Modified hepatic arterial infusion chemotherapy protocol for reducing perioperative pain and anesthetic consumption in patients with hepatocellular carcinoma

Abstract

Background

Hepatic arterial infusion chemotherapy (HAIC) with the FOLFOX (folinic acid + fluorouracil + oxaliplatin) regimen has emerged as a crucial treatment for advanced hepatocellular carcinoma (HCC), but oxaliplatin-induced neuropathic pain significantly reduces patients’ quality of life. This study investigated the impact of modified HAIC procedures on perioperative pain levels and analgesic requirements in patients with HCC.

Methods

This single-institution retrospective study analyzed 180 patients with HCC undergoing HAIC. Patients were divided into three groups: Group A (n=40), which received the standard FOLFOX-HAIC regimen; Group B (n=74), which received a reverse sequence FOLFOX-HAIC (REFOLFOX-HAIC), with oxaliplatin administered after fluorouracil and leucovorin; and Group C (n=67), which received a direct intraoperative infusion of oxaliplatin with FOLFOX-HAIC (OxDirect-FOLFOX-HAIC). The primary endpoints were the intraoperative and 24-hour postoperative analgesic utilization score and visual analogue scale (VAS) pain scores. Secondary outcomes included tumor response and safety.

Results

Both modified protocols demonstrated superior pain management. Compared to the standard regimen (Group A), both Group B (REFOLFOX-HAIC) and Group C (OxDirect-FOLFOX-HAIC) showed significantly lower analgesic utilization scores (P=0.021 and P=0.027, respectively). Similarly, VAS pain scores were significantly reduced in Group B and Group C (P=0.019 and P=0.039, respectively). Importantly, these modifications did not compromise therapeutic efficacy; after 3 months, there were no statistically significant differences between Groups A–C in terms of objective response rates (15.00% vs. 13.70% vs. 8.96%; P=0.074) or disease control rates (95.00% vs. 89.04% vs. 98.51%; P=0.591). The safety profiles were comparable, with no grade-3-or-higher adverse events reported.

Conclusions

The REFOLFOX-HAIC and OxDirect-FOLFOX-HAIC procedures significantly reduced perioperative pain and the need for analgesics in patients with HCC as compared to the conventional FOLFOX-HAIC protocol, without compromising short-term tumor control or safety.

Introduction

Hepatocellular carcinoma (HCC) presents a significant challenge in oncology, accounting for over 80% of primary liver cancer cases, with approximately 70% of patients being ineligible for curative treatments (1-4). HCC ranks sixth in incidence and third in mortality among all cancers, with about 50% of cases occurring in China (5). where surgical resection constitutes only 15–30% of the initial treatment for patients (6). Hepatic arterial infusion chemotherapy (HAIC) has emerged as a crucial treatment for advanced HCC, delivering localized high-concentration chemotherapy via a catheter in the hepatic artery (7). The FOLFOX (folinic acid + fluorouracil + oxaliplatin) regimen has provided significant improvements in tumor response rates, resection rates, and survival (8).

Research has confirmed the efficacy of FOLFOX-HAIC, showing it can extend overall survival from 16.1 to 23.1 months and increase the surgical resection rate from 11.5% to 23.8% when compared to transarterial chemoembolization (TACE) (9).

However, oxaliplatin, a key component of FOLFOX, is associated with neuropathic pain, significantly reducing patients’ quality of life (10). Rapid infusion of oxaliplatin has been linked to acute neuropathic symptoms due to peak drug concentrations disrupting peripheral nerve ion channels (11). Given the complexity and multifaceted nature of oxaliplatin-induced pain, it is crucial to develop refined and patient-tailored HAIC strategies. To address this, two modified HAIC methods were developed in this study. A reverse sequence FOLFOX-HAIC (REFOLFOX-HAIC) approach (Group B) was designed based on the hypothesis that preadministration of fluorouracil and leucovorin might provide a protective effect against oxaliplatin-induced neurotoxicity through the modulation of cellular stress responses. Similarly, an oxaliplatin direct-infusion with FOLFOX-HAIC (OxDirect-FOLFOX-HAIC) procedure (Group C) was devised to minimize prolonged exposure of peripheral nerves to oxaliplatin by utilizing rapid direct infusion, potentially reducing the duration of neurotoxic effects. This study retrospectively analyzed the application of these two improved HAIC methods at Cancer Hospital Chinese Academy of Medical Sciences and compared them to the conventional FOLFOX-HAIC regimen. The analysis focused on their ability to alleviate pain intensity, reduce the use of analgesic drugs, and maintain safety. By refining HAIC strategies, we aim to enhance patient outcomes and quality of life while mitigating the adverse effects associated with oxaliplatin. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2066/rc).

