TO THE EDITOR
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, originating from hepatocytes, the main liver cells. It accounts for approximately 75%-85% of all liver cancer cases. Globally, HCC is the sixth most common cancer and the third leading cause of cancer-related deaths, with higher prevalence in regions with endemic hepatitis B and C infections, such as East Asia and sub-Saharan Africa[1,2]. Several risk factors contribute to the development of HCC. Chronic hepatitis B and C infections are the leading causes of HCC, responsible for the majority of cases worldwide. Cirrhosis, characterized by scarring of the liver due to chronic liver diseases such as hepatitis, alcohol abuse, and non-alcoholic fatty liver disease, significantly increases the risk of HCC. Aflatoxin exposure, resulting from the consumption of foods contaminated with aflatoxins produced by certain fungi, is a known risk factor, particularly in developing countries. Chronic alcohol consumption leads to liver cirrhosis, which can progress to HCC. Metabolic disorders, including obesity, diabetes, and non-alcoholic fatty liver disease, are increasingly recognized as significant risk factors. Additionally, genetic factors, such as family history and genetic predispositions, can also play a role in the development of HCC. Treating advanced HCC presents several challenges due to the limited number of effective treatment options. Surgical resection and liver transplantation are often not viable for advanced stages, leaving systemic therapies and locoregional treatments as the primary options. However, these treatments often have limited efficacy and significant side effects. The prognosis for advanced HCC remains poor, with a median survival time of less than one year for many patients. This poor prognosis is attributed to several factors. HCC tends to be aggressive and rapidly progressive. Many patients with HCC also suffer from chronic liver diseases, which complicates treatment and worsens outcomes. HCC often exhibits resistance to conventional chemotherapy and targeted therapies. Additionally, HCC is frequently diagnosed at an advanced stage when curative treatments are no longer feasible. Hepatic arterial infusion chemotherapy (HAIC) is a targeted treatment approach for liver cancer, particularly HCC[3]. It involves the direct delivery of chemotherapeutic agents into the hepatic artery, which supplies blood to the liver. This method allows for higher concentrations of the drug to reach the tumor while minimizing systemic exposure and side effects. The mechanism of HAIC involves several key steps. Initially, a catheter is inserted into the hepatic artery, often via the femoral artery, and connected to an infusion pump. Chemotherapeutic agents are then infused directly into the hepatic artery, ensuring that the drug reaches the liver tumor in high concentrations. The tumor cells absorb these chemotherapeutic agents, leading to cell death and tumor shrinkage. By targeting the liver directly, HAIC reduces the amount of chemotherapy that circulates throughout the body, thereby minimizing systemic side effects. HAIC targets liver tumors by delivering chemotherapeutic agents directly into the hepatic artery. This artery supplies blood to the liver, allowing the drugs to reach high concentrations in the liver tumors while minimizing systemic exposure. The liver’s dual blood supply, from the hepatic artery and portal vein, enables HAIC to effectively target tumors that are primarily fed by the hepatic artery, thereby enhancing the treatment’s efficacy. The primary advantage of HAIC is its ability to deliver high doses of chemotherapy directly to the tumor site. This localized delivery increases the drug concentration in the tumor while reducing systemic side effects. Commonly used chemotherapeutic agents in HAIC include oxaliplatin, 5-fluorouracil, and cisplatin. These agents work by interfering with the DNA replication process in cancer cells, leading to cell death. Clinical studies have demonstrated the efficacy of HAIC in improving survival outcomes for patients with advanced HCC[4]. For instance, a study comparing HAIC alone to HAIC combined with lenvatinib (HAIC-Len), a multi-targeted tyrosine kinase inhibitor (TKI), found that the combination significantly improved overall survival (OS) rates. The one-year, two-year, and three-year cumulative OS rates in the HAIC-Len group were 63.6%, 12.1%, and 3.0%, respectively, compared to 47.2%, 11.8%, and 2.7% in the HAIC group. Another study evaluated the efficacy of HAIC-Len and programmed death-1 (PD-1) inhibitors in patients with high-risk advanced HCC. The results indicated that the combination therapy significantly prolonged median OS (19.3 months) compared to lenvatinib and PD-1 inhibitors alone (Len-PD1) (9.8 months). Additionally, progression-free survival (PFS) was notably extended in the HAIC-Len and PD-1 inhibitors (HAIC-Len-PD1) group (9.6 months) compared to the Len-PD1 group (4.9 months)[5,6]. Another study comparing one-day and two-day HAIC regimens with oxaliplatin and fluorouracil found no significant difference in OS between the two groups, with OS rates of 14.5 months for the one-day regimen and 15.3 months for the two-day regimen[7,8]. PFS was also similar between the regimens, at 7.3 months for the one-day regimen and 7.5 months for the two-day regimen. However, the one-day regimen was associated with fewer grade 3-4 adverse events. Another study investigated the combination of HAIC-Len vs HAIC alone[7,8]. The HAIC-Len group demonstrated significantly improved OS rates, with 63.6% at one year compared to 47.2% in the HAIC group. The combination therapy also exhibited acceptable toxicity levels[7,8]. OS for HAIC-treated patients ranges from 12 months to 18 months, depending on the study and patient population. PFS for HAIC-treated patients typically ranges from 6 months to 10 months. The objective response rate (ORR), which includes complete and partial responses, is significantly higher with HAIC, often reported between 40%-50%[9].
