1 The Philippine Clinical Practice Guidelines For The Diagnosis and Management of Hepatocellular Carcinoma 2021

Philippine Journal of Internal Medicine Clinical Practice Guideline
The Philippine Clinical Practice Guidelines for the Diagnosis

and Management of Hepatocellular Carcinoma 2021
Commissioned by the
Steering Committee. Ryan Ruel T. Barroso, MD, FPCS, Avril P. David, MD, FPCS, Irene F. Abisinia, MD, FPCS, Timothy
Joseph S. Orillaza, MD, FPSVIR, Bernadette Semilla-Lim, MD, FPSG, Jonathan C. Nolasco, MD, FPCS, Kitchie C. Antipuesto,
MD, FPSMO, Jennielyn C. Agcaoili-Conde, MD, FPSG, and Glenda Lyn Y. Pua, MD, DPSP
Technical Working Group. Evelyn O. Salido, MD, MSc, Maria Vanessa C. Villaruz-Sulit, RN, MSc, Howell Henrian G. Bayona,
MSc, Fides Roxanne M. Castor, MD, Eunice Victoria M. Co, RMT, MD, FPCP, Louie F. Dy, MD, Emmanuel P. Estrella, MD,
MSc, Aldrin B. Loyola, MD, MBAH, FPCP, Corinna M. Puyat, MD, Marvin Jonne L. Mendoza, MD, Beatrice J. Tiangco, MD,
MSc, Grazielle S. Verzosa, MD, DPPS, Marc Andrew O. Perez, MD, DPPS, DPSN, DPNSP, Myzelle Anne J. Infantado, PTRP,
MSc, and Leonila F. Dans, MD, MSc
Consensus Panel. Samuel D. Ang, MD, FPCS, Clarito U. Cairo Jr. MD, FPCOM, Ramon L. De Vera, MD, FPCS, Maria Vanessa
H. De Villa, MD, FPCS, Jade D. Jamias, MD, FPSG, Paulo Giovanni L. Mendoza, MD, FPSP, Janus P. Ong, MD, FPSG, Teresa
T. Sy Ortin, MD, FPROS, Evangeline Santiago, MD, FPAFP, Ray Sarmiento, MD, FASGE, Marvin Tamaña, MD, FPSVIR, Ernesto
C. Tan, MD, FPCS, Catherine SC Teh, MD, FPCS, Maria Luisa A. Tiambeng, MD, FPSMO, Edhel S. Tripon, MD, FPSG, Billie
James G. Uy, MD, FPCS, Primo B. Valenzuela, MD, FPCP, Ronald G. Yebes, MD, FPCR, and Pelagio C. Baldovino, MD, MPH
The PHILIPPINE JOURNAL OF INTERNAL MEDICINE is a peer reviewed journal and a copyrighted publication of the Philippine College of Physicians Volume 59 Number 3 Jul – Sep, 2021 166
PAHPBS, HSP, PSMO, SOSP, PSVIR, PSGS & PSG Hepatocellular Cancer CPG
Table of Contents
DISCLAIMER 167
EXECUTIVE SUMMARY 168
LIST OF MEDICAL ABBREVIATIONS AND ACRONYMS 169
Chapter 1. BACKGROUND 169
Chapter 2. GUIDELINE DEVELOPMENT METHODS 170
Chapter 3. FINAL RECOMMENDATIONS and EVIDENCE to DECISION ISSUES 173
BIANNUAL LIVER ULTRASOUND vs LIVER ULTRASOUND and ALPHA-FETOPROTEIN for Screening 173
Evidence to Decision 173
GRADE Evidence Profile 174
MULTIPHASIC CT SCAN vs. CONTRAST-ENHANCED ABDOMINAL MRI for Diagnosis 175
FINE NEEDLE ASPIRATION BIOPSY vs. CORE NEEDLE BIOPSY for diagnosis of patients who do not 177
fulfill the imaging criteria for HCC
LIVER TRANSPLANTATION vs. LIVER RESECTION for early-stage hepatocellular carcinoma (BCLC 0-A) 179
LIVER TRANSPLANTATION vs. ABLATION for early-stage hepatocellular carcinoma (BCLC 0-A) 181
LIVER RESECTION vs. ABLATION for early-stage hepatocellular carcinoma (BCLC 0-A) 182
TRANSARTERIAL CHEMOEMBOLIZATION vs. SELECTIVE INTERNAL RADIATION THERAPY for 184
intermediate-stage hepatocellular carcinoma
SELECTIVE INTERNAL RADIATION THERAPY vs. EXTERNAL BEAM RADIOTHERAPY for intermediate- 186
stage hepatocellular carcinoma
TRANSARTERIAL CHEMOEMBOLIZATION alone or combined with TARGETED THERAPY for 187
intermediate-stage hepatocellular carcinoma
SORAFENIB vs. COMBINATION of IMMUNUNOTHERAPY and BEVACIZUMAB for advanced-stage 189
hepatocellular carcinoma
Chapter 4. RESEARCH GAPS 190
DISCLAIMER
This guideline focuses on prioritized clinical issues in the management of hepatocellular carcinoma in the Philippines. It is
not meant to be a complete guideline on the diagnosis and management of hepatocellular carcinoma. Its target users are
specialists, general practitioners, and allied health professionals largely involved in or providing care for patients with or at
risk for hepatocellular carcinoma.
The contents of this CPG are not meant to restrict the clinicians in using their judgment and considering individual patient’s
values, needs, preferences, and institution’s available resources even if adherence to this guideline is encouraged by its
developers and the Department of Health.
Sound clinical decision-making based on patients’ current health status must be continually exercised as their responses to
treatment or diagnostic tests may vary.
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Hepatocellular Cancer CPG PAHPBS, HSP, PSMO, SOSP, PSVIR, PSGS & PSG
Policymakers and payers can also base regulations on this CPG, but nonconformance to this document should not be the
sole basis for granting or denying financial assistance or insurance claims. Recommendations from this guideline should
not also be treated as strict rules to base legal actions.
Developers of this CPG are aware of its limitations. Evidence summaries and recommendations are based on the best
available scientific evidence as of the time of its formulation. The clinical trials and observational studies may not have
addressed specific aspects of assessment, management, and surveillance, and as such, evidence bases are therefore not
all-inclusive. Nevertheless, considerations on these aspects were still deemed necessary in the current contexts of liver
cancer.
EXECUTIVE SUMMARY
The Clinical Practice Guideline (CPG) for the Diagnosis and Management of Hepatocellular Carcinoma (HCC) provides 12
recommendations for ten prioritized interventions in diagnosing and managing hepatocellular carcinoma in the Philippines.
It is the first CPG for HCC developed de novo in the country. It is not an adaptation of existing practice guidelines developed
by international organizations.
Recommendations are the product of appraisal of the best available evidence, consideration of costs, equity, feasibility,
acceptability, and appropriateness of utilizing diagnostic and therapeutic interventions for HCC, incorporation of different
clinical practices, and integration of patient values and preferences. This CPG is intended to be used not only by liver cancer
specialists but also other clinicians and stakeholders involved mainly in caring for patients with or at risk of developing
hepatocellular carcinoma. The target beneficiaries of this guideline are primarily the patients with HCC in different areas in
the country as applicable.
The guideline development process followed the 2018 DOH Manual using the Grading of Recommendations, Assessment,
Development, and Evaluation (GRADE) approach. This approach included (1) identification of critical research questions in
PICO format (population, intervention, comparison, and outcome), (2) retrieval, appraisal, and synthesis of the evidence,
(3) formulation of draft recommendations, (4) formulation of final recommendations and, (5) planning for dissemination,
implementation, impact monitoring, and updating.
Each recommendation is presented with the certainty of evidence (high, moderate, low, very low) and the strength of the
recommendation (strong, conditional, none). Evidence with high certainty is well-established and will unlikely be changed
by new research findings. Strong recommendations are those which are supported by evidence of high certainty or those
which the guideline development group believes will clearly benefit or harm the target population. These can be put forth
as policy. In contrast, a conditional recommendation indicates that the intervention is suggested and shared decision-
making would be necessary prior to its uptake. The absence of strength indicates insufficient evidence to recommend for
or against a particular intervention. Any dissonance between the certainty of evidence and the strength of recommendation
is explained under the Consensus Issues.
Table 1 shows the final recommendations for this clinical practice guideline on hepatocellular carcinoma.
Table 1. Summary of recommendations
Strength of Panel
Recommendation Certainty of Evidence
Recommendation
1.1. We recommend semi-annual screening of patients at risk of developing Strong Low
hepatocellular carcinoma.
1.2. We suggest the use of ultrasound, with or without alpha-fetoprotein test, for Conditional Very Low
screening patients at risk of developing hepatocellular carcinoma.
2. We recommend the use of a multiphasic, contrast-enhanced CT scan or Strong Low

contrast-enhanced MRI in the diagnosis of hepatocellular carcinoma.
3.1. We recommend the use of core needle biopsy over fine-needle aspiration Strong Low
biopsy among patients who do not fulfill the imaging criteria for hepatocellular
carcinoma.
3.2. We suggest the use of fine-needle aspiration biopsy among patients who do Conditional Low
not fulfill the imaging criteria for hepatocellular carcinoma when core needle
biopsy cannot be done.
4. There is insufficient evidence to recommend liver transplantation over liver None Very Low
resection among patients with early-stage hepatocellular carcinoma (BCLC 0-
A).
5. There is insufficient evidence to recommend liver transplantation over None Low
radiofrequency ablation or microwave ablation among patients with early-stage
hepatocellular carcinoma (BCLC 0-A).
Vol 59 No 3 168
6. We suggest liver resection over ablation, primarily radiofrequency ablation, for Conditional Very Low
patients with hepatocellular carcinoma BCLC 0-A and compensated liver
function.
7. We recommend transarterial chemoembolization over selective internal Strong Very Low
radiation therapy in intermediate stage (BCLC B) hepatocellular carcinoma.
8. There is insufficient evidence to recommend treatment with either selective None Very Low
internal radiation therapy or external beam radiation therapy for hepatocellular
carcinoma patients in the intermediate stage (BCLC B).
9. There is insufficient evidence to recommend the addition of targeted therapy None Low
to transarterial chemoembolization in BCLC B hepatocellular carcinoma.
10. We suggest the use of combination therapy (atezolizumab plus bevacizumab) Conditional Low
over sorafenib as a first-line treatment for advanced-stage hepatocellular
carcinoma in selected patients.
LIST OF MEDICAL ABBREVIATIONS AND ACRONYMS

AASLD American Association for the Study of Liver ICER incremental cost-effectiveness ratio
Diseases
AE adverse event ICTRP International Clinical Trials Registry Platform
AFP alpha-fetoprotein IHC Immunohistochemistry
AJCC American Joint Committee on Cancer JSTOR Journal Storage
APASL Asian Pacific Association for the Study of the Liver KLCA-NCC Korean Liver Cancer Association-National
Cancer Center
ASR age-standardized rate LI-RADS Liver Imaging Reporting and Data System
ASCO American Society of Clinical Oncology LR liver resection
BCLC Barcelona Clinic Liver Cancer mRECIST modified response evaluation criteria in
solid tumors
CCT controlled clinical trials MRI magnetic resonance imaging
CENTRAL Cochrane Central Register of Controlled Trials mUICC modified Union for International Cancer
Control
CoE certainty of evidence MWA microwave ablation
CNB core needle biopsy OS overall survival
CP consensus panel OR odds ratio
CPG clinical practice guideline PhilHealth Philippine Health Insurance Corporation
CT computed tomography QALY quality-adjusted life year
cTACE conventional transarterial chemoembolization QoE quality of evidence
DEB-TACE drug-eluting beads transarterial RCT randomized controlled trials
chemoembolization
DFS disease-free survival REILD radioembolization-induced liver disease
EASL European Association for the Study of the Liver RFA radiofrequency ablation
EBRT external beam radiotherapy ROB risk of bias
ECOG Eastern Cooperative Oncology Group RR relative risk
EHR extrahepatic recurrence SAE serious adverse event
EGD Esophagogastroduodenoscopy SC steering committee
EORTC European Organisation for Research and SIRT selective internal radiation therapy
Treatment of Cancer
FNAB fine needle aspiration biopsy TACE transarterial chemoembolization
GRADE Grading of Recommendations, Assessment, TARE transarterial radiotherapy
Development, and Evaluation
HCC hepatocellular carcinoma TRD treatment-related death
HCV hepatitis C virus TTP time to progression
HERDIN Health Research and Development Information US ultrasound
Network (Philippines)
HR hazard ratio WHO World Health Organization
IARC International Agency for Research on Cancer
Chapter 1. BACKGROUND liver CA ranks fourth in cancer incidence, with over ten
thousand new cases in 2020, and was the second
Liver cancers (CA) pose one of the most intensive
leading cause of cancer death.3 The most common
challenges to global health, especially in developing
histology of primary liver cancer globally is
countries. Primary cancer of the liver, which accounts
hepatocellular carcinoma (HCC), a tumor of the
for 75 to 90% of all liver cancers, is the sixth most
parenchymal cells of the liver, accounting for
common cancer worldwide and the second leading
approximately 80% of cases.1
cause of cancer-related mortality.1,2 In the Philippines,
169 Volume 59 No. 3