Methods

Selection criteria

This single-institution, retrospective study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences (approval No. 23/359-2143). Written informed consent was obtained from all patients for the procedure, along with subsequent follow-up and opt-out consent for the retrospective use of clinical data. Comprehensive data, including patient and tumor characteristics, treatment details, and outcomes, were extracted from medical records and imaging studies for thorough analysis, ensuring consideration of all relevant variables.

Prior to the intervention, patients underwent a comprehensive multidisciplinary evaluation involving specialists from oncology, surgery, radiation oncology, palliative medicine, and pain management. The eligibility criteria for the inclusion of patients undergoing HAIC were as follows: age 18–75 years; unresectable or recurrent HCC confirmed either histologically or clinically; Child-Pugh score A or B; Eastern Cooperative Oncology Group (ECOG) performance status 0–2; China Liver Cancer Staging (CNLC) stage IIb, IIIa, or IIIb, and particularly cases with high tumor burden, at risk of embolic complications, or with TACE resistance; and sufficient hematologic, hepatic, and renal function. The exclusion criteria for patients were as follows: presence of macrovascular invasion and extrahepatic metastasis prior to surgery; severe functional impairment of critical organs including the heart, brain, lung, kidney, and liver; active uncontrolled infection; allergy to any drugs related to the treatment or intolerance to HAIC; and a history of organ transplantation, neurological or psychiatric disorders, human immunodeficiency virus (HIV) infection, esophageal or gastric variceal bleeding, hepatic encephalopathy, or significant cardio-cerebrovascular events.

Treatment procedures

The treatment choice for each patient was made based on the patient’s request and after a thorough discussion with a multidisciplinary treatment team, which included radiologists, surgeons, hepatologists, and oncologists. To ensure precision, HAIC was administered to all patients following a structured protocol and under meticulous image guidance. The femoral artery was punctured percutaneously via the Seldinger technique, allowing for the insertion of a 5F catheter. The catheter tip was strategically placed in either the celiac trunk or superior mesenteric artery, and arteriography was performed to assess hepatic arterial blood supply and portal vein patency. After arterial catheterization, a 2.8F microcatheter was inserted through the arterial catheter and positioned in the artery that supplied blood to the tumor, which was followed by microcatheter angiography.

Three distinct HAIC protocols were employed for the patient cohort. Group A received the conventional FOLFOX-HAIC regimen. This included the administration of oxaliplatin at a dosage of 85–130 mg/m² via arterial infusion over 23 hours and calcium folinate at 400 mg/m² or levoleucovorin at 200 mg/m² via arterial infusion for 1–2 hours, which was followed by an arterial bolus injection of 5-fluorouracil (5-FU) at 400 mg/m², with arterial infusion continuing at 2,400 mg/m² over 23 or 46 hours. Group B received the reverse FOLFOX HAIC (REFOLFOX-HAIC) protocol, in which the infusion of calcium folinate and fluorouracil was followed by oxaliplatin infusion. Group C received direct intraoperative infusion of oxaliplatin and FOLFOX-HAIC (OxDirect-FOLFOX-HAIC), which involved percutaneous intraoperative oxaliplatin injection, followed by calcium folinate and fluorouracil infusion upon return to the postoperative ward (Figure 1).

Figure 1.

The patients were divided into three groups: Group A (standard FOLFOX-HAIC regimen), Group B (reverse FOLFOX-HAIC), and Group C (oxaliplatin direct infusion with FOLFOX-HAIC). FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin.

