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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 5  |  Page : 224-231

A proposed five-step simplified algorithm for the management of hepatocellular carcinoma in India


1 Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Medicine, University of South Dakota Sanford School of Medicine and Avera Transplant Institute, Sioux Falls, USA

Date of Submission18-Jul-2022
Date of Acceptance26-Aug-2022
Date of Web Publication31-Oct-2022

Correspondence Address:
Anil Arora
MD, DM, FRCP (Edinburgh), FRCP (London), FIAMS, FAGEI, FSGEI, Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Sir Ganga Ram Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_69_22

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  Abstract 


Hepatocellular carcinoma (HCC) is the eighth-most frequent cause of cancer mortality in India. The staging system most often used for treatment decisions in India is the Barcelona clinic liver cancer (BCLC) system. However, this staging system is often criticised for several reasons, such as heterogeneity of patient prognosis in each BCLC stage, limited guidance on expanding the role of liver transplantation (LT), no recommendation on combination therapies, no guidance on downstaging and limited treatment options for late presenters (stages C or D). Hence, we propose a simplified five-step algorithm for making treatment decisions for HCC patients in India. This algorithm incorporates evidence-based treatment allocations based on the step-by-step assessment of major prognostic and treatment-related parameters. The five steps of the algorithm are – Step 1: assessment of performance status, Step 2: assessment of extrahepatic spread and macrovascular invasion, Step 3: assessment for living donor LT, Step 4: assessment for the eligibility of liver resection and Step 5: assessment for appropriate locoregional therapy. Each of these steps does not require any separate investigations, and the initial workup for the diagnosis of HCC (dynamic computed tomography/magnetic resonance imaging and routine laboratory tests) would suffice in this five-step algorithm. We hope that this algorithm will not only simplify the management approach to HCC patients in India, but also it will bring uniformity in the treatment protocol for HCC in India.

Keywords: Ablation, Barcelona clinic liver cancer staging, best supportive care, hepatocellular carcinoma, liver cancer, living donor liver transplantation, performance status, sorafenib, transarterial chemoembolisation, transarterial radioembolisation


How to cite this article:
Arora A, Singal AK, Sharma P, Kumar A. A proposed five-step simplified algorithm for the management of hepatocellular carcinoma in India. Curr Med Res Pract 2022;12:224-31

How to cite this URL:
Arora A, Singal AK, Sharma P, Kumar A. A proposed five-step simplified algorithm for the management of hepatocellular carcinoma in India. Curr Med Res Pract [serial online] 2022 [cited 2022 Nov 27];12:224-31. Available from: http://www.cmrpjournal.org/text.asp?2022/12/5/224/359944




  Introduction Top


Hepatocellular carcinoma (HCC) is the eighth-most frequent cause of cancer mortality in India accounting for 3.3% of all cancer mortality.[1] The most frequently used HCC staging system in India is the Barcelona clinic liver cancer (BCLC) system, which is endorsed by various liver societies such as the Indian National Association for Study of the Liver,[2],[3] the American Association for the Study of Liver Disease[4] and the European Association for the Study of the Liver.[5] The BCLC staging system provides the treatment guidance for HCC based on the tumour burden, severity of hepatic disease and patients' performance status (PS); however, it is often criticised for several reasons.[6] The principal criticism is that within a given category of BCLC staging, there is heterogeneity of patient prognosis. The BCLC system provides only limited guidance on expanding the role of orthotopic liver transplantation (LT) in HCC treatment, such as better survival with LT in patients with tumours smaller than 2 cm in size. The emerging role of combination therapies (such as ablation combined with transarterial chemoembolisation [TACE]) for large tumours, the expanding role of transarterial radioembolisation (TARE) and the role of stereotactic body radiation therapy (SBRT) in patients with portal vein tumour thrombosis are also not adequately addressed. Further, there is no discussion of the potential advantages of combining systemic therapy with locoregional therapy for subsets of patients with intermediate stage or advanced stage. In addition, the applicability of the BCLC staging system in India is questionable because in India most HCC patients present late with either a very large tumour, macrovascular invasion, extrahepatic spread or Child C status.[7],[8] For this heterogeneous population of late presenters, the BCLC system clubs them into Stage C or D and provides very limited treatment options. Furthermore, in India, the majority of transplantations are living donor LT (LDLT), with donors being immediate family members of the patients. In the LDLT setting, there is an increasing role of downstaging of tumours not meeting transplant criteria, which has not been adequately addressed in the BCLC staging system.[6]