Incidence rates of liver cancer have been rising in the past Management is primarily based on individual physician
three decades, with trends expected to increase from preferences, which may be influenced by specialty and
841,080 in 2018 to 1,361,836 in 2040 (an overall change institutional protocol, resulting in significant variation in
of +61.9%).4 According to Cancer Today, an International practice that potentially affects clinical outcomes.
Agency for Research on Cancer (IARC), most of the Although several clinical practice guidelines on the
burden is in developing countries, with 80 to 85% of HCC management of HCC have been published worldwide9-11,
cases reported in Africa and Asia.4,5 However, even within their applicability in the local context may not be
these specific geographic regions, there is significant appropriate. In 2019, the Department of Health
variability in the distribution and incidence of HCC, commissioned the Rizal Medical Center in Pasig, Metro
primarily due to the variable prevalence of risk factors.6 Manila, to formulate an evidence-based clinical practice
For example, the age-standardized rate (ASR) in Cape guideline on hepatocellular carcinoma to standardize the
Verde, Africa, was 10.7 (per 100,000), while in Mongolia approach to the diagnosis and treatment of HCC.
and China, it was 93.7, which had the highest ASR in 2018.
In a study, the Philippines ranked 23rd.7
References
Survival rates of HCC, even in recent studies, are lacking
due to the advanced stage of the disease when 1. McGlynna K, Petricka J, London W. Global epidemiology of
diagnosed. The median survival of untreated HCC ranges hepatocellular carcinoma: an emphasis on demographic and
from 3 to 9 months, with 5-year mortality rates as high as regional variability. Clin Liver Dis 2015;19:223-38.
>95% annually and a mean age-standardized survival rate 2. Goodarzi E, Ghorat F, Jarrahi A, Adineh H, Sohrabivafa M,
Khazaei Z. Global incidence and mortality of liver cancers and its
at five years of approximately 12%.2,8 Geographic
relationship with the human development index (HDI): and
distribution of mortality in HCC is similar to that of ecology study in 2018. World Cancer Research Journal 2019;6:
incidence.2,4 e1255.
3. Estimated number of new cases in 2020, Philippines, both sexes,
Hepatocellular cancer occurs more often in males than in
all ages. World Health Organization International
females (2.4:1), and the incidence increases with age, with 4. Agency for Research on Cancer. at
the highest seen in the 60-70 years age group.2,4 https://gco.iarc.fr/today/online-
However, in populations where hepatitis B and C infection analysistable?v=2020&mode=cancer&mode_population=countri
is hyperendemic, the disease can develop at a younger es&population=900&populations=608&key=asr&sex=0&cancer
age, most often around the age of 40.5,7 =39&type=0&statistic=5&prevalence=0&population_group=11&
ages_group%5B%5D=0&ages_group%5B%5D=17&group_can
Several important risk factors have been identified, cer=1&include_nmsc=1&include_nmsc_other=1#collapse-
including chronic hepatitis B infection, chronic hepatitis C group-0-3.)
infection, non-alcoholic fatty liver disease, non-alcoholic 5. Rawla P, Sunkara T, Muralidharan P, Raj J. Update in global
steatohepatitis, alcoholic liver disease, and any other trends and aetiology of hepatocellular carcinoma. Contemp
condition of sustained inflammatory damage leading to Oncol (Pozn) 2018; 22:141–50.
6. El-Serag H. Epidemiology of viral hepatitis and hepatocellular
hepatocyte necrosis, regeneration, fibrotic deposition,
carcinoma. Gastroenterology 2012; 142:1264-73.
resulting in cirrhosis.4,6 Other risk factors include exposure 7. Mak L. Global epidemiology, prevention, and management of
to aflatoxin, tobacco, obesity, diabetes, birth control pills, hepatocellular carcinoma2018.
insulin resistance, hypothyroidism, and hyperlipidemia.2 8. Liver Cancer. 2018. at https://www.wcrf.org/dietandcancer/liver-
In the majority of cases of HCC (75 to 80%), the cancer/.
association with chronic hepatitis B virus (HBV) or hepatitis 9. Kulik L, El-Serag H. Epidemiology and management of
C virus (HCV) infections has been well-established.5 hepatocellular carcinoma. Gastroenterology 2019;156:47791.
Indeed, variations in the age-, sex-, and race-specific rates 10. Marrero J, Kulik L, Sirlin C, Zhu A, Finn R, Abecassis M.
Diagnosis, Staging, and Management of Hepatocellular
of HCC in different geographic regions are likely to be Carcinoma: 2018 Practice Guidance by the American
related to differences in the prevalence of viral hepatitis in Association for the Study of Liver Diseases. Hepatology 2018;68.
these populations.5 11. Omata M, Cheng A, Kokudo N, Kudo M, Lee J, Jia J. Asia–Pacific
clinical practice guidelines on the management of hepatocellular
In the Philippines, there is a paucity of local data on carcinoma: a 2017 update. Hepatol Int 2017:317-70. 11. EASL.
epidemiology, incidence, and treatment outcomes of EASL Clinical practice guidelines: management of hepatocellular
HCC. There is no local CPG to guide the approach to carcinoma. J Hepatol 2018; 69:182-236.
diagnosis and treatment.
Chapter 2. GUIDELINE DEVELOPMENT METHODS Developer or the Steering Committee (SC). The SC
created a roster of physicians, hospitals, and
Organization of the Process
organizations that provide liver cancer care and invited
The guideline development process followed the them as stakeholders in the development of this CPG. The
methodology outlined in the CPG Development Manual SC was tasked to oversee the CPG formulation process,
of the Department of Health1. First, the DOH selected one including setting up the working groups (i.e., Evidence
of its tertiary hospitals to organize the Lead CPG Review Experts and Consensus Panel). The SC was also
Vol 59 No 3 170
responsible for setting the scope of the CPG by assessing and synthesizing the evidence, generating the
identifying and prioritizing clinical questions and evidence summaries, draft recommendations, and
formulating these questions, with a specific population, strength of recommendations of the EREs, and in voting
intervention, comparator, and outcomes of interest on or discussing the final recommendations during the en
(PICO), before sending them to the Evidence Review banc review or in the Delphi of the Consensus Panel.
Experts.
The summary of the declaration of COIs is shown in
The EREs were tasked to perform a systematic literature Appendix A.
search, review existing CPGs, appraise and synthesize
Creation of the Evidence Base
relevant evidence, draft the evidence-based
recommendations, and present them to the consensus The ERE conducted a systematic search in electronic
panel. (MEDLINE via PubMed, CENTRAL, Google Scholar, and
ClinicalTrials.gov) and local databases using keywords
Lastly, the Consensus Panel was assigned to choose the
based on the PICO for each question (Table 2). To ensure
critical and important outcomes, review the evidence
a comprehensive search, the ERE contacted authors,
summaries and draft recommendations, discuss the
consulted local experts on the topic, and hand searched
merits of the evidence, consider other factors (cost,
articles for other relevant references. The last search was
patient’s values, and preferences, feasibility) during an en
conducted from March to April 2021.
banc meeting, and formulate the final recommendations
and strength. The EREs were tasked to look for international CPGs
published over the past five years that answer their
Composition of the CPG Consensus Panel
respective clinical questions. Two methodologists
The Consensus Panel is a multisectoral group of content appraised the relevant CPGs using the AGREE tool and
experts and key stakeholders in the care of patients with assessed for possible adaptation.
HCC. Selecting the members of the consensus panel was
For questions on therapeutic interventions, randomized
guided by the recommendations of DOH.1 The key
controlled trials (RCTs), controlled clinical trials (CCTs),
stakeholders who joined the series of online en banc
systematic reviews, or meta-analyses were sought. In their
meetings were general and hepatobiliary surgeons,
absence, quasirandomized and observational studies
medical and surgical oncologists, liver pathologists,
were considered. For questions on diagnostic tests, the
interventional radiologists, family physician, infectious
included studies were those that reported sensitivity and
disease specialists, a patient representative, private and
specificity or had data for their computation. Cost-
public physician practitioners, medical training officer,
effectiveness studies, if available, were included.
and a government representative.
Two members of the ERE independently appraised each
Declaration and Management of Conflicts of Interest
study for methodological quality. Results from studies
Each prospective member of the working groups of the with similar outcomes were pooled and estimates of effect
CPG was required to declare his/her financial and were determined. Review Manager version 5 was used for
intellectual conflicts of interest (COI) that may lead to quantitative synthesis of clinical outcomes identified for
biased decisions. The SC assessed the declared COIs and each of the ten questions. The ERE determined the
disqualified from the Consensus Panel anyone with major certainty of the evidence for each outcome (benefit or
potential COIs. Those with other COIs were to inhibit harm) after assessment of directness, risk of bias,
themselves from the discussion should this be related to consistency, and precision of results using the GRADE
their declared COI. approach (Table 3). The evidence obtained from the
review became the basis for the draft recommendations.
The Steering Committee facilitated the whole CPG
process, but its members had no direct participation in
Table 2. PICO questions of this guideline

1. Among patients at increased risk for hepatocellular carcinoma (those with liver cirrhosis secondary to alcohol,
hemochromatosis, non-alcoholic fatty liver disease, and other metabolic disorders, hepatitis B and hepatitis C
infection), should we use a biannual liver ultrasound (US) or a combination of biannual liver US and alphafetoprotein
(AFP) to improve HCC-related survival rate?
2. Among patients with suspected hepatocellular carcinoma, should we use multiphasic computed tomography scan
versus contrast-enhanced abdominal magnetic resonance imaging in diagnosing hepatocellular carcinoma?
3. Among patients suspected of having hepatocellular carcinoma but do not fulfill the imaging criteria for diagnosis,
should we use fine-needle aspiration biopsy versus core needle biopsy in diagnosing hepatocellular carcinoma?
4. Among patients with early-stage hepatocellular carcinoma (BCLC 0-A), should we do liver transplantation versus liver
resection to improve progression-free and overall survival, morbidity, and mortality?
171 Volume 59 No. 3

5. Among patients with early-stage hepatocellular cancer (BCLC 0-A), should we do liver transplantation versus ablation
(microwave ablation or radiofrequency ablation) to improve progression-free and overall survival, morbidity, and
mortality?
6. Among patients with early-stage hepatocellular cancer (BCLC 0-A), should we do liver resection versus ablation
(microwave ablation or radiofrequency ablation) to improve progression-free and overall survival, morbidity, and
mortality?
7. Among patients with intermediate-stage hepatocellular carcinoma (BCLC B), should we use transarterial
chemoembolization versus selective internal radiation therapy to improve progression-free and overall survival,
morbidity, and mortality?
8. Among patients with an intermediate stage (BCLC B) hepatocellular carcinoma, should we use selective internal
radiation therapy (SIRT) versus external beam radiotherapy to improve in terms of progression-free and overall survival,
morbidity, and mortality?
9. Among hepatocellular carcinoma patients with an intermediate stage (BCLC B), should we use the combination of
targeted therapy (e.g., sorafenib, lenvatinib) plus transarterial chemoembolization versus transarterial
chemoembolization alone to improve response rate, progression-free and overall survival, preservation of liver
function, and quality of life?
10. Among hepatocellular cancer patients with advanced-stage (BCLC C), should we use sorafenib versus combination
immunotherapy (e.g., atezolizumab, pembrolizumab, nivolumab, ipilimumab) plus bevacizumab to improve
progression-free and overall survival and quality of life?
Table 3. Bases for assessing the certainty of evidence using GRADE approach2
Observational studies Certainty of Evidence Randomized trials
Extremely strong association and no High No serious flaws in study quality
major threats to validity (Further research unlikely to change our
confidence in the estimate of effect)
Strong consistent association and Moderate Serious flaws in design or execution or
no plausible confounders (Further research is likely to have an quasi-experimental design
important impact)
No serious flaws in study quality Low Very serious flaws in design or
(Further research is very likely to have an execution
important impact)
Serious flaws in design and Very low Very serious flaws and at least one
execution (The estimate of effect is very uncertain) other serious threat to validity
Additional factors that lower certainty of the evidence are:
● Important inconsistency of results
● Some uncertainty about directness
● High probability of reporting bias
● Sparse data
● Major uncertainty about directness can lower the quality by two levels
Additional factors that may increase certainty are:

● All plausible residual confounding, if present, would reduce the observed effect
● Evidence of a dose-response gradient
Formulation of the Recommendations achieved. In case consensus was not reached in the first
round of voting, discussions occurred to determine
During the en banc consensus panel meeting, the draft
reasons for dissenting opinions and to revise the
recommendations and supporting evidence were
recommendation statement until it was approved. Two
presented and discussed. The nominal group technique
further rounds of voting on the issue were allowed. If
was used, wherein each panel member had the
consensus was not reached, the final approval was
opportunity to clarify matters about the evidence
obtained through a modified Delphi process.
presented and to systematically contribute his knowledge
and opinions about the issues under discussion. After Each recommendation may be for or against a specific
considering the certainty of the evidence, trade-offs intervention or diagnostic test and can be strong or
between benefits and harms, cost, equity, feasibility, conditional. The panel can also opt not to make a
acceptability in the current local setting, patient values, recommendation. A strong recommendation for an
and preferences, the CP members voted to approve of intervention or diagnostic test sets it as a standard of care
the recommendation and its strength. A consensus was for most patients and it may be adopted during health
reached when an approval vote of at least 75% was policy-making. In contrast, a conditional recommendation
Vol 59 No 3 172
indicates that the intervention or diagnostic test is 2. Guyatt G, Oxman A, Akl E, et al. GRADE guidelines: 1.
suggested and may be useful in certain situations. Shared Introduction—GRADE evidence profiles and summary of
decision-making would be crucial for its implementation. 3. findings tables. Journal of Clinical Epidemiology 2011; 64:383-
94.
References
1. DOH. Manual for Clinical Practice Guideline Development 2018.
Chapter 3. FINAL RECOMMENDATIONS and higher proportion of HCC detected at an early stage in the
EVIDENCE to DECISION ISSUES screened group. Surveillance improved four-year survival
in more than half of patients and five-year survival in more
The recommendations and evidence summaries are
than 40% of patients.3
briefly outlined in the following pages. More details of
the evidence can be found in a separate document Confirmatory US and contrast-enhanced CT scans carry a
(Evidence Base). 10% risk of mild adverse events.4 Needle track seeding
of cancer cells, a potential risk associated with biopsy of
BIANNUAL LIVER ULTRASOUND vs. LIVER
hepatic tumors, can be as high as 0.9% per annum.5 Less
ULTRASOUND and ALPHAtoFETOPROTEIN for
well-known is the psychological distress that a
Screening
presumptive or a missed diagnosis of HCC will inflict on
Recommendations screened patients.6,7
1.1. We recommend semi-annual screening of patients at Certainty of Evidence
risk of developing hepatocellular carcinoma. (Strong
1. The overall certainty of the evidence for the first
recommendation, low certainty of evidence)
recommendation was deemed to be low because of
1.2. We suggest the use of ultrasound, with or without the serious risk of bias and indirectness.2
alpha-fetoprotein test, for screening patients at risk of
1.2. The overall certainty of the evidence for the second
developing hepatocellular carcinoma. (Conditional
recommendation was very low due to the very
recommendation, very low certainty of evidence)
serious risk of bias and indirectness.3
Ultrasonography or US is a non-invasive imaging
Other Considerations
procedure that uses sound waves to produce images of
organs inside the abdomen or pelvis. Among adults, AFP Cost
is a tumor marker from the liver, testicles, or ovaries.
There is no local cost-benefit analysis of HCC screening
Semiannual US with or without AFP determination has
among at-risk patients. Based on an informal survey of
been recommended as a non-invasive surveillance
four stand-alone laboratories in Manila, liver US (single
strategy in a number of HCC clinical practice guidelines.1
organ) ranges from PHP 600 to PHP 700, and quantitative
Evidence to Decision AFP determination ranges from Php 850 to PHP 2,000. A
rapid qualitative AFP test kit costs PHP 10 to PHP 70 each
Benefits and Harms
(wholesale or retail value, respectively) exclusive of
There was no randomized controlled trial directly delivery, personnel salary, and other costs.
comparing US to US plus AFP test in HCC surveillance
Recommendations from Other Groups
among patients with cirrhosis, hepatitis B, and/or hepatitis
C infection with mortality or survival as an outcome APASL, KLCA-NCC, AASLD, and LI-RADS recommend US
measure. One RCT compared overall survival between together with AFP every 6 months for HCC surveillance.
the biannual US + AFP screening with usual care (no The EASL did not recommend the use of AFP due to cost-
screening).2,3 The investigators recruited 18,816 effectiveness issues.1 In general, CPGs from the Americas
participants with hepatitis B, 9,373 were randomized to and Europe recommend US while CPGs from Asia
semiannual screening, and 9,443 served as controls. From recommend US and AFP for semiannual screening.8-11
this study, the authors extracted the accuracy estimates
It is generally accepted that groups with hepatitis B and/or
for US alone, AFP alone, and US + AFP from the screening
C infection, those with cirrhosis of any cause, individuals
arm.
with a family history of liver cancer, those with prolonged
Based on this single RCT3, the reported sensitivity heavy alcohol consumption, and men older than 40 years
estimates of US alone, AFP alone, and US + are at an increased risk of developing HCC.12
AFP were 84%, 69%, and 92%, respectively.2 Moreover, Consensus Issues
screening patients at risk for HCC using US + AFP was
The CP members identified at-risk patients as those with
associated with a 40% lower risk of HCC-related mortality
liver cirrhosis of any etiology, hepatitis B, with a family
(95% CI 8 to 61%) compared to unscreened individuals.
history of hepatocellular carcinoma, males aged 40 years
There was no significant difference between the screened
and above, and females aged 50 years and above. They
group and the unscreened group regarding the number
were convinced of the net benefit of selective screening,
of cancers detected. However, there was a significantly
173 Volume 59 No. 3

thus the strong recommendation despite the low certainty GRADE Evidence Profile
of evidence. Moreover, despite the higher costs
P patients at increased risk for hepatocellular
associated with screening (increased number of patients
carcinoma
eligible for early management e.g., transplantation and
immunosuppression), its positive impact on a patient’s life I combination of biannual liver US and
(e.g., increased societal participation and fulfilled roles in alphatofetoprotein (AFP)
the family), was highly valued and difficult to equate with
economic gains. C biannual liver ultrasound (US)
Members of the panel favored using US alone, which O HCC-related survival rate, diagnostic accuracy
will cost less and is more available. However, combining
US with AFP when the latter test is available and
affordable is also acceptable in most urban places in the
country.
Table 4. Summary of findings on HCC screening vs. no screening

