Consensus Statements
Assessment of Underlying Liver Dysfunction in Unresectable HCC
Statement 1.1: Child–Pugh score is recommended as the primary tool in the assessment of liver dysfunction
prior to undertaking liver-directed and systemic therapies for intermediate stage
HCC. (IA)
Statement 1.2: ALBI (albumin-bilirubin) score can help in determining liver function prior to liver-directed
and systemic therapies in intermediate stage HCC but needs further validation. (IIA)
Statement 1.3: Further research is needed to validate the use of indocyanine green (ICG) clearance,
99Tc-iminodiacetic acid (IDA) scintigraphy, and elastography for the assessment of
liver function prior to liver-directed and systemic therapies for HCC. (IIIB)
Individual biochemical tests like serum bilirubin, albumin, or international normalized
ratio (INR) are poor predictors of overall liver function.[14] Child-Turcotte-Pugh (CTP) score is the most common score to assess functional status
of the liver. CTP score is incorporated as part of the BCLC and HKLC staging system
as a measure for functional assessment of liver.[15] The CTP score includes parameters of bilirubin, albumin, INR, ascites, and hepatic
encephalopathy. Patients with CTP A cirrhosis are considered fit for HCC-directed
therapy, whereas those with significant liver dysfunction (CTP class C cirrhosis)
are unfit for HCC-directed therapy due to high competing risk of mortality. Patients
with CTP B[7] can be considered on a case-by-case basis for HCC-directed therapy, after careful
consideration of what parameters drive the CTP score. Patients with overt hepatic
encephalopathy and moderate to severe ascites are unfit for any form of HCC-directed
therapy. CTP is easy to calculate but has limitations with floor effects, ceiling
effects, and subjectivity of parameters.[16]
Recently, the ALBI score has been used as a prognostic marker in patients with different
stages of HCC. It is easy to calculate and objective, providing three subclasses based
on the score (ALBI grade 1, 2, and 3). ALBI has been found to be a good prognosticator
in patients undergoing both surgery and nonsurgical HCC-directed therapies across
all stages.[17]
[18]
[19] However, larger validation studies are needed to include ALBI in the treatment algorithm
for HCC.
Other scores for assessment of liver function like ICG clearance (ICGC) (ICG R15),
99Tc-IDA scintigraphy, and elastography are not yet validated for use for liver functional
assessment in HCC. ICGC, although known to have predictive value for posthepatectomy
liver failure (PHLF) after hepatectomy, needs further studies for evaluating its predictive
potential prior to HCC-directed therapies. Also, the test performs poorly in patients
with raised bilirubin.[20] Technetium scintigraphy is known to be useful for prediction of liver function in
patients undergoing radioembolization.[21]
[22] However, data on its use to predict functional liver reserve prior to other LDTs
is sparse. Transient elastography is known to correlate with portal hypertension.[23]
[24] While elastography largely correlates with structure, its functional correlation
is not yet validated, so its utility as a test for functional assessment prior to
LDT remains unclear.
Statement 1.4: Decompensation of underlying chronic liver disease in the form of jaundice (total
bilirubin > 3 mg/dL), moderate-severe ascites, and overt hepatic encephalopathy, with
Child-Pugh class B[8]
[9]/C are contraindications for any LDTs or systemic therapies of HCC in most cases.
(IA)
Statement 1.5: Patients with Child-Pugh class A cirrhosis and no prior history of decompensation
should be considered for HCC-directed therapy. (IA)
Statement 1.6: Patients with Child-Pugh class B7 cirrhosis can be considered for HCC-directed therapy
on a case-by-case basis. (IIC)
Statement 1.7: LDTs and systemic therapies should be considered on a case-by-case basis after recompensation
of previously decompensated chronic liver disease, accounting for tumor burden, potential
for worsening liver function, and liver transplant eligibility. (IIC)
Statement 1.8: Early palliative care should be considered for patients with decompensated chronic
liver disease with HCC, specifically those who are ineligible for liver transplantation
or unlikely to become recompensated to offer any cancer-directed therapy. (IA)
Traditionally, treatment algorithms including both BCLC and HKLC recommend therapeutic
options for patients with Child-Pugh A cirrhosis.[25] In patients with decompensation in the form of jaundice (> 3 mg/dL), moderate-severe
ascites, and overt hepatic encephalopathy, LDT is typically of minimal benefit, outside
of liver transplant eligibility, given high competing risk of mortality and high risk
of worse decompensation. In patients undergoing thermoablation, there is a likely
increase in CTP score in patients who are CTP A in 3 to 7% and CTP B in 3 to 14%.[26]
[27] For transarterial therapies, select patients with CTP B are considered fit for LDT.[28] For systemic therapies, retrospective analyses have suggested safety and tolerability
in selected patients with CTP B cirrhosis although objective survival benefit in these
patients is unknown.[29] Palliative care in patients with HCC aims at management of symptoms, discussion
of treatment choices, and psychosocial support for patients and their caregivers.[26] Palliative care has been shown to reduce patient and family suffering, reduce health
care utilization, and even improve survival in the context of cancer. Early palliative
care should be offered to patients who are planned for therapy with palliative intent.
