Treatment for Hepatocellular Carcinoma in South Asia

Hepatocellular carcinoma (HCC) frequently occurs in patients with cirrhosis and chronic liver disease due to any aetiology and is associated with increased liver-related mortality globally, as well as in India.¹ The accurate prevalence of HCC in India is unclear, but the incidence seems to be is rising.² Chronic hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcoholic liver disease, nonalcoholic fatty liver disease are the most frequently recognised association in causing HCC.^1,2 Advances in identifying the aetiology, molecular pathogenesis, staging of HCC, and treatment have been impressive and beneficial. In addition, the advent of nucleoside or nucleotide analogue for HBV and directly acting antivirals (DAAs) for treatment against HCV have been associated with reduced incidence of HCC in those with such chronic infections.¹ Further, various specific molecular targeted therapies in HCC since 2008 have resulted in remarkably improved treatment outcomes even in advanced HCC, previously not amenable to treatment.^1,3

Management of HCC depends upon its clinical staging. Specific treatment is recommended for different clinical stages of HCC. Although many staging systems have been described in HCC, two of them have been extensively used globally, including in India. They are Barcelona Clinic Liver Cancer (BCLC) staging and Hongkong Liver Cancer (HKLC) staging systems.^1,3,4 Both these staging systems assess the burden of the liver cancer restricted to the liver (size and number of tumors) and outside liver (extrahepatic metastasis), their intrahepatic, as well as extrahepatic vascular invasion status, underlying liver function reserve, and the performance status (PST). These assessments are derived based on the clinical parameters, biochemical tests to assess liver function, and imaging techniques to assess tumor burden, vascular invasion, and extrahepatic spread. Both these staging systems, therefore, include specific treatment options for each stage based on the possible overall survival (OS) rates, progression-free survival (PFS), recurrence rate, and overall clinical benefits. Essentially, these staging systems classify the patients into three main groups (a) Patients with an “early-stage HCC” in whom treatment is aimed to provide a complete cure; (b) Patients with an “intermediated stage HCC” in whom the therapy is directed either to down-stage or to the “early-stage HCC” status so that they can avail curative therapy. Alternatively, if downstaging is not possible, one aims to keep the disease under control to improve survival; and (c) Patients with advanced HCC in whom the effort is directed to keep the disease under control to improve survival durations. The stage-based treatment in HCC providing all presently available treatment options have been depicted in Figure 1(BCLC staging-based treatment allocation), Figure 2 (HKLC staging-based treatment allocation), and Figure 3 (Summary of all treatment allocations).^1,3,4

Figure 1.

Barcelona Clinic Liver Cancer(BCLC) staging with treatment allocations as per recent advancesand results.^1,3,10 [PST: Performance Status as per Eastern Cooperative Oncology Group (ECOG) - Score 0: Asymptomatic and fully active - Score 1: symptomatic, restricted to strenuous activity but can do light work and ambulatory - Score2: Symptomatic and < 50% of the time in bed during the day but ambulatory and can do self-care - Score 3: Symptomatic, >50% in bed in the day time, limited self-care - Score 4: Bedbound completely - Score 5: Death; N: Nodule, M; metastasis RFA: Radio Frequency Ablation; PEI: percutaneous Ethanol Injection; PAI: Percutaneous Acetic (40%) injection; TACE: Transarterial Chemoembolization using Epirubicin/Doxorubicin; TARE; Transarterial Radioembolization using Yttrium-90 or Rhenium 188. OS: Over all Survival: Child-Pugh Score base on Serum bilirubin, albumin, INR, severity of ascites and encephalopathy status – Each variable have sores from 1 to 3/Total score 15/Child Pugh A: Score ≤6, Child-Pugh B: Score 7 to 9, Child Pugh C: Score 10–15].

Figure 2.

Hongkong Liver Cancer staging (HKLC) and stage-based treatment allocation.^3,4 [PST: Performance Status as per Eastern Cooperative Oncology Group (ECOG) - Score 0: Asymptomatic and fully active - Score 1: symptomatic, restricted to strenuous activity but can do light work and ambulatory - Score 2: Symptomatic and < 50% of the time in bed during the day but ambulatory and can do self-care - Score 3: Symptomatic, >50% in bed in the daytime, limited self-care - Score 4: Bed bound completely - Score 5: Death; EVM: Extrahepatic vascular invasion or metastasis.].

Figure 3.

Summary of HCC Therapy. [SR: Surgical resection; LT: Liver Transplant; TACE: Transarterial Chemoembolization; DEB: Drug Eluting beads used in TACE; TARE: Transarterial Radioembolization; SBRT: Stereotactic body radiotherapy; Drugs: Systemic therapy].