Effect
Outcomes Importance Basis 95% CI Interpretation Overall CoE
Estimate
1 RCT
Mortality Critical RR 0.60 0.39 - 0.92 Benefit Very Low
(n=18,816)
Proportion of 1 RCT
Critical RR 8.06 3.18 - 20.41 Benefit Very Low
resectable tumors (n=18,816)
1 RCT
Detected Stage 1 HCC Critical RR 82.07 5.16 - 1305.59 Benefit Very Low
(n=8,816)
Sn (US) Critical 1 CS 84.3% 71.4 - 93.0% - Low
Sp (US) Critical 1 CS 97.0% 96.8 - 97.2% - Low
PPV (US) Critical 1 CS 6.6% 5.8 - 7.6% - Low
False positive rate (US) Critical 1 CS 2.98% 2.75 - 3.23% Low
Sn (US + AFP) Critical 1 CS 92.2% 81.1 - 97.8% - Low

Sp (US + AFP) Critical 1 CS 92.5% 92.1- 92.9% - Low
PPV (US + AFP) Critical 1 CS 3% 2.7- 3.3% - Low
False positive rate (US
Critical 1 CS 7.5% 7.1 - 7.9% - Low
+ AFP)
Sn – sensitivity, Sp – specificity, PPV – positive predictive value, RCT – randomized controlled trial, CS – cross-sectional derived from the
RCT, US – ultrasound, AFP – alphatofetoprotein, HCC – hepatocellular carcinoma, RR – relative risk, COE – certainty of evidence
Table 5. Comparison of survival rate between HCC screening vs. no screening
Screened Group Usual Care Group

Outcomes Importance Basis Overall COE
(n=9,373) (n=9,443)
1-year survival Critical 1 RCT 65.9% 31.2% Very Low
3-year survival Critical 1 RCT 52.6% 7.2% Very Low
5-year survival Critical 1 RCT 46.4% 0 Very Low
References 5. Silva M, Hegab B, Hyde C, Guo B, Buckels J, Mirza D. Needle

track seeding following biopsy of liver lesions in the diagnosis of
1. Kim T, Kim S, Tang A, Lee J. Comparison of international hepatocellular cancer: a systematic review and meta-analysis.
guidelines for noninvasive diagnosis of hepatocellular carcinoma: Gut 2008; 57:1592-6.
2018 update. Clin Mol Hepatol 2019; 25:245-63. 6. Kansagara D, Papak J, Pasha A, O’Neil M, Freeman M, Relevo
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ultrasonography as a screening test for primary liver cancer. J disease: a systematic review. Ann Intern Med 2014; 161:261-9.
Med Screen 1999; 6:108-10. 7. Geh D, Rana F, Reeves H. Weighing the benefits of hepatocellular
3. Zhang B, Yang B, Tang Z. Randomized controlled trial of carcinoma surveillance against potential harms. J Hepatocell
screening for hepatocellular carcinoma. J Cancer Res Clin Oncol Carcinoma 2019; 6:23-30.
2004; 130:417-22. 8. Pinero F, Tanno M, Aballay G, Bana M, Dirchwolf M, Fassio E.
4. Chou R, Cuevas C, Fu R, Devine B, Wasson N, Ginsburg A. Argentinian clinical practice guideline for surveillance, diagnosis,
Imaging techniques for the diagnosis of hepatocellular staging and treatment of hepatocellular carcinoma. Ann Hepatol
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Med 2015; 162:697-711. 9. Yang J, Yu S, Gao L, Zhou Q, Zhan S, Sun F. Current global
development of screening guidelines for hepatocellular
Vol 59 No 3 174
carcinoma: a systematic review. Zhonghua Liu Xing Bing Xue Za 11. [Guideline for stratified screening and surveillance of primary liver
Zhi 2020; 41:1126-37. cancer (2020 Edition)]. Zhonghua Gan Zang Bing Za Zhi 2021;
10. Lu S, Wang J, Su C, Wang T, Dai C, Chen C. Management 29:25-40.
consensus guideline for hepatocellular carcinoma: 2016 updated 12. Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M. Guidelines
by the Taiwan Liver Cancer Association and the for diagnosis and treatment of primary liver cancer in China (2017
Gastroenterological Society of Taiwan. Journal of the Formosan Edition) Liver Cancer 2018;7:235-60.
Medical Association 2018; 117:381-403.
MULTIPHASIC CT SCAN vs. CONTRAST-ENHANCED is the greatest predisposing risk factor for an adverse
ABDOMINAL MRI for Diagnosis reaction. Other known risk factors were rate and route of
administration, larger contrast dose, and type of non-ionic
Recommendation
contrast use.6
2. We recommend the use of a multiphasic,
Certainty of Evidence
contrast-enhanced CT scan or contrast-enhanced
MRI in the diagnosis of hepatocellular carcinoma. The overall certainty of the evidence is low because of
(Strong recommendation, low certainty of inconsistency and the serious risk of bias. The biases stem
evidence) from different reference standards used, the unclear
interval between the performance of the index tests and
Diagnosis of HCC through non-invasive techniques has
reference standard, and unclear methods of patient
been advocated by different liver cancer technical
sampling. 7-17
groups and societies. Unique vascular derangements of
the tumor can be visualized through a multiphasic CT Other Considerations
scan or MRI with extracellular contrast.1,2 Using CT and
Cost
MRI with extracellular contrast, definite HCC diagnosis
is characterized by the presence of arterial phase Consensus Issues
hyperenhancement with washout in the portal venous
or delayed phases. MRI with hepatobiliary contrast will There was unanimous strong recommendation from the
show arterial phase hyperenhancement with washout in panel members for use of either of the two imaging tests,
the portal venous, delayed, or hepatobiliary phases in without prioritizing one imaging test over the other. The
HCC.3 majority of CP members who favored MRI did so because
of its higher sensitivity, ability to detect tumors of smaller
Evidence to Decision size, and no exposure to radiation. Furthermore, using
MRI as a first-line confirmatory test may turn out to be less
Diagnostic Accuracy and Harms
expensive if the diagnosis is arrived at earlier and the cost
Seventeen cross-sectional studies that compared of a failed CT scan is avoided.
contrast-enhanced abdominal MRI and multiphasic CT
However, CT scan was favored by some because it is (1)
were reviewed. Using lesion per lesion analysis,
already commonly used as initial diagnostic test by
contrast-enhanced abdominal MRI has higher pooled
specialists (2) more commonly available (3) able to
sensitivity (84% versus 67%) but with similar pooled
provide faster results, and (4) less costly. In addition, MRI
specificity (90% versus 93%) compared to multiphasic
is dependent on technical expertise and high-resolution
CT scan. Using lesion per patient analysis,
machine to produce good quality images, technology
contrastenhanced abdominal MRI has higher pooled
which is not widely available in the country.
sensitivity (86% versus 73%) and specificity (85% versus
78%). GRADE Evidence Profile
Contrast agents are considered safe but adverse effects P patients with suspected HCC
can present as mild allergic-like reactions to rare but
severe complications like contrast-induced nephropathy I multiphasic computed tomography scan
and nephrogenic systemic fibrosis.4 The incidence of C contrast-enhanced abdominal magnetic
adverse events is 1.5 events per 1000 doses (2.62% of resonance imaging
which are serious) with low-osmolar iodinated contrast
and 0.4 events per 1000 doses (6.25% of which are O diagnosing hepatocellular carcinoma
serious) with gadolinium-containing agents.5 A Canadian
review (2017) reported that a previous reaction to contrast
175 Volume 59 No. 3

Table 6. Summary of findings on multiphasic CT scan vs. contrast-enhanced abdominal MRI in diagnosis of
hepatocellular carcinoma: Lesion per lesion analysis
Multiphasic CT scan Contrast-enhanced abdominal MRI
Sensitivity 0.67 (95% CI: 0.59 - 0.74) Sensitivity 0.84 (95% CI: 0.77 - 0.89)
Specificity 0.78 (95% CI: 0.89 - 0.96) Specificity 0.90 (95% CI: 0.82 - 0.94)
Prevalence or Pre-test probability: 7.8%
Effect per 1,000 patients tested Pretest Interpretation

probability of 7.8%
Certainty of
Outcome Importance Basis
Multiphasic CT Contrast-enhanced Evidence
scan abdominal MRI
14 fewer TP in
True positives Critical 13 Cross-sectional 52 (46 - 58) 66 (60 - 69) multiphasic CT
studies (cohort type scan
Low
accuracy study) 14 more FN in
False
Critical n=1,069 26 (20 - 32) 12 (9 - 18) multiphasic CT
negatives
scan
27 more TN in
multiphasic
True negative Critical 857 (821 - 885) 830 (756 - 867)
13 Cross-sectional computed
studies (cohort type tomography scan
Low
accuracy study) 27 fewer FP in
False n = 1,609 multiphasic
Critical 65 (37 - 101) 92 (55 - 166)
positives computed
tomography scan
Table 7. Summary of findings on multiphasic CT scan vs. contrast-enhanced abdominal MRI in diagnosis of
hepatocellular carcinoma: Lesion per patient analysis
Multiphasic CT scan Contrast-enhanced abdominal MRI
Sensitivity 0.73 (95% CI: 0.63 - 0.80) Sensitivity 0.86 (95% CI: 0.78 - 0.91)
Specificity 0.78 (95% CI: 0.68 - 0.86) Specificity 0.85 (95% CI: 0.53 - 0.97)
Effect per 1,000 patients tested Pretest

probability of 7.8% Certainty of
Outcome Importance Basis Interpretation
Contrast-enhanced Evidence
Multiphasic CT scan
abdominal MRI
10 fewer TP in
True positives Critical 5 Crosssectional 57 (49 - 63) 67 (61 - 71) multiphasic CT
studies (cohort scan
Low
type accuracy 10 more FN in
False
Critical study) n = 309 21 (15 - 29) 11 (7 - 17) multiphasic CT
negatives
scan
67 fewer TN in
5 Cross-
True negative Critical 720 (626 - 790) 787 (488 - 892) multiphasic CT
sectional studies
scan
(cohort type Low
accuracy study) 67 more FP in
False
Critical n = 309 202 (132 - 296) 135 (30 - 434) multiphasic CT
positives
scan
References 4. Beckett K, Morjarity A, Langer J. Safe use of contrast media: what

