Hepatobiliary carcinomas

Incidence

There is considerable variability in the incidence of hepatocellular carcinoma (HCC) worldwide. ^, Overall, it is the fifth most common cancer diagnosed in men and the ninth most commonly diagnosed cancer in women. The incidence is more than two-fold higher in men compared with women. HCC is the fourth leading cause of cancer death in the world. The estimated annual incidence of HCC is rising in the United States and is currently 6/100,000. HCC incidence is also rising in Latin America and Europe.

Risk factors

The risk factors for HCC are well-established. They include chronic viral hepatitis (hepatitis B and C), excessive alcohol consumption, environmental toxins (e.g., aflatoxin), nonalcoholic fatty liver disease, diabetes, and iron overload disorders (e.g., hemochromatosis). ^, There is substantial variation in risk factors across the world. The majority of HCC cases occur in sub-Saharan African and Eastern Asia, mostly secondary to chronic hepatitis B and aflatoxin exposure. Nonalcoholic fatty liver disease, often associated with metabolic syndrome, is an increasingly recognized and important cause of HCC in the developed world.

Prognosis

The prognosis for patients with HCC is determined by the malignancy itself, as well as the underlying liver disease. Therefore, the prognostic evaluation of patients with HCC needs to take into consideration the stage of the malignancy itself, as well as the severity of the liver disease and the patient’s performance status. Several prognostic and staging systems have been proposed. One of the more commonly used systems is the Barcelona Clinic Liver Cancer, which has been extensively validated. No single system prognostic algorithm has been shown to be superior; however, some algorithms may perform better than others in predicting outcomes. The prognosis for patients with advanced disease is poor, with an average survival approaching 1 year. On the other hand, the prognosis for patients with localized disease varies greatly based on patient characteristics and underlying liver disease. In patients with resected tumors smaller than 5 cm, the 5-year overall survival can exceed 70%. In appropriately selected patients with HCC treated with liver transplantation, 5-year overall survival may exceed 70% as well, but multiple factors can influence outcomes following regional therapy, including tumor size, presence or absence of vascular invasion, alpha-fetoprotein level, and the treatment utilized. In patients not eligible for resection and/or transplantation and treated with catheter-based transarterial therapy, such as chemoembolization, radioembolization, or drug-eluting bead embolization, 5-year survival is generally less than 30%.

Treatment overview

The treatment of patients with HCC differs from the treatment of patients with other solid tumors given the high frequency of underlying liver disease, which can limit treatment options. As such, many patients with advanced HCC have advanced hepatic dysfunction at the time of diagnosis and may not be eligible for systemic therapy. Patients with Child-Pugh B and C liver disease are typically excluded from clinical trials; thus, limited data are available for treating these patients. For many of these patients, the prognosis is driven more by the end-stage liver disease than by the malignancy itself. Therefore, the optimal treatment is best done in a multidisciplinary setting involving multiple specialties, including gastroenterology/hepatology, surgery, interventional radiology, medical oncology, and radiation oncology. ^,

In patients with localized HCC without cirrhosis, hepatic resection is the treatment of choice if the tumor is considered resectable, and resection is favored over ablative therapy. For patients with HCC without cirrhosis, and who are candidates for resection, the 5-year survival rate can approach 90%. The prognosis (as mentioned above) is dictated by whether the tumor is a solitary lesion, the presence or absence of vascular invasion, and whether a negative margin was achieved on surgical resection. To date, no studies have shown that adjuvant therapy reduces the risk of recurrence. A trial of adjuvant sorafenib therapy showed no survival advantage. Liver transplantation may offer the best chances of long-term survival, but unfortunately, most patients are not eligible for transplantation. Several criteria are used to select patients for transplantation, with Milan criteria being the most commonly used (a single mass 5 cm or less or up to three masses 3 cm or less). Patients fulfilling these criteria have less than 15% chance of recurrence, and 5-year overall survival rates exceed 70% following liver transplantation.

In patients with localized HCC, who are not candidates for liver transplantation are awaiting transplantation, locoregional therapy, such as tumor ablation, is an option. Multiple ablative modalities exist, including radiofrequency ablation, microwave ablation, percutaneous injection therapy, and stereotactic body radiation therapy, but clinical trials comparing these different modalities have not been done. ^, The selection of the treatment modality depends on patient and tumor characteristics, equipment availability, and the experience of the treating physicians. Transcatheter embolization therapy (hepatic artery embolization therapy) has been extensively evaluated in patients with HCC who are not candidates for resection or transplantation, and as a bridge therapy in patients awaiting transplantation. Multiple different options exist, but transarterial chemoembolization is the one most commonly used, and it has been shown to improve survival. Transcatheter radioembolization with Yttrium-90-coated beads has also been studied in HCC, but few comparative studies exist. ^, Current guidelines recommend locoregional therapy over no therapy in patients with HCC who are not candidates for resection or transplantation.

