Update hepatocellular carcinoma - news from the system therapy

In hepatocellular carcinoma, an increase in incidence has been observed in industrialized countries. HCC patients have at least two diseases, namely carcinoma as well as severe liver disease. The interaction of these diseases influences prognosis and therapeutic options.

The increase in HCC cases is due to the growing number of patients with hepatitis B and hepatitis C infections on the one hand and the high number of patients with alcohol toxic liver disease on the other. The fatty liver epidemic (non-alcoholic steatohepatitis) will also lead to a significant increase in the number of hepatocellular carcinomas in the future – with women being affected more frequently than men due to metabolic factors. Due to these epidemiological trends and the high complexity and heterogeneity of the disease, challenges arise in the diagnosis as well as in the treatment of HCC (Fig. 1), Prof. Köberle said.

Potentially curative treatment options are so far only available in the early stages of the disease. However, the diagnosis is often made only at an advanced stage of the disease. The individual selection of the right treatment procedure for the patient depends on liver function, performance status, stage of tumor disease and concomitant diseases.

The prognosis of the patient suffering from HCC is determined not only by the tumor stage but also by liver function. HCC often occurs in the setting of cirrhosis, which is considered a precancerous condition and may be associated with significantly reduced organ function and increased mortality.

With liver transplantation, a curative treatment option exists for both the tumor and the underlying liver disease. However, few patients are eligible for this option, as only a maximum of 30% of diagnoses are made at an early stage.

Therefore, a prognostically relevant classification of HCC must take into account not only tumor stage but also liver function and the patient’s physical performance status.

Staging according to BCLC

The so-called “Barcelona Clinic Liver Cancer” (BCLC) classification considers above parameters in patients with liver cirrhosis. The early stage of the disease includes patients with cirrhosis in good general health, with preserved liver function and with a relatively small tumor extent. Surgical treatment consists of resection or local ablation. However, patients with HCC are at increased risk of tumor recurrence despite successful resection/ablation. This is either an intrahepatic metastasis (true recurrence) or a de novo carcinoma.

The risk for recurrence depends on the tumor stage at the time of resection/ablation and the underlying liver disease. It is around 70% overall. Studies with the aim of preventing tumor recurrence by means of system therapy have so far remained disappointing, the expert said.

Intermediate stage: TACE is procedure of choice

The intermediate HCC stage comprises a very heterogeneous patient group of usually asymptomatic patients with larger, multinodular tumors without extrahepatic spread. As a first-line palliative treatment, transarterial chemoembolization (TACE) can result in tumor control in a majority of patients, with a median survival of approximately 20 months.

TACE Combines the benefits of local chemotherapy with simultaneous targeted embolization of arteries. Certain contraindications must be taken into account (Overview 1). In recent years, this procedure has been further developed using “drug-eluting beads” (DEB-TACE): doxorubicin-loaded microspheres are injected and allow a slow and selective release of the chemotherapeutic agent.

An alternative to TACE or option after progression is radioembolization (selective internal radiotherapy, SIRT).

Advanced stages: systemic therapy

According to international guidelines for the treatment of hepatocellular carcinoma, advanced stage patients are the best candidates for systemic therapy. For ten years, sorafenib has been the only systemic therapy for hepatocellular carcinoma to date. The multityrosine kinase inhibitor was the first substance to convince in a phase III trial in HCC. In the so-called SHARP study, a multicenter randomized placebo-controlled phase III trial with a total of 602 patients enrolled, sorafenib prolonged median overall survival by 2.8 months compared to placebo (10.7 vs. 7.9 months) with an acceptable side effect profile.

In a recently published study [1], the combination of sorafenib with the DEB-TACE procedure did not yield a benefit in progression-free survival.

Many other studies in the field of targeted therapy have not yet led to the establishment of additional substances, either in first- or second-line therapy. The multityrosine kinase inhibitor lenvatinib showed promising results in a phase II trial (overall response rate 37%, median survival 18.7 months). The study showed “non-inferiority” in overall survival versus sorafenib as the primary endpoint. This will potentially make lenvatinib available as a second first-line agent in HCC alongside sorafenib.

Second line

In the second-line setting, some compounds have also been tested against placebo in phase III trials, although again most compounds failed. Finally, the multityrosine kinase inhibitor regorafenib showed a survival benefit (10.6 months vs. 7.8 months) in second-line therapy for patients who progressed on sorafenib [2]. This makes regorafenib the first agent to show a survival benefit in second-line HCC.

Conclusion

The different treatment modalities that can be used sequentially must be integrated into an overall concept that takes into account comorbidity as well as tumor disease.

Take-Home Messages

HCC patients suffer from two diseases: carcinoma and severe liver disease.
The interaction of these diseases influences prognosis and therapeutic options
The tyrosine kinase inhibitor sorafenib is established as an effective system therapy for advanced HCC
Do not combine local therapy with system therapy
Sequential therapies remain standard

Source: Annual Meeting DGHO, OeGHO, SGMO and SGH+SSH, September 29-October 3, 2017, Stuttgart, Germany.

Literature:

Meyer T, et al: Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2017 Aug; 2(8): 565-575.
Bruix J, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017 Jan 7; 389(10064): 56-66.