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Osho et al. Hepatoma Res 2020;6:55 I http://dx.doi.org/10.20517/2394-5079.2020.42 Page 9 of 15

Surveillance after liver transplantation
Liver transplantation has the advantage of curing not only HCC but also the underlying cirrhosis, and is
thus associated with significantly lower recurrence rates (~10% at 5 years) when restricted to patients within
the Milan criteria on imaging (one lesion < 5 cm or 2-3 lesions each < 3 cm, without vascular invasion
[82]
or extrahepatic spread) . More recently, liver transplant criteria have been expanded to include patients
who are “downstaged”, i.e., patients with larger tumor burden who are treated with locoregional therapy
(LRT) and brought to within Milan criteria. Radiographic response is used as a prognostic biomarker and
serves as a surrogate for tumor biology, with those who exhibit response likely having favorable tumor
biology. Several single and multicenter studies have shown similar survival and rates of post-transplant
recurrence among extended-criteria patients who were successfully downstaged with LRT compared to
those who initially presented within Milan criteria [83,84] . In the largest multicenter study to date including
[85]
patients with HCC from 10 of 11 UNOS regions that underwent liver transplantation, Kardashian et al.
found 5-year overall survival to be acceptable in patients downstaged to within Milan criteria compared to
those initially within Milan criteria (64% vs. 71%). In addition, the authors noted that AFP response to LRT
[85]
provided a useful adjunct to radiographic response in assessing likelihood of successful downstaging .
Post-transplant, HCC surveillance is evolving from a one-size-fits-all strategy to a tailored one based on
an individual’s risk of recurrence. The Risk Estimation of Tumor Recurrence After Transplant (RETREAT)
score developed and validated in a multicenter study by Mehta and colleagues includes 3 variables - AFP
at time of transplantation, presence of microvascular invasion, and the largest viable tumor diameter (cm)
plus the number of viable tumors on explant pathology . Patients are assigned a risk score of 0-8 based on
[86]
the presence or absence of these features. The RETREAT score accounts for the effect of pre-transplant LRT
(as only viable tumor on explant is counted) and stratifies 5-year HCC recurrence risk - noted to be < 3% in
patients with a score of 0 to > 75% in patients with a score ≥ 5. Post-operative imaging surveillance intervals
can then be tailored on the basis of an individual patient’s RETREAT score. For instance, a patient with a
RETREAT score of five might undergo surveillance with CT chest and abdomen every three to four months
for the first two years followed by every six months through year five, while patients with a RETREAT score
of zero might not require post-transplant imaging surveillance at all.

Surveillance after locoregional therapies
LRTs, including ablation, transarterial chemoembolization, transarterial radioembolization, and radiation
therapy, are a standard treatment for patients with early to intermediate stage HCC who are not candidates
for surgical resection or liver transplantation. Furthermore, as previously mentioned, LRT also has a role
in downstaging and “bridging” patients to surgical treatments including transplantation. Response to LRT
is typically assessed radiographically using CT or MRI, with serum biomarkers used as adjuncts. One
of these such systems is known as the Response Evaluation Criteria in Solid Tumors (RECIST), which
uses tumor size and characteristics, involvement of lymph nodes, maximum number of target lesions,
[87]
and disease progression to qualify treatment response for malignancy . The use of RECIST has several
limitations for HCC response assessment, as it does not consider tumor necrosis nor decrease in tumor size
in HCC treated with LRT, and antitumor activity may be poorly correlated. To overcome these limitations,
EASL recommended measuring change in area of tumor enhancement to assess treatment response, and
in 2008, the AASLD proposed modified RECIST (mRECIST) criteria to include change in lesion size,
lesion characteristics, and viable portions of the lesions determined by arterial phase enhancement to
determine the response to treatment [88,89] . Both RECIST and mRECIST criteria classify treatment response
for HCC lesions as complete, partial, stable disease, progressive disease, or development of new lesion(s).
Overall response by both the EASL and mRECIST criteria have been associated with survival and are
thus preferable to RECIST for HCC response assessment . Still, mRECIST has some notable limitations.
[90]
First, the response assessment requires radiologic expertise as ascertainment of viable tumor may not be
straightforward. Second, patients with underlying renal disease or impairment may be unable to tolerate
[91]
a contrast-enhanced examination and, therefore, mRECIST evaluation . In addition, timing of contrast