Statement 1.9: Treatment of underlying chronic liver disease affects outcomes of patients with intermediate
stage HCC. (IA)
Statement 1.10: In patients with chronic hepatitis B and HCC, therapy for hepatitis B should be started
using antivirals with high barrier to resistance (entecavir or tenofovir) and continued
lifelong. (IA)
Statement 1.11: In patients with chronic hepatitis C and HCC, therapy for hepatitis C should be considered
using directly acting oral antivirals (DAAs) in those with expected survival exceeding
1 year. Addition of ribavirin should be considered in patients with cirrhosis. In
patients with contraindications or intolerance to ribavirin, therapy should be considered
with DAAs alone for an extended period of 6 months. (IIA)
Status of underlying liver disease is known to impact therapeutic options for HCC.
Hepatitis B and C are two common causes of HCC in India.[30]
[31] Antivirals (entecavir or tenofovir [TAF/TDF]) improve CTP status and reduce risk
of decompensation in patients with hepatitis B virus (HBV)-related cirrhosis. Antivirals
are associated with reduced risk of HBV reactivation after surgery, TACE, and SBRT.
Choice of antivirals has largely been at the treating hepatologist's discretion. A
recent meta-analysis showed that tenofovir is better than entecavir for tertiary prevention
after LDT for HCC.[31] However, large-scale randomized trials are needed for further clarification on choice
of one antiviral over another.
Therapy for chronic hepatitis C is finite and is usually considered for patients with
life expectancy more than 1 year in the background of HCC.[32] Antivirals improve CTP score and reduce the risk of decompensation in compensated
hepatitis C virus (HCV)-related cirrhosis. Although there was initial concern about
increased risk of recurrence, recent multisite data have demonstrated no increased
risk of recurrence. Further, DAA improves overall survival (OS) in patients with a
history of HCC, independent of recurrence risk, for both patients undergoing curative
or palliative therapies.[33]
[34] In contrast to HBV antivirals, therapy for HCV does not need to be started prior
to HCC-directed therapy given lower concern for acute flares. Notably, patients with
HCC have lower rates of sustained virologic response compared to those without HCC.
Defining Criteria of Unresectability in HCC
The assessment of resectability in HCC is based on the presence of liver-related factors
(i.e., degree of dysfunction) and tumor-related factors (i.e., tumor burden and presence
of extrahepatic disease).
Statement 2.1: An inadequate future liver remnant (FLR) is a factor to define unresectable HCC.
Adequate FLR for resection is defined as 25 to 30% for noncirrhotic livers and > 40%
for cirrhotic livers. HCC (Category IIA).
Statement 2.2: CTP scoring is an indicator of liver function and predicts outcomes posthepatectomy.
CTP score above B7 should be considered unresectable (Category IIA).
Statement 2.3: ICG retention is a marker of functional capacity of liver and a value of > 15% for
major hepatectomy can be considered as a criterion for unresectability (Category IIA).
Statement 2.4: Clinically significant portal hypertension (CSPH) in the form of hepatic venous pressure
gradient (HVPG) of > 10 mm Hg, varices, and symptomatic splenomegaly is an indicator
of postoperative liver decompensation and long-term mortality. CSPH should be considered
as a contraindication for surgery, although thresholds for thrombocytopenia are being
reassessed for minor resections with increasing use of laparoscopic and robotic techniques
(Category IIA).