HAIC VS SYSTEMIC CHEMOTHERAPY
In terms of efficacy, HAIC has demonstrated superior response rates and disease control compared to systemic chemotherapy. The higher local concentration of chemotherapeutic agents in the liver allows for more effective tumor targeting. Regarding toxicity, HAIC generally results in lower systemic toxicity compared to systemic chemotherapy. This is because the drug is primarily concentrated in the liver, reducing exposure to the rest of the body. Studies have indicated that HAIC can lead to improved OS compared to systemic chemotherapy, making it a preferred option for certain patients with advanced HCC[10]. HAIC offers several advantages over systemic chemotherapy. One significant advantage is the higher local drug concentration achieved through direct infusion into the hepatic artery, allowing for elevated concentrations of the chemotherapeutic agent to reach the tumor site. Additionally, HAIC is associated with reduced systemic toxicity, as the lower systemic exposure to chemotherapeutic agents minimizes the risk of side effects commonly observed with systemic chemotherapy. Studies have demonstrated that HAIC can be more effective in controlling liver tumors compared to systemic chemotherapy, particularly in patients with advanced HCC[10].
INDICATIONS FOR HAIC IN HCC AND PATIENT SELECTION CRITERIA
HAIC is typically indicated for patients with advanced HCC who meet specific criteria. These criteria include the presence of unresectable tumors, which are characterized by their size, location, or number, rendering surgical removal unfeasible. Additionally, patients must exhibit preserved liver function, classified as Child-Pugh class A or B, to tolerate the procedure. The absence of significant extrahepatic spread is another essential criterion, ensuring that the cancer is primarily confined to the liver. Furthermore, patients should have a good performance status, indicating they are in relatively good overall health and capable of withstanding the treatment. HAIC is preferred in several clinical scenarios. It is particularly effective in patients with advanced HCC accompanied by portal vein thrombosis (PVT), a condition that precludes the use of other locoregional therapies such as transcatheter arterial chemoembolization (TACE). Patients who have demonstrated refractoriness to systemic therapies, including sorafenib or lenvatinib, may also benefit from HAIC. Moreover, HAIC can serve as a bridging therapy to control tumor growth in patients awaiting liver transplantation[11].
HAIC VS TACE
The mechanism of action differs between HAIC and TACE. While both involve the delivery of chemotherapy directly to the liver, TACE also includes embolization, which blocks the blood supply to the tumor, leading to ischemia and necrosis of the tumor. In terms of efficacy, HAIC may be more suitable for patients with PVT, as TACE can exacerbate this condition. HAIC has shown promising results in such patients, whereas TACE is often contraindicated. Regarding safety, HAIC tends to have a more favorable safety profile in patients with compromised liver function, as it avoids the ischemic effects associated with TACE. Both treatments have shown efficacy in improving survival and response rates, but the choice between HAIC and TACE often depends on the patient’s specific clinical scenario, including liver function and the presence of PVT[12]. Rationale for combining HAIC with immune checkpoint inhibitor (ICI), such as anti-PD-1 and anti-programmed death ligand-1 antibodies, aims to enhance the anti-tumor immune response. HAIC delivers high concentrations of chemotherapeutic agents directly to the liver, causing tumor cell death and releasing tumor antigens. These antigens can then be recognized by the immune system, which is further activated by ICIs to attack the cancer cells more effectively. Recent studies have shown promising results for the combination of HAIC with immune therapy[13]. For instance, a study combining HAIC with camrelizumab (an anti-PD-1 antibody) and rivoceranib (a targeted therapy) demonstrated significantly improved OS and PFS compared to standard treatments[13]. Another study highlighted the potential of HAIC combined with anti-PD-1/programmed death ligand-1 immune therapy and molecularly targeted agents, showing an ORR of 54.1% and a disease control rate of 94.6%[13]. A study compared the efficacy of HAIC-Len-PD1 vs Len-PD1 in