the radiologist needs to know. RadioGraphics 2015; 35:1738-50.
1. Roberts L, Sirlin C, Zaiem F, et al. Imaging for the diagnosis of 5. Hunt C, Hartman R, Hesley G. Frequency and severity of adverse
hepatocellular carcinoma: A systematic review and meta- effects of ionated and gadolinium contrast materials:
analysis. American Association for the Study of Liver Diseases Retrospective review of 456,930 doses. American Journal of
2018; 67:401-21. Roentgenology 2009; 193:1124-7.
2. EASL-EORTC. Clinical Practice Guidelines: Management of 6. Morzycki A, Bhatia A, Murphy K. Adverse reactions to contrast
hepatocellular carcinoma. European Journal of Cancer 2012; material: a Canadian update. Canadian Association of
48:599-641. Radiologists Journal 2017; 68:187-93.
3. 2018 Korean Liver Cancer Association - National Cancer Center 7. Golfieri R, Marini E, Bazzocchi A, Fusco F, Trevisani F, Sama C.
Korea practice guidelines for the management of hepatocellular Small (< or 53 cm) hepatocellular carcinoma in cirrhosis: the role
carcinoma. Korean Journal of Radiology 2019; 20:1042.
Vol 59 No 3 176
of double contrast agents in MR imaging vs. multidetector-row comparison of US, CT and MR imaging. Eur Radiol 2013; 23:887-
CT. Radiol Med 2009;114. 96.
8. Haradome H, Grazioli L, Tinti R, et al. Additional value of 15. Baek C, Choi J, Kim K, et al. Hepatocellular carcinoma in patients
gadoxetic acid-DTPA-enhanced hepatobiliary phase MR imaging with chronic liver disease: a comparison of gadoxetic acid-
in the diagnosis of early-stage hepatocellular carcinoma: enhanced MRI and multiphasic MDCT. Clin Radiol 2012 2012;
comparison with dynamic triple-phase multidetector CT imaging. 67:148-56.
Journal of Magnetic Resonance Imaging; 34:69-78. 16. Imbriaco M, Luca S, Coppola M, et al. Diagnostic accuracy of
9. Hassan A, Al-ajami R, Dashti K, Abdoelmoneum M. Sixty-four Gd-eob-dtpa for detection hepatocellular carcinoma (HCC): a
multi-slice computed tomography and magnetic resonance comparative study with dynamic contrast-enhanced magnetic
imaging in evaluation of hepatic focal lesions. Egyptian Journal of resonance imaging (MRI) and dynamic contrast-enhanced
Radiology and Nuclear Medicine 2011; 42:101-10. computed tomography (CT). . Polish Journal of Radiology 2017;
10. Leoni S, Piscaglia F, Golfieri R, Camaggi V, Vidili G, Pini P. The 82:50-7.
impact of vascular and nonvascular findings on the noninvasive 17. Maiwald B, Lobsien D, Kahn T, Stumpp P. Is 3-tesla Gd-EOB-
diagnosis of small hepatocellular carcinoma based on the EASL DTPA-enhanced MRI with diffusion-weighted imaging superior to
and AASLD criteria. Am J Gastroenterol 2010; 105:599-609. 64-slice contrast-enhanced CT for the diagnosis of hepatocellular
11. Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G. carcinoma? PLoS One 2014;9:e111935.
Small nodule detection in cirrhotic livers: 18. Chen N, Motosugi U, Morisaka H, et al. Value of a gadoxetic acid-
12. evaluation with US, spiral CT, and MRI and correlation with enhanced hepatocyte-phase image to the LIRADS system for
pathologic examination of explanted liver. J Comput Assist diagnosing hepatocellular carcinoma. Magn Reson Med Sci
Tomogr 2001; 25:327-36. 2016; 15:49-59.
13. Sangiovanni A, Manini M, Lavarone M, Romeo R, Forzenigo L, 19. Lima P, Fan B, Berube J, et al. Cost-utility analysis of imaging for
Fraquelli M. The diagnostic and economic impact of contrast surveillance and diagnosis of hepatocellular carcinoma.
imaging techniques in the diagnosis of small hepatocellular American Journal of Roentgenology 2019; 213:17-25.
carcinoma in cirrhosis. Gut 2010;59. 20. Galle P, Forner A, Llovet J, Mazzaferro V, Piscaglia F, Raoul J.
14. Martino M, Filippis G, Santis A, Geiger D, Monte MD, Lombardo EASL Clinical Practice Guidelines: Management of hepatocellular
C. Hepatocellular carcinoma in cirrhotic patients: prospective carcinoma. Journal of Hepatology 2018; 69:182-236.
FINE NEEDLE ASPIRATION BIOPSY vs. CORE NEEDLE benign and malignant liver masses. The FNAB had an 83%
BIOPSY for diagnosis of patients who do not fulfill the sensitivity (95% CI 79%, 86%) while CNB had a 79%
imaging criteria for HCC sensitivity (95% CI 76%, 83%). Specificity for both FNAB
and CNB was at 100%.
Recommendations
The three cohort studies did not report any adverse
3.1. We recommend the use of core needle biopsy over
events. However, fine-needle aspiration biopsy (FNAB),
fine-needle aspiration biopsy among patients who
because it uses a smaller gauge needle ( 20), is
do not fulfill the imaging criteria for hepatocellular
considered a safer procedure than CNB when tissue
carcinoma. (Strong recommendation, low
diagnosis is needed in the definitive diagnosis of HCC.
certainty of evidence)
However, there may be a need for multiple passes, with a
3.2. We suggest the use of fine-needle aspiration biopsy higher risk of seeding and bile leak if the patient has
among patients who do not fulfill the imaging portal hypertension.5 Core needle biopsy (CNB), with the
criteria for hepatocellular carcinoma when core availability of more material on a single pass, provides
needle biopsy cannot be done. (Conditional tissue for immunohistochemical studies, but it may lead to
recommendation, low certainty of evidence) more bleeding complications especially in patients with
chronic liver disease.
The imaging criteria are globally accepted in diagnosing
HCC even in the absence of biopsy results. However, Certainty of Evidence
images are less readily seen when the size of a liver lesion
The overall certainty of the evidence is low because of
is small and/or when the liver is cirrhotic. In such cases, a
serious risk of bias and indirectness. All studies were
biopsy is needed to come up with a definitive diagnosis
retrospective and the performance of definitive surgery
of the liver mass, which could be benign regenerating
was largely dependent on the biopsy result that may
nodules or early HCC.1
overestimate accuracy. There was indirectness
Evidence to Decision because the population of interest had liver masses
seen on imaging but were not all suspected to have
Diagnostic Accuracy and Harms liver cancer.
We reviewed three retrospective cohort studies Other Considerations
comparing the diagnostic accuracy of fine-needle
aspiration biopsy (FNAB) and core needle biopsy (CNB) Cost
in the diagnosis of liver masses seen on prior imaging of
There is no study on cost-effectiveness.
the liver.2-4 These tests were compared with an accepted
reference standard (histopathology and/or fulfillment of
clinical criteria). FNAB and CNB were shown to have
similar sensitivity, specificity, and accuracy for diagnosing
177 Volume 59 No. 3

Recommendations from Other Groups FNAB was preferred by other panelists because (1) of
consistently good experience in obtaining a diagnosis as
2018 ESMO: Pathological diagnosis of HCC is based on a
long as it is imaging-guided and the adequacy of the
biopsy or a surgical specimen of the tumor.6
specimen is immediately checked, (2) patients favor it
2021 NCCN: A biopsy is recommended when a lesion is over CNB due to its less invasive nature, less risk of
highly suspicious for malignancy at multiphasic CT or MRI bleeding, and less cost, (3) accessible to more patients
but does not meet imaging criteria for HCC.7 These and its use will be more feasible and equitable.
guidelines, however, do not recommend a particular
Some panelists did not want to recommend one
biopsy.
procedure over the other because of the low certainty of
Consensus Issues the evidence, variation in institutional practices, and lack
of experienced specialists in certain areas of the country.
The discussions centered on accuracy in diagnosis, harm, Some surgeons proceed with resection of a suspicious
cost, feasibility, equity, and patient preferences. CNB was but small lesion on imaging and obtain the definitive
preferred because of the following reasons: (1) It tissue diagnosis post-operatively.
completely shows features of the liver architecture that
may not always be possible with FNAB. (2) It provides The final recommendations allow room for discussion
more tissue specimens, sufficient for between the patient and practitioner with regard to
immunohistochemistry (IHC) staining should this be individual preferences prior to choosing between CNB
needed. (3) It is the first-line procedure in obtaining a and FNAB.
histological diagnosis in most countries. (4) The
GRADE Evidence Profile
procedure can be performed by interventional
radiologists or by surgeons (both general or liver P patients with suspected HCC
specialists) and the tissue analyzed by a cytopathologist
I FNAB
or a general or liver pathologist. (5) Its cost does not differ
much from FNAB. (6) FNAB frequently gives inconclusive C CNB
results and this may lead to higher costs due to repeated
tests. (7) The risk of bleeding post-CNB may be offset by O diagnosing hepatocellular carcinoma
using a hemostatic matrix.
Table 8. Summary of findings on FNAB vs. CNB in the diagnosis of hepatocellular carcinoma
Fine needle aspiration biopsy Core needle biopsy
Sensitivity 0.74 - 0.81 Sensitivity 0.73 - 0.84
Specificity 0.98 - 0.99 Specificity 0.98 - 0.99
Effect per 1,000 patients tested

Certainty of
Outcome Importance Basis Pretest probability of 7.8% Interpretation
Evidence
FNAB CNB
1 more to 2 fewer
2 Cross- 59 - 65
True positives Critical 58 - 67 TP in
sectional studies
FNAB
(cohort type accuracy Low
study) 10 more FN in
False negatives Critical n = 534 15 - 21 13 - 22 multiphasic CT scan
0 fewer - 0
fewer TN in
True negative Critical 2 Cross-sectional 902 - 911 902 - 911
FNAB
studies (cohort type
Low
accuracy study)
0 fewer - 0
n = 534
False positives Critical 9 - 18 9 - 18 fewer FP in
FNAB
References diagnostic accuracy of cut needle biopsy of focal liver lesions.

Acta Cytol 2003; 47:332-36.
1. McGahan J, Bishop J, Webb J, Howell L, -rok N, Lamba R. Role 3. Pupulim L, Felce-Dachez M, Paradis V, Vullierme M, Zappa M,
of FNA and core biopsy of primary and metastatic liver disease. Bedossa P. Algorithm for immediate cytologic diagnosis of
Int J Hepatol 2013; 2013:174103. hepatic tumors. AJR Am J Roentgenol 2008;190: W208-12.
2. Franca A, Valerio H, Trevisan M, Escanhoela C, Seva-Pereira T, 4. Goldhoff P, Vohra P, Kolli K, Ljung B. Fine-needle aspiration
Zucoloto S. Fine needle aspiration biopsy for improving the biopsy of liver lesions yields higher humor fraction for molecular
Vol 59 No 3 178
studies: a direct comparison with concurrent core needle biopsy. diagnosis treatment and follow-up. Ann Oncol 2018;29: IV238-
J Natl Compr Canc Netw 2019; 17:1075-81. 55.
5. Wee A. Fine needle aspiration biopsy of the liver: Algorithmic 7. Hepatobiliary Cancers. at
approach and current issues in the diagnosis of hepatocellular https://www.nccn.org/professionals/physician_gls/pdf/hepatobili
carcinoma 2005. ary.pdf.)
6. Vogel A, Cervantes A, Chau I, Daniele B, Llovet J, Meyer T.
Hepatocellular carcinoma: ESMO Clinical practice guidelines for
LIVER TRANSPLANTATION vs. LIVER RESECTION for Singapore to $156,300/QALY in Switzerland. All ICERs
early-stage hepatocellular carcinoma (BCLC 0-A) were all below the threshold for cost-effectiveness
when the 5-year cumulative survival of LT exceeded
Recommendation
84.9%. In addition, the one-time cost of transplant and
4. There is insufficient evidence to recommend liver the 5year cumulative HCC recurrence rates associated
transplantation over liver resection among patients with LR were identified as sensitive parameters
with early-stage hepatocellular carcinoma (BCLC 0-A). dictating cost-effectiveness.18
(No recommendation, very low certainty of
evidence)
Across all guidelines from relevant organizations18-23, LR
Liver resection (LR) is the treatment of choice for
is strongly recommended for early-stage HCC cases
patients with HCC without cirrhosis, while liver
that were characterized by solitary tumors, well-
transplantation (LT) is considered for those with
preserved liver function, without portal hypertension or
decompensated cirrhosis.1 Because of its ability to offer
hyperbilirubinemia. LT is strongly recommended for
radical resection of the primary tumor/s, treat
patients who fail to meet the criteria for resection or
underlying liver disease and portal hypertension and
patients who satisfy certain clinical criteria (Milan,
minimize the risk of tumor recurrence, liver
Hangzhou, UCSF).
transplantation is believed to be superior to resection.
However, liver transplantation is not always feasible due Consensus Issues
to cost, scarcity of organs, and the risks associated with
The majority agreed that both interventions are
immunosuppression.
acceptable since they are already treatment
Evidence to Decision procedures for hepatocellular carcinoma (HCC) in the
country. However, BCLC 0 is too early a cancer stage for
Benefits and Harms
LT. The need to analyze prognosis and outcomes for
Sixteen observational studies2-17 compared the patients with or without portal hypertension or with
outcomes of early-stage HCC who received LT or LR. different Child-Pugh’s classes was pointed out as a
Both surgical interventions were comparable in survival research gap. Liver resection was favored because of
at 1- 3-, and 5 years and associated postoperative good outcomes and minor complications from clinical
morbidity and mortality. However, LT was associated experience. It is more cost-effective, more accessible,
with better disease-free survival at 3 years (OR 0.26, feasible, and less complicated than LT.
95% CI 0.12 - 0.56)2-4,7,10,13,15-17 and 5 years (OR 0.20,
95% CI 0.11 - 0.36)2-4,6-8,10,11,13,15-17.
P patients with early stage hepatocellular carcinoma
(BCLC 0-A)
The overall certainty of the evidence is very low due to
I liver transplantation
the risk of bias, inconsistency, and imprecision.
C liver resection
O progression-free and overall survival, morbidity,
Cost
and mortality
LR was considered more cost-effective than cadaveric
LT.18 The incremental cost-effectiveness ratios (ICERs)
of LT versus LR ranged from $111,821/QALY in
Table 9. Summary of findings: liver transplantation vs. liver resection for early-stage hepatocellular carcinoma
Effect Certainty of
Outcome Importance Basis 95% CI Interpretation
Estimate Evidence
1-yr Overall Survival 8 observational
Critical studies OR 0.97 0.63 - 1.50 Inconclusive Very Low
(n = 1,288)
179 Volume 59 No. 3

(n = 1,266)
3-yr Disease-Free 10 observational
Survival Critical studies OR 0.26 0.12 - 0.56 Net benefit with LT Very Low
(n=1,629)
(n=2,245)
5-yr Disease-Free
Survival 13 observational
Critical OR 0.20 0.11 - 0.36 Net benefit with LT Very Low
studies (n=2,274)
Post-op Mortality 7 observational

(n=1,070)
Post-op 3 observational
Complications Critical studies OR 0.52 0.12 - 2.19 Inconclusive Very Low
(n=414)
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transplantation: impact on long-term survival. Ann Surg 2007; EASL Clinical Practice Guidelines: Management of hepatocellular
245:51-8. carcinoma. Journal of Hepatology 2018; 69:182-236.
12. Facciuto M, Rochon C, Pandey M, Rodriguez-Davalos M.
Surgical dilemma: liver resection or liver transplantation for
hepatocellular carcinoma and cirrhosis. Intentionto--treat
Vol 59 No 3 180
LIVER TRANSPLANTATION vs. ABLATION for early- rates are PHP 18,000 and PHP 9,700, for laparoscopic and
stage hepatocellular carcinoma (BCLC 0-A) open or percutaneous ablation, respectively.6 In private
hospitals in Metro Manila, the cost ranges from PHP
Recommendation
112,000 - 190,700.8
5. There is insufficient evidence to recommend
liver transplantation over radiofrequency
ablation or microwave ablation among patients The Barcelona Clinic Liver Cancer (BCLC) staging
with early-stage hepatocellular carcinoma (BCLC algorithm and most other algorithms suggest liver
0-A). (No recommendation, low certainty of transplantation only for unresectable disease9, and
evidence) selection of recipients is done chiefly according to the
Milan Criteria.1
Liver transplantation (LT) is a procedure for tumors that
are cannot be surgically resected because of severe liver In Korea, where the modified Union for International
dysfunction.1 Radiofrequency ablation (RFA) is the local Cancer Control (mUICC) Staging System is used, liver
application of radiofrequency thermal energy to the transplantation is the first treatment choice for patients
lesion, while microwave ablation (MWA) involves an with single tumor <5 cm or those with small multinodular
implanted electrode delivering a high-frequency tumors (≤3 nodules ≤3 cm) and advanced liver
microwave into the tumor tissue. These ablative dysfunction, who are not candidates for resection.10
procedures are usually done for patients with liver-only
In the 2018 EASL guidelines, radiofrequency is the
disease but do not meet resectability criteria for HCC. In
standard care for patients with BCLC 0 - A tumors not
practice, it is done in Child-Pugh A or B patients with a
suitable for surgery (strong recommendation, high-quality
single tumor <4 cm in diameter.1
evidence).11 It is considered first-line treatment for tumors
Evidence to Decision ≤2 cm because of at least equal cost-effectiveness and
minimal adverse effects on liver function compared to a
Benefits and Harms
surgical procedure such as LR. Radiofrequency ablation is
One cohort study2 (n = 1894) directly showed that first-line strongly recommended as first-line therapy among
LT is associated with an increase in overall survival patients with very early-stage HCC (BCLC 0) as long as
compared with ablation (HR 4.19, 95% CI 2.2 - 8.01) tumors are located in favorable locations (deep/central
among newly diagnosed adult patients with location) (moderate-quality evidence).11
hepatocellular carcinoma BCLC 0toA.
Consensus Issues
There is no study that directly compares adverse events
Ablation was preferred because (1) evidence favoring LT
between LT and ablation. Adverse events from RCTs
from one retrospective cohort study and indirect
comparing ablation and liver resection (LR), a more
evidence on safety (i.e. study on liver resection versus
limited surgical procedure than LT, are presented. One
ablation) are inadequate; (2) the complications of LT are
RCT3 (n = 120) reported that the number of patients with
of concern, not only from the surgery but also from
serious adverse events is higher in LR than ablation (OR
prolonged immunosuppression; and (3) the cost of LT is
17.96, 95% CI 2.28 to 141.60). Two other RCTs4,5 (n = 391)
much higher and donors are scarce.
reported that the number of serious adverse events is also
higher in LR (RR 7.02, 95% CI 2.29 - 21.46; I2 = 0%). Both procedures are expensive and there is concern
about equity. Those in the high-income group can avail
themselves of these interventions more easily. The equity
The overall certainty of the evidence is low because of the gap can be narrowed if the government would provide
risk of bias and indirectness. There was a high risk of bias comprehensive reimbursement coverage for those who
due to issues on random allocation and blinding that may cannot afford LT or ablation.
affect outcome measurements. There was serious
indirectness as the studies compared liver resection, not
transplantation, to ablation. P patients with early-stage hepatocellular carcinoma
(BCLC 0-A)
I liver transplantation
Cost
C Ablation
The PhilHealth case rate for liver transplantation is PHP
55,000.6 In private hospitals in Metro Manila, the cost for O mortality, adverse events, serious adverse events
liver transplantation is estimated to range from PHP 6
million - 9 million.7 On the other hand, the Philhealth case
Table 10. Summary of findings: liver transplantation vs. ablation for early-stage hepatocellular carcinoma
Effect Certainty of
Estimate Evidence
Serious adverse events Critical 1 RCT OR 17.96 2.28 - 141.60 Net harm with LR Low
181 Volume 59 No. 3