To overcome these shortcomings of BCLC staging, and to provide a uniform treatment guidance more applicable in India, we hereby propose a simplified five-step algorithm for making treatment decisions for HCC patients in India. Rather than being another staging system, this is a treatment algorithm, and it incorporates evidence-based treatment allocations based on the step-by-step assessment of major prognostic and treatment-related parameters. This algorithm assumes that a confirmed diagnosis of HCC has already been made by appropriate investigations (such as triple- or quadruple-phase computed tomography/magnetic resonance imaging [CT or MRI]) and the underlying liver condition is cirrhosis. The proposed five steps of the algorithm are – Step 1: assessment of PS, Step 2: rule out extrahepatic spread and macrovascular invasion, Step 3: assess for LDLT, Step 4: check eligibility for liver resection and Step 5: assessment for appropriate locoregional therapy [Figure 1]. Each of these steps would not require any separate investigations, and the initial workup done for HCC (such as dynamic CT or dynamic MRI and routine laboratory tests) would suffice to carry out this five-step algorithm. These steps are described in detail in the following sections.
Figure 1: The five-step algorithm. HCC: Hepatocellular carcinoma, PS: Performance status, CTP: Child–Turcotte–Pugh, TARE: Transarterial radioembolisation, SBRT: Stereotactic body radiation therapy, LDLT: Living donor liver transplantation, CSPH: Clinically significant portal hypertension, ALBI: Albumin–bilirubin, TACE: Transarterial chemoembolisation, TARE: Transarterial radioembolisation

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Step 1: Assessment of performance status

Once the diagnosis of HCC has been made, the first proposed step in the algorithm [Figure 1] is the assessment of PS of the patient, which is an evaluation of functional status and capability of self-care. PS is an independent factor determining the prognosis and outcome of patients with advanced cancer and plays a significant role in treatment decision-making. It is crucial to accurately document PS for each patient as many treatment decisions are based on this. PS assessment tool, designed by the Eastern Cooperative Oncology Group (ECOG), is the most frequently used PS tool for recruiting appropriate patients in HCC clinical trials.[9] The ECOG uses a 5-point score to assess PS and is graded as – 'PS 0: fully active and is able to perform all pre-disease activities without any restriction; PS 1: ambulatory patient able to carry out sedentary or light work, for example, office work and light housework, but restricted in physically strenuous activity; PS 2: ambulatory and capable of self-care (up and about for more than 50% of waking hours) but is unable to carry out any work activities; PS 3: confined to chair or bed for more than 50% of waking hours and able to perform only limited self-care; PS 4: completely disabled, mostly confined to bed or chair and cannot carry on any self-care and PS 5: dead'.

PS is an important survival-determining factor in patients with HCC. Regardless of liver status or tumour-related features, patients with poor PS such as PS 3–4 are categorised in the BCLC staging system as Class D.[10] Hsu et al. demonstrated PS to be strongly associated with tumour burden and the severity of liver function impairment, and more importantly, it accurately predicted prognosis and long-term survival in HCC patients.[11] Best supportive care is the only treatment recommended by all the major guidelines for patients with PS 3–4 (BCLC Class D) because the risk attributed to HCC treatments, such as ablation, resection, LT, TACE, TARE, SBRT and systemic therapy, is expected to outweigh the potential gains in survival and the quality of life (QoL).[2],[4],[5]

Hence, as a first step of the algorithm, the PS of the patient needs to be assessed, and if found to have PS 3–4, these patients should receive only the best supportive care and should be excluded from any form of curative or palliative treatment.

