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Page 10 of 15 Osho et al. Hepatoma Res 2020;6:55 I http://dx.doi.org/10.20517/2394-5079.2020.42

administration and imaging acquisition must be precise to prevent misinterpretation. LI-RADS has also
proposed a nomenclature for reporting response, categorizing patients as having residual disease (LR-TR
viable), having complete response with no viable tumor (LR-TR non-viable), or situations in which it is
unclear if there is viable tumor remaining (LR-TR equivocal). There are few, if any, data comparing LI-RADS
response assessment to other response assessments such as mRECIST.

Surveillance after systemic therapy
Systemic therapy is the mainstay of treatment for patients with advanced HCC, and valid radiologic
response criteria are critical for the assessment of treatment response in clinical trials. Sorafenib, an oral
multikinase inhibitor, was the first chemotherapy agent approved for first-line treatment of HCC in the
U.S. on the basis of data from the multicenter, randomized, double-blind placebo-controlled Sorafenib
Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial [92,93] . Since 2017, several
additional tyrosine kinase inhibitors (TKIs) for HCC have been approved for first- and second-line
[97]
indications, including lenvatinib, regorafenib and cabozantinib [94-96] . A study by Edeline et al. compared
RECIST to mRECIST in patients receiving sorafenib for treatment of advanced HCC and found mRECIST
[98]
objective response correlated with an increased overall survival. Similarly, Kudo et al. demonstrated
that objective response per mRECIST was associated with improved survival in a post-hoc analysis of
the REFLECT Trial including patients treated with sorafenib or lenvatinib. Median overall survival for
[98]
patients with an objective response was 22.4 months, compared to 11.4 months for non-responders .
Most recently, Llovet and colleagues evaluated 21 clinical trials in HCC and found a moderate correlation
between progression-free survival or time to progression and overall survival; however, a hazard ratio
[99]
of ≤ 0.6 appeared to be a potential surrogate for improved survival . Overall, these data highlight the
importance of monitoring for both response and progression.

With the introduction of checkpoint inhibitors (e.g., nivolumab, pembrolizumab, atezolizumab/
bevacizumab), durable response rates in approximately 15%-30% of patients have been observed [100] . In
an exploratory analysis of data from Checkmate 040, patients with durable objective responses appeared
to have prolonged survival compared to those with stable disease or progressive disease [101] . However,
it is possible some patients treated with immunotherapy may display “pseudoprogression”, a distinct
radiologic pattern in which deep and durable responses occur after initial progression [102,103] . Although this
is well described for other tumor types, e.g., melanoma, it is currently unclear how commonly this occurs
in patients with HCC. This phenomenon has resulted in the development of specific imaging response
assessment guidelines (irRECIST and iRECIST) for this population, in which radiographic progression
must be confirmed with repeat imaging 4-8 weeks after the first response assessment [104,105] . These various
response assessment classifications are being used in ongoing HCC clinical trials and there has yet to
emerge a standard across all trials [106] . Despite this potential uncertainty regarding optimal ways to assess
response, monitoring for treatment response or disease progression can identify patients who are benefiting
from therapy and those who may benefit from transition to an alternative treatment. Our institutional
practice is to monitor patients with cross-sectional imaging every 2 months while on systemic therapy.

FUTURE DIRECTIONS FOR IMAGING IN HCC
Radiomics, the automated high-throughput extraction and analysis of quantitative and phenotypic features
from radiographic images [107] , has emerged as a non-invasive tool for diagnosis and prognostication in
several cancers, including HCC [108] . Qualitative and quantitative radiomics features may predict HCC
recurrence and treatment response [109] , and are promising as novel biomarkers that may be complementary
to existing serum biomarkers for HCC surveillance and treatment response assessment. However, lack
of reproducibility is a major challenge and further validation studies are needed prior to the adoption of
radiomics in routine clinical practice.