Achieving Health Equity in Liver Cancer

Primary liver cancer is a leading cause of cancer-related illness and death worldwide. It is the sixth most-common cancer and the third most-common cause of death from cancer globally.¹ Primary liver cancer includes hepatocellular carcinoma (HCC) (75%-85% of primary liver cancers) and intrahepatic cholangiocarcinoma or bile duct cancer (10%-15% of primary liver cancers). The major risk factors for liver cancer include chronic infection with the hepatitis B virus or hepatitis C virus, alcohol-induced liver disease, and nonalcoholic fatty liver disease. Globally, more than half of liver cancers are caused by chronic viral hepatitis B or hepatitis C virus infections.² These infections are most common in Asia and Africa. In sub-Saharan Africa, including West Africa, approximately 3% to 12% of the population have chronic viral hepatitis, primarily hepatitis B.³ In these regions, liver cancer is typically the first or second most common cause of death from cancer in men and the third to fifth most common cause of death from cancer in women.¹

In Asia and Africa, liver cancer often develops in younger individuals. Study results have shown that in most countries in sub-Saharan Africa, the average age of development of liver cancer is between 40 and 45 years.⁴

In West African countries such as Nigeria, Ghana, Senegal, and Gambia, the high incidence of death from primary liver cancer occurs in part due to the coinciding of risk factors with disparities in diagnosis and care of patients with liver cancer.

Risk Factors and Etiology

Many individuals are infected with the hepatitis B virus either at birth or, more commonly, before they are 5 years old. Although the means of transmission are not fully understood, it appears that children who live in close contact with a mother or siblings who are infected with the hepatitis B virus are most likely to become infected with the virus. This may be largely due to blood contact, most commonly from less obvious contact such as from wounds, sores, and abrasions, as hepatitis B is highly transmissible through the blood.⁵ In some places, practices such as circumcision or skin scarifications performed by a traditional healer, for which unsterilized instruments may be used, appear to be associated with a higher risk of transmission.

Environmental and Genetic Factors

In addition to the early age of infection with chronic hepatitis B, there are other environmental and genetic factors that predispose individuals to developing liver cancer at a young age. Exposure to dietary fungal aflatoxins, which contaminate grains such as corn and millet, and legumes such as peanuts that are not dried completely prior to storage, are known to damage liver-cell DNA and prime the development of liver cancer. In addition, the hepatitis B virus strains or genotypes circulating in sub-Saharan Africa appear to have a high ability to promote chronic liver disease and integrate into the liver-cell DNA of infected persons in such a way as to induce the development of liver cancer.^6-8

Additional predisposing factors to the onset of liver cancer in sub-Saharan Africa include alcohol use and obesity- and diabetes-related nonalcoholic fatty liver disease, which interact synergistically with viral risk factors in increasing the risk of liver cancer. The consequences of these factors and perhaps yet unrecognized factors such as chronic Helicobacter pylori infectionand infection by liver schistosomiasis mean that whereas the mean age of liver cancer diagnosis in Japan is in the 70s, in most of North America and Europe in the 60s, and in parts of Asia such as China in the 50s, the mean age of liver cancer diagnosis is in sub-Saharan Africa in the 40s. Consequently, because many individuals in Africa who develop liver cancer receive a diagnosis at a late stage, when they have very poor survival rate of approximately 2½ months, the years of life lost from liver cancer in Africa are very high.⁹ Liver cancer affects individuals when they are at the most productive part of their lives and creates a substantial social and economic burden on African countries.¹⁰ In addition, as is the case with a number of other cancers, such as breast cancer and cervix cancer, it is possible that individuals of African descent have inherited familial genetic variants that are associated with an early age of onset of cancer.