(n =120)
2 RCTs
Serious adverse events Critical RR 7.02 2.29 - 21.46 Net harm with LR Low
(n = 391)
Death 1 observational study
Critical HR 4.191 2.192 - 8.013 Net benefit with LT Low
(Tumors 31-50 mm) (n = 709)
(Tumors 31-35mm) (n = 236)
(Tumors 21-30 mm) (n = 637)
(Tumors ≤ 20mm) (n = 548)
References HCC conforming to the Milan criteria. Ann Surg 2010; 252:903-
12.
1. Overview of treatment approaches for hepatocellular carcinoma. 6. Annex 2: List of Procedure Case Rates (Revision1). at
2021. (Accessed 18 Mar 2021, at http://www.uptodate.com.) https://www.philhealth.gov.ph/.)
2. Kutlu O, Chan J, Aloia T, Chun Y, Kaseb A, Passot G. 7. Living Donor Liver Transplantation in the Philippines. 2021. at
Comparative effectiveness of first-line radiofrequency ablation https://www.stlukes.com.ph/health-library/healtharticles/living-
versus surgical resection and transplantation for patients with donor-liver-transplantation-in-the-philippines.)
early hepatocellular carcinoma. Cancer 2017; 123:1817-27. 8. Radiofrequency Ablation MDsave, 2021. at
3. Fang Y, Chen W, Liang X, Li D, Lou H, Chen R. Comparison of https://www.mdsave.com/procedures/radiofrequencyablation/d
long-term effectiveness and complications of radiofrequency 482f9cb.)
ablation with hepatectomy for small hepatocellular carcinoma. J 9. Galle P, Forner A, Llovet J, Mazzaferro V, Piscaglia F, Raoul J.
Gastroenterol Hepatol 2013; 29:193-200. EASL Clinical Practice Guidelines: Management of hepa-cellular
4. Chen M, Li J, Zheng Y, Guo R, Liang H, Zhang Y. A prospective carcinoma. Journal of Hepa-logy 2018; 69:182-236.
randomized trial comparing percutaneous local ablative therapy 10. KLCA. National Cancer Center Korea practice guidelines for the
and partial hepatectomy for small hepatocellular carcinoma. management of hepatocellular carcinoma. Korean Journal of
Annals of Surgery 2006; 243:321-8. Radiology 2019; 20:1042.
5. Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J. A randomized 11. EASL. EASL Clinical practice guidelines: management of
trial comparing radiofrequency ablation and surgical resection for hepatocellular carcinoma. J Hepatol 2018; 69:182-236.
LIVER RESECTION vs. ABLATION for early-stage carcinoma (BCLC 0-A). The overall survival (OS) did not
hepatocellular carcinoma (BCLC 0A) differ between the two treatments. For solitary tumors
≤ 3cm, LR had significantly better OS at 5 years than
Recommendation
RFA. The disease-free survival (DFS) was higher with LR.
6. We suggest liver resection over ablation, primarily
Post-procedure adverse events were significantly
radiofrequency ablation, for patients with
higher in LR. Ablation causes fewer complications
hepatocellular carcinoma BCLC 0-A and
(including death, infections, pneumonia, blood loss,
compensated liver function (conditional
liver failure, and pain), has shorter hospital stays, and
recommendation, very low certainty of evidence).
smaller costs. Early recurrence and intrahepatic
Liver resection (LR) is a surgical modality that removes recurrence were more common in ablation.
cancerous tissue but maintains preserved functional
liver volume for early-stage HCC.1 LR can create tumor-
free margins under direct vision and resect satellite The overall certainty of the evidence is very low due to
nodules not identified on preoperative imaging.2 These the very serious risk of bias and imprecision. The biases
are notable advantages of LR over ablation. identified are selection bias and reporting bias.
Thermal ablation is an imaging-guided procedure Other Considerations
wherein heat is generated to destroy tumor cells. It is an
Cost
alternative treatment option to LR and transplantation
for tumors BCLC 0-A.1 It can minimize iatrogenic injury RFA is more cost-effective for very early HCC and in the
to surrounding parenchyma, especially in a cirrhotic presence of two to three tumors measuring ≤3 cm.
liver. Resection offers better survival outcomes at an
acceptable cost for solitary early-stage tumors >3 cm.11
Evidence to Decision
LR and ablation are procedures available in highly
Benefits and Harms
specialized centers in the Philippines. The cost of LR or
Eight randomized controlled trials3-10 compared liver ablation ranges from PHP 150,000.00 - 300,000.00.
resection (LR) versus ablation (radiofrequency or RFA, Laparoscopic LR and MWA entail higher costs compared
microwave, or MWA) for early-stage hepatocellular to RFA.
Vol 59 No 3 182
The Philhealth case rates updated in 2014 for these are as longer in LR, can significantly add to the cost. Those
follows: laparoscopic RFA, PHP 18,000; open and favoring LR gave the following reasons: (1) LR is feasible
percutaneous RFA, PHP 9,700; CT-guidance, additional in more hospitals (2) Ablation is more costly and fewer
PHP 8,020; and liver resection, PHP 53,000 to PHP 55,000. centers have the necessary equipment. (3) The studies
that were reviewed had a wide range of ablation
techniques and those may not be appropriate for the
The 2018 EASL1 recommends both LR and RFA for early overall population of patients with HCC.
and very early HCC. Resection is recommended for HCC
The panel raised the importance of proper patient
tumors on a non-cirrhotic liver (strong recommendation,
selection, a thorough evaluation of available resources
low-quality evidence) and solitary HCC of any size,
(i.e., patient’s finances, institution’s resources, clinician’s
especially for >2 cm with preserved hepatic function
expertise), and discussion of patient’s values and
(strong recommendation, moderate-quality evidence).1
expectations before proceeding with any of these
Radiofrequency is the standard care for patients with treatment procedures. Shared decision-making was
BCLC 0 - A tumors not suitable for surgery (strong raised as a practice that must be highly encouraged.
recommendation, high-quality evidence).1 It is the first-
The important role of the government in making the
line treatment for tumors ≤ 2 cm because of at least equal
services available nationwide and help decrease the
cost-effectiveness and minimal adverse effects on liver
equity gap in access to these expensive life-saving
function compared to LR. Patients with very early-stage
procedures were highlighted.
HCC (BCLC 0) can use RFA as first-line therapy as long as
tumors are located in favorable locations (deep/central GRADE Evidence Profile
location) (strong recommendation, moderate-quality
P patients with early-stage hepatocellular carcinoma
evidence).1
(BCLC 0-A)
The 2018 KLCA-NCC12 recommends LR as first-line
I liver resection
treatment for patients with solitary HCC (<3 cm) and well-
preserved liver function with Child-Pugh A, and no portal C Ablation
hypertension, hyperbilirubinemia (A1).
O progression-free and overall survival, morbidity, and
Consensus Issues mortality
Those favoring ablation did so because the overall cost
may be lower since the duration of hospital stay, which is
Table 11. Summary of findings: liver resection vs. ablation for early-stage hepatocellular carcinoma
Effect Certainty of
Estimate Evidence
3 RCTs RR 1.10
5-yr OS Critical 0.88 - 1.38 Inconclusive Very Low
(n =511)
3 RCTs RR 1.46 Net benefit with
5-yr DFS Critical 1.13 - 1.90 Moderate
(n = 511) LR
7 RCTs Net benefit with
Overall recurrence Critical RR 0.81 0.73 - 0.91 Low
(n = 994) LR
Treatment-related 7 RCTs Net harm with
Critical RR 2.97 1.79 - 4.94 Very Low
complications (n = 994) LR
2 RCTs
Liver failure Critical RR 1.60 -12.90 - -0.75 Inconclusive Very Low
(n=440)
1 RCT Net benefit with
Physical performance Critical RR 0.47 0.20 - 0.30 Low
(n=48) ablation
Early recurrence 3 RCTs Net benefit with
Critical RR 0.75 0.60 - 0.93 Moderate
≤3 years (n = 616) LR
10-yr DFS Critical RR 1.67 1.04 - 2.67 Moderate
(n=218) LR
1 RCT
10-yr OS Critical RR 1.13 - 1.52 Inconclusive Moderate
(n=218)
5 RCTs
In-hospital mortality Critical RR 3.31 -32.41 Inconclusive Very Low
(n=799)
6 RCTs
1-yr DFS Critical RR 1.01 -1.06 Inconclusive Low
(n=931)
7 RCTs
3-yr DFS Critical RR 1.16 0.92 - 1.48 Inconclusive Very Low
(n=994)
183 Volume 59 No. 3

2 RCTs
3-yr OS Critical RR 1.15 0.98 - 1.35 Inconclusive Moderate
(n=157)
3 RCTs Net harm with
Overall infection Critical RR 5.08 1.87 - 13.82 Very Low
(n=600) LR
6 RCTs
Extrahepatic recurrence Critical RR 1.10 -1.97 - -1.32 Inconclusive Very Low
(n=918)
5 RCTs
2-yr DFS Critical RR 1.03 0.62 - 0.80 Inconclusive Very Low
(n=713)
Physical performance 1 RCT Net benefit with
D7 (n=105) ablation
6 RCTs
1-yr OS Critical RR 1.00 0.95 - 1.06 No effect Very Low
(n = 904)
4-yr OS Critical RR 1.25 1.07 - 1.46 Moderate
(n=230) LR
Blood loss Critical RR 3.61 1.27 - 10.25 Very Low
(n=931) LR
Local intrahepatic 6 RCTs Net benefit with
recurrence (n=888) LR
4-yr DFS Critical RR 1.62 1.19 - 2.19 Very Low
(n=230) LR
Distant intrahepatic 6 RCTs Net benefit with
recurrence (n=888) LR
6 RCTs
2-yr OS Important RR 1.04 0.92 - 1.14 Inconclusive Very Low
(n=713)
Pain Important RR 31.61 16.86- 59.29 Low
(n=350) LR
Pneumonia Important RR 6.32 1.14 - 34.96 Low
(n=368) LR
References 7. Feng K, Yan J, Li X, Xia F, Ma K, Wang S. A randomized trial

comparing radiofrequency ablation and surgical resection for
1. EASL. EASL Clinical practice guidelines: management of HCC conforming to the Milan criteria. J Hepatol 2012; 57:794-
hepatocellular carcinoma. J Hepatol 2018; 69:182-236. 802.
2. Hsiao C, Hu R, Ho C, Wu Y, Lee P, Ho M. Surgical resection 8. Fang Y, Chen W, Liang X, Li D, Lou H, Chen R. Comparison of
versus radiofrequency ablation for Barcelona Clinic Liver Cancer long-term effectiveness and complications of radiofrequency
very early-stage hepatocellular carcinoma: long-term results of a ablation with hepatectomy for small hepatocellular carcinoma. J
single-center study. Am J Surg 2020; 220:958-64. Gastroenterol Hepatol 2013; 29:193-200.
3. Fang L, Meng X, Luo W, Zhou X. Treatment of primary hepatic 9. Ng K, Chok K, Chan A, Cheung T, Wong T, Fung J. Randomized
carcinoma through ultrasound guided microwave ablation. Niger clinical trial of hepatic resection versus radiofrequency ablation
J Clin Pract 2019; 22:1408-11. for early-stage hepatocellular carcinoma. Br J Surg 2017;
4. Xu J, Zhao Y. Comparison of percutaneous microwave ablation 104:1775-84.
and laparoscopic resection in the prognosis of liver cancer. Int J 10. Lee H, Lee J, Yoon J, Kim Y, Park J, Park S. A prospective
Clin Exp Pathol 2015; 8:11665-9. randomized study comparing radiofrequency ablation and
5. Lü M, Kuang M, Liang L, Xie X, Peng B, Liu G. Surgical resection hepatic resection for hepatocellular carcinoma. Ann Surg Treat
versus percutaneous thermal ablation for earlystage Res 2018; 94:74-82.
hepatocellular carcinoma: a randomized clinical trial. Zhonghua 11. Cucchetti A, Piscaglia F, Cescon F, et al. Cost-effectiveness of
Yi Xue Za Zhi 2006; 86:801-5. hepatic resection versus percutaneous radiofrequency ablation
6. Huang J, Yan L, Cheng Z, Wu H, Du L, Wang J. A randomized for early hepatocellular carcinoma. J Hepa-l 2013.
trial comparing radiofrequency ablation and surgical resection for 12. KLCA, NCC. 2018 Guidelines for the Management of
HCC conforming to the Milan criteria. Ann Surg 2010; 252:903- Hepatocellular Carcinoma. Gut and Liver 2018; 13:227-99.
12.
TRANSARTERIAL CHEMOEMBOLIZATION vs. Most patients with HCC are diagnosed at the
SELECTIVE INTERNAL RADIATION THERAPY for intermediate and advanced tumor stages with poor
intermediate stage hepatocellular carcinoma liver function, and less than 20% are eligible for
surgery.1 Conventional transarterial
Recommendation
chemoembolization (TACE) or drug-eluting beads
7. We recommend transarterial chemoembolization over (DEB-TACE) and selective internal radiation therapy
selective internal radiation therapy in intermediate (SIRT, also called transarterial radioembolization or
stage (BCLC B) hepatocellular carcinoma. (strong TARE) are alternative treatment strategies for
recommendation, very low certainty of evidence) unresectable hepatocellular carcinoma. The main
Vol 59 No 3 184
advantages of radioembolization are the reduced can increase to PHP 350,000 and DEBTACE to PHP
number of treatments needed and the small size of the 500,000, but this can greatly vary based on the specific
embolization particles with resultant preserved patency needs of the patient and the rates of different
of the tumor feeding arteries. Since this maintains direct institutions. However, final costing would greatly
access to the tumor vessels, another local treatment, depend on the number of sessions needed by the
e.g., TACE, could still be performed as a second line patient, which depends on the size of the tumor.
treatment in case of SIRT failure.3
Evidence to Decision
2018 EASL: For BCLC B, TACE should be carried out
Benefits and Harms selectively (e.g., patients with unito or paucinodular
disease without vascular invasion or metastases, no
We found three randomized control trials (PREMIERE2,
symptoms, and Child-Pugh stage of ≤ B7. (Evidence
the Mainz trial3, and SIRTACE4) comparing the use of
high; recommendation strong).7
SIRT - either conventional transarterial
chemoembolization (cTACE) or DEB-TACE in treating KLCA 2018: TACE for HCC patients with a good
hepatocellular carcinoma (HCC) belonging to different performance status without major vascular invasion or
BCLC stages. extrahepatic spread who are ineligible for surgical
resection, liver transplantation, RFA, or PEIT (A1). TARE
There was no significant difference in the overall
is an alternative treatment to TACE when patients have
survival and one-year progression-free survival
preserved liver function and reduction of post-
between SIRT and TACE. There was also no significant
embolization syndrome is required (B2).8
difference in the occurrence of adverse events between
SIRT and cTACE. Adverse events include vascular Brazilian Society of Hepatology: TACE as the treatment
complications, clinical and laboratory parameters. of choice for intermediate HCC (BCLC B) (high level of
evidence; strong recommendation).9
Consensus Issues
The overall certainty of evidence is very low because of
(1) serious risk of bias due to lack of blinding and The panel concurred that TACE is the standard of care
selective reporting (2) indirectness because the for intermediate stage HCC, and evidence did not show
population was a mixed group with various BCLC the superiority of SIRT over TACE, in terms of efficacy
stages (3) inconsistency, and imprecision. and safety. It was also important that TACE is much less
costly than SIRT and is found in more medical centers.
The panelists recognized though that TACE can still be
Cost too expensive for the disadvantaged.
Based on a cost comparison study5 in UK, TACE costs GRADE Evidence Profile
slightly lower than that of Y-90 glass microspheres SIRT.
P patients with intermediate stage hepatocellular
In 2011, the cost of SIRT in the Philippines was carcinoma (BCLC B)
estimated to be at PHP 500,000 to 1,000,000.6 In a
I transarterial chemoembolization
personal communication with an expert in the field
(April 2021), the current estimated procedure cost for C selective internal radiation therapy
conventional TACE is PHP 150,000 to 170,000, DEB-
O overall survival, progression-free survival, adverse
TACE is PHP 200,000/session and SIRT PHP 1,000,000
events
to 1,200,000. Other costs such as hospital and
laboratory fees can increase the estimated cost of TACE
Table 12. Summary of findings: TACE vs. SIRT for intermediate stage (BCLC B) hepatocellular carcinoma
Effect Certainty of
Estimate Evidence
1-yr Overall Survival Critical 3 RCTs (n = 97) RR 0.83 0.49 - 1.41 Inconclusive Very Low
1-yr PFS Critical 3 RCTs (n = 97) RR 2.75 0.43 - 17.73 Inconclusive Very Low
Adverse Events Critical 3 RCTs (n = 73) RR 0.74 0.51 - 1.07 Inconclusive Very Low
References 2. Salem R, Gordon A, Mouli S, Hickey R, Kallini J, Gabr A.

