Introduction

Hepatocellular Carcinoma (HCC) or primary liver cancer is highly prevalent in many Asian countries especially in China and Southeast Asia.¹ Globally, it is the 6th most common cancer and it has become the 2nd most common cause of cancer-related mortality. In Singapore, liver cancer was reported to be the 3^rd most common cause of cancer deaths in males and 4th most in females according to the 2015 Singapore Cancer Registry annual report.²

Chronic hepatitis B infection is currently the predominant risk factor for HCC in Southeast Asia, including Singapore. However, the incidence of hepatitis B infection is now declining in our country with the introduction of routine screening and immunisation. Nonetheless, with the increasing prevalence of diabetes and obesity in Singapore which is associated with Non-Alcoholic Fatty Liver Disease (NAFLD), the incidence of HCC is not expected to decline but conversely may instead increase as seen in North America, whereby HCC is now the fastest rising cause of cancer deaths.³

STAGING AND PROGNOSTICATION OF HCC

HCC is a complex heterogenous cancer. The prognosis of HCC not only depends on the extent of the cancer but also on the severity of the underlying chronic liver disease which frequently also influences the choice of treatment.

Hence, unlike most cancers which can be accurately staged/ prognosticated solely according to the extent of the cancer with the widely-used American Joint Committee on Cancer/ International Union Against Cancer tumour-lymph node-metastasis (TNM) staging system⁴, prognostication systems for HCC such as the Barcelona Clinic Liver Cancer (BCLC) system usually incorporate both parameters which not only determine the extent of the cancer but also the severity of liver disease.⁵

The BCLC staging system has been endorsed by both the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) to guide treatment of HCC and has been widely adopted in the West but not in Asia.¹

TREATMENT OPTIONS FOR HCC

The treatment of HCC can be simplified into curative and non-curative treatment options.⁶ Curative options for HCC provide a high-chance for durable long-term survival and include partial liver resection (LR)/hepatectomy, local ablation and liver transplantation (LT).

When patients are not suitable for curative treatment due to disease extent, diminished liver function or poor fitness; non-curative options which can prolong life such as transarterial chemoembolisation (TACE), selective internal radiation therapy (SIRT) with yittrium-90 and systemic therapy are commonly administered. These “non-curative” treatment options are also occasionally used as neoadjuvant treatment to downstage patients for curative therapy.⁷

Partial liver resection

LR remains the most widely-used first-line treatment modality for HCC in Asia especially for solitary primary HCC in patients with a well-preserved liver function.^{8, 9} This usually provides patients with 5-year survival outcomes of between 60-70%. ^{3, 9}

In Asia, LR is also frequently used for recurrent HCC, multifocal HCC and patients with borderline liver function.^1,10-12 Although, LT would be the optimal treatment for many of these patients, the severe shortage of organs particularly in Asia have resulted in the more aggressive use of LR.^1,10,11 Although, LR was considered a high-risk surgical procedure with significant mortality especially for HCC two decades ago, rapid improvement in perioperative care and surgical technique have resulted in a decrease in 90-day postoperative mortality rates to less than 5%, especially in Asia.^9-11

More recently, minimally-invasive surgery (robotic/laparoscopic) ^13-15 has increasingly been adopted for LR especially in high-volume tertiary-care specialised centres resulting in improved perioperative outcomes such as lower morbidity and shorter hospital stay without compromising oncological outcomes.

Liver transplantation

LT frequently offers the most durable and effective long-term survival for most patients with HCC.¹⁶ It is undoubtedly the curative treatment of choice for suitable patients with recurrent HCC, multifocal HCC and patients with a compromised liver function or decompensated liver disease.^16,17

LT offers the advantage of “killing 2 birds with one stone” as not only does it remove the offending malignancy but it also replaces the underlying damaged liver which acts as a “soil” for new recurrent cancers. The main obstacle of LT for HCC in Asia including Singapore is the severe shortage of both deceased and living donor organs resulting in many patients receiving “alternative” treatment options.¹⁸

