Holistic Management of Hepatocellular Carcinoma

The Hepatologist's Comprehensive Playbook

Ariel Jaffe; Tamar H. Taddei; Edoardo G. Giannini; Ysabel C. Ilagan-Ying; Massimo Colombo; Mario Strazzabosco

Liver International. 2022;42(12):2607-2619.

Abstract and Introduction

Abstract

Hepatocellular carcinoma (HCC) is a common complication in patients with chronic liver disease and leads to significant morbidity and mortality. Liver disease and liver cancer are preventable by mitigating and managing common risk factors, including chronic hepatitis B and C infection, alcohol use, diabetes, obesity and other components of the metabolic syndrome. The management of patients with HCC requires treatment of the malignancy and adequate control of the underlying liver disease, as preserving liver function is critical for successful cancer treatment and may have a relevant prognostic role independent of HCC management. Hepatologists are the ideal providers to guide the care of patients with HCC as they are trained to identify patients at risk, apply appropriate surveillance strategies, assess and improve residual liver function, evaluate candidacy for transplant, provide longitudinal care to optimize and preserve liver function during and after HCC treatment, survey for cancer recurrence and manage its risk factors, and prevent and treat decompensating events. We highlight the need for a team-based holistic approach to the patient with liver disease and HCC and identify necessary gaps in current care and knowledge.

Introduction

Hepatocellular carcinoma (HCC), a common and dreaded consequence of liver disease, leads to significant morbidity and mortality worldwide. HCC develops in one-third of patients with cirrhosis, accounts for 80%–90% of all primary liver cancers, and is currently the fifth most common cancer worldwide and the third most common cause of cancer-related mortality.^[1,2] In addition to its increasing incidence, there has been a 43% increase in deaths from HCC in the United States between 2000 and 2016, and the World Health Organization (WHO) predicts over 1 million deaths from liver cancer by 2025.^[1] Current 5-year survival for HCC is only 18%, making it the second most lethal cancer.^[3,4]

The worldwide increase in HCC incidence is a consequence of several epidemics, all of which are preventable and treatable. Globally, 257 million people are affected by chronic hepatitis B (CHB) and 58 million by chronic hepatitis C (CHC) infection,^[5] while 280–370 million people suffer from alcohol-use disorder with alcohol-associated liver disease (ALD) affecting 71 million people globally.^[6] Obesity and diabetes, the major risk factors for the development of nonalcoholic fatty liver disease (NAFLD, also referred to as metabolic-associated fatty liver disease—MAFLD), affect 650 and 578 million people, respectively, with a precipitously rising incidence.^[7,8] These epidemics, coupled with deepening inequities in health care, threaten large sectors of the population with poor access to care, regardless of national wealth per capita.

Management of HCC requires a strong multidisciplinary team, generally consisting of hepatologists with expertise in primary liver cancer and liver transplantation; surgeons with training in transplant, hepatobiliary surgery or surgical oncology; interventional radiologists; diagnostic radiologists; medical oncologists; radiation oncologists; pathologists; palliative care physicians; primary care physicians; psychologists; social workers; nutritionists; nurse navigators; and tumour registrars. The core elements that currently impact staging and treatment options for patients with HCC are based on tumour characteristics (size, location, presence of metastases), specific liver-related risk factors, liver function and performance status.

We seek to delineate the need for a holistic and team-based approach to the patient with liver disease and HCC. The primary providers caring for patients with liver disease and HCC vary by country, ranging from general internal medicine providers to hepatologists trained in advanced liver disease and hepato-oncology. Clinical hepatologists are physicians or advanced providers, who, independently from their primary speciality, spend most of their professional time caring for patients affected by diseases of the liver. Managing patients with HCC and their co-existing liver disease is complex and includes optimizing liver function; evaluating and treating the underlying aetiology of liver disease; preventing further hepatotoxicity; managing liver disease decompensation both before and after treatment; assessing eligibility for liver transplantation and coordinating care among various providers. Therefore, we recommend that hepatologists who are trained in the diagnosis and management of advanced liver disease and liver transplantation and well-versed in all HCC treatment options and their adverse effects (AEs) and toxicities serve a central role in the backbone of this complex care. These tasks are critical for achieving the best patient outcomes (Figure 1, Table 1). We also strongly emphasize the role of multidisciplinary meetings. We also note the shifting landscape in the aetiologies of liver disease, namely NAFLD, and thus recognize the essential expertise of our primary care colleagues, endocrinologists and cardiologists in managing the various metabolic comorbidities and cardiovascular diseases. We also review the evaluation and management process for patients with liver disease and HCC with an emphasis on prevention and treatment strategies.