The FLR determines risk of posthepatectomy liver dysfunction. Cirrhotic livers have
a decreased ability to tolerate injury and regenerate. Hence, there is general consensus
that a higher FLR for cirrhotic livers is needed to prevent PHLF. Compared to FLR
of > 25 to 30% for noncirrhotic livers being considered standard, an FLR of > 40%
is required in the setting of cirrhosis. Portal vein embolization can be considered
to increase FLR in patients initially considered unresectable with good long-term
survival outcomes, and there is now increasing data for use of TARE to induce hypertrophy
of contralateral lobe.[35]
[36] CTP score is an indicator of liver function and CTP score of B8 and above correlates
with postoperative mortality as high as > 20% as well as reduced OS; therefore, major
liver resection should not be considered for these patients.[37] ICGC is a marker of metabolic function of the liver as the dye gets excreted without
enterohepatic circulation. ICGC value of 14% or less is suitable for a major hepatectomy
and values > 20% should not be considered for major liver resection.[38] CSPH with HVPG > 10 mm Hg or portal vein pressure of > 20 cm H2O, esophageal varices,
platelet < 100,000/mm3, and splenomegaly > 12 cm is associated with a higher risk of death at 3 and 5 years
as well as an increased risk of clinical decompensation and therefore should be considered
a criteria for unresectability.[39] Recent data suggest that lower platelet counts of 90,000 may be tolerated with laparoscopic
and robotic techniques when performing a minor resection.
Statement 2.5: Size of tumor should not be considered as a factor determining unresectability (Category
IIA).
Statement 2.6: Invasion of second order portal vein is not a contraindication, however, invasion
of first order branches or main portal vein should be considered unresectable unless
downstaged (Category IIA).
Statement 2.7: Hepatic vein invasion with or without tumor extension into infra- or suprahepatic
inferior vena cava (IVC) is not a contraindication to surgery if can be performed
safely with extraction of tumor thrombus with or without IVC resection (Category IIC).
Statement 2.8: Tumor compression of bile duct causing jaundice is not unresectable if surgery or
drainage feasible. Tumor thrombus of bile duct is not a contraindication to surgery
unless invasion of contralateral bile duct system (Category IIC).
Statement 2.9: Multicentric (bilobar) HCC is generally considered unresectable; however, localized
multinodular HCC that can be resected with a safe resection margin and preserve adequate
FLR is not a contraindication (Category IIC).
Statement 2.10: Presence of extrahepatic disease in HCC is unresectable (Category IIC).
The size of primary HCC tumors even larger than 10 cm have 5-year survival outcomes
of 33 to 35% with partial hepatectomy. The previous stress on tumor size as a criteria
for consideration of resection does not hold significant validity in the current era,
if adequate FLR is possible.[40]
[41] Liver resection for HCC with branch portal vein thrombus (Vp1 or Vp2) is associated
with improvement in survival outcome without major perioperative mortality (< 5%)
as compared to other treatment modalities and hence these patients can be offered
surgery beyond BCLC criteria.[42] In contrast, patients with Vp3 or Vp4 disease have high risk of metastatic disease
and upfront resection is likely of limited benefit. Similarly, patients with hepatic
vein invasion have reasonable 5-year outcomes with surgery and should be considered
for resection prior to assessment for other treatment modalities.[43] Hepatic vein invasion involving IVC by tumor has a superior survival outcome with
surgery compared to nonsurgical approaches and should be offered surgery. In patients
with hepatic vein invasion or hepatic vein thrombosis (especially those without portal
vein thrombosis [PVT]), surgery possibly offers survival benefits compared to nonsurgical
approaches and can be considered as the initial modality of treatment.[44] HCC with bile duct tumor invasion, wherein the thrombus is resected or otherwise,
results in 5-year survival outcomes of 28 to 36% with surgical approaches.[45]
[46] While transplant is the preferred approach in HCC with multinodular disease given
high risk of recurrence, resection can be considered safely in such patients, though
factors such as tumor number, total tumor diameter, and the presence of microvascular
invasion may be associated with decreased survival after resection in cirrhotic patients
with multinodular HCC.[47]
[48]
Though patients with HCC who have been resected or ablated are usually observed, there
is emerging data to suggest that adjuvant atezolizumab-bevacizumab may be of benefit
in patients with high-risk characteristics. The interim analysis of the IMbrave050
trial has shown that adjuvant atezolizumab-bevacizumab planned for a period of 12
months might improve survival compared to observation in this setting. However, data
with a longer follow-up will be required before this can be considered as a treatment
option.[49] Presence of extrahepatic disease should be considered as unresectable as a standard.
However, isolated adrenal lesions or single lung nodule or single bone lesions can
be considered as oligometastatic disease. The definitive management of oligometastatic
disease should depend on performance status, disease-free interval, or response to
therapy to consider for curative options either in the form of surgery or ablative
measures.[50] Although important in all patients, management at high-volume centers and a multidisciplinary
approach are particularly critical for these patients.
Liver-Directed Therapy in Unresectable HCC
LDT in the form of TACE forms the backbone of treatment in patients with BCLC B HCC.