Health Disparities

Health disparities also contribute to rates of primary liver cancer in sub-Saharan Africa. Perhaps the greatest disparity is attributed to socio-economic status.¹¹ Low incomes and lack of accessible education and health infrastructure and disease expertise in sub-Saharan Africa result in a lack of health awareness in the population.¹¹ Further, a lack of access to methods for prevention of chronic viral hepatitis—such as administration of the birth dose of the hepatitis B vaccine—lack of screening and vaccination of adults who are unvaccinated for chronic viral hepatitis, lack of assessment of whether adults with viral hepatitis qualify for treatments thatare known to suppress the development of liver cancer, and lack of surveillance of individuals found to have chronic liver disease and are at risk of development of liver cancer, all contribute to the challenge of identifying new liver cancers at the earliest possible stages when they are most amenable to curative treatments.¹² The lack of resources for curative surgical or ablative treatments for liver cancer or for locoregional treatments such as hepatic artery embolization and chemoembolization, which are effective for treating intermediate-stage liver cancer, also poses a challenge. There is a lack of availability of systemic therapies for advanced-stage liver cancer, such as the recently approved combination of atezolizumab (Tecentriq) and bevacizumab (Avastin), which has been shown to be extremely effective in the treatment of patients with advanced primary liver cancer.¹³

Within low and lower-middle income countries, there is also a particular disparity between those who live in urban areas and those who live in more rural settings. In the case of viral hepatitis, rates of chronic viral hepatitis are generally higher in the more rural and less developed parts of sub-Saharan Africa where there is also the least access to high-quality affordable health care.

HCC in the United States

In many ways, HCC or primary liver cancer in the United States mirrors HCC in the rest of the world. Studies on HCC in the United States has shown that the age of onset of HCC is related to a person’s country of birth.¹⁴ Thus, whereas the overall mean age of onset of HCC in the United States is between 60 and 65 years, for individuals born in sub-Saharan Africa who receive a diagnosis of HCC in the United States, the mean age is less than 50, and more than 50% of individuals from sub-Saharan Africa who receive a diagnosis of primary liver cancer in the United States are under the age of 50.

There are substantial disparities within the United States in the stage at diagnosis of liver cancer. Work by Kali Zhou, MD, and her colleagues in Los Angeles, California, have shown that there are hotspots of late-stage development of liver cancer in Los Angeles County and that these hotspots are associated with communities of low social economic status with high proportions of immigrants.¹⁵ Studies such as this show that geographic information systems can identify areas where public health and other interventions can be applied to reduce the frequency of diagnosis of liver cancer at a late stage by identifying and enhancing individuals at risk for developing liver cancer in the community. This would improve early-stage diagnosis and consequently improve the outcomes of patients with liver cancer.

Role of the Community Oncologist

Community oncologists and primary care physicians play key roles in enhancing community awareness of the risk factors for liver cancer and encouraging identification and promoting surveillance of individuals at risk of developing HCC. This is particularly important in communities with high proportions of immigrants from Africa or Asia who have higher rates of chronic viral hepatitis, or with higher proportions of Hispanic or Native American ancestry who have higher rates of nonalcoholic fatty liver disease.

It is important that community oncologists engage with a multidisciplinary care team of practitioners to promote and support efforts at identifying the at-risk population, enrolling those at risk in surveillance programs for HCC, and providing comprehensive care for those who receive a diagnosis of HCC. The range of specialties engaged in the care of individuals with HCC includes hepatologists, diagnostic and interventional radiologists, pathologists, surgeons, liver transplant teams, medical oncologists, radiation oncologists, and palliative care professionals. These individuals should ideally form a collaborative and complementary multidisciplinary team.

A tumor board can be the infrastructure used by the multidisciplinary care team for formalizing the assessment and review of patients with HCC. By jointly reviewing the patient’s history, imaging features, laboratory test results, and personal preferences with experts in relevant disciplines, the tumor board incorporates all the different care perspectives and helps to determine the optimal treatment approach for the patient.