The administration sequence and method of the three drugs varied across the group assignments according to the standard dosages outlined in the FOLFOX-HAIC regimen. After chemotherapy, the catheters were removed. The median dosage of oxaliplatin was 130 mg/mg [interquartile range (IQR), 120–150 mg] via intra-arterial (IA) infusion. Leucovorin was administered at a median dosage of 400 mg (IQR, 350–600 mg) via IA infusion, and fluorouracil was administered at a median dosage of 2,000 mg (IQR, 2,000–2,250 mg) via IA infusion.

Patient evaluation

The pain intensity associated with the targeted tumor was systematically recorded with the visual analogue scale (VAS). The scale ranged from 0 (indicating no pain) to 10 (representing the most intense conceivable pain). The analgesic utilization score during the HAIC procedure and within 24 hours following the operation was measured via the World Health Organization (WHO) three-step analgesic ladder. Opioid analgesics were scored as follows: opioid injections (e.g., 5 mg morphine hydrochloride injection) received 3 points per standard dose, oral opioids received 2 points per standard dose, nonsteroidal anti-inflammatory drugs (NSAIDs) received 1 point per standard dose, and adjuvant sedative medications received 0.5 points per standard dose. Safety measures included monitoring adverse events (AEs) during and after the procedure, as well as hospitalization after the procedure.

Tumor response assessment

All patients underwent tumor response evaluation after 3 months of HAIC treatment. Treatment responses were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Based on these classifications, the objective response rate (ORR)—calculated as CR + PR—and the disease control rate (DCR)—calculated as CR + PR + SD—were determined. Tumor response outcomes were compared across the three treatment groups.

AEs and serious adverse events (SAEs) were carefully monitored and documented by professional nursing staff who were unaware of the treatment assignments. AEs were assessed diligently during each treatment procedure, after each procedure, and during all follow-up visits until the study treatment was discontinued. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 was used as a grading guide. SAEs included instances of treatment-related hospitalization, extension of hospital stay, functional impairment or disability, life-threatening events, and deaths. A death was considered treatment-related if it occurred within 30 days of the procedure due to a complication.

Statistical analysis

All participants undergoing treatment were included in the analysis. Continuous variables are presented as the median and IQR or as the mean ± standard deviation, while categorical variables are presented as frequencies and percentages. For comparing baseline characteristics between the three groups, one-way analysis of variance or the Kruskal-Wallis test was used for continuous variables depending on normality of distribution, while the Pearson chi-squared test or Fisher exact test was applied for categorical variables. Standardized mean differences were calculated to assess the magnitude of differences between groups and control for potential confounding factors. For missing data (<5%), multiple imputation was used to minimize potential bias. The Kruskal-Wallis test was performed to detect overall differences between the three groups, followed by pairwise comparisons with Bonferroni correction to control for multiple testing. Tumor response rates were compared with the Fisher exact test. All statistical analyses were performed with R version 4.1.0 (The R Foundation for Statistical Computing) and SPSS version 26.0 (IBM Corp., Armonk, NY, USA). All P values were two-sided, and P values <0.05 were considered statistically significant.

Results

Patient characteristics

Between September 2022 and November 2023, the study center treated a total of 180 patients with various HAIC regimens. Among them, 98 cases were pathologically confirmed as HCC, while 78 cases were diagnosed based on clinical criteria (Figure 2). There were 145 (80.56%) males and 35 (19.44%) females, and the average age was 57.36±9.59 years. The treatment regimens were as follows: 40 (22.22%) patients received standard FOLFOX-HAIC; 74 (41.11%) received REFOLFOX-HAIC, which involved subsequent administration of oxaliplatin following calcium folinate and fluorouracil; and 67 (37.22%) underwent the OxDirect-FOLFOX-HAIC procedure, which included percutaneous intraoperative oxaliplatin infusion followed by postoperative calcium folinate and fluorouracil infusion (Table 1). Table 2 presents the technical parameters and drug administration protocols across all treatment groups. Technical success was achieved in all procedures (100%), with the median dose range for oxaliplatin, calcium folinate, and fluorouracil being 130–150, 300–600, and 2,000–2,250 mg, respectively. The right hepatic artery was the predominant infusion site in Group A (60%) and Group C (59.7%), while the proper hepatic artery was more frequently used in Group B (54.79%).

Figure 2.