Some patients in this group are also candidates for a combination of TACE and radiofrequency
ablation (RFA), while a certain proportion of patients can also be considered for
TARE. Current guidelines deal predominantly with patients with unresectable HCC as
opposed to inoperable HCC, wherein surgery has not been considered due to patient-related
or logistic factors. In a scenario where anatomic factors preclude resection, the
predominant modality of treatment remains TACE with a lesser role for RFA and microwave
ablation (MWA).
Statement 3.1: In patients with BCLC B (Intermediate stage), the use of TACE alone is the standard
of care treatment option, with systemic therapy to be considered when there is development
of liver lesions not addressable by further TACE or extrahepatic disease. (I, A)
Statement 3.2: In patients with BCLC B (Intermediate stage) with tumors larger than 5 cm, TACE can
be combined with RFA or MWA. (II B)
TACE is the primary modality of treatment in patients with unresectable HCC with most
older studies showing benefits compared to systemic therapeutic options. While there
are limited studies in the current era comparing TACE with IO or newer tyrosine kinase
inhibitors (TKIs), practice patterns have overwhelmingly used TACE as the primary
modality in unresectable HCC and it occupies a central position in both the BCLC and
HKLC systems as a treatment of choice in unresectable HCC.[51]
[52]
However, the frequent development of local tumor recurrence and impaired liver function
reserve after TACE leads to unsatisfactory outcomes, especially in larger tumors.
Additionally, repeated TACE potentiates the expression of vascular endothelial growth
factor, thereby increasing tumor angiogenesis and possibility of recurrence. There
is evidence to suggest that patients with larger tumors (> 5 cm) might benefit from
addition of RFA or MWA to TACE in unresectable HCC. While there is no strict single
cutoff in terms of tumor size for the additional use of RFA/MWA, the synergism of
TACE and RFA/MWA and the available evidence supports their combined use in larger
unresectable HCCs.[53]
[54]
Statement 3.3: Drug-eluting beads (DEBs)-TACE can be considered a preferred option compared to conventional
TACE (cTACE) in patients with BCLC B and single large tumors. (II B)
Statement 3.4: TACE is relatively contraindicated in BCLC C patients with main PVT (MPVT); however,
it can be considered safely in patients with branch PVT (BPVT). (IIIB)
Statement 3.5: TARE can be considered as an alternative to TACE or in patients with contraindications
to TACE in HCC BCLC B tumors as well as select patients with PVT, particularly those
in whom downstaging to transplant is intended. (II B)
Section 3.6: Transarterial embolization (TAE) is the treatment of choice in patients with ruptured
unresectable HCC. (II A)
cTACE acts by the selective obstruction of tumor-feeding arteries by injection of
chemotherapeutic agents (predominantly doxorubicin and rarely, cisplatin) mixed with
lipiodol. This leads to ischemic necrosis of the targeted tumors by cytotoxic and
ischemic effects. DEB-TACE purports to improve on the effects of cTACE by sustained
release of chemotherapeutic agents over a prolonged period of time. This also entails
higher concentrations of drugs within the target tumor and lower systemic absorption
and concentrations compared with cTACE. While this is appealing conceptually, there
is controversy over the actual benefits of DEB-TACE over cTACE.[55] The largest trial comparing the two options, the PRECISION V study showed numerically
improved response rates and disease control rates as well as a significant decrease
in chemotherapeutic agent-related systemic and liver toxicity with DEB-TACE compared
to cTACE. However, the trial did not achieve statistical significance in terms of
primary endpoint of tumor response at 6 months.[56] A majority of the studies comparing the two modalities have shown similar results
wherein there is some improvement in response rates, but without unequivocal survival
benefits.
The presence of PVT entails poor survival outcomes in the current era, irrespective
of the treatment modality used in management of this subset of HCC. Traditionally,
the use of TACE has been avoided in HCC with PVT due to the potential for embolization
to cause hepatic infarction and worsened liver function. However, multiple studies
as well as a meta-analysis have shown that TACE can be safely used in patients with
PVT, though survival continues to remain poor. As expected, patients with BPVT perform
better than patients with MPVT. The development of “super selective” or “ultra selective”
catheterization techniques and “microcatheters” has enabled advancement of catheters
into smaller vessels of the hepatic vasculature, allowing the safe use of TACE in
patients with PVT. This has entailed a very low risk of ischemic necrosis and liver
failure with the use of TACE in patients with PVT.[57] However, it is to be emphasized that treating HCC BCLC C patients with PVT with
TACE does not lead to significantly improved outcomes and the predominant modality
of treatment remains systemic therapy.
