Keywords
HCC - LR-TRA - mRECIST - response
Introduction
Hepatocellular carcinoma (HCC) is one of the leading causes of morbidity and mortality.
The incidence of HCC has a rising trend globally as well as in India. This has been
attributed to rising lifestyle diseases like obesity, diabetes, nonalcoholic fatty
liver disease (NAFLD), and alcoholic liver disease (ALD). Hepatitis B virus (HBV)
and hepatitis C virus (HCV) infections continue to be leading causes of HCC in India.[1] As per the National Comprehensive Cancer Network (NCCN) guidelines for hepatobiliary
cancers, version 2.2022, and Liver Imaging Reporting and Data System (LI-RADS),[2] features like arterial phase hyperenhancement (APHE), nonperipheral venous or delayed
phase washout appearance, enhancement of capsule appearance, and threshold growth
are considered characteristics of HCC in high-risk (cirrhosis, chronic hepatitis B,
or current or prior HCC) patients with liver nodule(s), which are 10 mm or more in
size.
Depending on the disease burden and patient's condition, the intent of therapy can
be curative, bridge to transplant/downstaging for transplant eligibility, or palliation.
Curative measure include surgery, locoregional therapies (LRTs), or liver transplant.[3] LRTs ([Fig. 1]) comprise thermal ablation methods (radiofrequency ablation [RFA], microwave ablation
[MWA], and cryoablation), transarterial therapies (bland transarterial embolization
[TAE], transarterial chemoembolization [TACE], drug-eluting bead transarterial chemoembolization
[DEB-TACE], and transarterial radioembolization/selective internal radiation therapy
[TARE/SIRT]), and stereotactic body radiotherapy (SBRT;).
Fig. 1 Locoregional therapies.
The LRTs lead to alterations in tumor morphology, predominantly, secondary to ischemia
and coagulation necrosis. In addition, TACE has local cytotoxic effect on the tumor.
Traditional response evaluation criteria like WHO and response evaluation criteria
for solid tumors (RECIST) define tumor response based on alterations in the size of
the tumor, which do not provide optimal indication of response to LRTs, since LRTs
can induce intratumoral necrosis without reduction in the tumor size. On the contrary,
ablative therapies result in increase in the size of the ablation zone, since ablative
therapies incorporate additional margin of at least 5 mm to address satellite micrometastasis
and microvascular tumor extension, and reduce the likelihood of tumor recurrence.
To address the limitation of the traditional response evaluation criteria, modified
RECIST (mRECIST) was developed, which assessed tumor response at patient level based
on the residual viable enhancing portion of the treated tumor. The LI-RADS tumor response
working group (TRWG) created a lexicon for lesion level response assessment to LRTs,
which targets specific lesions with single or multiple therapies over time or even
different therapies to different lesions. The LI-RADS treatment response algorithm
(LR-TRA) applies only to HCC treated with LRTs like ablation, TAE/TACE, and localized
radiotherapy (SIRT/SBRT). The criteria are to be used with due precautions in patients
receiving systemic therapy and/or concurrent/combined LRT.
Protocol and Imaging Strategy
Protocol and Imaging Strategy
As for diagnosis of HCC, imaging protocol should include triple-phase CT along with
unenhanced acquisition, or dynamic contrast-enhanced magnetic resonance imaging (MRI)
using extracellular or hepatobiliary contrast agents, with arterial, venous, and delayed
phase acquisitions and subtraction imaging. With hepatobiliary contrast, additional
hepatobiliary phase can be acquired at 20 minutes after injection of gadoxetate or
90 to 120 minutes after administration of gadobenate.