Patient selection flowchart. FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin; HCC, hepatocellular carcinoma; OxDirect-FOLFOX-HAIC, direct intraoperative infusion of oxaliplatin with FOLFOX-HAIC; REFOLFOX-HAIC, reverse sequence FOLFOX-HAIC.

Table 1. Baseline clinical characteristics of patients.

Characteristics	Group A	Group B	Group C	Statistic	P value	SMD
Sex				χ2=0.878†	0.645	0.127
Total	40	73	67
Male	34 (85.00)	59 (80.82)	52 (77.61)
Female	6 (15.00)	14 (19.18)	15 (22.39)
Age (years)	52.98±7.76	55.44±9.54	62.07±8.71	F=16.075‡	<0.001	0.704
Pathological diagnosis				χ2=18.426†	<0.001	0.500
Yes	24 (60.00)	51(69.86)	23 (34.33)
No	16 (40.00)	22 (30.14)	44 (65.67)
Tumor size (cm)	7.6 [5.6, 11.0]	7.9 [3.3, 10.9]	8.4 [5.3, 12.6]	χ2=0.640§	0.726	0.120
Tumor number				–¶	0.732	0.125
Solitary	1 (2.50)	1 (1.37)	3 (4.48)
Multiple	39 (97.50)	72 (98.63)	64 (95.52)
Portal vein invasion				χ2=0.870†	0.647	0.103
Yes	17 (42.50)	35 (47.95)	27 (40.30)
No	23 (57.50)	38 (52.06)	40 (59.70)
Lymph node metastasis				χ2=0.648†	0.723	0.082
Yes	12 (30.00)	26 (35.62)	20 (29.85)
No	28 (70.00)	47 (64.38)	47 (70.15)
Extrahepatic metastasis				χ2=2.267†	0.322	0.204
Yes	6 (15.00)	20 (27.40)	15 (22.39)
No	34 (85.00)	53 (72.60)	52 (77.61)
BCLC stage				–¶	0.106	0.281
A	0	1 (1.37)	0
B	19 (47.50)	21 (28.77)	29 (43.94)
C	21 (52.50)	51 (69.86)	37 (56.06)
ECOG performance status				χ2=0.606†	0.739	0.089
0	32 (80.00)	59 (80.82)	57 (85.08)
1	8 (20.00)	14 (19.18)	10 (14.93)
HBV infection				χ2=0.858†	0.651	0.113
Yes	32 (80.00)	63 (86.30)	55 (82.09)
No	8 (20.00)	10 (13.70)	12 (17.91)
Child-Pugh classification				χ2=2.860§	0.239	0.337
A	30 (75.00)	58 (79.45)	59 (88.06)
B	10 (25.00)	15 (20.55)	6 (8.96)
C	0	0	2 (2.99)
ALT (U/L)	33.00 [20.20, 72.30]	34.00 [18.00, 44.80]	36.90 [25.00, 55.40]	χ2=4.042§	0.133	0.107
AST (U/L)	67.80 [38.33, 117.60]	49.40 [35.70, 78.50]	61.00 [40.00, 99.05]	χ2=4.830§	0.089	0.112
Albumin (g/L)	35.38±3.56	35.65±4.24	35.30±3.83	F=0.149‡	0.862	0.059
Total bilirubin (μmol/L)	20.50 [15.40, 31.05]	21.20 [13.90, 28.00]	20.10 [14.30, 27.00]	χ2=0.570§	0.752	0.101
AFP (ng/mL)	42.90 [3.91, 1,730.00]	199.00 [8.59, 8,335.00]	125.00 [5.17, 3,623.00]	χ2=3.247§	0.197	0.104

Data are presented as n, n (%), mean ± standard deviation or median [interquartile range]. Group A: standard FOLFOX-HAIC regimen. Group B: reverse FOLFOX-HAIC. Group C: oxaliplatin direct infusion with FOLFOX-HAIC. Statistical tests: ^†, Pearson chi-squared test; ^‡, one-way analysis of variance; ^§, Kruskal-Wallis test; ^¶, Fisher exact test. AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin; HBV, hepatitis B virus; SMD, standardized mean difference.

Table 2. Technical characteristics and drug administration details.

