cancers, such as those of the lung and breast [62,63]. HAIC may also induce substantial local immune modulation in the intrahepatic tumor microenvironment of HCC. Whether HAIC plus PD1/PD-L1 blockade would have synergistic effects warrants further investigations. Preliminary results of early phase trials of PD-1 blockade plus MKIs have been promising [59], and investigations of triplet therapy, namely anti-PD-1, MKIs, and HAIC, are ongoing. Gu et al. [49] reported a single-center experience for six patients who received HAIC combined with apatinib and toripalimab as the first-line treatment for advanced HCC. All six patients responded to treatment (ORR, 100%), and three of the patients (50%) exhibited complete responses. He et al. [50] presented a retrospective study in which 71 patients underwent treatment involving a combination of HAIC, lenvatinib, and toripalimab; they reported a high ORR (59%) after treatment. These encouraging results support further research on HAIC combined with other immune-based therapeutic agents.

In summary, many studies have shown positive signs for HAIC combination treatments. In particular, for patients with major PVT, HAIC plus sorafenib provided a longer OS [45,47]. Regarding the combination of HAIC with other therapeutic modalities, HAIC plus RT or PD-1/PD-L1 blockade also demonstrated promising results [49,50,52,53,54]. It's believed that these HAIC-based combination treatments will become the dominant trend in clinical practice and clinical trials.

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Int J Mol Sci. 2021 Nov 28;22(23):12880. doi: 10.3390/ijms222312880.