The American College of Radiology (ACR) LI-RADS recommends imaging at 1 month post-LRT
and every 3 months thereafter, during the first year of therapy, followed by longer
scanning intervals (3–6 months) subsequently, in the event of involution of the treatment
zone.[4]
Treatment Related Appearances
Treatment Related Appearances
Thermal Ablation
Thermal ablative LRTs include RFA, MWA, and cryotherapy. To achieve adequate ablation
and reduce likelihood of posttreatment recurrence, an ablation margin, 5- to 10-mm
larger than the tumor, is ensured ([Fig. 2]). This addresses adjoining satellite micrometastasis and microvascular invasion,
reducing tumor recurrence likelihood. Usually, the larger the tumor, the larger the
ablation margin. Hence, the ablation zone is always larger than the native tumor.
It starts shrinking 6 months after ablation, until it stabilizes into a smaller ablation
zone.[5] On ultrasonography (USG), the HCC is usually hypoechoic on B mode and demonstrates
increased echogenicity on the arterial phase followed by diminishing (washout) echogenicity
on subsequent phases of contrast-enhanced ultrasound (CEUS). The posttreatment ablation
zone is echogenic on B mode and is hypoechoic (lacks contrast uptake) on all phases
of CEUS ([Fig. 3]).
Fig. 2 Ablation margin.
Fig. 3 Pre-LRT CEUS (top row) demonstrates arterial phase enhancement followed by washout
in subsequent phases, consistent with LR5 observations. Post-LRT CEUS (bottom row)
of same case, demonstrates complete absence of enhancement in the ablation zone, consistent
with LR TR non-viable observation.
The ablation zone initially has a core, which is hyperdense on computed tomography
(CT) and hyperintense on T1-weighted MR image, owing to coagulation necrosis. Thermal
ablation can also result in tissue vaporization and gas production. Most of the gas
is usually absorbed in the blood stream. However, some gas can be entrapped in the
ablation zone for several weeks in some cases, and should not be confused with infection
at the initial (1-month) follow-up. Tumors undergoing cryoablation, however, demonstrate
T1 hypointensity, after successful therapy.
Rim enhancement is an expected finding in the posttreatment setting. A peripheral,
reactive arterial hyperenhancement may also be seen along the ablation zone. This
transient hepatic attenuation defect/transient hepatic intensity defect (THAD/THID)
is probably secondary to arterioportal fistula resulting from ablative procedure.
It becomes isodense/isointense on the delayed images, does not washout, and resolves
over time.
Transarterial Therapies
Transarterial LRTs involve bland embolization (TAE), conventional TACE, DEB-TACE,
and TARE.
Nonradiation-based transarterial therapies involve administration of ethiodized oil
(lipiodol) along with embolic and chemotherapeutic agents (single, double, or triple
cocktail combination of 10 mg mitomycin C, 50 mg doxorubicin, and 100 mg cisplatin).
Lipiodol is hyperdense on CT (unenhanced as well as postcontrast scan; [Fig. 4]). Lipiodol is a good surrogate of tumor response that correlates well with histological
evidence of tumor necrosis.[6]
[7]
[8] However, lipiodol, being hyperdense, can mask arterial phase enhancement of residual
viable tumor. MRI signal is not affected by lipiodol and hence is favored for posttreatment
assessment.[9]
Fig. 4 (A) Pre-transarterial chemoembolization (pre-TACE) unenhanced computed tomography (CT).
(B) Post-TACE unenhanced CT.
Like ablative therapies, the posttreatment area can be larger due to the presence
of necrosis and hemorrhage and shrink over time, in the absence of residual disease.
Findings suggestive of tumor viability include irregular/nodular APHE, associated
with washout, with or without pseudocapsule. Increase in the enhancing component is
also an indicator of viability.