Characteristic	Group A	Group B	Group C
Infusion dose
Oxaliplatin (mg)	150 [100, 150]	130 [120, 130]	150 [127.5, 150]
Calcium folinate (mg)	600 [400, 600]	600 [400, 600]	300 [300, 350]
Fluorouracil (mg)	2,000 [2,000, 2,000]	2,000 [2,000, 2,000]	2,250 [2,250, 2,500]
Technical success
Yes	40 (100.0)	73 (100.0)	67 (100.0)
No	0	0	0
Infusion arteries
Left hepatic artery	5 (12.5)	5 (6.85)	9 (13.43)
Right hepatic artery	24 (60.0)	28 (38.36)	40 (59.7)
Proper hepatic artery	11 (27.5)	40 (54.79)	18 (26.87)

Data are presented as median [IQR] or n (%). Technical parameters, chemotherapeutic dosing regimens, and arterial access routes for hepatic arterial infusion chemotherapy in patients with hepatocellular carcinoma. Group A: standard FOLFOX-HAIC regimen. Group B: reverse FOLFOX-HAIC. Group C: oxaliplatin direct infusion with FOLFOX-HAIC. FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin; IQR, interquartile range.

Pain palliation

Analgesic utilization score was significantly different between the groups [Kruskal-Wallis, H =8.637; P=0.013; degrees of freedom (df) =2] (Figure 3A). The comparison between Group B and Group A revealed a significant reduction in analgesic utilization score for Group B, with an Z value of −2.704 (P=0.007) and an adjusted P value of 0.021. This indicates that Group B achieved better pain management as compared to Group A. Similarly, Group C, as compared to Group A, exhibited a significant reduction in analgesic utilization score, with an Z value of −2.608 (P=0.009) and an adjusted P value of 0.027, suggesting enhanced pain management in Group C relative to Group A. No significant difference was observed between Group B and Group C (Z =0.065; P=0.949; adjusted P=1.00), indicating comparable analgesic efficacy between these two modified treatment approaches.

Figure 3.

Comparison of analgesic utilization and VAS pain scores among the three treatment groups. (A) Analgesic utilization scores across Groups A, B, and C, with significant differences (Kruskal-Wallis test H =8.637; P=0.013; df =2). Group A showed greater variability in analgesic usage. (B) VAS pain scores for the same groups, revealing significant variations in pain levels (H =8.402; P=0.015; df =2). Group A: standard FOLFOX-HAIC regimen. Group B: REFOLFOX-HAIC regimen. Group C: OxDirect-FOLFOX-HAIC regimen. *, p<0.05. df, degrees of freedom; FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin; H, Kruskal-Wallis test statistic; VAS, visual analogue scale.

In terms of VAS pain score, the Kruskal-Wallis test revealed significant differences across groups (Z =2.735; P=0.015; df =2) (Figure 3B), with Group B demonstrating a significantly lower score as compared to Group A (Z =2.480; P=0.006; adjusted P=0.019). This significantly lower score in Group B suggests more effective pain relief than in Group A. Group C also had a significantly lower VAS pain score compared to Group A (Z =0.251; P=0.013; adjusted P=0.039), indicating that the Group C regimen provides better pain control than does the standard regimen. The comparison between Group B and Group C revealed no significant differences (H =−2.18; P=0.80; adjusted P=1.00), reflecting similar levels of pain control between the two modified regimens (Table 3).

Table 3. Pairwise comparison of VAS pain score and analgesic utilization score between different HAIC regimens.

Variables	Z	P value	Adj. P value
Analgesic utilization score
A–B	−2.704	0.007	0.021
A–C	−2.608	0.009	0.027
B–C	0.065	0.949	1.00
VAS pain score
A–B	−2.735	0.006	0.019
A–C	−2.480	0.013	0.039
B–C	0.251	0.80	1.00

The Kruskal-Wallis test was used to evaluate the differences between three distinct treatment groups: Group A (standard FOLFOX-HAIC regimen), Group B (reverse FOLFOX-HAIC), and Group C (oxaliplatin direct infusion with FOLFOX-HAIC). The Bonferroni correction was used to adjust for multiple comparisons, with a significance threshold set at 0.05. adj., adjusted; FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin; VAS, visual analogue scale; Z, Z-score for pairwise comparison.

