HAIC-Administered FOLFOX Lengthens DFS and Provides a Tolerable Safety Profile in HCC

Patients with hepatocellular carcinoma (HCC) with microvascular invasion who received FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) through hepatic arterial infusion chemotherapy (HAIC) experienced improved disease-free survival (DFS) rates compared with those who received no adjuvant treatment, according to updated extended follow-up data from an open-label, multicenter phase 3 study (NCT03192618).

In the intention-to-treat (ITT) population, FOLFOX elicited a median DFS of 20.3 months (95% CI, 10.4-30.3) vs 10.0 months (95% CI, 6.8-13.2) in those who received routine follow-up alone (HR, 0.59; 95% CI, 0.43-0.81; P = .001). Additionally, the respective 1-, 2-, and 3-year DFS rates were 62.2% (95% CI, 54.2%-71.3%), 46.8% (95% CI, 38.0%-57.6%), and 41.1% (95% CI, 31.8%-53.0%) in the treatment group and 47.2% (95% CI, 39.2%-56.7%), 30.1% (95% CI, 22.1%-41.0%), and 22.6% (95% CI, 14.8%-34.5%) in the control group.

“To our knowledge, no standard treatment has been proposed as the adjuvant therapy for the HCC patients with microvascular invasion, and our study is the first phase 3 trial to evaluate the value of hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin as the adjuvant therapy in this population,” lead study author Shao-Hua Li, MD, of Sun Yat-sen University Cancer Center in Guangdong, China, and colleagues, wrote.

To be eligible for this trial, patients needed to be between 18 and 75 years of age with treatment-naïve, histologically confirmed HCC with microvascular invasion. Additionally, patients needed to have an ECOG performance score of 2 or less and adequate hepatic, hematologic, and renal functions. Patients could not have macrovascular invasion, distant metastases, and intrahepatic or extrahepatic recurrence at a radiological follow-up of 4 to 6 weeks after surgery. Patients were also excluded if they had histologically proven R1 resection, severe organ functional impairment, intolerance to HAIC, allergy to related drugs, previous or concomitant antitumor therapy, or a history of organ transplantation, neurologic diseases, psychiatric diseases, human immunodeficiency virus infection, esophageal or gastric variceal bleeding, hepatic encephalopathy, or cardio-cerebrovascular events within 30 days of randomization.

Between June 2016 and August 2021, 315 patients across 5 centers in China were randomized 1:1 to receive 1 to 2 cycles of adjuvant HAIC in the treatment group (n = 157) or routine follow-up with no adjuvant treatment in the control group (n = 158). These patients comprised the ITT population. Patients in the treatment group received oxaliplatin at 85 mg/m2 from 0 to 3 hours once on day 1, leucovorin at 400 mg/m2 from 3 to 4.5 hours once on day 1, fluorouracil at 400 mg/m2 from 4.5 to 6.5 hours once on day 1, and fluorouracil at 2,400 mg/m2 once over 46 hours from days 1 to 3.

This trial’s primary end point was DFS by ITT analysis. Secondary end points included overall survival (OS), recurrence rate, and safety. At each follow-up, which occurred every 2 to 3 months, patients received physical examination, blood tests, and enhanced abdominal computed tomography or magnetic resonance imaging scans. When recurrence or metastases were detected, further examinations, including hepatic biopsy or arteriography, were performed.

Baseline demographics and clinical characteristics were comparable between the 2 groups in the ITT population. The median age was 50 years (range, 25-75) and 54 years (range, 27-75) in the treatment and control groups, respectively, and 86.6% (n = 136) and 88.0% (n = 139) were male. The maximum tumor diameter was 5.6 cm (range, 1.8-30.0) in the treatment group and 5.4 cm (range, 1.5-16.0) in the control group, and 57.3% (n = 90) and 59.5% (n = 94) of patients in the treatment and control groups, respectively, had minor resections.

A total of 148 patients in the treatment group received at least 1 cycle of HAIC and were included in the safety analysis. Of the ITT population, 15.3% (n = 24) received only 1 cycle of HAIC. Of the per-protocol population, which included all patients who planned to complete 2 cycles of adjuvant HAIC, 86.7% (n = 124) completed the planned 2 cycles of HAIC, 9.8% (n = 14) refused the second cycle for personal reasons, 2.8% (n = 4) had intrahepatic recurrence during the second cycle of HAIC and were diverted to receive transarterial chemoembolization (TACE), and 1 patient was diverted to receive TACE upon intrahepatic recurrence during the first cycle of HAIC.

