HAIC monotherapy demonstrated a relatively mild adverse reaction spectrum. Adverse reactions primarily involved hepatobiliary and hematological systems, showing a “dual-peak” distribution. Prospective studies revealed that hepatobiliary manifestations mainly included transaminase elevation (53.2%) and hypoalbuminemia (57.2%), while hematological manifestations primarily included anemia (43.0%) and thrombocytopenia (35.2%) ( Figure 2A ). Although retrospective studies showed lower incidence rates, the distribution characteristics were similar, with transaminase elevation (31.1%) and thrombocytopenia (14.1%) remaining the primary manifestations. Gastrointestinal reactions such as nausea (35.9%), vomiting (38.0%), and abdominal pain (47.0%), although not infrequent, were almost entirely mild to moderate, with good overall patient tolerability ( Figure 2B ). Grade III-IV adverse reactions showed a “low-level dispersed” distribution, with only transaminase elevation reaching 14.5%, while others remained below 10% ( Figures 2C, D ).

Compared to intravenous chemotherapy, HAIC demonstrated a milder adverse reaction profile with better tolerability (68, 69). While intravenous chemotherapy (FOLFOX4) showed higher incidences of hematological toxicity, including neutropenia (59.02%) and thrombocytopenia (60.66%), HAIC primarily involved hepatobiliary toxicity, such as transaminase elevation (53.2%) and hypoalbuminemia (57.2%). Notably, HAIC had significantly fewer Grade III-IV adverse reactions, with transaminase elevation at 14.5% as the most common, while severe hematological toxicities were rare (e.g., neutropenia 3.4%). In contrast, FOLFOX4 demonstrated a markedly higher rate of severe adverse reactions, particularly neutropenia (30.6%) and thrombocytopenia (7.65%), highlighting its stronger bone marrow suppressive effects ( Figure 3A ).

When HAIC was combined with targeted agents, both prospective and retrospective study data showed significantly expanded adverse reaction spectra, presenting a “multi-system balanced” distribution ( Figures 2A, B ). First, the incidence of thrombocytopenia increased significantly to 59.0%, with Grade III-IV reaching 14.3%; transaminase elevation increased to 66.7%, with Grade III-IV at 18.9%. Additionally, characteristic adverse reactions specific to targeted therapy emerged: hand-foot syndrome (48.0%, with Grade III-IV at 13.4%) and hypertension (49.9%, Grade III-IV at 12.8%) became issues requiring special attention. The incidence of fatigue (62.2%) also increased significantly compared to monotherapy ( Figures 2C, D ). Although overall adverse reaction rates increased, most remained controllable Grade I-II reactions.

Comparative analysis between HAIC + targeted therapy versus targeted therapy alone demonstrated distinct safety patterns (70–77). The HAIC combination showed higher incidences in several adverse events, particularly in hepatic dysfunction (elevated transaminases: 66.7% vs 20.35%, grade III-IV: 18.9% vs 5.3%) and certain hematological toxicities, especially thrombocytopenia (59.0% vs 21.1%, grade III-IV: 14.3% vs 4.1%). Interestingly, neutropenia was less frequent in the HAIC combination group (13.5% vs 41.5%, grade III-IV: 1.5% vs 12.0%). Gastrointestinal reactions showed varied patterns, with notably higher rates of nausea (52.5% vs 14.7%) but similar rates of diarrhea (35.8% vs 36.5%). The HAIC combination also resulted in increased incidences of fatigue (62.2% vs 25.0%) and hypertension (49.9% vs 31.5%). Although most adverse events remained grade I-II, these findings suggest that while the combination strategy may potentially offer therapeutic benefits, it requires careful monitoring, especially for hepatic function and platelet counts ( Figure 3B ).

HAIC + targeted + immunotherapy demonstrated the most complex adverse reaction characteristics, showing an “overall elevation” pattern ( Figures 2A, B ). The most significant changes were substantial increases in hematological toxicity: neutropenia reached 82.9%, leukopenia 57.1%, and anemia 71.4%. Liver function abnormalities reached peak levels, with transaminase and ALT elevations reaching 97.1% and 94.3%, respectively. Meanwhile, immune-related adverse reactions emerged as new challenges, including RCCEP (37.1%), hypothyroidism (27.8%), and immune-related dermatitis (16.7%). Furthermore, regarding more serious complications such as gastrointestinal bleeding, the incidence increased from 1.9% in the HAIC monotherapy group to 7.7% in the HAIC + targeted + immunotherapy group, with a notable increase in Grade III-IV bleeding (3.6%) ( Figures 2C, D ). This difference may be related to the additional effects of immunotherapy and anti-angiogenic therapy on gastrointestinal mucosa.

Grade III-IV adverse reactions showed a “prominent peak” pattern, with neutropenia (34.3%) and transaminase elevation (28.6%) showing markedly increased incidence rates. Although overall adverse reaction rates were highest, most were Grade I-II reactions, with relatively controllable proportions of Grade III-IV reactions.