Tumor response

Table 4 presents the tumor responses of patients in the three groups after 3 months of HAIC treatment. According to RECIST 1.1, there was no statistically significant difference in overall tumor response between the three groups (P=0.128). In Group A (standard FOLFOX-HAIC), 6 (15.00%) achieved PR, 32 (80.00%) had SD, and 2 (5.00%) experienced PD; in Group B (reverse FOLFOX-HAIC), 10 (13.70%) patients achieved PR, 55 (75.34%) had SD, and 8 (10.96%) experienced PD; in Group C (OxDirect-FOLFOX-HAIC), 6 (8.96%) patients achieved PR, 60 (89.55%) had SD, and 1 (1.49%) experienced PD. No patients in any group achieved CR.

Table 4. Tumor response after 3 months of treatment.

Tumor response	Patients, n (%)			P value	SMD
	Group A	Group B	Group C
RECIST1.1				0.128	0.317
CR	0	0	0
PR	6 (15.00)	10 (13.70)	6 (8.96)
SD	32 (80.00)	55 (75.34)	60 (89.55)
PD	2 (5.00)	8 (10.96)	1 (1.49)
ORR	6 (15.00)	10 (13.70)	6 (8.96)	0.074	0.273
DCR	38 (95.00)	65 (89.04)	66 (98.51)	0.591	0.125

Group A: standard FOLFOX-HAIC regimen. Group B: reverse FOLFOX-HAIC. Group C: oxaliplatin direct infusion with FOLFOX-HAIC. CR, complete response; DCR, disease control rate; FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease; SMD, standardized mean difference.

The ORR was 15.00% in Group A, 13.70% in Group B, and 8.96% in Group C, with no statistically significant difference between groups (P=0.074). The DCR was 95.00% in Group A, 89.04% in Group B, and 98.51% in Group C and also did not significantly differ between groups (P=0.591). These results suggest that despite differences in administration sequence and method, all three HAIC regimens demonstrated similar efficacy in tumor control.

Safety

To evaluate procedural safety in a pragmatic clinical context, we examined the incidence of AEs apart from pain: eight patients experienced nausea and vomiting during or after the infusion, with three patients in Group A, three in Group B, and two in Group C; additionally, five patients developed fever, with two in Group A and three in Group B; there was no grade 3 or higher AEs reported. It is important to note that all adverse reactions improved significantly with postsymptomatic treatment, and there were no cases of mortality or rehospitalization due to complications (Table 5).

Table 5. Complications and side effects.

AE	Group A (n=40)	Group B (n=73)	Group C (n=67)
Nausea (grade 1–2)	7 (17.5)	13 (17.8)	9 (13.4)
Fever (grade 1–2)	4 (10.0)	6 (8.2)	7 (10.4)

Data are presented as cases (%). Group A: standard FOLFOX-HAIC regimen. Group B: REFOLFOX-HAIC regimen. Group C: OxDirect-FOLFOX-HAIC regimen. AE, adverse event; FOLFOX-HAIC, hepatic arterial infusion chemotherapy with folinic acid, fluorouracil, and oxaliplatin.

Discussion

In this real-world study, both Group B (REFOLFOX-HAIC) and Group C (OxDirect FOLFOX-HAIC) demonstrated significantly better pain management compared to the standard regimen (Group A), with no significant differences between the two modified approaches. The study’s strength lies in using both subjective (VAS pain scores) and objective (analgesic utilization scores) pain measures. While primarily focused on pain management, our short-term efficacy data showed comparable tumor control across all three regimens, with high DCRs (89.04–98.51%) indicating that modifications to oxaliplatin administration improved patient comfort without compromising therapeutic outcomes. Potential long-term efficacy differences will be the primary focus of our subsequent research.