In the presence of posttreatment residual enhancing viable disease, it is apt to provide
the largest dimension of the enhancing portion and its pretreatment measurement, to
succinctly communicate the magnitude of treatment response, for example, LR-TR viable,
largest enhancing dimension of 0.5 cm (pretreatment LR-5 HCC: 3 cm).[10]
Transarterial Radioembolization
TARE/SIRT includes administration of β-emitting radioisotope Yttrium-90, via superselective
catheterization of the feeding arteries, in the tumor bed. Radiation leads to gradual
cell death by apoptosis, over a long duration of time; hence, the arterial enhancement
can persist for over 1 year. Posttreatment, CT/MRI may reveal necrosis or persistent
arterial hyperenhancement involving the treated tumor bed. In some cases, the arterial
enhancement can persist beyond 1 year post-TARE. Follow-up involves imaging every
3 months during the first year posttreatment. There tends to be gradual diminution
of the arterial enhancement in the treated tumor bed, although it may remain stable
as well.[5]
[11]
[12]
[13]
[14]
Stereotactic Body Radiotherapy
SBRT is another form of locoregional radiation–based external radiotherapy. Imaging
appearances are similar to SIRT, and identical response assessment criteria are applicable.
Response Assessment
The size-based bidimensional WHO and unidimensional RECIST criteria are not commonly
used for posttreatment response assessment of HCC.
Table 1
Treatment response categories
|
Treatment response categories
|
Criteria
|
|
LR-TR nonviable
Treated, probably or definitely not viable
|
No lesional enhancement OR
|
|
Treatment-specific expected enhancement pattern
|
|
Equivocal findings: stable or reduced >1 y
|
|
LR-TR equivocal
Treated, equivocally viable
|
Enhancement atypical for treatment-specific expected enhancement pattern and not meeting
criteria for probably viable or definitely viable
|
|
LR-TR viable
Treated, probably or definitely viable
Nodular, masslike, or thick irregular tissue in or along the treated lesion with any
of the following:
|
Arterial phase hyperenhancement OR
|
|
Washout appearance OR
|
|
Enhancement similar to pretreatment
|
EASL and mRECIST
The European Association for the Study of the Liver (EASL) criteria was the first
functional response evaluation approach for HCC treated with LRT.[11] EASL applied the WHO bidimensional measurement to residual arterially enhancing
portion of treated HCC, with ≥50% reduction in the sum of the product of enhancing
diameters after 4 weeks of treatment representing partial response and ≥25% increase
as disease progression. Absence of arterial enhancement implies complete response.
Any tumor not conforming to the above criteria would be categorized as a stable disease.
mRECIST incorporates both the EASL and the RECIST criteria, utilizing a single long-axis
dimension of at least 1 cm of the residual arterially enhancing component of the treated
HCC, for response assessment. A treated case would be considered as partial response,
if the sum of long-axis dimensions of the residual arterial-phase enhancing components
reduces by at least 30% and progressive disease if there is increase by at least 20%.
Complete response represents absence of any arterial enhancement. Any treated lesion
not qualifying the above criteria would be considered a stable disease. mRECIST, like
RECIST, limits response estimation to no more than two lesions per organ and no more
than five in total.
The limitation of EASL and mRECIST criteria is that these criteria rely only on arterial
phase enhancement, which may not be able to always correctly estimate the disease
burden, for example, in cases of atypical HCC, which do not exhibit arterial enhancement.
An important concept to remember is that these criteria provide a systemic as well
as patient level response assessment rather than lesion level estimation. For example,
if a patient who has complete response to LRT develops a new lesion at a site remote
from the treated lesion, he or she would be categorized progressive disease using
these criteria. This should, however, not be considered as failure of locoregional
treatment.
LI-RADS Treatment Response Assessment
The LR-TRA was first established in 2014 by the ACR ([Fig. 5]; [Table 1]). LR-TRA applies to HCC treated with LRTs like ablation, TAE (bland as well as chemoembolization),
TARE, or SBRT. LR-TRA cannot be applied to patients undergoing systemic therapy. ACR
recommends caution while applying LR-TRA in patients treated with a combination of
systemic and LRT.[4]
Fig. 5 Liver Imaging Reporting and Data System (LI-RADS) treatment response assessment.