The present issue of the journal includes an article by Tohra S et al⁵ based on retrospective analysis of 785 HCC patients seen in a major tertiary care hospital, describing their finding in two parts; (a) the demography, etiology and the stage of HCC referred to the center; and (b) an assessment of 3-year overall survival, disease-free survival and recurrence rate in a selected group of patients who were eligible for curative treatments, namely radiofrequency ablation (RFA) and surgical resection (SR). This study could identify 173 (22%) of all the HCC patients as early HCC (BCLC 0-A) but included 110 (14%) of the patients with a single nodule for analyzing the outcome of the said interventions (RFA: n = 72; SR: n = 38). The authors claim that the paper describes real-life events and outcomes in patients with HCC in a referral hospital. The curative treatment allocated is as per established criteria as outlined in Figure 1 (BCLC staging-based allocation). The paper reiterates several observations described earlier from India.¹ These include a median age of 60 years with male dominance. HBV/HCV with or without alcohol is the etiology in two-thirds of patients. The majority (more than 80%) of all patients had intermediate to advanced unresectable HCC, and 87% of their patients had underlying cirrhosis. The nonalcoholic fatty liver disease (NAFLD) as a cause of HCC has become a global phenomenon and more frequently is being reported from all the nations. NAFLD affects about 25% of the world population,⁶ and features of metabolic syndrome associated with NAFLD such as diabetes mellitus have been identified to further enhance the probability of developing HCC even in noncirrhotic individuals with fatty liver.⁶ The paper by Tohra et al⁵ indicates that about one-third of their patients with HCC had diabetes and the frequency of NAFLD associated HCC over 9 years was varying between 15 and 19%. Although these results are not surprising, another interesting fact has come to light. The study documented a gradual rise in alcohol-associated HCC from about 10% during 2005–7 to about 21% during 2013–15. It raises concern about prevention rather than expanding curative therapy in early HCC, which can be detected by surveillance programs in high-risk individuals.^1,3 Surveillance programs in most of the resource constraint nations are suboptimal and are expensive. This study emphasizes the point that early diagnosis, and therefore curative therapy in most patients with HCC may not be possible. However, the paper has tried to compare the overall survival and disease-free survival amongst patients with SR and RFA, which may not reveal any appropriate message. The disease characteristics among the groups were dissimilar. For example, the tumor size was smaller in the RFA group, and the Child’s status, frequency of underlying cirrhosis, and liver functions were worse. A propensity score-matched study would have made a more meaningful analysis. The study by Tohra S et al followed the recommended criteria by BCLC for selecting the patients for either SR or RFA. SR is recommended in patients with early HCC who (a) have a good liver function and no portal hypertension when cirrhosis is present, or (b) do not have associated cirrhosis, and (c) adequate postresection residual liver volume can be ensured. The RFA is recommended in those patients with early HCC who are not amenable to SR. Therefore, comparing the two groups may not be appropriate to document the superiority of SR over RFA.

Early HCC would indicate that the tumor burden is small. This includes patients with either one tumor nodule of less than 5 cm or up to three nodules of ≤3 cm without any intrahepatic or extrahepatic vascular invasion and distant metastasis. Such early HCC can occur with good liver function (Child-Pugh A/B) or poor liver function (Child-Pugh C). Their performance status is also a consideration, and generally, in the early stages, the individual performance status is good (0–1). In those with poor liver functions, the ideal therapy is liver transplantation, as it removes the underlying diseased liver as well. Liver transplantation is also an excellent option even for those with good liver function. However, organ shortage, access, costs, and availability of expertise are limiting factors for offering this therapy. Therefore, for patients with early HCC and good liver functions, alternative treatment options are either surgical resection of the tumor or ablative therapy using physical energy like radiofrequency (RFA-most widely used globally), microwave, electroporation, cryotherapy, or chemical agents like ethanol/acetic acid. Transplantation, ablation, and surgical resection are curative treatments with an overall 5-year survival varying between 60 and 75%.^1,3

While 5-year HCC recurrence rate following liver transplantation is less than 15%, it exceed 70% (60–85%)⁷ in patients with ablation and surgical resection.^1,3 Surgical resection have been claimed to have an edge over ablation due to lessor recurrence rate in some studies, but a meta-analysis and systematic review comparing RFA and resection reported similar over-all 5-year survival rate of ≥80% and RFA is relatively less expensive.⁸ Results of surgical resection are excellent (∼5% postoperative decompensation) in the absence of portal hypertension (hepatic venous pressure gradient <8 mmHg/absence of any gastrointestinal varices/Fibro scan liver stiffness value < 13 KPa), presence of good liver function (Model End stage Liver Disease score of ≤9).⁹ Other considerations are the tumor should be accessible for surgery (deep or on surface), postresection remnant liver volume (in patients with Cirrhosis), should be more than 40% and the extent of resection (≤3 segments).¹⁰ In absence of these latter criteria the postoperative decompensation rates exceed 30% resulting in enhanced morbidity, mortality, and hospital stay. Therefore, in cases where SR is not a suitable treatment, ablative measures are preferred.^1,3,7 Treatment of choice in HCC occurring in the noncirrhotic liver and in very early suitable HCC is resection as is depicted in BCLC staging in figure.^1,3

However, early or very early HCC can be detected by instituting surveillance of high-risk patients by using regular screening techniques like abdominal ultrasonography with alfa-fetoprotein (AFP), as recommended in various guidelines on HCC, at every 6 months.^1,3 Approximately about 10–40% of HCCs (depending upon whether or not a surveillance program is implemented at a center/region) can be treated with such curative therapies.^1,3