Oxaliplatin is a frequently used platinum-based chemotherapy drug. One of the comprehensive adverse reactions associated with oxaliplatin is peripheral neurotoxicity, commonly referred to as oxaliplatin-induced peripheral neuropathy (OIPN). Acute OIPN is characterized by cold-sensitive sensory symptoms and neuropathic pain in the limbs (11). Additionally, almost 90% of patients experience an acute peripheral pain syndrome immediately after receiving oxaliplatin treatment. This pain syndrome is believed to be mediated by lysophospholipid-mediated lipid signaling (12). Wu et al. identified the factors contributing to pain in patients with advanced HCC undergoing HAIC, emphasizing the efficacy of IA lidocaine injection in reducing pain for most patients. They also identified factors such as oxaliplatin preparation time and hepatic artery diameter as influential in pain scores (13).

The role of the serotonergic system has been emphasized in relation to OIPN. Although 5-hydroxytryptamine (5-HT) may not directly contribute to the development of allodynia, the modulation of its receptors, specifically 5-HT1A, 5-HT2A, and 5-HT3, may play a crucial role in pain management (14). According to Marcotti et al., the modulation of TRPA1 channels by sigma-1 receptor antagonists suggests a novel approach for preventing and treating chemotherapy-induced peripheral neuropathy, which could lead to the development of innovative therapeutics for neuropathic pain (15). The analgesic effects of venlafaxine in the treatment of OIPN show that the modulation of β2-adrenergic and 5-HT3 receptors may help alleviate pain (16). Moreover, Tat-HA-NR2B9c has the potential to treat OIPN, possibly without significant side effects (17). These findings highlight the complex nature of pain management in HAIC, with various factors, including drug preparation and anatomical considerations, intersecting to shape the patient’s pain experience and the efficacy of pain-relieving interventions. The differences in pain management observed with the same drugs infused in different sequences may be attributed to the tendency in real-world settings to administer analgesics postinfusion rather than during the infusion process. In our study, this could have alleviated the oxaliplatin-induced pain more effectively in Groups B and C due to the timely administration of pain relief.

This research highlights the efficacy of REFOLFOX-HAIC and OxDirect-FOLFOX-HAIC procedures in reducing the use of narcotics during and after surgery and improving pain management outcomes in patients with HCC. These findings suggest the need for further research and clinical investigation. Future studies should focus on understanding the underlying mechanisms of these benefits, examining the long-term outcomes of these modified HAIC procedures, and assessing their efficacy in different patient populations and stages of HCC.

Our study involved several limitations that should be mentioned. To begin, we employed real-world data and a small-scale, single-center, retrospective design. However, there was a lack of randomized allocation for the treatment groups, potentially introducing selection bias. Therefore, further large-scale prospective studies are needed to enhance the level of evidence. Moreover, the OxDirect-FOLFOX-HAIC procedure modifies the conventional infusion method of HAIC, positioning itself as an intermediate procedure between TACE and HAIC. It is still unclear whether the metabolic alterations to hepatic tumors during direct intraoperative infusion are similar to those of conventional HAIC. Additionally, the study focused on analyzing the impact of two modified procedures on patient pain and the success rate of surgical techniques, but it did not examine the DCRs or survival among patients. These areas should be considered for further exploration and analysis in future research.

In summary, managing pain and optimizing the use of analgesics during and after the HAIC procedure are integral components of the comprehensive treatment strategy for HCC. The presented research indicates that, in comparison to the conventional HAIC approach, the modified REFOLFOX-HAIC and OxDirect-FOLFOX-HAIC techniques offer distinct advantages. These advanced procedures not only significantly reduce pain experienced by patients but also lead to a marked improvement in their overall quality of life, highlighting the potential of these modifications to enhance the therapeutic outcomes for patients with HCC.

Conclusions

The REFOLFOX-HAIC and OxDirect-FOLFOX-HAIC procedures significantly reduce perioperative pain and analgesic requirements in patients with HCC as compared to the standard FOLFOX-HAIC protocol while maintaining comparable therapeutic efficacy and safety profiles. These modified protocols offer a practical approach to improving patient comfort and quality of life during HAIC treatment without compromising oncological outcomes.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This retrospective study was conducted at a single institution and was approved by the institutional review board of the Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences (approval No. 23/359-2143). Written informed consent was obtained from all patients for the procedure, with subsequent follow-up, and opt-out consent was obtained for the retrospective use of clinical data. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Data Sharing Statement

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DOI: 10.21037/qims-24-2066