For patients with metastatic HCC or locally advanced HCC not suitable for regional therapy, systemic therapy has been shown to be effective in prolonging survival when compared with placebo. A landmark, randomized clinical trial of tyrosine kinase inhibitor (TKI) sorafenib versus placebo in patients with advanced HCC confirmed survival advantage of sorafenib over placebo. In this trial, patients on sorafenib had a longer median overall survival than patients on placebo, 10.7 months versus 7.9 months, respectively. Sorafenib was the treatment of choice and the only systemic therapy with proven survival benefit for over a decade until a randomized trial of another TKI, lenvatinib, compared with sorafenib was published in 2018. In this trial, median overall survival was noninferior in the lenvatinib group compared with the sorafenib group (13.6 months for lenvatinib, 12.3 months for sorafenib, [HR 0.92 to 95% CI 0.79 to 1.06]). The adverse event profile of sorafenib and lenvatinib differs, with sorafenib causing more palmar-plantar erythrodysesthesia (also known as hand-foot syndrome) and lenvatinib more likely to result in hypertension. Lenvatinib is a reasonable option as first-line TKI therapy, especially in patients where a radiographic response is desired, as lenvatinib was associated with a higher response rate compared with sorafenib, 40.6% versus 12.4% ( P ≤ .0001), respectively. In late 2019, the results of the IMbrave150 were presented (in abstract form), suggesting a potentially new standard of therapy for advanced HCC with the combination of atezolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1) and bevacizumab. In this trial, 501 patients were randomized to the combination of atezolizumab plus bevacizumab versus sorafenib. The atezolizumab and bevacizumab combination resulted in a longer median overall survival (not estimable for atezolizumab/bevacizumab, 13.2 months for sorafenib [HR 0.58, 95% CI 0.42 to 0.79]). Six-month overall survival was superior for atezolizumab/bevacizumab, 85%, versus 72% for sorafenib. The combination of atezolizumab and bevacizumab was also superior in terms of median progression-free survival and response rate.

For patients with progressive HCC following sorafenib, there are several treatment options. To date, no data are available regarding systemic therapy following progression of first-line therapy with atezolizumab and bevacizumab because most trials have evaluated patients who have previously progressed on sorafenib as first-line therapy. These options include checkpoint inhibitor, TKIs targeting vascular endothelial growth factor (VEGF), and ramucirumab (a monoclonal antibody against VEGF receptor 2). Regorafenib, a VEGF TKI, was shown to be superior to placebo in a randomized phase 3 clinical trial improving median overall survival (10.7 months for regorafenib, 7.8 months for placebo). Similarly, cabozantinib was shown to improve median overall survival compared with placebo in a phase 3 randomized clinical trial. In this trial, the median overall survival of patients treated with cabozantinib was 10.2 months compared with 8.0 months for placebo. Ramucirumab was also shown to have modest activity in patients with HCC and elevated alpha fetoprotein defined as 400 ng/mL or more and improved overall survival compared with placebo (8.5 months vs. 7.3 months). Earlier data were showing promising activity of immune checkpoint inhibitors based on a phase 1/2 clinical trial studying nivolumab in the second-line setting. This study showed an overall response rate of 15% to 20% and a 6-month progression-free survival and overall survival rate of 37% and 83%, resepcitvely. However, the role of ICIs as monotherapy in the second-line setting is now being called into question, with the negative results of a randomized trial showing lack of superiority of pembrolizumab compared with best supportive care (BSC) in the second-line setting.

Cardiovascular risk

Systemic therapy for HCC can result in cardiovascular complications, mostly owing to the cardiotoxicity of the drugs used to target the VEGF pathway and, more rarely, related to immune checkpoint inhibitor therapy. The locoregional therapy used in treating patients with HCC is unlikely to result in cardiovascular complications, although it is conceivable that transarterial embolization therapy could result in arterial embolic events. Patients with HCC frequently have substantial liver dysfunction, which could potentially affect drug metabolism, resulting in cardiotoxicity and other noncardiac adverse events. Care must be taken in patients with liver dysfunction when prescribing drugs other than antitumor-directed therapy out of concerns for impaired metabolism and elimination of drugs in these patients.

Cancer treatments with potential cardiovascular side effects