Most comparisons between TACE and TARE comprise small retrospective heterogeneous
cohort studies where drawing firm conclusions are not feasible. However, the available
evidence suggests that the two modalities have similar OS although TARE induces greater
progression-free survival (PFS) than TACE in patients with unresectable HCC. A recently
published overall and individual patient-level meta-analysis also showed a similar
trend with TARE resulting in a longer time to progression (TTP) than TACE (mean TTP
17.5 vs. 9.8 months; mean TTP difference 4.8 months, 95% confidence interval [CI]
1.3–8.3 months). The same meta-analysis also comprised an individual patient analysis
of three studies showing no difference in OS between the two modalities including
among subgroups stratified by tumor stage and liver function.[10]
One of the major criticisms of studies evaluating TARE has been the lack of adequate
dosing in patients and whether a personalized and potentially higher dose would have
greater efficacy than techniques using the standard dosimetry. This was the question
evaluated in the phase II randomized DOSISPHERE-01 study, comparing standard dosimetry
(120 ± 20 Gy) targeted to the perfused lobe or personalized dosimetry (≥ 205 Gy targeted
to the index lesion) in patients with locally advanced HCC. The results showed a near
doubling of response rates (71% vs. 36%), as well as increased resection rates (36%
vs. 4%) and median OS (26.6 vs. 10.7 months) in the personalized dosimetry group.
Additionally, there were lesser safety issues, despite the increased dosimetry in
the personalized dosimetry group.[58] While this was a phase II study, it does show the potential benefits of personalized
dosimetry with TARE as opposed to older studies with standard dosimetry.
Radiotherapy in Unresectable HCC
Radiation-based regimens were historically limited by radiation-induced liver injury,
though there is emerging evidence to suggest that newer techniques, such as SBRT,
can safely be used in HCC with reasonable efficacy. In regions where access or technical
expertise with TARE is difficult or contraindications to TACE exist, SBRT is a reasonable
alternative as a standalone option or with systemic therapy.
Statement 4.1: SBRT can be considered an alternative treatment for localized or recurrent HCC especially
when accompanied with tumor thrombus. The role of SBRT is limited to patients with
preserved liver function (Child A5-B7) and where at least > 700 mL of the normal liver
volume can be spared. (Category IIC)
Statement 4.2: The combination of systemic therapy with SBRT can be considered for localized or
recurrent HCC especially when accompanied with tumor thrombus. The role of SBRT is
limited to patients with preserved liver function (Child A5-B7) and where at least > 700 mL
of the normal liver volume can be spared. (Category IIB)
In patients with HCC where TACE is not feasible, SBRT is a good alternative in carefully
selected patients with liver confined disease based on multiple phase I/II prospective
and retrospective studies (local control at 2 years ≥ 80%). Most patients in these
trials had well-compensated baseline liver function (Child-Pugh A5-B7) with single
or multiple tumors (up to 5) and technically feasibility of SBRT like a minimum of
700 mL of spared normal liver volume. Bujold et al in a prospective study of 102 patients
reported excellent outcomes in patients treated by SBRT with median tumor size of
7.2 cm with maximum up to 23.1 cm.[59] Local control rate at 1-year was 87.5% and median OS of 17 months. Fukuda et al
reported the outcomes of 129 patients with Child A/B and median tumor size of 3.9 cm
(1–13.5 cm) treated by protons.[60] The 5-year local tumor control (LTC), PFS, and OS rates were 94, 28, and 69% for
patients with 0/A stage disease (n = 9/21), 87, 23, and 66% for patients with B stage disease (n = 34), and 75, 9, and 25% for patients with C stage disease (n = 65), respectively. The interim results of a randomized study comparing protons
with TACE in the setting of bridge to transplant showed a trend to improved 2-year
LTC (88% vs. 45%, p = 0.06) and PFS (48% vs. 31%, p = 0.06) in favor of protons.[61] The results of other ongoing studies comparing SBRT versus TACE are awaited.
In recurrent unresectable HCC, Kim et al conducted a phase 3 randomized controlled
trial comparing protons to RFA and concluded that 2-year local PFS with protons was
noninferior to RFA (92.8% for protons vs. 83.2% for RFA) and 4-year survival (75%)
was similar between the two arms.[62] While this study included small tumors (size < 3 cm, number ≤ 2), a prospective
phase II study by Jang et al reported the SBRT (3 fractions) outcomes in 65 recurrent
HCC patients primarily after 1 to 5 sessions of TACE with median tumor size of 2.4 cm
(1–9.9 cm). The 3-year LTC rate was 95% and 3-year OS was 76%[63]
In de novo or recurrent HCC with secondary PVT or MPVT, TACE is not feasible and systemic
therapies are recommended as first-line treatment. The recently presented phase III
randomized controlled trial RTOG-NRG 1112 at ASTRO 2022 compared addition of SBRT
to sorafenib versus sorafenib alone and showed a trend toward superiority of SBRT
plus sorafenib over sorafenib alone in terms of PFS and OS.[64] This study included patients with large HCC not amenable to TACE or RFA, 84% were
BCLC C and 74% had macrovascular invasion.