The median follow-up periods were 23.7 months (95% CI, 21.0-26.5) and 21.5 months (95% CI, 17.6-25.4) in the ITT treatment and control groups and 23.2 months (95% CI, 17.9-28.5) and 20.5 months (95% CI, 15.4-25.5) in the per-protocol treatment and control groups, respectively. At the time of the last follow-up, 151 total recurrences occurred in the ITT population, 63 and 88 in the treatment and control groups, respectively. Additionally, 144 recurrences occurred in the per-protocol population, 58 and 86 in the treatment and control groups, respectively. Five patients had no observable recurrence before death.

In the per-protocol population, the median DFS was 19.3 months (95% CI, 12.2-26.4) vs 8.9 months (95% CI, 5.9-11.8) in the treatment and control groups, respectively (HR, 0.52; 95% CI, 0.38-0.72; P < .001). The respective 1-, 2-, and 3-year DFS rates were 61.6% (95% CI, 53.2%-71.4%), 44.6% (95% CI, 35.4%-56.2%), and 39.0% (95% CI, 29.6%-51.5%) in the treatment group and 43.2% (95% CI, 35.0%-53.4%), 24.0% (95% CI, 16.3%-35.2%), and 16.8% (95% CI, 9.9%-28.5%) in the control group.

In the ITT population, the respective 1-, 2-, and 3-year OS rates were 93.8% (95% CI, 89.8%-98.1%), 86.4% (95% CI, 80.0%-93.2%), and 80.4% (95% CI, 71.9%-89.9%), in the treatment group and 92.0% (95% CI, 87.6%-96.7%), 86.0% (95% CI, 79.9%-92.6%), and 74.9% (95% CI, 65.5%-85.7%) in the control group (estimated HR, 0.64; 95% CI, 0.36-1.14; P = .130). In the per-protocol population, the respective 1-, 2-, and 3-year OS rates were 93.9% (95% CI, 89.6%-98.4%), 85.3% (95% CI, 78.4%-93.0%), and 80.9% (95% CI, 72.3%-90.6%) in the treatment group and 91.8% (95% CI, 87.1%-96.8%), 84.9% (95% CI, 78.1%-92.2%), and 72.9% (95% CI, 62.8%-84.6%) in the control group (estimated HR, 0.57; 95% CI, 0.31-1.04; P = .067).

The recurrence rates were 40.1% (n = 63) and 55.7% (n = 88) in the treatment and control groups, respectively. Of the patients who had recurrence, 76.2% (n = 48) of those in the treatment group and 67.0% (n = 59) of those in the control group received subsequent antitumor therapies.

The investigators observed no significant difference in the incidence of operation-related adverse effects (AEs) between the treatment and control groups (P = .597). In total, 83.8% (n = 124) of AEs in the patients who received adjuvant HAIC were grade 0 or 1. Specifically, 70.1% of AEs (n = 110) in the treatment group and 74.1% of AEs (n = 117) in the control group were grade 1. Among the grade 3 AEs were elevated alanine transaminase levels, hyperbilirubinemia, thrombocytopenia, and anemia.

In total, 47 deaths occurred in the ITT population, 19 in the treatment group and 28 in the control group. In the per-protocol population, 44 deaths occurred, 17 in the treatment group and 27 in the control group. No AE-related deaths occurred during hospitalization in either group, and there were no deaths from HAIC or surgery.

“At this juncture, the results from our current study substantiated that adjuvant HAIC with FOLFOX provided acceptable survival benefits. In addition, our study suggests that FOLFOX-HAIC has acceptable safety profiles and was well tolerated,” the study authors concluded.

Reference

Li S, Mei J, Cheng Y, et al. Postoperative adjuvant hepatic arterial infusion chemotherapy with FOLFOX in hepatocellular carcinoma with microvascular invasion: a multicenter, phase III, randomized study. J Clin Oncol. Published online December 16, 2022. doi:10.1200/JCO.22.01142