(Adapted from Kielar et al.[10])
The initial LR-TRA only categorized a lesion as either treated or untreated, without
any reference to tumor viability in the treated lesion. The LR-TRA was revised in
2017 to indicate viability of an observation undergoing LRT.[12] The current v2018 LR-TR assessment categorizes the types of response as follows:
-
LR-TR viable: Viable lesion implies any posttreatment change with residual arterial phase enhancement
or washout or enhancement pattern similar to the pretreatment pattern ([Fig. 6]). For assessment of viable tumor, LR-TRA extends the mRECIST system of response
assessment to lesions treated with LRT. In the presence of residual viable enhancement,
single largest dimension of the viable enhancing portion should be stated. For measurement,
it is recommended to avoid the intervening nonenhancing portion ([Fig. 7]).
-
LR-TR nonviable: Complete absence of enhancement or expected perilesional enhancement qualifies as
LR-TR nonviable ([Fig. 8]). Expected perilesional enhancement can include rim enhancement and reactive geographic
peripheral arterial phase enhancement without washout ([Fig. 9]).
-
LR-TR equivocal: Any findings not meeting the above criteria are categorized LR-TR equivocal.
Fig. 6 Pre-radiofrequency ablation (RFA) magnetic resonance imaging (MRI; top row) demonstrated
arterial phase hyperenhancement (APHE) and washout on the venous phase with a pseudocapsule,
consistent with LR-5 observation. Post-transarterial chemoembolization (post-TACE)
computed tomography (CT) and magnetic resonance imaging (MRI; bottom row) of the same
patient showed lipiodol deposition in the arterially enhancing areas, which were masked
by the high lipiodol density; however, dynamic contrast-enhanced MRI (DCE-MRI) revealed
few nodules with APHE and washout on the venous phase, which represented LIRADS treatment
response (LR-TR) viable observation.
Fig. 7 Measurement approach.
Fig. 8 Pre-locoregional treatment (pre-LRT) magnetic resonance imaging (MRI; top row) showed
a well-circumscribed T2 hyperintense observation in segment 6 of the liver. It was
isointense on T1-weighted image and exhibited arterial phase hyperenhancement and
capsule on delayed phase postcontrast T1-weighted fat-suppressed image, consistent
with the LR-5 observation. Post-LRT MRI (bottom row) showed predominantly T2 hypointense
ablation in segment 6, which was isointense on unenhanced T1-weighted image and did
not enhance on dynamic contrast-enhanced MRI, consistent with LIRADS treatment response
(LR-TR) nonviable observation.
Fig. 9 Pre-transarterial chemoembolization (pre-TACE) magnetic resonance imaging (MRI; top
row) demonstrated T2 heterogeneous observation, which had arterial phase hyperenhancement
(APHE), washout, and pseudocapsule on delayed phase dynamic contrast-enhanced (DCE)
MRI, consistent with LR5 observation. Post-TACE MRI (bottom row) showed predominantly
T2 hyperintense treated observation with only a peripheral arterial enhancement without
any washout, consistent with expected posttreatment observation—LIRADS treatment response
(LR-TR) nonviable.
As discussed earlier, persistent arterial enhancement is now a known phenomenon in
the post-TARE/SBRT setting. There is now growing consensus that this should be categorized
as LR-TR equivocal ([Fig. 10]) rather than viable tumor, unless there is increase in the size of the arterial
enhancing component on follow-up. Lack of increase in the enhancing component on serial
follow-up for a year can be considered as a surrogate of nonviability.[12]
[13] Please note that this is not yet incorporated in the current v2018 LR-TRA criteria.
Fig. 10 Baseline magnetic resonance imaging (MRI; top row) 1 month after transarterial radioembolization
(TARE) revealed peripheral arterial enhancement without washout or internal enhancement,
consistent with Liver Imaging Reporting and Data System LIRADS treatment response
(LR-TR) equivocal observation. Third month follow-up MRI (bottom row) showed resolution
of peripheral arterial enhancement with faint delayed peripheral enhancement, consistent
with LR-TR nonviable observation.