Statement 4.3: For patients with liver-confined multifocal and/or unresectable HCC, SBRT/proton
beam therapy (PBT) alone or sequenced with TACE/RFA is conditionally recommended.
(Category IIB)
For unresectable tumors, TACE (especially the superselective TACE) has been the preferred
local treatment modality. However, for larger lesions the response rates with TACE
are only 40 to 60%. Several retrospective, prospective, and randomized trials have
suggested addition of radiation (external beam radiotherapy or SBRT) to improve complete
response rates and OS. A prospective phase II study by Buckstein et al evaluated addition
of SBRT after 2 TACE in 32 patients with solitary HCC 4 to 7 cm, Child-Pugh A5-B7,
and unsuitable for resection/transplant.[65] The overall response rate was 91% with 63% complete response. The median OS was
not yet reached and median PFS was 35 months. The 2- and 3-year local control was
85% and 2- and 3-year OS 64 and 60%, respectively. A recent phase III randomized trial
by Comito et al comparing SBRT versus further TACE in patients with incomplete response
after 1 TAE/TACE showed superior local control with SBRT versus TAE/TACE rechallenge
(median not reached vs. 8 months, p = 0.0002). The 1-year PFS was 37% with SBRT compared to 13% with TAE/TACE.[66] A randomized trial by Yoon et al compared the combination of TACE and radiation
with sorafenib in 90 patients with Child-Pugh A HCC with PVT and showed improved PFS
(86.7% vs. 34.3%; p < 0.001), TTP (31.0 vs. 11.7 weeks; p < 0.001), and OS (55.0 vs. 43.0 weeks; p = 0.04) with TACE-RT.[67] It is important to note the potential for additive toxicities when SBRT is used
as a single option or in combination with other modalities such as TACE. The most
common form of radiation-induced toxicity is radiation-induced liver disease, followed
by gastrointestinal toxicities. Available data suggests an incidence of severe toxicities
of 3 to 30% and this needs to be kept in mind when combination therapies including
SBRT are being considered.
When the tumors are resectable and undergo hepatectomy with removal of portal vein
tumor thrombus (PVTT), RT has shown to have improved outcomes in neoadjuvant settings.
In a randomized trial by Wei et al, patients were randomly assigned to receive neoadjuvant
RT followed by hepatectomy or hepatectomy alone.[68] Neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates
compared with surgery alone leading to a superior disease-free survival and OS. The
optimal role of SBRT/PBT and patient selection for patients with liver-confined unresectable
HCC remain an area of need.
Systemic Therapy in Unresectable HCC
The advent of IO has changed the paradigms of treatment in patients with advanced
HCC. Such has been the impact that IO is now being explored in patients postresection
as well as in combination with various modalities of LDT to improve survival outcomes.
However, TKIs continue to remain a backbone for the management of advanced HCC because
of their ease of administration and relatively lower costs when compared with IOs.
Statement 5.1: In patients with BCLC B (Intermediate stage) the use of sorafenib 800 mg per day
or lenvatinib (weight-based) can be associated with improved survival when used concurrently
with TACE. This should be limited to patients with CTP A-B7 and PS 0-1 only. (II,
A)
A majority of older studies have not shown benefit for the use of systemic therapy
(predominantly sorafenib) in combination with LDT in terms of increases in survival.[69] However, two well-conducted studies have suggested that a combination of TKIs and
LDT might improve outcomes. The TACTICS trial, wherein a combination of sorafenib
with TACE improved PFS compared to TACE alone (25.2 vs. 13.5 months; p = 0.006), though OS was not statistically improved in the final analysis. Important
points to note in this study was the use of a novel primary endpoint as an equivalent
of PFS called time to untreatable (UnTACEable) progression and the selection of an
extremely fit cohort of patients in the study.[70]
[71] The second study is the LAUNCH 3, a phase 3 clinical trial comparing lenvatinib
plus TACE with lenvatinib alone in patients with advanced HCC (as defined by the American
Association for the Study of Liver Diseases 2018 Guideline on Liver Cancer Diagnosis).