Comparative analysis between HAIC + targeted therapy + immunotherapy versus targeted therapy + immunotherapy demonstrated notably increased adverse events (78–86). The HAIC combination showed significantly higher incidences of hepatic dysfunction (elevated transaminases: 97.1% vs 37.5%, grade III-IV: 28.6% vs 4.15%) and hematological toxicities, particularly in neutropenia (82.9% vs 33.3%, grade III-IV: 34.3% vs 8.75%), leukopenia (57.1% vs 31.55%, grade III-IV: 17.1% vs 3.1%), and thrombocytopenia (65.7% vs 33.55%, grade III-IV: 22.9% vs 5.8%). The combination also led to increased rates of hypoalbuminemia (88.6% vs 17.3%). Gastrointestinal reactions showed a similar pattern of elevation, with higher rates of nausea (38.9% vs 20.5%) and vomiting (34.3% vs 13.0%). While most adverse events remained at grade I-II, the substantial increase in grade III-IV events, particularly in hematological and hepatic parameters, suggests the need for more intensive monitoring and management strategies ( Figure 3C ).

Limited data is available for this combination therapy. Compared to other combination regimens, this showed milder toxicity characteristics, presenting a “relatively concentrated” pattern. Overall adverse reaction rates were significantly lower compared to other combination protocols ( Figures 2A, B ). Hematological toxicity was relatively mild, with leukopenia at only 23.3% and no Grade III-IV adverse reactions; liver function-related adverse reactions also decreased significantly, with transaminase elevation at only 13.3%. Special attention was required for hypertension (23.3%, Grade III-IV 10%) and proteinuria (28.8%). Gastrointestinal reactions were generally controllable, with diarrhea occurring in 10% of cases, including 6.7% Grade III-IV ( Figures 2C, D ). However, current data on this aspect is limited, possibly due to economic factors.

In contrast to other combination approaches, HAIC + anti-angiogenic + immunotherapy demonstrated unique safety characteristics (87–92). Unexpectedly, this combination showed lower incidence rates of adverse events in several aspects compared to anti-angiogenic + immunotherapy. Notably, reduced frequencies were observed in hepatic dysfunction (elevated transaminases: 13.3% vs 26.9%), anemia (6.7% vs 30.55%), and fatigue (6.7% vs 25.2%), suggesting better tolerability. The only markedly increased adverse event was thrombocytopenia (40.0% vs 25.8%). Furthermore, grade III-IV adverse events were relatively infrequent, with hypertension being the primary concern (10.0%). These findings suggest that HAIC plus anti-angiogenic and immunotherapy might represent a relatively well-tolerated treatment option, although careful monitoring of thrombocytopenia and hypertension remains essential ( Figure 3D ).

Patient baseline status is a key consideration when selecting treatment protocols. For patients with good liver function reserve and no significant underlying diseases, HAIC + targeted + immunotherapy may provide maximum benefit. However, this protocol has higher adverse reaction rates (neutropenia 82.9%, transaminase elevation 97.1%), and the increased risk of gastrointestinal bleeding with HAIC + targeted + immunotherapy requires caution in patients with high-risk factors for gastrointestinal bleeding. Nevertheless, these adverse reactions are mostly controllable through standardized management. For patients with certain underlying diseases or moderate liver function reserve, HAIC combined with targeted therapy may be more suitable, with primary focus on specific adverse reactions such as hand-foot syndrome (48.0%) and hypertension (49.9%). For high-risk patients (poor liver function reserve or significant underlying diseases), HAIC monotherapy’s mild adverse reaction profile (transaminase elevation 53.2%, thrombocytopenia 35.2%) makes it a better choice.

Further research on the mechanisms of adverse reactions and their prevention is needed. For instance, a retrospective study showed that 64.6% of patients experienced abdominal pain during HAIC, possibly due to vascular spasm caused by oxalate (a degradation product of oxaliplatin) irritating blood vessels, or insufficient hepatic blood supply due to small vessel diameter (32). Effective pain management and the use of lidocaine for antispasmodic effects during infusion can effectively relieve abdominal pain during treatment.

Management of adverse reactions should be based on severity level. Grade I-II adverse reactions usually allow continued treatment with symptomatic support; Grade III reactions require considering treatment suspension or dose adjustment, with gradual resumption after improvement; Grade IV reactions require immediate drug discontinuation and active treatment. Specific monitoring plans should be developed for characteristic adverse reactions of different treatment protocols ( Figure 4 ):

Successful treatment requires a comprehensive long-term management system. First, establish standardized follow-up protocols, including regular efficacy assessment and adverse reaction monitoring. Second, enhance patient education to improve awareness of early adverse reaction symptoms, promoting early detection and management. Finally, maintain good physician-patient communication to ensure timely handling of problems.

This stratified management strategy should be based on standardized monitoring. Set appropriate monitoring items and frequencies according to different treatment protocols, including routine hematological examinations, biochemical indicator monitoring, and screening for specific adverse reactions. Meanwhile, regularly evaluate treatment effectiveness and adjust treatment protocols based on patient tolerance and response.

Overall, management of HAIC and its combination therapies should be an individualized and dynamically adjusted process. Through reasonable protocol selection, systematic monitoring systems, and timely intervention measures, adverse reactions’ impact can be minimized while ensuring treatment effectiveness and improving patient quality of life. Importantly, the higher adverse reaction rates shown in prospective studies suggest that we may need closer monitoring in actual clinical work to detect and address potential problems promptly.