Step 2: Rule out extrahepatic spread and macrovascular invasion

HCC can spread to extrahepatic regions by: direct extension, haematogenous spread, lymphatic invasion or peritoneal rupture.[12] Reported metastatic sites for HCC are lymph nodes (53%), lungs (55%), bone (28%), peritoneum and/or omentum (11%), adrenal glands (11%) and brain (2%).[12],[13]

HCC patients with extrahepatic metastasis of tumour are categorised as BCLC Class C, and these patients bear a poor prognosis, with an expected 1-year survival of 25% and a median overall survival of 6–8 months.[14] Extrahepatic spread is considered a contraindication for LT or any form of locoregional therapy such as ablation, TACE or TARE, and most guidelines recommend that these patients should be treated with systemic therapy alone if eligible.[2],[4],[5]

Patients with extrahepatic spread should be assessed for eligibility of systemic therapy. The most important eligibility criterion for systemic therapy is the Child–Turcotte–Pugh (CTP) status, and generally, patients with CTP scores of >8 have been excluded from trials of systemic therapy. Till now, the standard of care first-line systemic drugs was either sorafenib or lenvatinib. However, with the recent Food and Drug Administration approval of atezolizumab in combination with bevacizumab following the IMbrave150 study,[15] this combination should be the new first-line standard of care.

Macrovascular invasion of the portal vein or hepatic vein branches has been documented in 10%–40% of patients at presentation, and this leads to significantly reduced overall survival as compared to HCC patients with no macrovascular invasion.[14],[16] Tumour thrombosis of the portal vein is much more frequently encountered than the tumour thrombosis of hepatic vein, and most studies on natural history, diagnosis and treatment of patients with macrovascular invasion are mainly focused on patients with portal vein tumour thrombus (PVTT). Even the anatomical extent of tumour thrombus in the portal vein further affects the prognosis: patients with distal PVTT have a better survival than patients with PVTT involving the main portal trunk or the first-order branches.[17] Similarly for HVTT, the extension of hepatic vein thrombus to inferior vena cava portends a poorer prognosis than without extension.[18],[19]

Macrovascular invasion represents an absolute contraindication for transplantation, since it is an independent risk factor for post-LT recurrence of HCC and for a significant reduction in survival.[5],[20] Patients with macrovascular invasion are categorised into BCLC Class C, and according to most guidelines, the only recommended option for these patients is a systemic therapy.[2],[4],[5] Lenvatinib and sorafenib are considered the first-line drugs for patients with PVTT while regorafenib is considered the second-line agent for these patients.[21] Most of the locoregional therapies such as ablation and TACE are also generally not recommended for patients with PVTT. Only TARE and SBRT can be safely performed in patients with PVTT without major concerns.[22]

TARE, also called as selective internal radiation therapy (SIRT), is an intra-arterial tumour embolic procedure combined with radiotherapy that involves the embolisation of radioactive therapeutic agents into hepatic arteries supplying the tumour. Currently, TARE is commonly used for patients with advanced-stage HCC (BCLC-C), such as Child A patients with PVTT. The radio-embolic agent used for TARE can be either ethiodized oil (commonly known as Lipiodol) or micron-range particles that adsorb or encapsulate radioactive agents. The Lipiodol is usually tagged with therapeutic radionuclide agents such as iodine-131 or rhenium-188. The micron-range particles can be either yttrium-90 (Y-90)-bearing glass spheres (TheraSphere®) or selective internal radiation spheres (SIR-Spheres®). The therapeutic benefit of all these agents is due to the local deposition of radiotherapy dose by high-energy beta radiation. Globally, Y-90 microspheres are a more commonly used form of TARE. In contrast to chemoembolisation, for which main portal vein thrombosis is a contraindication due to the high risk of hepatic necrosis, TARE can be safely performed in patients with benign or malignant obstruction of the portal vein without the risk of liver ischaemia.[23],[24],[25] In three retrospective studies, TARE was found to be superior to systemic therapy using sorafenib in improving the survival of patients with PVTT.[26],[27],[28] However, two large Phase III trials (SARAH and SIRveNIB) did not show a significant superiority of TARE as compared to sorafenib.[29],[30] In a systematic review, Jia et al. showed that Y-90 radioembolisation could achieve a median disease control rate of 74% and a median survival time of 9.7 months in patients of HCC with PVTT.[31]