When the tumor burden in the liver exceeds that defined as early HCC, the patients are classified as Intermediate stage HCC (BCLC B or HKLC 2/3). This includes (a) a single tumor >5 cm or > 3 tumor nodules with size varying between 3 and 5 cm; (b) with or without intravascular tumor invasion; but (c) without extrahepatic tumor invasion/metastasis; and (d) with good liver function (Child-Pugh A/B) and performance status (PST 0–2). These patients should undergo Transarterial chemoembolization (TACE). The median OS using TACE alone is around 20 months; however, the 5-year survival is limited to around 20–30%.^1,3 If the tumor progress beyond 2 or 3 sessions of TACE, then further sessions are not recommended as there is no robust evidence that further TACE sessions alone can provide a survival advantage. However, further refinement in TACE treatment is being done by combining it with adjuvant molecular targeted drugs like sorafenib or other newer drugs.¹¹ There is also an option of a multimodality approach combining RFA/other ablative techniques post-TACE, which could not only enhance the duration of OS¹² but also downsize the tumor burden to make them eligible for transplant by bringing the HCC within Milan or University of California San Francisco (UCSF) criteria. Such patients may have outcomes similar to those subjected to transplant de novo without prior downsizing and satisfying the transplant criteria.¹³ Currently, we have four multikinase inhibitor drugs (Sorafenib, Lenvatinib, Regorafenib, and Cabozantinib), three immunotherapy agents (Nivolumab, pembrolizumab, and atezolizumab) and two antivascular growth factor agents (Bevacizumab, Ramucirumab) that have been cleared by various licensing agency to be used against the HCC with various intermediate and advanced stages.^1,3

Sorafenib, Lenvatinib, Regorafenib, and Cabozantinib are drugs that target and inhibit the molecular driving pathways messengers that are predominantly Tyrosine kinases. Multiple such kinases are involved in the growth and dissemination of HCC and can also be inhibited by these drugs to varying extents. Immune checkpoint inhibitors like Nivolumab, Atezolizumab, and Pembrolizumab are anti-PD1 (programed death receptors expressed on T-cell to which PD ligands expressed by tumor cells bind to induce immune escape) and thereby induces enhancement of antitumor immune response. However, atezolizumab is the only drug that has been licensed to be used, and Nivolumab and pembrolizumab await licensing authorities’ go-ahead for use in real-life situations.¹⁴ Bevacizumab and Ramucirumab are monoclonal antibodies against vascular endothelial growth factors (VEGF) associated with angiogenesis, which when inhibited prevents tumor growth and necrosis.

Advanced HCC is characterized by invasion of major portal veins (right, left, or main portal veins) or other intrahepatic vascular structures, at best with one metastasis, but with a good liver function (Child-Pugh A/B) and PST between 1 and 2. Such tumors usually are not amenable to therapies like curative treatment or treatment offered in intermediate stage HCC such as TACE with or without additional combination treatment. TACE is not indicated with major portal vein tumor thrombus compromising the blood supply to the liver. TACE may decrease the hepatic arterial supply further, with resultant deterioration of liver function due to marked hepatic ischemia. Therefore, Transarterial radioembolization (TARE) using Yttrium 90 or Rhenium 188, or Stereotactic Body Radiation Therapy (SBRT) has been extensively used, particularly for tumor emboli in major portal veins with some success. Various guidelines recommend molecular targeted drugs, immunotherapy, antivascular growth factor either alone or in combinations.^1,3

Terminal stage HCC is characterized by poor liver function (Child-Pugh C) with poor performance status (PST >2) irrespective of tumor burden or with extensive tumor burden or more than one distant metastasis. These patients are unlikely to benefit from any of the therapy mentioned earlier, and there is no evidence that the above-mentioned therapies in them provide any improvement.^1,3,10 All the studies that evaluated the therapies mentioned earlier were tried in patients with cirrhosis and good liver function (Child-Pugh-A/B) without extensive distant metastasis. Further, patients with a poor liver-specific score such as Child-Pugh > 9 (1-year mortality 55%)¹⁵ or MELD score >18 (3-month mortality ∼20%)¹⁶ may succumb to primary liver failure and complications not allowing adequate time for the specific drugs to act. On the other hand, such therapy leads to accelerated adverse effects, further compromising the quality and quantity of life. In patients with poor liver function (Child-Pugh C) with limited tumor burden, without vascular involvement or distant metastasis and without other associated comorbidity (cardiopulmonary/other diseases which de-novo may compromise life), liver transplant as per HKLC staging and therapeutic allocation may be an excellent curative option.⁴ In such patients only supportive symptomatic therapy with adequate nutritional supplementation have been recommended by most guidelines.^1,3,10

It would have been worthwhile to include the results of real-life scenarios in all the above-mentioned stages of HCC to assess stage-based therapeutic recommendations by Tohra S et al. Their study had a large number of patients with HCCs of various stages to provide a holistic Indian scenario of treatment of HCC. Hopefully such a report will be published soon to fill these gaps in knowledge from India.