Coping With Comorbidities in Hepatocellular Cancer

Richard S. Finn, MD

Hepatocellular carcinoma (HCC) remains one of the most common tumors worldwide, and frequently carries a poor prognosis, with most patients being diagnosed at late stages of disease.^1,2HCC may be treated through surgery (resection or transplantation), percutaneous interventions (ethanol injection or radiofrequency ablation), or transarterial interventions (chemoembolization).¹

More recently, the development of targeted therapies has been a major advance in the treatment of patients with advanced HCC, for which there had previously been no survival-prolonging therapy.³In particular, for patients with well-preserved liver function, systemic treatment with the multikinase inhibitor sorafenib has been shown to significantly improve survival and time to radiologic progression over placebo.^3-5

Unfortunately, HCC is frequently complicated by the presence of comorbid conditions, which can affect liver function, limit treatment options, and lead to poor outcomes; these include cirrhosis, coinfection with hepatitis B (HBV) or hepatitis C (HCV), and diabetes.^1,6As such, the use of multidisciplinary teams (MDTs) comprised of medical oncologists, hepatologists, radiologists, transplant surgeons, and pathologists, in addition to general practitioners, has become important in the management of patients with HCC. These teams can collaborate to optimize patient outcomes and to manage the diverse and challenging symptoms in HCC, which can result both from the tumor and the underlying liver disease process.³

There is a close correlation between chronic liver disease and HCC, and clinicians need to consider both when deciding on treatment.³HCC is believed to occur after years of chronic liver injury, regeneration, and cirrhosis from chronic conditions such as viral hepatitis and alcohol abuse, as well as from nonalcoholic steatohepatitis (NASH), and nonalcoholic fatty liver disease (NAFLD).¹

Comorbidities associated with HCC vary depending on geographic region. For example, comorbid HBV or HCV infections occur more commonly in African and Asian populations, and, although most patients (70%-90%) have liver cirrhosis at diagnosis, in Asian populations HCC may develop in individuals at a younger age without cirrhosis.^1,6The most commonly used tumor staging systems (eg, the tumor node metastasis [TNM] system) are of limited benefit for determining prognosis in patients with HCC because these take into account only tumor characteristics (ie, tumor size, lymph node involvement, presence of metastases) but do not account for comorbid conditions such as cirrhosis, HBV, or HCV infection, all of which can impact outcomes and treatment.⁶

Staging of patients with HCC is necessary to determine prognosis and to guide treatment decisions; however, there is currently no globally applicable consensus system in place, although a number of multidimensional systems, which take into account both underlying liver disease and cancer stage, have been developed for this purpose.^3,6

Among these, the Barcelona Clinic Liver Cancer, or BCLC system, has been most widely accepted, with endorsements from both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).³

Using this system, which takes into account multiple variables—including tumor stage/extension, liver function, disease symptoms, and physical status—treatment approaches can be assigned based on the BCLC classification.³For example, potentially curative therapies (eg, resection, transplantation) can be applied to patients with early-stage disease (BCLC-A). Locoregional therapies, such as transarterial chemoembolization (TACE), can be applied to those with asymptomatic, multinodular, and/or intermediate-stage tumors that have not spread beyond the liver (BCLC-B).

Pierre M. Gholam, MD

Systemic therapy with sorafenib is indicated in patients with symptomatic or extrahepatic disease (BCLC-C), while palliative treatment of symptoms is reserved for terminal patients with severe cancer symptoms or decompensated cirrhosis (Child-Pugh Class C).³

Because of the regional differences in HCV comorbidities, it is also important that staging systems be validated in different populations, and, notably, BCLC has been validated in the US, Europe, and Taiwan.⁶

Regarding the influence of comorbid conditions on treatment decisions, Richard S. Finn, MD, assistant professor of medicine at the Geffen School of Medicine, and the division of hematology/oncology, at the University of California, Los Angeles, said: “Ninety percent of patients with HCC have underlying liver disease as well as a malignancy. We always need to consider that comorbidity of liver disease as well as other medical comorbidities. When deciding on certain treatment options, such as surgical resection, comorbidities come under even more scrutiny.”

Clinical Pearls

• HCC remains one of the most common malignancies worldwide and carries a poor prognosis, with most patients diagnosed at a late stage.
• HCC is frequently complicated by the presence of comorbid conditions that can impact outcomes (eg, cirrhosis, HBV, HCV).
• Comorbid conditions can vary depending on geographic region (eg, differing incidence of HBV/HCV infection in Western vs Asian populations).
• Staging systems in HCC such as the Barcelona Clinic Liver Cancer (BCLC) system have been developed that take into account not only cancer stage but also comorbid conditions.
• Comorbid conditions such as frequent underlying liver disease must be considered when making treatment decisions.

Pierre M. Gholam, MD, medical director of the Liver Center of Excellence, at University Hospitals, Case Medical Center in Cleveland, Ohio, added, “We know that patients who have Child-Pugh C cirrhosis typically die very quickly of their liver disease and this usually antecedes mortality from cancer. In those patients, the consensus guidelines generally agree that treating cancer would be of limited value.”

Gholam said, however, “In a patient with adequate liver function, studies have shown that systemic therapy with sorafenib would be adequately tolerated, and could be tried as long as the patient is closely followed, adverse events are managed, and dose modifications or adjustments are made as needed.”

References

1. Blum HE. Hepatocellular carcinoma: therapy and prevention.World J Gastroenterol. 2005;11(47):7391-7400.
2. Giannini EG, Cucchetti A, Erroi V, Garuti F, Odaldi F, Trevisani F. Surveillance for early diagnosis of hepatocellular carcinoma: how best to do it?World J Gastroenterol. 2013;19(47):8808-8821.
3. Barone C, Koeberle D, Metselaar H, Parisi G, Sansonno D, Spinzi G. Multidisciplinary approach for HCC patients: hepatology for the oncologists.Ann Oncol. 2013;24(suppl 2):ii15-ii23.
4. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008;359(4):378-390.
5. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma.Hepatology. 2008;48(4):1312-1327.
6. Marrero JA, Kudo M, Bronowicki JP. The challenge of prognosis and staging for hepatocellular carcinoma.Oncologist. 2010;15(suppl 4):23-33.