The other modality which can be effectively and safely used in patients with PVTT is SBRT. In a large retrospective multicentre study, Im et al. retrospectively reviewed the details of 985 patients who received SBRT for PVTT. The response rate was 51.8% with a median overall survival of 10.2 months.[32] Adjuvant sorafenib use can further enhance survival in patients receiving SBRT.[33],[34]

Step 3: Assess for living donor liver transplantation

In patients of HCC with cirrhosis with good PS (0–2), once extrahepatic spread and macrovascular invasion have been ruled out, the next step is to assess whether they qualify for LDLT. In 1996, Mazzaferro et al. achieved a 4-year disease-free survival and overall survival of 75% and 83%, respectively, in a selected group of HCC patients, transplanted for either a single tumour not exceeding 5 cm in diameter or 3 tumours each not exceeding 3 cm.[35] These, soon called 'Milan criteria', became an established transplant criterion on which later decisions for 'deceased donor LT' (DDLT) for HCC were made. In contrast to DDLT, recipient selection criteria for LDLT are not limited by organ allocation systems. Hence, many LDLT centres have developed their own centre-specific expanded criteria with acceptable results, including the UCSF criteria,[36] Up-to-seven criteria,[37] total tumour volume and alpha-foetoprotein (AFP) criteria,[38] Kyoto criteria[39] and extended Toronto criteria,[40] amongst others. However, for patients with HCC beyond the Milan criteria, the survival after transplantation incrementally decreases with increasing tumour size and number; hence, the benchmark Milan criteria remain the gold standard transplant criteria for selecting HCC patients for the best outcome with LT.[5],[41]

If the patient does not fit into Milan criteria, he should be assessed for 'downstaging', which is defined as the locoregional therapy performed to make the patients acceptable within transplant criteria for LT. There is evidence to show that superior LT outcomes are achieved with downstaging to within Milan criteria, and it should be the preferred approach over expanding the criteria for LDLT.[42],[43] The benefit of downstaging to within Milan criteria (as opposed to choosing an expanded criterion for LT) is that it not only allows a superior post-LT outcome comparable to patients within Milan criteria not needing downstaging, but also it allows time for studying the tumour biology and response to locoregional downstaging therapy.

There is no consensus on the best locoregional therapy for downstaging; most evidence has been obtained from studies using TACE or TARE. A recent systematic review on results of downstaging patients of HCC that included 950 patients demonstrated a success rate of 48%. The difference between the results of TARE and TACE was not significant.[44] However, the selection of the appropriate candidate for downstaging is essential and patients with advanced liver disease such as Child B or C and those with AFP >1000 are unlikely to benefit from downstaging.[45]

Step 4: Check eligibility for liver resection

If the patient could not receive LT, he should be screened for eligibility for hepatic resection. In patients with cirrhosis with HCC, liver resection is indicated if the tumour is solitary and technically resectable, provided that there is good liver function, clinically significant portal hypertension (CSPH) can be excluded and adequate future liver remnant can be ensured.[2]

When assessing the technical resectability of HCC in a cirrhotic liver, these important considerations need to be evaluated: size and location of tumour, vascular inflow, vascular outflow, biliary drainage and future liver remnant quality and size.[46] Tumours located in the periphery can be easily removed if the quantity and quality of the remaining hepatic parenchyma allow so. The anatomical relationship of the tumours to the inflow structures such as hepatic artery, portal vein and bile duct as well as outflow vessels such as hepatic veins has an important influence on how the resection will be performed. If the tumours are located deep within the hepatic parenchyma and near the major portal veins, hepatic veins or biliary pedicles, major hepatic resection will be needed to achieve an R0 resection. Careful attention must be given to the size and quality of the future liver remnant and the adequacy of hepatic function post-surgery. The usual practice is to leave a minimum of 40% of the liver volume behind, with 3–4 contiguous liver segments, to maintain the patient's needs after surgery.[46],[47] There is no cut-off for tumour size, and even large-size tumours can be safely removed, if there is an adequate-size future liver remnant. In patients, in whom a large resection with more than three segments is anticipated, portal vein embolisation pre-surgery may be used to increase the size of the contralateral hepatic lobe and thus reduce the risk of liver insufficiency.[4]