(Enlarge Image)

Figure 1.

In this figure, we emphasize the central role of the hepatologist in managing patients with hepatocellular carcinoma (HCC) and highlight the primary providers associated with each stage of care. Hepatologists are specialized providers well versed in the understanding and treatment of various forms of chronic liver disease which often coexist and precede the development of HCC. They are therefore essential to identify high-risk patients to ensure surveillance protocols are implemented to aid in the early detection of HCC. Additionally, thorough assessment of risk factors and aetiologies of underlying liver disease is imperative, as the majority are either preventable or treatable. Once diagnosed with HCC, hepatologists should work promptly to stage patients and evaluate their underlying liver function and performance status which are critical elements in assessing treatment candidacy. We denote the importance of an integrated, multidisciplinary team approach when it comes to discussing treatment of these complex patients and recommend care management in tertiary centres with experienced providers when possible. After treatment has been implemented, hepatologists are key players for longitudinal care to help manage complications of liver disease, assess for disease recurrence, evaluate for transplant candidacy and integrate palliative care services when necessary.

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Table 1. Holistic approach to the patient with hepatocellular carcinoma
Preventative measures to promote "liver health" at all levels: "to inform is to cure"
Recognition of subjects with risk factors for liver disease and aggressive management
Assessment and management of social determinants of health and removal of barriers to care
Early treatment of liver disease to prevent chronicity
Preservation of liver function in patient with cirrhosis and chemoprevention of progression
Oncologic surveillance of patients at risk
Diagnosis of liver cancer and treatment strategy
Team-based multimodal treatment with personalization of care
Establishment of a treatment strategy going beyond the single episode
Management and treatment of comorbidities
Evaluation of potential candidacy for liver transplant
Post-treatment oncologic surveillance
Retreatment of recurrence as needed and feasible, again through a team-based approach
Identifying the transition time to palliative care and participation in palliative care delivery

Table 2. Benefit of Hepatologist Care for Management of HCC
Study	Study period	Country	Study population	HCC outcomes
Davila et al.	1994–2002	United States	1873 adults with HCC from the SEER database	HCC surveillance with GI/hepatologist vs. PMD care (OR 2.8, 95% CI 1.73–4.53)
Dirchwolf et al.	October 2018–October 2019	Argentina	301 patients with HCC diagnosis and known risk factors (advanced fibrosis/cirrhosis or chronic hepatitis B with Page-B score ≥ 10 points)	98.2% of cohort followed by hepatologist underwent surveillance (p < .001)
Serper et al	January 2008—December 2010	United States	3988 patients from Veterans Administration (128 centres)	Hepatology care within 30-days of HCC diagnosis reduced mortality (HR 0.70; 95% CI 0.63–0.78)
Tapper et al.	2001–2015	United States	389 257 adults with cirrhosis from Optum database	Hepatology care reduced mortality (0.78 [0.75, 0.80])
Yeo et al.	2007–2016	United States	82 427 adults with cirrhosis from Truven Health MarketScan Research Database	HCC surveillance with PMD versus GI/ID care (OR 0.48, 95% CI 0.46–0.52)
Marquardt et al.	2011–2019	United States	Database of 1.1014 patients with cirrhosis and HCC from Parkland Health and Hospital System and University of Texas Southwestern Medical Center	Risk of screening within 1 year of HCC diagnosis if care provided by GI versus PCP (OR 12; 95% CI 4.74–30.6) versus GI + PCP (OR 11.8; 95% CI 4.89–28.5)