At the outset of the tumor board discussion, the physician who is coordinating the patient’s care usually provides a summary of the diagnostic evaluation, including results of laboratory testing for the underlying etiology of the tumor; the extent of underlying liver disease including fibrosis, cirrhosis, or signs of clinically significant portal hypertension such as splenomegaly, ascites, esophageal varices, and hepatic encephalopathy; and proof of adequate liver function from measures of the serum albumin, bilirubin, pseudocholinesterase, and prothrombin time. A diagnostic radiologist then reviews the available imaging studies with the group, highlighting the features that are typical or atypical for HCC. For atypical masses, there is discussion of whether a biopsy is indicated to determine whether the patient might have a mixed HCC-cholangiocarcinoma or an intrahepatic cholangiocarcinoma. Serum biomarker levels that may be helpful in making this distinction or in prognostic prediction are also reviewed. Increasingly, there is growing interest in a policy of biopsying and performing genomic analysis on all intermediate- and advanced-stage tumors, for which the patients may be candidates for systemic therapy. The tumor is then staged—the Barcelona Clinic Liver Cancer staging system is most often used for HCC. Unique features of the tumor are then reviewed, including features such as the number and location of the tumor nodules or the presence of vascular invasion that might lead the tumor board to deviate from the standard approach recommended by society guidelines. At this point the patient’s preferences may be discussed, as well as nuances of the tumor location with the liver, which might dictate a preference for a particular treatment modality, such as microwave ablation, stereotactic body radiation therapy, or transarterial radioembolization.

Unmet Needs

Key unmet needs in the ecosystem of assessment, evaluation, and care of patients with primary liver cancer include the need for stimulating community engagement and awareness of the risk factors and determinants of outcomes of patients with HCC, providing a patient voice through advocacy, and incorporating comprehensive measures for reduction of risk of chronic liver disease and HCC as part of universal health care coverage systems.

Patient and Health Policy Advocacy

The Global Liver Institute, Blue Faery, Fibrolamellar Cancer Foundation, The Cholangiocarcinoma Foundation, and similar organizations are helping to fill the gaps by training advocates. Their efforts influence public policy relating to the major risk factors for liver cancer, including viral hepatitis prevention, viral hepatitis elimination, prevention of alcoholic liver disease and obesity- and diabetes-related fatty liver disease, and advocacy for health policy measures that reduce alcohol consumption and improve food quality for all communities. They also fulfill a critical need for funding support of early-stage investigators and high-risk projects that are often in the early conceptual phases and require development of the key preliminary results needed to make them competitive for major funding.

SPORE, National, and Global Programs

The National Cancer Institute (NCI) Trans-lational Research Program supports Specialized Programs of Research Excellence (SPOREs) that perform translational research in cancer. The program supports the Mayo Clinic Hepatobiliary SPORE, The University of Texas MD Anderson Cancer Center’s Hepatocellular Carcinoma SPORE, and a recently funded award to the University of Washington focused on Liver Cancer Disparities in Alaska Native and American Indian people. In addition, NCI support for the Consortium on Translational Research in Early Detection of Liver Cancer, the intramural NCI Liver Cancer Program, and the Hepatocellular Carcinoma Epidemiology Consortium over the past few years reflects an increasing recognition of the large burden of illness and death from liver disease, particularly due to chronic viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease.

Although there has been an increase in governmental commitments to incorporate liver disease care into universal health care and non-communicable disease coverage in many countries, there is still a severe shortage of sustainable development goals for reducing the transmission of viral hepatitis, increases in birth dose vaccination, identification of high viral loads in chronic viral hepatitis-infected pregnant women, and identification and treatment of individuals eligible for treatment of chronic viral hepatitis B and C. Despite the increasing number of active research programs that are funded by national and international science groups in North America, Europe, and Asia, there remains a dearth of research on the epidemiology, pathogenesis, risk factors, prognostic factors, and response to treatment for primary liver cancer in Africa. Recent commitments by the NCI Center for Global Health, the International Liver Cancer Association, and the newly formed Africa Hepatopancreatobiliary Cancer Consortium all bode well for a coordinated and effective initiative to reduce the high burden of these diseases in sub-Saharan Africa.