patients with high-risk advanced HCC[13]. The results demonstrated that the HAIC-Len-PD1 group had significantly better OS and PFS compared to the Len-PD1 group. Specifically, the median OS was 19.3 months for the HAIC-Len-PD1 group vs 9.8 months for the Len-PD1 group. The median PFS was 9.6 months for the HAIC-Len-PD1 group compared to 4.9 months for the Len-PD1 group. The ORR was 76.7% for the HAIC-Len-PD1 group vs 23.0% for the Len-PD1 group. Additionally, the disease control rate was 92.2% for the HAIC-Len-PD1 group compared to 72.1% for the Len-PD1 group[13]. Another study evaluated the combination of HAIC with camrelizumab and apatinib (a vascular endothelial growth factor receptor-2 inhibitor) (HAIC-Cam-Apa) vs camrelizumab and apatinib alone in patients with advanced HCC[14,15]. The findings indicated that HAIC-Cam-Apa significantly improved survival outcomes[14,15]. Specifically, the median OS was not reached in the HAIC-Cam-Apa group compared to 19.9 months in the Cam-Apa group. The median PFS was 11.5 months for the HAIC-Cam-Apa group vs 9.6 months for the Cam-Apa group. Grade 3/4 adverse events were reported in 82.1% of patients in the HAIC-Cam-Apa group compared to 71.3% in the Cam-Apa group[14,15]. The combination of HAIC with TKIs, such as sorafenib and regorafenib, leverages the strengths of both therapies. HAIC provides localized high-dose chemotherapy, while TKIs inhibit pathways critical for tumor growth and angiogenesis. This dual approach can enhance the overall anti-tumor effect and improve patient outcomes[16,17]. Clinical studies have shown that combining HAIC with TKIs can lead to better survival outcomes and higher response rates compared to either treatment alone[18]. For example, a study combining HAIC with regorafenib reported a median OS of 22.2 months and a median PFS of 10.8 months[18]. The combination was also found to be tolerable, with manageable side effects such as hand-foot skin reaction and fatigue. A multicenter study assessed the efficacy and safety of HAIC combined with TKIs vs HAIC monotherapy for advanced HCC[18]. The results demonstrated that the combination therapy (HAIC-TKI) significantly prolonged survival outcomes[18]. The median OS was 18.0 months for the HAIC-TKI group compared to 8.8 months for the HAIC monotherapy group. The median PFS was 6.0 months for the HAIC-TKI group vs 4.7 months for the HAIC monotherapy group. Additionally, the ORR was 41.1% for the HAIC-TKI group compared to 25.2% for the HAIC monotherapy group[18]. Combining HAIC with radiotherapy aims to exploit the synergistic effects of both treatments. HAIC delivers high concentrations of chemotherapy to the liver, sensitizing tumor cells to radiation. Radiotherapy then targets these sensitized cells, enhancing the overall treatment efficacy. Several studies have demonstrated the benefits of combining HAIC with radiotherapy[19-22]. For instance, a study on advanced HCC with portal vein tumor thrombosis (PVTT) showed that the combination of HAIC and radiotherapy significantly improved OS and PFS compared to HAIC alone[19-22]. The combination therapy was well-tolerated, with no significant increase in adverse effects[19-22]. In a recent phase III clinical trial evaluating HAIC-oxaliplatin plus fluorouracil, researchers identified a 15-gene mutation panel that can predict treatment responsiveness. The study found that 83% of patients with these mutations experienced significantly longer OS compared to those without (19.3 months vs 10.6 months, P = 0.002)[20,21].
HAIC generally exhibits a favorable safety profile, with adverse events being manageable and often less severe compared to systemic chemotherapy. Common side effects include liver dysfunction, characterized by elevated liver enzymes (aspartate aminotransferase and alanine transaminase) and bilirubin levels, which can be monitored and managed with dose adjustments or temporary discontinuation of therapy. Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain are frequently reported and can be managed with antiemetics and supportive care. Hematological toxicities, including leukopenia, thrombocytopenia, and anemia, are observed in some patients and can be managed with regular blood tests and supportive treatments such as growth factors or transfusions. Other side effects, such as fatigue, loss of appetite, and mild infections, are generally manageable with appropriate supportive care[3].