The study showed an improvement in PFS (10.6 vs. 6.4 months; hazard ratio [HR], 0.43;
95% CI, 0.34–0.55; p < 0.001) and OS (17.8 vs. 11.5 months, HR, 0.45; 95% CI, 0.33–0.61; p < 0.001).[72] Both the above studies, while exploring different subsets in the spectrum of HCC,
suggest that combining TKIs with TACE may provide some survival benefit in well-selected
patients. While there is a greater quantum of data with sorafenib in this setting,
the noninferiority of lenvatinib with respect to sorafenib in the advanced setting
as well as potentially better tolerability means there will be increased use of lenvatinib
with LDT in the aforementioned scenario.
There is limited data to suggest benefits of adding immunotherapeutic agents like
durvalumab, tremelimumab, and atezolizumab-bevacizumab to LDT, though they are being
evaluated in a similar scenario in clinical trials. It is important to note that BCLC
B intermediate stage includes patients with Eastern Cooperative Oncology Group (ECOG)
Performance Status (PS) 0 only. Patients with ECOG PS 1 are classified as BCLC C and
will only be candidates for systemic therapy. In clinical practice patients with ECOG
PS 1 are usually included in the same bracket as BCLC B and treated with LDT, with
or without systemic therapy.[73]
Statement 5.2: In patients with BCLC B (Intermediate stage) the use of sorafenib 800 mg per day
concurrently with TARE can be used on a case-to-case basis. This should be limited
to patients with CTP A-B7 and PS 0-1 only. (II, B)
Statement 5.3: In patients with BCLC B (Intermediate stage) the use of lenvatinib (weight-based)
concurrently with TARE can be used on a case-to-case basis. This should be limited
to patients with CTP A-B7 and PS 0-1 only. (II, C)
Available evidence suggests that TARE in unresectable HCC (BCLC B and BCLC C) has
not improved survival compared to sorafenib. This is true in patients who would have
been candidates for TACE and have been treated with TARE (BCLC B) or patients who
have been candidates for systemic therapy alone (BCLC C).[74]
[75] Additionally, the addition of TARE to sorafenib in patients with unresectable HCC
or HCC with limited extrahepatic disease has also not improved survival compared to
sorafenib alone.[76] However, the increasing realization that such patients are at a high risk for the
development of distant metastases or disease progression can entail the use of systemic
therapy on a case-to-case scenario based on a multidisciplinary assessment.
Statement 5.4: In patients with BCLC C with PVT (VP3/VP4), the primary modality of therapy should
be systemic therapy. (I, A)
Statement 5.5: In patients with BCLC C with PVT (VP3/VP4), TARE alone can be considered in select
cases. (II, B)
Statement 5.6: In patients with BCLC C with PVT (VP3/VP4), systemic therapy and TARE can be considered
in select cases. (II, C)
The presence of PVTT designates advanced disease (BCLC C) and confers a poor prognosis.
Out of various classification systems for PVTT, the Vp classification system from
the Liver Cancer Study Group of Japan is the most commonly used and the knowledge
of the location of PVTT impacts prognosis and therapeutic options.[73] The risk of extrahepatic spread is high in patients with Vp3 and Vp4 disease so
use of systemic therapy may be an optimal option with the addition of local therapy
in those without evidence of extrahepatic spread on subsequent imaging, particularly
in those with evidence of initial response and stable liver function.
The standard of care in such patients should be appropriate systemic therapy as detailed
below under systemic therapeutic options used in advanced HCC. It is important to
note that not all trials evaluating systemic therapeutic options have included MPVT
as an inclusion criterion. For example, the REFLECT study evaluating lenvatinib systematically
excluded patients with PVT, whereas these patients were included in IMBrave150 evaluating
atezolizumab-bevacizumab.[4]
[6] However, there is retrospective evidence to suggest that lenvatinib can be used
in the setting of PVT.[77]
[78] Hence, in clinical practice, most systemic therapeutic options can be used in HCC
with PVT with the understanding that outcomes may not be commensurate with those seen
in clinical trials.
Conceptually, in patients with liver-limited disease, but PVT, there is a propensity
to consider LDT and TARE is an attractive option in this scenario. Although initial
prospective studies showed promise, three randomized controlled trials have failed
to demonstrate superiority of TARE compared to sorafenib, even when TARE was combined
with sorafenib.[74]
[75]
[76] Some of the lack of benefit with TARE in older studies can be attributed to lower
than effective doses of radiation delivered, though this has been standardized with
time. The effectiveness of TARE, with or without systemic therapy, in this patient
population is an area of need.