Global Liver Institute (GLI) is the only liver-focused nonprofit organization operating in both the United States and Europe. GLI’s mission is to improve the lives of individuals and families affected by liver disease through promoting innovation, encouraging collaboration, and scaling optimal approaches to help eradicate liver diseases. By working across disease states and convening all stakeholders, GLI aims to amplify the voices of those affected by liver diseases and cancers. One of these initiatives is GLI’s Liver Cancers Council, in which Lewis Roberts, PhD, MB, ChB, is an active and engaged member helping to lead the charge for patient advocacy. Roberts also serves on the Board of Directors for GLI. For more information and resources, please visit https://www.globalliver.org/.

_REFERENCES

_{1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249. doi:10.3322/caac.21660}

_{2. Thomas London W, Petrick JL, McGlynn KA. Liver cancer. In: Thun M, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, eds. Cancer Epidemiology and Prevention, 4th ed. Oxford University Press; 2018:635-660}

_{3. Polaris Observatory Collaborators. Global prevalence, treat-ment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3(6):383-403. doi: 10.1016/S2468-1253(18)30056-6}

_{4. Yang JD, Gyedu A, Afihene MY, et al; Africa Network for Gastroin-testinal and Liver Diseases. Hepatocellular carcinoma occurs at an earlier age in Africans, particularly in association with chronic hepatitis B. Am J Gastroenterol. 2015;110(11):1629-1631. doi:10.1038/ajg.2015.289}

_{5. Martinson FE, Weigle KA, Royce RA, Weber DJ, Suchindran CM, Lemon SM. Risk factors for horizontal transmission of hepatitis B virus in a rural district in Ghana. Am J Epidemiol. 1998;147(5):478-487. doi:10.1093/oxfordjournals.aje.a009474}

_{6. Kramvis A. Molecular characteristics and clinical relevance of African genotypes and subgenotypes of hepatitis B virus. S Afr Med J. 2018;108(8b):17-21. doi:10.7196/SAMJ.2018.v108i8b.13495}

_{7. Wongjarupong N, Yonli AT, Nagalo BM, et al. Characteristics of Patients With Chronic Hepatitis B Virus Infection With Genotype E Predominance in Burkina Faso. Hepatol Commun. 2020;4(12):1781-1792. doi:10.1002/hep4.1595}

_{8. Mak D, Kramvis A. Molecular characterization of hepatitis B virus isolated from Black South African cancer patients, with and without hepatocellular carcinoma. Arch Virol. 2020;165(8):1815-1825. doi:10.1007/s00705-020-04686-4}

_{9. Global Burden of Disease Cancer Collaboration; Fitzmaurice C, Abate D, Abbasi N, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2019;5(12):1749-1768. doi:10.1001/jamaoncol.2019.2996}

_{10. Nartey YA, Awuku YA, Agyei-Nkansah A, et al. Ambulatory end-stage liver disease in Ghana; patient profile and utility of alpha fetoprotein and aspartate aminotransferase: platelet ratio index. BMC Gastroenterol. 2020;20(1):428. doi:10.1186/s12876-020-01581-9}

_{11. Yang JD, Mohamed EA, Aziz AOA, et al; Africa Network for Gastrointestinal and Liver Diseases. Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium. Lancet Gastroenterol Hepatol. 2017;2(2):103-111. doi:10.1016/S2468-1253(16)30161-3}

_{12. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604. doi:10.1038/s41575-019-0186-y}

_{13. Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745}

_{14. Yang JD, Altekruse SF, Nguyen MH, Gores GJ, Roberts LR. Impact of country of birth on age at the time of diagnosis of hepato-cellular carcinoma in the United States. Cancer. 2017;123(1):81-89. doi:10.1002/cncr.30246}

_{15. Zhou K, Thompson LK, Terrault N, Cockburn M. Population-based geographic hotspot detection of late stage hepatocellular carcinoma: novel approach to cancer control. Hepatol. 2020;72(S1):403A-404A. doi:10.1002/hep.31579}