Radioembolization significantly prolongs time to progression
1. Ni J. Conventional transarterial chemoembolization vs compared with chemoembolization in patients with hepatocellular
microsphere embolization in hepato-cellular carcinoma: A meta- carcinoma. Gastroenterology 2016; 151:1155-63. e2.
analysis. World Journal of Gastroenterology 2014; 20:17206.
185 Volume 59 No. 3

3. Pitton M, Kloeckner R, Ruckes C, Wirth G, Eichhom W, Worns M. 6. Samaniego T. Many liver cancer patients survive using SIR-
Randomized comparison of selective internal radiotherapy (SIRT) Spheres microspheres. Philippine Daily Inquirer 2011.
versus drug-eluting bead transarterial chemoembolization (DEB- 7. EASL. EASL Clinical practice guidelines: management of
TACE) for the treatment of hepatocellular carcinoma. hepatocellular carcinoma. J Hepatol 2018; 69:182-236.
CardioVascular and Interventional Radiology 2014; 38:352-60. 8. KLCA, NCC. 2018 Korean Liver Cancer Association-National
4. Kolligs F, Bilbao J, Jakobs T, Iñarrairaegui M, Nagel J, Rodriguez Cancer Center Korea Practice Guidelines for the Management of
M. Pilot randomized trial of selective internal radiation therapy vs. Hepatocellular Carcinoma. Gut Liver 2019; 13:227-99.
chemoembolization in unresectable hepatocellular carcinoma. 9. Chagas A, Mattos A, Carrilho F, Bittencourt P, et. a. Brazilian
Liver International 2015; 35:1715-21. Society of Hepatology Updated recommendations for diagnosis
5. Muszbek N, Evans R, Remak E, Brennan V, Colaone F, Sherill S. and treatment of hepatocellular carcinoma. Arq Gastroenterol
Cost-comparison analysis of selective in internal radiation 2020;57.
therapy (SIRT) and transarterial chemoembolization (TACE) in
unresectable hepatocellular carcinoma (HCC). Value in Health
2019;22: S455.
SELECTIVE INTERNAL RADIATION THERAPY vs. Certainty of Evidence

EXTERNAL BEAM RADIOTHERAPY for intermediate
The overall certainty of evidence is very low due to (1)
serious risk of bias (selection and detection bias) (2)
Recommendation indirectness due to difference in the population in the
studies (AJCC 7th edition stages I - III) but the desired
8. There is insufficient evidence to recommend treatment
population is BCLC B (equivalent to AJCC Stage IIIA) and
with either selective internal radiation therapy or
no direct comparison in morbidity, and (3) imprecision.
external beam radiation therapy for hepatocellular
carcinoma patients in the intermediate stage (BCLC Other Considerations
B). (no recommendation, very low certainty
Cost
evidence)
There is no published cost-effectiveness study on SIRT and
Radiotherapy can offer local control of unresectable HCC,
EBRT. The estimated cost of procedures in one private
including cases with major vascular involvement, and can
tertiary hospital in Manila was obtained: SIRT (one-time
provide a modality to help bridge patients to potentially
treatment, two admissions) costs PHP 1.3 to 1.5 million;
curative resection or transplantation.1 Radiation may be
SBRT costs PHP 300,000 to 500,000; and intensity
from an internal or an external source.1 Trans-arterial
modulated radiotherapy (IMRT, a form of EBRT) ranges
radioembolization (TARE) or selective internal radiation
from PHP 250,000 to 300,000.
therapy (SIRT) involves injection of microspheres with β-
emitting radioisotope, commonly 90Yttrium. It is usually Recommendation from Other Groups
done as a single therapy or sometimes in two-staged
treatments, especially in bilobar HCC. Stereotactic body 2021 ESMO: TACE is the standard of care for BCLC B, with
radiotherapy (SBRT) is a form of external beam radiation transplantation, resection, systemic therapy, and SIRT as
therapy (EBRT) that can accurately deliver high dose alternative treatments.5,6
radiation in small fractions and in a shorter period of time Consensus Issues
- HCC with acceptable damage to the surrounding normal
liver.2 The following concerns were highlighted:
Evidence to Decision 1. The need for more studies, especially on specific forms of
beam radiation, since different modes of therapy can be
Benefits and Harms categorized into one form of beam radiation but the
There is no randomized controlled trial that directly techniques are different.
answers the research question. However, two 2. Performing radiation in large and multifocal lesions can be
retrospective cohort studies taken from large nationwide challenging.
databases directly compared SIRT (selective internal 3. The importance of proper patient selection for positive
beam radiation) and EBRT (external beam radiation outcomes
therapy).3,4 There was no significant difference between 4. Both procedures are costly and available in limited
the two treatments in terms of overall survival. However, centers.
EBRT/SBRT showed a longer mean overall survival by 3.8 GRADE Evidence Profile
months.
P patients with intermediate stage hepatocellular
Specific adverse events, radiation-related complications, carcinoma (BCLC B)
or morbidities were reported in singlearm studies,
including fatigue (28% in EBRT vs. 43% in SIRT), I selective internal beam radiation
lymphopenia (61%), gastritis (11.4%), abdominal pain C external beam radiation therapy
(17.5%), thrombocytopenia (15.4%).
O progression-free and overall survival, morbidity
and mortality
Vol 59 No 3 186
Table 13. Summary of findings: SIRT vs. EBRT for intermediate stage (BCLC B) hepatocellular carcinoma
Effect Certainty of
Estimate Evidence
2 observational
Overall survival Critical studies HR 1.111 0.81 to1.51 Inconclusive Very Low
(n = 2,874)
2 observational
Net benefit with
Overall survival in months Critical studies MD 4.74 months 1.73 - 7.75 Low
SIRT
(n = 2,874)
1 observational
Disease-specific survival Critical study HR 0.70 0.46 - 1.01 Inconclusive Low
(n = 189)
1 observational
Disease-specific survival in
Critical study MD 0 month 11 – 21 SIRT = EBRT Low
months
(n = 189)
References a comparison of treatment outcomes for hepatocellular

carcinoma. J Gastrointest Oncol 2016; 7:433-40.
1. Chen C. Role of radiotherapy in the treatment of hepatocellular 5. Rim C, Kim C, Yang D, Yoo W. Comparison o radiation therapy
carcinoma. J Clin Transl Hepatol 2019; 7:183-90. modalities or hepatocellular carcinoma with portal vein
2. External beam radiation therapy. n.d. (Accessed April 1, 2021, at thrombosis: a meta-analysis and systematic review. Radiother
https://www.cancercenter.com/treatmentoptions/radiationtother Oncol 2017; 129:112-22.
apy/external-beam-radiation.) 6. eUpdate – Hepatocellular Carcinoma Treatment
3. Bitterman D, Sanford N, Niemierko A, et al. Patterns of care and Recommendations. European Society for Medical Oncology,
outcomes of definitive external beam radiotherapy and 2021. (Accessed 1 April 2021, at
radioembolization for localized hepatocellular carcinoma: a https://www.esmo.org/guidelines/gastrointestinal-
propensity score-adjusted analysis. Am J Clin Oncol 2019; cancers/hepatocellularcarcinoma/eupdate-hepatocellular-
42:564-72. carcinoma-treatment-recommendations.)
4. Oladeru O, Miccio J, Yang J, Xue Y, Ryu S, Stessin A. Conformal
external beam radiation or selective internal radiation therapy to
TRANSARTERIAL CHEMOEMBOLIZATION alone or Evidence to Decision

combined with TARGETED THERAPY for intermediate
Benefits and Harms
Based on three RCTs, there were no significant differences
Recommendation
between response rate, progression free survival (PFS),
9. There is insufficient evidence to recommend the overall survival (OS), and time to progression (TTP) for
addition of targeted therapy to transarterial TACE compared with TACE and sorafenib in intermediate
chemoembolization in BCLC B hepatocellular stage hepatocellular carcinoma (HCC).3-5 Measures of
carcinoma. (no recommendation, low certainty of patient-reported quality of life (QOL) were worse and
evidence) adverse events, including treatment-related deaths
(TRDs) were more common for the targeted therapy
Transarterial chemoembolization (TACE) is considered
group.
standard treatment for intermediate stage HCC. This
transcatheter procedure combines the embolization of Certainty of Evidence
the tumor-feeding arterial vessels and the infusion of
The overall certainty of evidence is low due to serious risk
chemotherapeutic agents (e.g., doxorubicin) to achieve
of bias, inconsistency, and imprecision. The serious risk
both ischemic and cytotoxic effects.1 Targeted therapy
of bias was due to attrition3-5, unclear randomization3,5,
(e.g., sorafenib) modulate specific genes or proteins
unclear allocation and pharmaceutical funding.1
which affect cell cancer proliferation and are usually
reserved for the advanced stage of the disease. It is Other Considerations
hypothesized that the combination of targeted therapy
and TACE can improve intermediate stage HCC cases that Cost
do not respond to TACE alone.2 One cost-effectiveness analysis compared TACE
monotherapy and TACE-sorafenib combination therapy
in unresectable (intermediate-advanced stage) HCC. In
China, TACE costing $26,951 yields 0.71 quality-adjusted
life-years (QALYs), while TACE-sorafenib costing $44,542
187 Volume 59 No. 3

yields 1.02 QALYs. The incremental cost-effectiveness panel preferred to make no recommendation for now
ratio of the combination vs. TACE was $56,745 per QALY because of awaited results of ongoing trials on newer
gained and it can be inferred that TACE monotherapy is targeted therapy drugs (other than sorafenib) that may
more cost-effective.6 show less toxicities. Patients with residual illness or lesions
that are not or poorly treated with TACE and are still
In the Philippines, one session of TACE is approximately
classified intermediate stage, according to some experts,
PHP 70,000 to PHP 200,000 while the drug cost for a 21-
may benefit from targeted treatment.
day treatment with sorafenib (400mg tablet 2x a day) is
PHP 208,600.7 GRADE Evidence Profile
Recommendations from Other Groups P patients with intermediate stage hepatocellular
carcinoma (BCLC B)
Currently, there is no recommendation regarding the
simultaneous use of targeted therapy and TACE.2 I targeted therapy (e.g. sorafenib, Lenvatinib) plus
Hepatology and oncology associations, including the TACE
EASL, recommend TACE recommended for intermediate
C TACE alone
stage HCC while targeted therapy is for advanced stage
HCC.8-11 O response rate, progression-free and overall survival.
preservation of liver function, and quality of life
Consensus Issues
TACE was preferred because of higher net benefits and
lower costs compared to the combination therapy The
Table 14. Summary of findings: SIRT vs. EBRT for intermediate stage (BCLC B) hepatocellular carcinoma
Effect Certainty of
Estimate Evidence
2 RCTs
Overall survival Critical HR 0.91 0.71 - 1.15 Inconclusive Low
(n = 620)
1 RCT
Progression-Free Survival Critical HR 0.99 0.77 - 1.27 Inconclusive Low
(n = 313)
3 RCTs
Time-to-Progression Critical HR 0.67 0.44 - 1.03 Inconclusive Low
(n = 700)
2 RCTs
Overall Response Critical RR 1.11 0.91 - 1.34 Inconclusive Very Low
(n = 620)
2 RCTs
Complete Response Critical RR 1.22 0.89 - 1.68 Inconclusive Very Low
(n = 620)
2 RCTs
Partial Response Critical RR 1.05 0.68 - 1.61 Inconclusive Very Low
(n = 620)
Adverse Events Critical RR 1.37 1.07 - 1.75 Moderate
(n = 617) targeted therapy
Bleeding Critical RR 1.68 1.12 - 2.52 Moderate
(n = 697) targeted therapy
2 RCTs
Treatment-Related Deaths Critical RR 3.45 0.72 - 16.50 Inconclusive Low
(n = 617)
References randomized placebo-controlled, double-blind, phase 3 trial. The

