INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide.¹ HCC commonly occurs in patients with chronic hepatitis or liver cirrhosis due to viral infection, alcohol use, or metabolic dysfunction-associated steatohepatits.²

Previously, the only treatment for patients with unresectable HCC was intrahepatic locoregional therapy with fluorouracil-based continuous infusion therapy through a venous port system^3-6 or with cisplatin arterial infusion through a catheter,^{7, 8} but patients with metastatic HCC could not be treated. In the SHARP study⁹ and an Asia–Pacific study,¹⁰ sorafenib (SOR) was shown to be efficacious and well-tolerated in patients with advanced HCC. After 2008, the treatment strategy for HCC changed due to the availability of sorafenib, which enabled the treatment of patients with metastatic HCC. In 2017, lenvatinib (LEN) demonstrated a treatment effect on overall survival (OS) by statistical confirmation of non-inferiority when compared with SOR in the REFLECT study.¹¹ Next, the combination of atezolizumab, a programmed cell death ligand 1 inhibitor, with bevacizumab showed longer OS and progression-free survival than SOR in the IMbrave 150 trial.¹² Recently, combination therapy with durvalumab, a programmed cell death ligand 1 inhibitor, and tremelimumab, a cytotoxic T-lymphocyte-associated antigen 4 inhibitor, was approved for patients with unresectable HCC based on the results of the HIMALAYA study,¹³ and systemic treatment for unresectable HCC has changed to immune therapy. In a previous report,¹⁴ the prognosis of hepatitis B virus- and hepatitis C virus-related HCC patients by era group was compared. Following this study, we assessed the outcome of systemic therapy in Hiroshima University Hospital (Hiroshima, Japan) in each era to devise a new treatment strategy in the era of immunotherapy for HCC.

METHODS

Patients

A total of 397 patients with unresectable HCC who were treated with SOR, lenvatinib (LEN), atezolizumab plus bevacizumab combination therapy (Atez + Bev), or durvalumab plus tremeliumab combination therapy (Dur + Tre) as first-line systemic therapy in our hospital from November 2009 to October 2023 were enrolled in the present retrospective cohort study. Their functional hepatic reserve score was Child–Pugh 5–7, and Eastern Cooperative Oncology Group performance status was 0 or 1. Unresectable HCC was defined as a liver cancer not eligible for liver resection given the disease extension, patients who were not suitable for resection because of the location of tumor, or who rejected surgery. We divided the years from 2009 to 2023 into the following three periods: cohort I, 2009–2016, the single-molecular targeted agent (MTA) era; cohort II, 2017–2020, the multi-MTA era; and cohort III, 2020–2023, the immuno-oncology era (Figure 1).

The present study was carried out in accordance with the ethical principles of the Declaration of Helsinki, and was approved by the Institutional Review Board of Hiroshima University. Written informed consent was obtained from each patient after a detailed explanation of the study procedures. Patients continued therapy until death or until they met one of the following criteria: (i) adverse events that required termination of treatment; (ii) deterioration of Eastern Cooperative Oncology Group performance status; (iii) worsening liver function; or (iv) withdrawal of consent.

RESULTS

Overall survival

The median survival time (MST) was 9.5 months in cohort I, 15.8 months in cohort II, and 20.2 months in cohort III. The MST in cohort III was significantly (p < 0.001) longer than in the other eras (Figure 2a). In patients with Child–Pugh score 7 liver function, the MST was 6.3 months in cohort I, 6.9 months in cohort II, and 7.1 months in cohort III, and there were no significant differences among eras (Figure 2b). In the Barcelona Clinic Liver Cancer (BCLC) stage B group, the MST was 9.6 months in cohort I, 17.9 months in cohort II, and 20.1 months in cohort III, which was significantly longer than in earlier eras (p < 0.001; Figure 2c). In the BCLC stage C group, the MST was 9.5 months in cohort I, 12.8 months in cohort II, and 21.2 months in cohort III, with MST again significantly longer in cohort III (p < 0.001). In the MVI present group, the MST was 8.3 months in cohort I, 11.1 months in cohort II, and 23.6 months in cohort III. The MST in cohort III was significantly (p < 0.001) longer than the other cohorts (Figure 2e).

