In Italy only 10% of the diagnoses of liver cancer occur at an early stage and the healing rates are still low: consider that only 20% of patients are alive five years after the diagnosis of hepatocarcinoma.

However, there are important novelties for patients with advanced disease who have already undergone treatment, as emerges from the Celestial study, the results of which were presented in an oral session by Dr. Ghassan K. Abou-Alfa (Memorial Sloan Kettering Cancer Center, New York) at ASCO-GI, the meeting of ASCO (American Society of Clinical Oncology) dedicated to gastrointestinal tumors, held in January in San Francisco. These results were presented again at the 54th ASCO meeting (1-5 June, Chicago) in a Poster Discussion Session by Dr. Abou-Alfa.

As Dr. Lorenza Rimassa, Deputy Head of the Medical Oncology Operational Unit at Humanitas, explains, she presented a sub-analysis of the Celestial study to ASCO: “Celestial is an international, phase III, randomized, multicenter trial involving more than 700 patients and evaluating cabozantinib (a target drug) towards placebo in the second or third line in patients with advanced hepatocarcinoma previously treated with sorafenib, the standard therapy for this disease. The study was conducted towards placebo because at its inception there was still no second line standard.


Results of the study

“Italy and in particular Humanitas have made a key contribution to this study, the results of which are very interesting in that it has demonstrated an advantage of cabozantinib over placebo with a survival that increases by two months (10.2 months with cabozantinib compared to 8 months with placebo) and a disease-free survival more than doubled (5.2 months with cabozantinib and 1.9 months with placebo) in patients previously treated with sorafenib and possibly treated with an additional line of treatment; patients who had therefore received a first and a second line of treatment.

This study included patients who had not tolerated the previous line with sorafenib as well as patients who had gone into disease progression and therefore, because the study was positive, we have a new treatment option for both patients intolerant to sorafenib and those who did not respond to its intake.

As the study allowed the entry of patients who had received two previous treatment lines, cabozantinib proved effective not only in the second line, but also in the third line where until now we had no treatment available,” said Dr. Rimassa.


The two sub-analyses presented to ASCO

During the meeting two sub-analyses of the Celestial study in the form of posters were presented, one by Dr. Rimassa and one by Dr. Robin Kate Kelley (University of California San Francisco).

The poster presented by Dr. Rimassa was dedicated to the efficacy and tolerability of the drug according to the age of patients, divided into two groups: one under 65 years and one 65 years or older. It was found that effectiveness can be superimposed in the two groups and that tolerability is good for both.

The second sub-analysis was dedicated to patients treated only with sorafenib and confirmed the efficacy of cabozantinib.


Hepatocarcinoma: late diagnosis and limited treatment options

“Therapeutic options in hepatocarcinoma are still limited. We have had sorafenib for about ten years, which was the only drug for treating patients with this tumor until two years ago. In the last two years some phase III studies have been positive, paving the way for other drugs such as regorafenib (soon available in Italy), lenvatinib, cabozantinib and ramucirumab, but hepatocarcinoma remains a disease yet to be studied.

The diagnosis of this tumor is often late. In 80-90% of cases, cirrhotic patients are detected and although surveillance with ultrasound scanning is recommended every six months, in many cases it is not performed. Then we add the number of patients who do not know they have hepatopathy and are therefore not under control. Moreover, in patients with cancer in a healthy liver (and therefore without cirrhosis), the diagnosis only takes place when symptoms or metastases appear at a distance, thus preventing early diagnosis”, the specialist points out.


Risk factors and the future of research

In 2017, 12,900 new cases of liver cancer were diagnosed in Italy (8,900 men and 4,000 women), a tumor whose cases occur mainly in the South because, as Rimassa explains: “Hepatocarcinoma occurs mainly in cirrhotic patients and cirrhosis has infection with hepatitis B and C viruses among its main causes, as well as alcohol and metabolic syndrome (diabetes, hypertension, dyslipidemia). Infections with hepatitis B and C viruses are more frequent in the South of Italy, which is why the tumor is more widespread in the southern regions.

Treatment involves surgery, liver transplantation or locoregional therapies (such as ablation or chemoembolization), as long as it is localized to the liver.

“When the disease is at an advanced stage, there is an indication for systemic therapy and patients should often have access to such therapies first. In fact, there is a strong debate in the scientific community on when to make the transition from locoregional to systemic treatments. Another problem to be addressed is the almost complete absence of biomarkers to select patients eligible for specific therapy. The future of research goes precisely in this direction,” concluded Dr. Rimassa.