FUTURE DIRECTIONS AND INNOVATIVE APPROACHES IN HAIC
Advancements in drug formulations and delivery methods are crucial for enhancing the efficacy and safety of HAIC. Some innovative approaches include nanoparticle-based drug delivery, which utilizes nanoparticles to deliver chemotherapeutic agents directly to the tumor site, improving drug concentration in the tumor while minimizing systemic toxicity. Nanoparticles can be engineered to release the drug in response to specific stimuli, such as pH changes or enzymes present in the tumor microenvironment. Liposome-encapsulated drugs can protect chemotherapeutic agents from degradation and allow for controlled release at the tumor site, enhancing the therapeutic index of the drugs used in HAIC. Drug-eluting beads can be loaded with chemotherapeutic agents and delivered via the hepatic artery, providing a sustained release of the drug and maintaining high local concentrations over an extended period[23,24]. Personalized medicine aims to tailor treatments based on the individual characteristics of each patient, including genetic, molecular, and clinical factors. In the context of HAIC, personalized approaches may involve genomic profiling to analyze the genetic mutations and molecular pathways involved in a patient’s tumor, helping to identify the most effective chemotherapeutic agents and combination therapies. Biomarker-guided therapy uses biomarkers to predict response to HAIC and monitor treatment efficacy, optimizing therapy and reducing unnecessary toxicity. Adaptive treatment strategies involve continuously adjusting the treatment plan based on the patient’s response and emerging data, improving outcomes and minimizing side effects[25,26]. Several ongoing and future clinical trials are exploring the potential of combining HAIC with other therapies to enhance its efficacy. Promising combination strategies include HAIC and immunotherapy, where trials are investigating the combination of HAIC with ICIs, such as pembrolizumab and nivolumab, to boost the anti-tumor immune response. HAIC and targeted therapy involve combining HAIC with targeted agents such as sorafenib, lenvatinib, and regorafenib to inhibit key pathways involved in tumor growth and angiogenesis. HAIC and radiotherapy research is ongoing to evaluate the synergistic effects of combining HAIC with radiotherapy, particularly in patients with PVTT.
POTENTIAL BREAKTHROUGHS IN HAIC TREATMENT
Future research and clinical trials hold the potential for significant breakthroughs in HAIC treatment. Areas of focus include developing novel chemotherapeutic agents with higher efficacy and lower toxicity for use in HAIC, identifying the most effective combinations of HAIC with other therapies to maximize treatment benefits, improving catheter placement and drug delivery methods to enhance patient comfort and reduce complications, and utilizing advanced imaging and monitoring technologies to assess treatment response in real-time and adjust therapy accordingly[27,28]. HAIC has shown promise in treating advanced HCC, but several challenges and areas remain for future research. The lack of standardization in HAIC protocols, including differences in chemotherapy regimens, dosages, and administration techniques, creates significant variability. This lack of standardization makes it difficult to compare results across studies and establish best practices. Additionally, HAIC is primarily used in East Asia and is not widely recognized or adopted internationally. This limits the generalizability of study results and hinders the global acceptance of HAIC as a standard treatment for advanced HCC. Clinical trials involving HAIC often have heterogeneous designs, patient populations, and endpoints, complicating the interpretation of results and the establishment of clear evidence for HAIC’s efficacy and safety. While HAIC generally has a favorable safety profile, it is not without risks. Common adverse events include liver dysfunction, gastrointestinal symptoms, and hematological toxicities, which require careful monitoring and supportive care[29-31]. Future research should focus on standardizing HAIC protocols, including chemotherapy regimens, dosages, and administration techniques, to establish best practices and improve the comparability of study results. Conducting large-scale, randomized controlled trials is essential to validate the efficacy and safety of HAIC in diverse populations. These trials should aim to provide high-quality evidence to support the use of HAIC as a standard treatment for advanced HCC. Exploring the combination of HAIC with other therapeutic agents, such as TKIs, ICIs, and radiation therapy, is a promising area of research. These combinations have the potential to enhance treatment efficacy and improve patient outcomes. It is critical to identify the groups of patients most likely to benefit from HAIC. Future studies should focus on refining patient selection criteria to ensure that HAIC is used in those who will derive the most benefit. Encouraging international collaboration in HAIC research can help overcome regional biases and promote the global acceptance of HAIC. Collaborative efforts can lead to more comprehensive studies and a better understanding of HAIC’s role in treating advanced HCC[30,31]. HAIC treatment is not included in the guidelines of the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, or Asian Pacific Association for the Study of the Liver. This omission is due to the lack of sufficient clinical evidence to support its recommendation in these guidelines[32]. The Japanese Society of Implantable Port Assisted Treatment recently introduced clinical practice guidelines for HAIC using a port system. These guidelines aim to facilitate the broader adoption of HAIC. This treatment shows promise for locally advanced HCC, including cases with microvascular invasion and PVTT[33].
CONCLUSION
HAIC is a valuable treatment for advanced HCC, especially in high-prevalence areas. It delivers high local concentrations of chemotherapy directly to liver tumors, offering an advantage over systemic chemotherapy. Ongoing research and trials are essential to refine HAIC protocols and expand its global use.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: Greece
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Alshammary RAA S-Editor: Bai Y L-Editor: Webster JR P-Editor: Zheng XM