Presently, the Milan criteria and the University of California San Francisco (UCSF) criteria (used in Singapore) are the 2 most widely-used criteria for selecting patients with HCC for deceased donor (DD) LT (Refer to Figure 1).¹⁹

Figure 1 Commonly used criteria for deceased donor liver transplant for HCC

These 2 stringent criteria are used to select the best HCC patients for LT as they have been proven to be the most robust criteria to give rise to 5-year survival rates of about 80% which is comparable to that of LT for benign disease. It is important to bear in mind that due to the limited deceased donor organ supply which are “shared” between patients with HCC and those with benign disease; ethically, the survival after LT for both groups must be comparable for the optimal use of deceased donor grafts.

Presently, many major transplant centres throughout the world including our centre use a more liberal expanded criteria for living donor (LD) LT. This is because although LT in these patients may not give rise to the same survival outcomes as for those within the Milan or UCSF criteria²⁰, LT still frequently offers by far the best chance of cure or long-term survival compared to palliative treatment options such as TACE, SIRT or systemic treatment.

Hence, as the organ from a living donor is not a public resource but a personal gift from the donor to the recipient1; LD organs are not ethically subjected to the same stringent requirements as that for DD organs.

Other treatment options

Percutaneous local ablation is a commonly utilised less-invasive treatment modality for the treatment of HCC.1,6 It is considered potentially curative for small (< 3 cm) solitary HCC and is frequently used as an alternative treatment option to LR or LT.

Its main advantage is its decreased morbidity compared to LR and LT but it is associated with a higher local recurrence rate. Local ablation is especially useful for solitary tumours which are deep-seated in the liver requiring extensive liver resection, especially in patients whom are less fit for major surgery. Presently, the 2 most common ablation modalities used in Singapore are radiofrequency ablation and microwave ablation.

Locoregional treatment either via TACE or SIRT are frequently used as non-curative treatment options for HCC within the liver which is not amenable to curative treatment. TACE is most commonly indicated for multifocal HCC limited to the liver and has been proven to prolong survival in these patients.²¹

SIRT with Y90 is a newer treatment modality which is similarly commonly used for multifocal HCC limited to the liver.22 It is especially useful for patients who have previously been treated via TACE, large tumours or HCC associated with portal vein tumour thrombus.^1,22

External-beam radiation therapy has now also been recognised and has been included in several guidelines as a treatment option for advanced HCC.⁶

Although locoregional treatment is most commonly used as non-curative treatment for advanced HCC, it may also occasionally be used for downstaging of HCC prior to PLR or LT.^7,16

Systemic treatment is usually indicated in patients with advanced HCC with extrahepatic disease. Globally, sorafenib is widely accepted as the standard of care for the first-line treatment of advanced HCC which is not amenable to locoregional treatment.²³ More recently, regorafenib²⁴ and nivolumab²⁵ have been approved by the FDA as 2^nd line treatment for HCC patients following prior sorafenib.

CONCLUSION

HCC is a complex cancer whereby its prognosis and treatment is not only determined by the extent of disease but also frequently by the severity of underlying liver disease. LR, LT and local ablation are curative-treatment options for HCC. Although, LT frequently provides the optimal and most durable cure for selected patients with HCC, its use is severely limited by a severe shortage in donor organs.

Professor Brian K. P. Goh, Deputy Head, SingHealth Duke-NUS Liver Transplant Centre, Senior Consultant, Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital

Professor Brian K. P. Goh (MBBS, MMed, MSc, FRCSEd) is certified by both the American Society of Transplant Surgeons and the Ministry of Health Singapore to perform liver, kidney and pancreas transplants. He is a highly-experienced surgeon having performed over 1000 major Hepato-pancreato-biliary and Transplant Surgeries (HPB/ transplant surgeries) since becoming a board-certified surgeon. Dr Goh has a special interest and is presently one of the leaders of minimally-invasive HPB surgery in Southeast Asia. He is also a pioneer of the application of robotic surgery for major HPB surgery in the region.

GPs can call for appointments through the GP Appointment Hotline at 6321 4402.

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