Since CSPH is a significant predictor affecting survival in patients of cirrhosis undergoing resection for HCC,[48] the absence of CSPH should be documented before referring for hepatic resection. Hepatic venous pressure gradient >10 mmHg, presence of oesophageal or gastric varices and/or platelet count <100,000 indicate CSPH. A recent meta-analysis documented that pre-operative platelet count could act as a significant predictor in the prognosis of HCC, especially if the platelet count was ≥100,000/cumm.[49]

For assessing the liver function before resection, the albumin–bilirubin (ALBI) grade as proposed recently by Johnson et al.[50] seems to be a good model. The model includes only two parameters (serum bilirubin and albumin). The ALBI score is computed by applying the formula: '(log10 bilirubin level × 0.66) + (albumin level × −0.085)', where bilirubin is in μmol/L and albumin in g/L. ALBI is then categorised into three Grades – 'ALBI Grade 1: ≤−2.60, ALBI Grade 2: −2.60 to −1.39 and ALBI Grade 3≥−1.39'. According to a recent meta-analysis,[51] the ALBI grade is an effective predictive biomarker for prognosis in patients undergoing hepatic resection, and hence, patients with ALBI grade 1 only should be selected for liver resection.

Step 5: Assessment for appropriate locoregional therapy

If the patient does not qualify for hepatic resection, he should be evaluated for locoregional therapy in the form of ablation, TACE or TARE. In a patient with cirrhosis, with solitary HCC of size ≤2 cm, the clinical outcome of ablation is similar to liver resection (LR). Therefore, if the tumour is located at a favourable site, using radiofrequency ablation (RFA) or microwave ablation (MWA) should be the first-line treatment option. For tumours of size >2 cm, ablation should be performed if LT and liver resection cannot be performed, provided that tumour size is <3 cm and at a favourable location, whereas ablation plus TACE should be performed if the size of the tumour is between 3 and 5 cm.[2] For large tumour burden involving both lobes, TARE seems to be a better treatment option than TACE. In patients with advanced tumours, a combination of locoregional therapy with systemic therapy seems to offer better tumour control rates.

Ablation is considered one of the most effective treatment methods for small tumours. It includes percutaneous ethanol injection (PEI), RFA, cryoablation, MWA and irreversible electroporation. PEI is the oldest of all the ablative techniques, is less invasive and can be easily repeated for recurrences. However, experience with RFA is most extensive and has now replaced PEI in most centres as the most used ablative therapy. New-generation MWA can achieve a larger volume of ablation in a shorter time period. A recent meta-analysis showed a similar efficacy between RFA and MWA with a superiority of MWA in large-size tumours.[52] Neoadjuvant or adjuvant systemic therapy has not been shown to improve the clinical outcome of HCC patients successfully treated with ablation.[53]

Lipiodol TACE (also known as conventional TACE or [cTACE]) is considered the treatment of choice for intermediate-stage HCC as per the BCLC staging system (BCLC-B). The main indication of TACE is large or multinodular, inoperable and non-invasive tumours limited to the liver with tumour occupying <50% of liver volume, and there is no hepatic decompensation such as ascites or jaundice. TACE can also be used in patients of early HCC (BCLC Stage A), in whom hepatic resection or ablation is not possible, and for purpose of downstaging HCC before LT. TACE combined with ablation is also indicated in patients with tumours of size between 3 and 5 cm. As per a recent meta-analysis, the use of RFA plus TACE for intermediate-stage HCC can achieve higher tumour objective response rates and improve survival as compared to TACE alone.[54] Contraindications of TACE include patients with decompensated advanced liver disease (Child Class C), patients with refractory hepatic encephalopathy, patients with poor PS (>2), patients with main portal vein thrombosis, patients with hepatofugal blood flow, patients with uncorrectable coagulopathy, patients with allergy to contrast agents and pregnant women. According to a recent systematic review by Lencioni et al., the tumour objective response rate with TACE is 52%. The overall survival is 70% at 1 year, 52% at 2 years, 40% at 3 years and 32% at 5 years. The median overall survival is 19.4 months.[55] Similar survival has been reported by Indian studies also.[56] Two techniques of TACE have been used since the early 2000s: cTACE and TACE using the drug-eluting beads (DEB-TACE). DEBs are used to slowly release chemotherapy agents and to increase the duration and intensity of ischaemia.[57] DEB-TACE has a similar tumour response and similar overall survival to cTACE but has less incidence of systemic side effects. Thus, DEB-TACE should be preferred in suitable patients.