The above criteria can be applied if the treated observation is evaluable. The LR-TR
nonevaluable criteria can be used when there is degradation of image or lack of multiphase
study. Post-TACE observations on CT scan with hyperdense lipiodol deposition may be
considered nonevaluable, as enhancement, used for response assessment, would be masked
by the density of lipiodol.[14]
[15]
LR-TRA, unlike the rest of the response evaluation criteria, allows for a lesion level
rather than patient level assessment, by assigning an appropriate response category
to individual lesions. For example, in a patient with complete response to RFA to
one observation and partial response with residual enhancement post-TACE for another,
the observations would be assigned LR-TR nonviable and LR-TR viable categories, respectively.
Current Challenges and Future of Response Assessment
Current Challenges and Future of Response Assessment
The mRECIST and EASL criteria allow patient level response assessment, whereas LR-TRA
is a lesion level response assessment system. Both have their own significance, as
assessing treatment response on a lesion-by-lesion basis is important to understand
the respective efficacy of various LRT modalities, while a holistic patient assessment
would require an overall impression of the disease burden as well.
LR-TRA relies on the enhancement characteristics of the treated tumor for response
assessment. Ancillary findings like T2 hyperintensity and diffusion restriction are
not considered, given that associated coagulative necrosis and hemorrhage may cause
pseudo-restriction and T2 hypointense signal. In practice, one can often observe soft-tissue
enhancement in viable tumors without arterial hyperenhancement or washout. This can
represent residual disease as well, especially when the treated observations did not
exhibit characteristic APHE or washout, prior to therapy. It is important to note
the type of LRT used, as radiation-related treatment response may have a different
appearance. The upcoming updated version of LR-TRA will address these issues and provide
separate diagnostic algorithms for patients treated with thermal ablation or nonradiation
intra-arterial embolic therapy and for those treated with radiation. Treated stable
or regressing lesions postradiations could potentially be described as “evolving”[12] or “nonprogression.” Increasing the follow-up interval to more than 3 months between
successive studies may be optimal for observations treated with radiation-based LRT.[12]
Clarity on assessing the treatment response in patients on a combination of locoregional
and systemic therapy is also needed. In such situations, it is more important that
the referring oncologist is clear on overall and lesion level picture, rather than
just getting into the semantics of the response criteria to be used. Furthermore,
immunotherapy is being increasingly offered for patients with HCC, and would warrant
newer approaches like immunotherapy modified Response Evaluation Criteria in Solid
Tumors (iRECIST). Quantitative imaging assessment like apparent diffusion coefficient
(ADC) measurements or ADC threshold maps and volumetric assessment of treated observations
can be of incremental value in addition to the current response assessment algorithm.
In addition to imaging-based response assessment, serum alpha-fetoprotein (AFP), AFP-L3
(lens culinaris agglutinin-reactive fraction of AFP), and prothrombin induced by vitamin
K absence-II (PIVKA-II) also known as des-gamma-carboxyprothrombin (DCP) levels are
potential complementary biomarkers for detection as well as response assessment of
HCC. These biomarkers have recently been incorporated in the internationally validated
GALAD (gender, age, AFP-L3, AFP, and DCP) model for diagnosis and prognosis of HCC.[16]
[17]
[18]
Conclusion
LRTs have expanded the therapeutic options for patients with HCC, encompassing curative,
palliative, and bridge therapies for transplant candidates. Each of the LRTs can have
different posttreatment appearances. The mRECIST criteria assess the patient level
response in patients undergoing liver-directed therapies or targeted systemic therapy.
LR-TRA is used for lesion level response criteria, applicable to patients receiving
LRT. Further revision of the LR-TRA criteria is likely, in the light of knowledge
of radiation-based LRT appearances.