Lancet Gastroenterology & Hepatology 2017; 2:565-75.
1. Lee M, Ryoo B, Hsu C, et al. Atezolizumab with or without 5. Sansonno D, Lauletta G, Russi S, Conteduca V, Sansonno L,
bevacizumab in unresectable hepatocellular carcinoma Dammacco F. Transarterial chemoembolization plus sorafenib: a
(GO30140): an open-label, multicentre, phase 1b study. The sequential therapeutic scheme for HCV-related intermediate-
Lancet Oncology 2020; 21:808-20. stage hepatocellular carcinoma: a randomized clinical trial. The
2. Kudo M. A new treatment option for intermediate-stage Oncologist 2012; 17:359-66.
hepatocellular carcinoma with high tumor burden: initial 6. Zhao R, Zhou J, Wei Y, Liu F, Chen K, Li Q. Cost-effectiveness
lenvatinib therapy with subsequent selective TACE. Liver Cancer analysis of transcatheter arterial chemoembolization with or
2019; 8:299-311. without sorafenib for the treatment of unresectable hepatocellular
3. Lencioni R, Llovet J, Han G, Tak W, Yang J, Guglielmi A. carcinoma. Hepatobiliary & Pancreatic Diseases International
Sorafenib or placebo plus TACE with doxorubicin-eluting beads 2017;16:493-8.
for intermediate stage HCC: The SPACE trial. Journal of 7. Sorafenat 200mg Tablet Price, Dosage, Side-Effects and Generic
Hepatology 2016; 64:1090-8. Alternatives.2020. at https://www.sastimedicine.com/medicine-
4. Meyer T, Fox R, Ma Y, Ross P, James M, Sturgess R. Sorafenib price/12207-2202647/Sorafenat-200mg-Tab-30s-Price-
in combination with transarterial chemoembolisation in patients Dosage-SideEffects-and-Generic-Alternatives.)
with unresectable hepatocellular carcinoma (TACE 2): a
Vol 59 No 3 188
8. Chagas A, Mattos A, Carrilho F, Bittencourt P, et. a. Brazilian 10. Vogel A, Cervantes A, Chau I, et al. ESMO Clinical Practice
Society of Hepatology Updated recommendations for diagnosis Guidelines for diagnosis, treatment and follow-up. Ann Oncol
and treatment of hepatocellular carcinoma. Arq Gastroenterol 2018;29: iv238-iv55.
2020;57. 11. KLCA, NCC. 2018 Korean Liver Cancer Association-National
9. EASL-EORTC. Clinical Practice Guidelines: Management of Cancer Center Korea Practice Guidelines for the Management of
hepatocellular carcinoma. European Journal of Cancer 2012; Hepatocellular Carcinoma. Gut Liver 2019; 13:227-99.
48:599-641.
SORAFENIB vs. COMBINATION of Other Considerations

IMMUNUNOTHERAPY and BEVACIZUMAB for
Cost
advanced stage hepatocellular carcinoma
Economic evaluation from the US and China showed that
Recommendation
combination therapy had incremental benefits over
10. We suggest the use of combination therapy sorafenib but it was not a cost-effective option.14-16
(atezolizumab plus bevacizumab) over sorafenib as first-
Based on informal surveys in the country, the drug cost for
line treatment for advanced stage hepatocellular
a 21-day treatment with sorafenib (400mg tablet 2x a day)
carcinoma in selected patients. (Conditional
is PHP 208,600.00. Combination therapy with
recommendation, low certainty of evidence)
atezolizumab 1200mg and bevacizumab 15mg/kg for a
The standard of care for advanced hepatocellular 60kg patient) is PHP 366,815.56. This is reduced to PHP
carcinoma is sorafenib.1-4 Sorafenib is an oral multikinase 139,063.12 upon availing of the manufacturer’s access
inhibitor of the Raf serine-threonine kinases and receptor program. Additional costs for pre-medications,
tyrosine kinases implicated in tumorigenesis, tumor administration fees, and other expenses incurred in giving
progression, and angiogenesis.1-7 intravenous medications are applicable.
Immunotherapy (e.g., atezolizumab, pembrolizumab, Recommendations from Other Groups
nivolumab, ipilimumab) with bevacizumab, on the other
The international guidelines (ASCO5, ESMO17, NCCN18)
hand, is a novel systemic treatment for advanced HCC.
state that the combination therapy may be offered as a
Bevacizumab is a humanized monoclonal IgG1 antibody
first-line treatment among patients with advanced HCC.
that inhibits VEGF binding to cell surface receptors, and
The NCCN particularly recommend the combination
reducing microvascular growth of tumor blood vessels.1,5-
therapy for advanced or metastatic and/or unresectable
12
Atezolizumab reduces immunosuppressive signals
HCC while sorafenib was in the other recommended
found within the tumor microenvironment thereby
regimens (Category 1).
increasing T-cell mediated immunity against the tumor by
blocking the PD-L1/PD-1 immune checkpoint.1,5-12 Both Consensus Issues
bevacizumab and atezolizumab are given intravenously.
Combination immunotherapy was favored because of the
Evidence to Decision following reasons: (1) net benefit (2) acceptability (3)
subsidy from health insurance is possible making it
Benefits and Harms
affordable. However, cost remains a barrier to
One randomized controlled trial6,13 shows better implementation. Moreover, selection of patients who will
progression-free and overall survival outcomes and a benefit most from combined treatment (similar to those
delay in deterioration of the patient-reported quality of enrolled in the RCT) remains crucial.
life in combination therapy compared to sorafenib in
patients with advanced stage hepatocellular cancer
(HCC). However, a greater predilection for bleeding P locally advanced, metastatic, and/or unresectable
complications is associated with bevacizumab, thus HCC without prior systemic therapy
caution should be exercised when using it among patients
with advanced liver disease and portal hypertension. I combination therapy atezolizumab plus
bevacizumab (CT)
C sorafenib (S)
The overall certainty of evidence is low due to imprecision
and serious risk of bias due to lack of blinding. O overall survival, progression-free survival, quality of
life, adverse events
189 Volume 59 No. 3

Table 15. Summary of findings: combination therapy (atezolizumab plus bevacizumab) vs. sorafenib for advanced
HCC
Effect Certainty of
Estimate Evidence
1 RCT
Overall Survival Critical HR 0.58 0.42 - 0.79 Net benefit with CT Moderate
(n = 501)
1 RCT
Progression-Free Survival Critical HR 0.59 0.47- 0.76 Net benefit with CT Moderate
(n = 501)
Quality of life
Critical 1 RCT HR 0.63 0.46 - 0.85 Net Benefit with CT Moderate
(Median time - deterioration)
1 RCT
Serious adverse events Critical RR 1.23 0.94 - 1.62 Inconclusive Low
(n = 485)
Discontinuation due - adverse 1 RCT
Critical RR 1.51 0.89 – 2.56 Inconclusive Low
events (n = 485
CT- combination therapy, S-sorafenib, RCT-randomized controlled trial, HR- hazard ratio, RR-relative risk
References 10. Boige V, Malka D, Bourredjem A, et al. Efficacy, safety, and

biomarkers of single-agent bevacizumab therapy in patients
1. Vogel A, Cervantes A, Chau I, Daniele B, Llovet J, Meyer T. with advanced hepatocellular carcinoma. The Oncologist
Hepatocellular carcinoma: ESMO Clinical practice guidelines 2012; 17:1063-72.
for diagnosis treatment and follow-up. Ann Oncol 11. Fang P, Hu J, Cheng Z, Liu Z, Wang J, Jiao S. Efficacy and
2018;29:IV238-55. safety of bevacizumab for the treatment of advanced
2. Llovet J, Ricci S, Mazzaferr V, et al. Sorafenib in advanced hepatocellular carcinoma: a systematic review of Phase II trials.
hepatocellular carcinoma. The New England Journal of PLoS One 2012;7: e49717.
Medicine 2008; 359:378-90. 12. Geiger-Gritsch S, Stollenwerk B, Miksad R, Guba B, Wild C,
3. Cheng A, Kang Y, Chen Z, et al. Efficacy and safety of sorafenib Siebert U. Safety of bevacizumab in patients with advanced
in patients in the Asia-Pacific region with advanced cancer: a meta-analysis of randomized controlled trials. The
hepatocellular carcinoma: a phase III randomised, double- Oncologist 2010; 15:1179-91.
blind, placebo-controlled trial. The Lancet Oncology 2009; 13. Finn R, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab
10:25-34. in unresectable hepatocellular carcinoma. N Engl J Med 2020;
4. EASL. EASL Clinical practice guidelines: management of 382:1894-905.
hepatocellular carcinoma. J Hepatol 2018; 69:182-236. 14. Su D, Wu B, Shi L. Cost-effectiveness of atezolizumab plus
5. Gordan J, Kennedy E, AboutoAlfa G, et al. Systemic therapy for bevacizumab vs. sorafenib as first-line treatment of
advanced hepatocellular carcinoma: ASCO guideline. Journal unresectable hepatocellular carcinoma. JAMA Network Open
of clinical oncology: Official journal of the American Society of 2021;4:e210037.
Clinical Oncology 2020; 38:4317-45. 15. Zhang X, Wang J, Shi J, Jia X, Dang S, Wang W. Cost-
6. Finn R, Qin S, Ikeda M, et al. IMbrave150: Updated overall effectiveness of atezolizumab plus bevacizumab vs sorafenib
survival (OS) data from a global, randomized, openlabel phase for patients with unresectable or metastatic hepatocellular
III study of atezolizumab (atezo) + bevacizumab (bev) versus carcinoma. . JAMA Network Open 2021;4: e214846.
sorafenib (sor) in patients (pts) with unresectable 16. Hou Y, Wu B. Atezolizumab plus bevacizumab versus sorafenib
hepatocellular carcinoma (HCC). J Clin Oncol 2021; 39:267. as first-line treatment for unresectable hepatocellular
7. Sonbol M, Riaz I, Naqvi S, et al. Systemic therapy and carcinoma: a cost-effectiveness analysis. Cancer
sequencing options in advanced hepatocellular carcinoma: a Communications 2020; 40:743-5.
systematic review and network meta-analysis. JAMA Oncology 17. Vogel A, Martinelli E, ESMO. Updated treatment
2020;6: e204930. recommendations for hepatocellular carcinoma (HCC) from
8. Lee M, Ryoo B, Hsu C, et al. Atezolizumab with or without the ESMO Clinical Practice Guidelines. Ann Oncol 2021;
bevacizumab in unresectable hepatocellular carcinoma 5:0923-7534.
(GO30140): an open-label, multicentre, phase 1b study. The 18. Hepatobiliary Cancers. at
Lancet Oncology 2020; 21:808-20. https://www.nccn.org/professionals/physician_gls/pdf/hepatob
9. Siegel A, Cohen E, Ocean A, et al. Phase II trial evaluating the iliary.pdf.)
clinical and biologic effects of bevacizumab in unresectable
hepatocellular carcinoma. Journal of Clinical Oncology: Official
Journal of the American Society of Clinical Oncology 2008;
26:2992-8.
Chapter 4. RESEARCH GAPS clinical decision-making. Unfortunately, many of the

surgical or radiotherapeutic modalities for HCC (LT, LR,
In the search for high-quality evidence for each clinical
ablation, SIRT, EBRT) did not have direct comparative
question and formulation of the recommendations, many
studies. Some intervention studies which enrolled
queries remain unanswered. These clinical queries on
subjects with different stages of disease or liver function
diagnostic and therapeutic interventions provide fertile
status (cirrhotics versus non-cirrhotics) did not
ground for further research.
segregate data for the different subgroups. Results of
Evidence from well-conducted and replicated RCTs on new systemic treatments for advanced HCC
randomized controlled trials serves as solid basis for are not yet available.
Volume 59 No. 3 190

For diagnostic modalities of interest, there is no study Studies on disease prevalence, disease presentation,
comparing the diagnostic accuracy and safety of mapping of available diagnostic and treatment expertise,
multiphasic CT scan and contrast-enhanced abdominal evaluation of manpower needs, cost, patients’ values and
MRI in patients with comorbidities (i.e., ascites, renal preferences, response to treatment can provide much-
disease, and pulmonary diseases); conditions wherein the needed information to further aid the decision-making
choice of non-invasive imaging modality is critical. There process of the relevant stakeholders. These research
is also no direct comparison between FNAB and CNB in a projects would support holistic care for patients with
population suspected with HCC. Given the expertise and hepatocellular carcinoma in the country.
interest in HCC in the country, these studies are feasible
and can reduce much of the uncertainty in the choice of
the appropriate diagnostic pathway for individual
patients.
Chapter 5. DISSEMINATION AND IMPLEMENTATION curricula, with the support of the faculty members and
OF THE GUIDELINES heads of hospital-based departments, including but
not limited to surgery, radiology, pathology, and
Dissemination to Industry Partners, Regulatory
internal medicine.
Agencies, and Payors
Dissemination to Patients and Public in General
The Task Force will submit the full-text manuscript of this
CPG to the Department of Health. The Disease Prevention The Taskforce, headed by the Steering Committee, will
and Control Bureau of DOH will transmit copies of this develop a simplified version of this CPG and make it
CPG to the Philippine Health Insurance Corporation, available in a format ready for reproduction and
health maintenance organizations, and pharmaceutical dissemination to patients in clinics and hospitals.
industry partners. DOH will release a memorandum to
Implementation and Monitoring
notify all stakeholders of the publication.
The Taskforce will distribute a questionnaire annually,
Dissemination to Medical Societies and Training
aiming to determine the best practices of relevant
Institutions
stakeholders in terms of diagnosis and management of
This CPG will be presented during conferences and hepatocellular carcinoma. Monitoring the use of this
annual conventions of medical societies. Copies of this clinical practice guideline may also be a subject of
CPG with the endorsement of relevant medical research by interested parties.
institutions will be sent to medical schools and libraries
to integrate the recommendations in their training
Chapter 6. UPDATING OF THE GUIDELINES hepatocellular cancer emerges or other contingencies