Although TARE or SIRT can be performed in all HCC patients who are candidates for TACE, studies have not demonstrated any better survival with TARE as compared to TACE. In patients of HCC who are suitable for both TACE and TARE, TACE should be preferably sued, because of its lower cost and comparable median survival. In a recent meta-analysis that compared the outcomes of TARE versus TACE in unresectable HCC, there was no statistically significant survival difference between the groups for up to 4 years. Furthermore, the complete and partial response rates were similar in both the groups.[58] TARE should be used in situations where TACE is contraindicated, cannot be technically done or has failed. In the SARAH trial, which was an open-label Phase 3 randomised controlled, the investigators compared the safety and efficacy of TARE using 90Y resin microspheres to that of sorafenib in HCC patients with locally advanced tumours or intermediate-stage HCC (BCLC-B) following unsuccessful attempts of TACE.[29] They reported that the overall median survival did not differ between the groups receiving TARE and sorafenib. However, tumour objective response rates and the health-related QoL were significantly superior in the TARE group than in the group receiving sorafenib. In addition, patients in the TARE group had fewer adverse effects as compared to patients in the sorafenib group. The investigators suggested that tolerance and QoL considerations might help when deciding between the two treatment modalities. In a study comparing Y-90 radioembolisation and TACE in patients of BCLC stages A or B, the investigators found that Y-90 radioembolisation provided a significantly longer time to progression than TACE. Furthermore, TARE was associated with a better tumour response rate and could substantially reduce the dropout rate from the transplant waitlist.[59]


  Exceptions and Further Considerations Top


Although this five-step algorithm simplifies the treatment decisions for HCC patients, since the clinical stage of HCC patients is a dynamic parameter reflecting the dynamic nature of the underlying liver function and tumour status, each of the above steps should have flexibility in application. In many circumstances, a reworking of the steps may be required once the condition of the patients improves or deteriorates with time and treatment. For example, in patients with PS 3 or 4, with good nutrition, treatment of liver disease and supportive care, there could be an improvement in performance to PS 2 or 1, and then, they could be allocated to further steps. Similarly, in many of the algorithm steps, the CTP score is used for treatment decisions, with patients having a CTP score >8 being allocated to only the best supportive care. However, with appropriate treatment of liver disease, such as antivirals, abstinence and diuretics, the CTP score may improve to ≤8, and then, these patients will qualify for the alternative treatment.

The present algorithm is based on LDLT, which is the most commonly available form of LT in India. However, many times, patients not having the LDLT option due to the unavailability of suitable donors are placed in the DDLT waiting list. Such patients will require some form of bridging therapy, if the waitlist time is anticipated to exceed 3–6 months. The other important consideration for patients being worked up for LT is the role of tumour biomarkers such as AFP for determining the suitability of LT. Many centres exclude patients for LT when the baseline AFP is very high (typically >1000 ng/dL).


  Conclusions Top


We have proposed the above simplified five-step algorithm for facilitating treatment decisions for HCC patients in India. We hope that this algorithm will not only simplify the management approach to HCC patients in India, but also it will bring a uniformity in the treatment protocol for HCC in India. We also propose a multicentre study comparing our five-step algorithm with the BCLC staging system to document any survival advantage with either approach.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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