Statement 5.7: In patients with BCLC C (Advanced disease) HCC, the following systemic therapeutic
can be considered as first-line therapy;
-
Atezolizumab plus bevacizumab (no prior history of transplantation/autoimmune disorders
and should have an endoscopic evaluation within prior 6 months with properly treated
esophageal varices and no history of major bleeding) (I, A)
-
Durvalumab plus a single priming dose of tremelimumab (1A)
-
Lenvatinib (I, B)
-
Sorafenib (I, A)
-
Durvalumab monotherapy (I, B)
-
Pembrolizumab or nivolumab (IIC)
Over the last decade several different systemic therapy options have been approved
for the management of advanced HCC and these broadly include TKIs, IO, and antiangiogenic
agents. For patients naive to systemic therapy, sorafenib prolongs OS compared to
placebo, lenvatinib provides a noninferior OS compared to sorafenib, atezolizumab-bevacizumab
prolongs OS compared to sorafenib, and the STRIDE regimen (tremelimumab 300 mg as
a single dose with durvalumab followed by durvalumab every 4 weeks) improved OS compared
to sorafenib alone.[4]
[5]
[79]
[80]
[81]
[82] Additionally, durvalumab alone appears to be noninferior to sorafenib. Limited Indian
retrospective data with regard to sorafenib and the use of IO has shown outcomes similar
to available data from seminal clinical trials. While most therapeutic treatment options
have been compared in trials with sorafenib as the standard arm, there are no large
trials comparing individual IO regimens or IO regimens with lenvatinib. While IO has
shown numerically longer survival and objective responses when cross-compared to lenvatinib
in network meta-analysis, this has not been conclusively borne out from recently published
high-volume multi-institutional retrospective data.[83]
[84] Hence, we recommend both regimens as first-line systemic therapeutic options in
advanced HCC. As previously noted, the REFLECT trial showing noninferiority of lenvatinib
compared to sorafenib had strict exclusion criteria (main portal vein invasion and > 50%
liver involvement excluded). Similarly, the HIMALAYA trial evaluating the STRIDE regimen
excluded patients with MPVT. However, this does not necessarily preclude the use of
these drugs and regimens in routine clinical practice with the understanding of the
relative pros and cons of such an approach. In rare scenarios, nivolumab or pembrolizumab
can be considered in advanced HCC, though both drugs did not improve survival compared
to sorafenib in first-line and second-line trials, respectively.[85]
[86]
Statement 5.8: In patients with BCLC C (Advanced disease) HCC and CTB7, the following systemic therapeutic
can be considered as first-line therapy:
-
Sorafenib (I, A)
-
Nivolumab (II, B)
A majority of clinical trials have systematically excluded patients with CTP-B or
have only included patients with CTP B7 alone. Real-world data has suggested that
certain agents, including lenvatinib and atezolizumab-bevacizumab, can be used safely
with caution in this scenario. If atezolizumab-bevacizumab is considered, careful
assessment of gastrointestinal bleeding risk and adequate treatment of varices must
be performed. Based on the available current evidence, sorafenib and nivolumab are
the first-line therapy options with the most robust data for patients with advanced
unresectable HCC who are unsuitable for LDT and have CTP score B/7.[87]
[88]
Statement 5.9: In patients who have disease progression or intolerance to first-line IO, TKIs like
sorafenib, lenvatinib, regorafenib, and cabozantinib or ramucirumab can be considered.
(IIIC)
Given recency of approvals for IO agents, there are limited data on the use of subsequent
therapies post-progression on first-line IO and such decisions need to be individualized.
Existing data among small cohorts have suggested similar PFS as use post-sorafenib.
Patients with preserved functional status liver functions may be treated with second-line
therapeutic options. This is more a reflection on the lack of trials in this scenario
as immunotherapeutic options have only recently entered the management paradigm of
advanced HCC.
Statement 5.10: In patients who have disease progression or intolerance to first-line sorafenib or
lenvatinib, the following options can be considered as further therapy:
-
Regorafenib (patients must have previously tolerated sorafenib well) (IB)
-
Cabozantinib (1B)
-
Ramucirumab (if alpha-fetoprotein > 400 ng/mL) (1B)
-
Nivolumab + ipilimumab (IIB)
-
Pembrolizumab (IIB)
-
Nivolumab (IIB)
The majority of second-line treatment options have been evaluated post-progression
or intolerance to sorafenib. Similar indications can be used when lenvatinib has been
used as initial therapy, though there are limited prospective data with regard to
the same. Most of the second-line treatment options have shown superiority to placebo
or best supportive care, with no prospective trials comparing the different treatment
options head-to-head.[85]
[86]
[89]
[90]
[91]
[92]
[93]
