A new randomized, double-blind, placebo-controlled clinical trial has found that combining all-trans retinoic acid (ATRA) with the FOLFOX4 chemotherapy regimen significantly improved survival outcomes in patients with advanced hepatocellular carcinoma (HCC) and extrahepatic metastasis. The study, published on August 23, 2023 in Signal Transduction and Targeted Therapy, provides evidence for a novel treatment approach for this difficult-to-treat patient population.
The multicenter phase III trial was conducted across three hospitals in eastern China between October 2017 and September 2021. It was funded by several Chinese national research grants, including support from the National Natural Science Foundation of China and the National Key R&D Program of China. The primary goal was to assess whether adding ATRA to standard FOLFOX4 chemotherapy could improve overall survival compared to FOLFOX4 alone in patients with advanced HCC and extrahepatic metastasis.
A total of 108 patients were enrolled and randomly assigned in a 1:1 ratio to receive either FOLFOX4 plus ATRA or FOLFOX4 plus placebo. Key eligibility criteria included unresectable HCC with measurable extrahepatic metastasis, an Eastern Cooperative Oncology Group performance status of 1 or less, Child-Pugh class A liver function, and a life expectancy of more than 3 months. Patients who had received previous systemic therapies were eligible if treatment had been completed at least 4 weeks prior to randomization. Those with central nervous system metastases or poor liver function were excluded.
The study population had a median age of about 52 years and was predominantly male (86%). Most patients had hepatitis B virus infection (71%) and lung metastases (78%). Approximately 30% had received prior targeted therapy or immunotherapy. Baseline characteristics were well-balanced between the two treatment arms.
In the intention-to-treat analysis, the addition of ATRA to FOLFOX4 resulted in a significant improvement in median overall survival - 16.2 months versus 10.7 months with FOLFOX4 alone (hazard ratio 0.56, 95% CI 0.33-0.93, p=0.025). Progression-free survival was also prolonged in the ATRA group at 7.1 months compared to 4.2 months (hazard ratio 0.62, 95% CI 0.41-0.94, p=0.024). The objective response rate was higher with ATRA (24.5% vs 9.1%, p=0.031), including more complete responses (7.5% vs 1.8%).
Importantly, the combination therapy appeared to be well-tolerated. While over 90% of patients in both arms experienced adverse events, the rates of grade 3-4 toxicities were similar (39.6% with ATRA vs 47.2% with placebo). The most common side effects were hematologic and gastrointestinal. Headache, likely related to ATRA, occurred in 20.8% of patients in the combination arm but was generally mild.
To explore potential biomarkers of response, the researchers conducted proteomic analyses on patient blood samples. They identified several proteins that were differentially expressed in responders versus non-responders prior to treatment initiation. A panel combining these proteins showed promise for predicting complete or partial responses to FOLFOX4-ATRA therapy. Additionally, the proteomic data suggested the combination regimen may exert effects on complement and coagulation cascades.
The authors concluded that FOLFOX4 plus ATRA represents a safe and effective new treatment option for patients with advanced HCC and extrahepatic metastasis in eastern China. They highlighted the regimen's favorable efficacy-to-cost ratio compared to newer targeted and immunotherapy approaches. However, they acknowledged several limitations of the study, including its relatively small sample size, potential unblinding due to ATRA-related side effects, and heterogeneity in prior and subsequent treatments.
This trial provides the first randomized evidence supporting the addition of ATRA to chemotherapy for advanced HCC. If confirmed in larger studies, the findings could lead to a new standard of care for this poor-prognosis patient population. The combination may be particularly valuable in resource-limited settings given its lower cost compared to targeted agents and immunotherapies. However, several questions remain, including whether the benefits extend to Western populations and how the regimen compares to current first-line standards like atezolizumab plus bevacizumab.
From a clinical perspective, the FOLFOX4-ATRA combination could offer a new treatment option for patients with advanced HCC and extrahepatic spread, particularly those who have progressed on or are ineligible for immunotherapy. The tolerability profile appears manageable, with headache being the main ATRA-specific toxicity. If validated, the proteomic biomarkers identified in this study may help select patients most likely to benefit from the combination approach.
Notably, this trial focused specifically on HCC patients with extrahepatic metastasis - a group with very limited treatment options and poor outcomes. The significant survival improvement seen with ATRA is therefore particularly meaningful. The researchers suggest ATRA may enhance the effects of chemotherapy through mechanisms like inducing differentiation of liver cancer stem cells and cell cycle arrest. Further research into these potential mechanisms of synergy is warranted.
While promising, these results require confirmation in larger, international phase III trials before the FOLFOX4-ATRA combination can be widely adopted. Key questions for future studies include assessing efficacy in non-Asian populations, comparing the regimen to current standards of care like atezolizumab-bevacizumab, evaluating quality of life outcomes, and validating the proposed biomarker panel. Additionally, studies combining ATRA with other systemic therapies for HCC may be of interest.
In conclusion, this well-designed randomized trial provides compelling evidence that adding ATRA to FOLFOX4 chemotherapy can significantly improve survival outcomes in advanced HCC patients with extrahepatic metastasis. The combination demonstrated a manageable safety profile and potential biomarkers of response were identified. If confirmed, these findings could expand the limited treatment armamentarium for this challenging patient population. However, further research is needed to fully elucidate the role of this regimen in the evolving therapeutic landscape for advanced HCC.
References
Sun J, Mao F, Liu C, et al. Combined FOLFOX4 with all-trans retinoic acid versus FOLFOX4 with placebo in treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a randomized, double-blind comparative study. Signal Transduct Target Ther. 2023;8(1):368. Published 2023 Sep 27. doi:10.1038/s41392-023-01604-3
