Hepatic arterial infusion chemotherapy with oxaliplatin, fluorouracil, and leucovorin significantly improved overall survival compared with transarterial chemoembolization in patients with unresectable hepatocellular carcinoma.
Results from a randomized, open-label, multi-center, phase 3 trial conducted in China found that hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) significantly improved overall survival (OS) compared with transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC).
The study, presented at the 2020 ESMO Virtual Congress, included 315 patients who either received HAIC (n = 159) or TACE (n = 156). Patients were mostly men, at least 18 years old, with a primary HCC tumor measuring more than 7 centimeters, and had an ECOG performance status of 0 or 1. The majority of participants (90%) had hepatitis B infection, 60% had confirmed liver cirrhosis, and about half of patients had more than 3 lesions.
“The patient demographics were generally similar across arms and are representative of our Chinese intermediate-staged HCC population,” study author Ming Shi, MD, PhD, from the Department of Hepatobiliary Oncology at the Cancer Center at Sun Yat-sen University in Guangzhou, China, said during the virtual meeting.
Currently, TACE is the standard of care for patients with unresectable intermediate-stage HCC, and a previous phase II study demonstrated higher treatment response with HAIC with FOLFOX versus TACE, according to Shi.
“Intermediate or BCLC B stage HCC is a largely heterogenous group that includes patients who do not benefit from TACE—the standard of care—with a median overall survival of only 9 to 13 months,” Lorenza Rimassa, MD, associate professor of medical oncology at Humanitas University and Humanitas Research Hospital-IRCCS in Milan, Italy, said in a discussion following the presentation. “This represents an important unmet clinical need and new data are strongly needed.”
Investigators of this trial examined OS as their primary endpoint, with secondary endpoints of objective response rate (ORR) using RECIST criteria, progression-free survival (PFS), and safety. Treatment response was also assessed using mRECIST.
The patients were randomized 1:1 to HAIC (oxaliplatin 130 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2) on day 1 and fluorouracil infusion 2400 mg/m2 for 24 hours, every 3 weeks via repeated catheterization up to 6 cycles, or TACE (50 mg of epirubicin, 50 mg of lobaplatin, and lipiodol and polyvinyl alcohol particles) on demand. Treatment was continued until tumor progression or intolerable toxicity.
An average of 4 sessions were received by patients in the HAIC arm, whereas patients in the TACE arm received an average of 2 sessions. Treatment crossover occurred between both arms with 8 patients crossing over from HAIC to TACE and 20 patients crossing over from TACE to HAIC.
“There was no significant difference in the number of patients receiving either subsequent treatment between the 2 arms,” Shi said.
Patients who received HAIC saw a higher median OS compared with those who received TACE (23.1 months [95% CI, 18.23-27.97] versus 16.07 months [95% CI, 14.26-17.88], respectively). Hazard ratio was 0.58 (95% CI, 0.45-0.75; P <0.001).
In addition, compared with the TACE arm, patients in the HAIC arm had a higher ORR (RECIST: 45.9% versus 17.9%, P <0.001; mRECIST: 48.4% versus 32.7%, P = .004). Median PFS was also longer at 9.63 months (95% CI, 7.40-11.86) in the HAIC group compared with 5.4 months (95% CI, 3.82-6.98) in the TACE group.
“We can appreciate that overall survival is longer than expected in the TACE arm, overall survival curves seem to separate after 6 months, [and] progression-free survival curves seem to separate from the beginning,” Ramissa said. “So, we have further questions, is there an impact of the crossover? And which is the median duration of the treatment? And we don’t have the answers.”
More patients in the HAIC group underwent subsequent resection compared with the TACE group (23.8% versus 11.5%, P = 0.004).
Although both groups experienced serious adverse events (AEs), HAIC had a better safety profile compared with TACE, Shi said. Serious AEs occurred in the TACE arm (30%) versus the HAIC arm (19%). These included ascites, hyperbilirubinemia, upper gastrointestinal bleeding, cholangitis, and infection. However, the HAIC group experienced more occurrences of thrombocytopenia, neutropenia, and diarrhea. Two treatment-related grade 5 events were seen in each arm.
Although Rimassa called the data encouraging, she believes there are still many unanswered questions, such as “Can this treatment be extrapolated to other patient populations? My answer is no,” she said.
The cut-off for the present analysis was April 2020 and patient follow-up is on-going.
“HAIC is not a globally accepted treatment for HCC,” Rimassa said regarding trial design. “It is mainly used in China where this trial has been conducted and more clinical trials are needed to define it’s true.”
Shi M, Li Q, He M, et al. Hepatic arterial infusion chemotherapy with oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for unresectable hepatocellular carcinoma: A randomised phase III trial. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract 981O.