compel the updating of this CPG.
The recommendations herein shall hold until such time
that new evidence on screening strategies, diagnostic The HCC Task Force intends to review this CPG no later
tests, medicines, and surgical interventions for than 2024.
Chapter 7. AUTHORSHIP, CONTRIBUTIONS, management and is accountable for the overall quality of
ACKNOWLEDGEMENT this clinical practice guideline.
This project would not have been possible without the Ryan Ruel T. Barroso, MD, FPCS (Hepatopancreatobiliary
initiative and funding from the Department of Health. Surgery and Liver Transplantation, Lead of CPG), Avril P.
David, MD, FPCS (Hepatopancreatobiliary Surgery); Irene
The DOH neither imposed any condition nor exerted any
F. Abisinia, MD, FPCS (Surgical Endoscopy and Minimally-
influence in formulating the final recommendations.
invasive Surgery); Timothy Joseph S. Orillaza, MD, FPSVIR
Steering Committee. The steering committee was (Vascular and Interventional Radiology); Bernadette
indispensable in creating working groups and Semilla-Lim, MD, FPSG (Gastroenterology); Jonathan C.
coordinating the preparatory work, evidence review, and Nolasco, MD, FPCS (Hepatopancreatobiliary Surgery);
formulation of the recommendations. It organized the Kitchie C. Antipuesto, MD, FPSMO (Medical Oncology);
consensus panel and facilitated the en banc meeting. The Jennielyn C. Agcaoili-Conde, MD, FPSG (General and
SC was responsible for the overall organization and Transplant Hepatology); and Glenda Lyn Y. Pua, MD,
DPSP (Gastrointestinal and Hepatobiliary Pathology).
191 Vol 59 No 3
Technical Working Group. Asia-Pacific Center for Evangeline Santiago, MD, FPAFP (Family Medicine); Ray
Evidence Based Healthcare, Inc. undertook extensive Sarmiento, MD, FASGE (Surgical Endoscopy, Minimally-
technical work in (1) searching and summarizing the invasive Surgery and Upper GI Surgery); Marvin Tamaña,
evidence while ensuring objectivity in each stage of the MD, FPSVIR (Vascular and Interventional Radiology);
process, (2) presenting the evidence in the panel meeting, Ernesto C. Tan, MD, FPCS (Hepatopancreatobiliary
and (3) documenting and writing the final output. Surgery); Catherine SC Teh, MD, FPCS
(Hepatopancreaticobiliary Surgery and Liver
Evelyn O. Salido, MD, MSc (Lead); Maria Vanessa C.
Transplantation); Maria Luisa A. Tiambeng, MD, FPSMO
Villaruz-Sulit, RN, MSc (Technical Coordinator); Howell
(Medical Oncology); Edhel S. Tripon, MD, FPSG (General
Henrian G. Bayona, MSc; Fides Roxanne M. Castor, MD;
and Transplant Hepatology); Billie James G. Uy, MD, FPCS
Eunice Victoria M. Co, RMT, MD, FPCP; Louie F. Dy, MD
(Hepatopancreatobiliary Surgery); Primo B. Valenzuela,
(cand.); Emmanuel P. Estrella, MD, MSc; Aldrin B. Loyola,
MD, FPCP (Internal Medicine); Ronald G. Yebes, MD,
MD, MBAH, FPCP; Corinna M.
FPCR (Diagnostic Radiology); and Pelagio C. Baldovino,
Puyat, MD (cand.); Marvin Jonne L. Mendoza, MD, MD, MPH (General Medicine and patient representative).
Beatrice J. Tiangco, MD, MSc, Grazielle S. Verzosa, MD,
The developers of this guideline would like to express
DPPS, Marc Andrew O. Perez, MD, DPPS, DPSN, DPNSP
gratitude to the following physicians:
(Evidence Reviewers); Myzelle Anne J. Infantado, PTRP,
MSc (cand.) (Technical Writer); and Leonila F. Dans, MD, Dr. Arlyn Canones, MD, FPCS for her participation during
MSc (Technical Adviser). the consensus panel meetings as a resource expert in the
field of advanced therapeutic endoscopy; Drs. Sharlene
Consensus Panel. This CPG is invaluable because of the
Marie L. Lao, MD, DPBS; Paul Michael Vincent Lugtu, MD,
involvement and active participation of the panelists from
DPBS; Wesley Wendell B. Cruz, MD, FPCS; Raymond
various sectors of healthcare who dedicated their time
Joseph De Vera, MD DPBS; Onofree O’Connor, MD,
and effort to share their expertise, experience, and
DPBS; Lauren Victoria Rellora, MD; Jared Trent Matthew
knowledge in scrutinizing the scientific evidence with
Chua, MD; and Xandra Regina Martinez, MD for their
consideration of other critical factors such as patient
invaluable contribution in the formulation of the clinical
values and preferences and current healthcare system in
questions.
the Philippines. The Panel is composed of the following:
This project would not have been successful without the
Samuel D. Ang, MD, FPCS (Surgical Oncology); Clarito U.
leadership and guidance of Dr. Evelyn O. Salido, Dr.
Cairo Jr. MD, FPCOM (Public Health); Ramon L. De Vera,
Leonila F. Dans, and Dr. Maria Rica Lumague.
MD, FPCS (Hepatopancreaticobiliary Surgery); Maria
Vanessa H. De Villa, MD, FPCS (Hepatopancreaticobiliary The developers of this guideline would also like to give
Surgery and Liver Transplantation); Jade D. Jamias, MD, special thanks to Dr. Bernadette Heizel Manapat-Reyes
FPSG (General and Transplant Hepatology); Paulo for facilitating the consensus panel meeting and to Ms.
Giovanni L. Mendoza, MD, FPSP (Liver Pathology); Janus Myzelle Anne Infantado for collating the evidence base
P. Ong, MD, FPSG (General and Transplant Hepatology); and writing the CPG manuscript.
Teresa T. Sy Ortin, MD, FPROS (Radiation Oncology);
Volume 59 No. 3 192

APPENDIX A. Declaration of Conflicts of Interest
COIs of the Consensus Panel members
Name Summary of Disclosure or other
Expertise/Representation Affiliation
relevant interest
Samuel D. Ang, MD, FPCS Surgical oncology Chinese General Hospital & None declared
Medical Center
Pelagio C. Baldovino, MD, MPH General medicine/ Patient Baldovino Medical Family None declared
advocate Clinic
Clarito U. Cairo, Jr., MD Public health Department of Health Non-financial interest: Medical
Officer IV of Department of Health –
Program Manager of Cancer Control
Ramon L. De Vera, MD, FPCS Hepatopancreatobiliary surgery Philippine General Hospital None declared
Maria Vanessa H. De Villa, MD, Hepatopancreatobiliary surgery, The Medical City Received study research support from
FPCS Liver transplantation Planet-NCCS Emerald- AstraZeneca
(2017present),
participated in SIRveNIB/SARAH
Advisory
Board Meeting -SIRTEX
(Makers of SIR Spheres for SIRT) with
paid travel and accommodations
(August 2017)
Co-author, Current role of SIRT in liver
tumor
Jade D. Jamias, MD, FPSG General and transplant National Kidney & Participated in round table discussion
hepatology Transplant Institute with drug companies (Systemic
treatment and tyrosine kinase inhibitor
for HCCA), with at least two lectures
(2020)
Paulo Giovanni L. Mendoza, MD, Liver pathology Cardinal Santos Medical None declared
FPSP Center
Janus P. Ong, MD, FPSG General and transplant The Medical City Received money and honoraria
hepatology from clinical trial (Exelixis in
2020 and Hi-Eisai in 2020);
Received research support from
AstraZeneca (2017), SCRI
(2021)
Non-financial interest:
Member, Hepatology Society of the
Philippines
Teresa T. Sy Ortin, MD, FPCR Radiation oncology Benavides Cancer None declared
Institute, University of
Santo Tomas Hospital
Evangeline P. Santiago, MD, FPAFP Family medicine Rizal Medical Center None declared
Ray I. Sarmiento, MD, FASGE Surgical endoscopy, MIS and Rizal Medical Center, St. Non-financial interest:
upper GI surgery Luke’s Medical Board of Director, Philippine
Center, Asian Medical Association of Laparoscopic and
Center Endoscopic Surgeons (PALES),
Philippine Association of
Hepatopancreatobiliary Surgeons
(PAHPBS)
Marvin T. Tamaña, MD, FPSVIR Vascular and interventional Philippine Heart Center, None declared
radiology Philippine Society of Vascular
and Interventional Radiology
Ernesto C. Tan, MD, FPCS Hepatopancreatobiliary surgery Rizal Medical Center Non-financial interest:
Cardinal Santos Medical Independent Director, Davao Doctors
Center Hospital
Catherine S.C. Teh, MD, FPCS Hepatopancreatobiliary surgery National Kidney and Non-financial Interest:
and liver transplantation Transplant Institute President, PAHPBS
St. Luke’s Medical Center Director, Philippine College of
Makati Medical Center Surgeons Cancer Commission
193 Volume 59 No. 3

Maria Luisa A. Tiambeng, MD, Medical oncology Rizal Medical Center Consultant – Advisory board member
FPSMO Cardinal Santos Medical (Hi-Eisei, Roche),
Center 2020-2021
Received monetary compensation as
Principal investigator of Roche (2010-
2017), paid traveltomeetings from Hi-
eisai and Roche (2010-2019) and
speaker’s honoraria from Hieisai and
Roche (2005-2021)
Edhel S. Tripon, MD, FPSG General and transplant Hepatology Society of the Technical consultant – HP
hepatology Philippines Diagnostics (2012topresent)
Investment interests (stocks) –
Amihan Corp. The Medical City
(2012-present)
Received honoraria from
SIRTEX, Abbott (2017-2018) with
continuous exposuretocompanies with
commercial interest in HCC
diagnostics, medications,
interventions because of work as
present board member of HSP Board
Billie James G. Uy, MD, FPCS Hepatopancreatobiliary surgery Rizal Medical Center Non-financial interest.
Board Member, Philippine Society of
General Surgeons, Metro Manila
Chapter,
Philippine Association of Hepato-
Pancreato-Biliary Surgeons
Primo B. Valenzuela, MD, FPCP Internal medicine Rizal Medical Center None declared
Ronald G. Yebes, MD, FPCR Diagnostic radiology The Medical City None declared
COIs of the Lead CPG Developers/Steering Committee
Name Expertise/Representation Affiliation Summary of Disclosure or other

relevant interest
Ryan Ruel T. Barroso, MD, FPCS Hepatopancreatobiliary surgery and Rizal Medical Center, Board member of
liver transplantation Cardinal Santos Medical Philippine Association of
Center, Chinese General Hepatopancreatobiliary Surgeons, Inc.
Hospital
Irene F. Abisinia, MD, FPCS Surgical endoscopy and MIS Rizal Medical Center None declared
Jennielyn C. Agcaoili-Conde, MD, General and transplant hepatology Hepatology Society of the None declared
FPSG Philippines
Kitchie C. Antipuesto, MD, FPSMO Medical oncology Cardinal Santos Medical None declared
Center
Avril P. David, MD, FPCS Hepatopancreatobiliary surgery Rizal Medical Center None declared
Jonathan C. Nolasco, MD, FPCS Hepatopancreatobiliary surgery Rizal Medical Center None declared
Timothy Joseph S. Orillaza, MD, Vascular and interventional Rizal Medical Center None declared
FPSVIR radiology
Glenda Lyn Yu Pua, MD, DPSP Gastrointestinal and hepatobiliary Rizal Medical Center None declared
pathology
Bernadette Semilla-Lim, MD, FPSG Gastroenterology Rizal Medical Center None declared
COIs of the Evidence Review Experts
Name Affiliation Summary of Disclosure or other relevant

interest
Evelyn O. Salido, MD, MSc, FPCP, FPRA UP Manila None declared
Maria Vanessa V. Sulit, MSc, RN Asia-Pacific Center for EvidenceBased Non-financial interest:
Healthcare, Inc. Coordinator, Asia-Pacific Center for
Evidence-Based Healthcare, Inc. Engage in
CPG and EBM work and trainings
Howell Henrian G. Bayona, MSc University of the Philippines Manila (UP None declared
Manila), St. Luke’s Medical
Center Global City, The Medical City
Fides Roxanne M. Castor, MD Philippine General Hospital None declared
Eunice Victoria M. Co, RMT, MD, FPCP None None declared
Louie F. Dy, MD UP College of Medicine None declared
Vol 59 No 3 194
Emmanuel P. Estrella, MD, MSc UP Manila None declared
Aldrin B. Loyola, MD, MBAH, FPCP UP College of Medicine Received funding for clinical trial
Bayer AG (2013-2018); Cadila (2012-2021);
Astra Zeneca (2009-2016)
Non-financial interest: Chair, Committee on
CME of the Philippine College of Physicians
(FY 2020-2021)
Director, Happy to be 10B Inc.
Director, Adult Medicine Research Unit
Corinna M. Puyat, MD (cand.) UP College of Medicine None declared
Marvin Jonne L. Mendoza, MD Philippine General Hospital Cancer Institute Non-financial interest: Chief fellow, PGH
Division of Medical Oncology (until March
31, 2021)
Marc Andrew O. Perez, MD, DPPS, DPSN, The Medical City Pangasinan None declared
DPNSP
Beatrice J. Tiangco, MD, MSc The Medical City Received monetary compensation for
CANDLE study (5 years) from Philippine
Council for Health Research and
Development (PCHRD); non-financial
support from PCHRD in Early cancer
diagnosis in the liver of the Filipinos with
chronic hepatitis B infection
Grazielle S. Verzosa, MD, DPPS East Avenue Medical Center None declared
195 Volume 59 No. 3

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1 The Philippine Clinical Practice Guidelines For The Diagnosis and Management of Hepatocellular Carcinoma 2021

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Philippine Journal of Internal Medicine Clinical Practice Guideline

The Philippine Clinical Practice Guidelines for the Diagnosis

167 Volume 59 No. 3

2. We recommend the use of a multiphasic, contrast-enhanced CT scan or Strong Low

LIST OF MEDICAL ABBREVIATIONS AND ACRONYMS

169 Volume 59 No. 3

Table 2. PICO questions of this guideline

171 Volume 59 No. 3

Additional factors that may increase certainty are:

173 Volume 59 No. 3

Table 4. Summary of findings on HCC screening vs. no screening

False positive rate (US) Critical 1 CS 2.98% 2.75 - 3.23% Low

Sn (US + AFP) Critical 1 CS 92.2% 81.1 - 97.8% - Low

Table 5. Comparison of survival rate between HCC screening vs. no screening

Screened Group Usual Care Group

References 5. Silva M, Hegab B, Hyde C, Guo B, Buckels J, Mirza D. Needle

175 Volume 59 No. 3

Effect per 1,000 patients tested Pretest Interpretation

Effect per 1,000 patients tested Pretest

References 4. Beckett K, Morjarity A, Langer J. Safe use of contrast media: what

177 Volume 59 No. 3

Effect per 1,000 patients tested

References diagnostic accuracy of cut needle biopsy of focal liver lesions.

179 Volume 59 No. 3

Post-op Mortality 7 observational

References analysis in patients within and outwith Milan criteria. HPB

181 Volume 59 No. 3

183 Volume 59 No. 3

References 7. Feng K, Yan J, Li X, Xia F, Ma K, Wang S. A randomized trial

References 2. Salem R, Gordon A, Mouli S, Hickey R, Kallini J, Gabr A.

185 Volume 59 No. 3

SELECTIVE INTERNAL RADIATION THERAPY vs. Certainty of Evidence

References a comparison of treatment outcomes for hepatocellular

TRANSARTERIAL CHEMOEMBOLIZATION alone or Evidence to Decision

187 Volume 59 No. 3

References randomized placebo-controlled, double-blind, phase 3 trial. The

SORAFENIB vs. COMBINATION of Other Considerations

189 Volume 59 No. 3

References 10. Boige V, Malka D, Bourredjem A, et al. Efficacy, safety, and

Chapter 4. RESEARCH GAPS clinical decision-making. Unfortunately, many of the

Volume 59 No. 3 190

Chapter 6. UPDATING OF THE GUIDELINES hepatocellular cancer emerges or other contingencies

Volume 59 No. 3 192

193 Volume 59 No. 3

COIs of the Lead CPG Developers/Steering Committee

Name Expertise/Representation Affiliation Summary of Disclosure or other

COIs of the Evidence Review Experts

Name Affiliation Summary of Disclosure or other relevant

195 Volume 59 No. 3

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