Figure 2f shows comparison by regimens, the MST of SOR, LEN, Atez + Bev, and Dur + Tre were 9.5, 17.9, 22.3, and 16.0 months, respectively. There were significant differences between SOR and the other regimens; however, there were no significant differences among LEN, Atez + Bev, and Dur + Tre.

DISCUSSION

In the present study, we analyzed the history of systemic therapy in our institutions. We divided this 15-year span into three eras, as follows: cohort I, the era of single-MTA; cohort II, the era of multi-MTA; and cohort III, the era of immno-oncology.

There were many differences in the backgrounds of the patients in each era. The age of the patients increased in each era. A previous report determined that there were no significant differences in the incidence of severe adverse effects and therapeutic effects between elderly and non-elderly patients treated with SOR or LEN.¹⁵ Therefore, we should decide patient eligibility based on hepatic functional reserve and general condition instead of age.

The ratio of patients with HCC derived from NBNC hepatitis increased between cohort I and cohort III. In Japan, the percentage of patients with HCV-induced HCC was 70% in the 1990s, but the incidence has decreased over time.¹⁶ Nagaoki et al. reported that the ratio of NBNC-HCC increased from 26.5% in 2009 to 46.3% in 2018¹⁷ because of precautions against hepatitis C virus and hepatitis B virus infection, and the evolution of antiviral drugs.

The ratio of patients with BCLC B stage HCC treated with systemic therapy increased. The patients with BCLC B stage HCC were eligible for transarterial chemoembolization, but it is known that repeated transarterial chemoembolization leads to deterioration of hepatic functional reserve.¹⁸ It has been reported that initiation of systemic therapy leads to a favorable prognosis before deterioration of functional reserve induced by repeated transarterial chemoembolization.¹⁸

For patients with Child–Pugh B liver function, MST of patients with Child–Pugh 7 in cohort III in the present study was 7.1 months, which was a longer prognosis than the previous eras, although the difference was not significant among eras. Our previous study reported that the patients treated with Atez + Bev had significantly better progression-free survival than patients treated with LEN and SOR among patients with Child–Pugh B liver function.¹⁹ However, in the Child–Pugh B group, the effect of systemic therapy remains unclear, more studies are needed.

In cohort II, MST was longer than in cohort I, with an MST of 9.5 months in cohort I and 15.8 months in cohort II. We conclude from this that LEN and sequential therapy improved the prognosis. In cohort III, MST was 20.2 months, which suggests that immune checkpoint inhibitors improved the prognosis further. The ORR was 4.1% in era I, similar to the SHARP study⁹ and the Asia–Pacific study,¹⁰ suggesting that SOR might improve MST, but not lead to tumor shrinkage. After the era of cohort II, patients treated with LEN, sequential therapy, and immune checkpoint inhibitors experienced tumor shrinkage at a higher rate; the ORR was 28.7% in cohort II and 47.2% in cohort III. In real-world practice, several reports said that sequential therapy and immune checkpoint inhibitors improved the prognosis of HCC patients.^20-25

The prognosis for advanced cases of HCC with vascular invasion, which is considered a poor prognostic factor, has been improving. In addition, there is no significant difference in prognosis when comparing LEN, Atez + Bev and Dur + Tre. In the present study, the rate of sequential transition in discontinuation cases were higher in cohorts II and III than cohort I. The reason for improvement in prognosis is not only improvement in regimens or admission of systemic drug therapy at earlier stages, but also the change in treatment strategy, switching to the next therapy even after disease progression, so-called sequential therapy.

The present study had some limitations in that this research was retrospective and performed only in our institution.

We assessed the efficacy of treatment for patients with unresectable HCC in our hospital. The prognosis was improved as the eras progressed because of changes in treatment strategies, although there were many differences in the backgrounds of the patients, and the drugs for systemic therapy improved.

CONFLICT OF INTEREST STATEMENT

Tomokazu Kawaoka received honoraria (lecture fees) from Chugai Pharmaceutical and AstraZeneca. The other authors declare no Conflict of Interests for this article.

ETHICS STATEMENT

Approval of the research protocol by an institutional review board: This study was conducted in accordance with the ethics principles of the Declaration of Helsinki, and was approved by the Institutional Review Board of Hiroshima University (IRB number 695).

Informed consent: Written informed consent was obtained from each patient after a detailed explanation of the study procedure.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.