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Hepatology Research 2016; 46: 3–9
doi: 10.1111/hepr.12542
Special Report
Response Evaluation Criteria in Cancer of the Liver (RECICL)
(2015 Revised version)
Masatoshi Kudo, Kazuomi Ueshima, Shoji Kubo, Michiie Sakamoto, Masatoshi Tanaka,
Iwao Ikai, Junji Furuse, Takamichi Murakami, Masumi Kadoya and Norihiro Kokudo, for the
Liver Cancer Study Group of Japan
Committee for Response Evaluation Criteria in Cancer of the Liver, Liver Cancer Study Group of Japan, Department of
Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
The Response Evaluation Criteria in Solid Tumors (RECIST) is
inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies such as
radiofrequency ablation (RFA) and transarterial chemoembolization
(TACE). Therefore, establishment of response evaluation criteria
solely devoted to HCC is needed urgently in clinical practice as well
as in clinical trials of HCC treatment, such as molecular-targeted
therapies, which cause necrosis of the tumor. The Response
Evaluation Criteria in Cancer of the Liver (RECICL) was revised in
2015 by the Liver Cancer Study Group of Japan based on the 2009
version of RECICL, which was commonly used in Japan. Major
revised points of the RECICL 2015 is to define the target lesions of
two lesions per organ or three lesions per liver, up to a maximum
of five lesions. The second revised point is that setting the timing
at which the overall treatment response has been changed. The
third point is that the definition of treatment effect 1 has been
changed to more than 50% tumor enlargement, excluding the area
of necrosis after treatment. Overall evaluation of treatment
response has been amended to make it possible to evaluate the
overall response including extrahepatic lesions by systemic
therapy, which is similar to RECIST or modified RECIST. We hope this
new treatment response criteria, RECICL, proposed by the Liver
Cancer Study Group of Japan will benefit HCC treatment response
evaluation in the setting of daily clinical practice and clinical trials,
not only in Japan, but also internationally.
INTRODUCTION
transcatheter arterial therapy; (iv) is also applicable in radiation therapy and systemic chemotherapy as additional
treatment methods; (v) provides separate criteria for the
assessment of direct treatment effects on intrahepatic target
lesions and overall response; and (vi) complies with the
sixth edition of the General Rules for the Clinical and
Pathological Study of Primary Liver Cancer.10 However,
because the 2009 version was not applicable in all clinical
cases following the introduction of molecular-targeted
therapy as a systemic chemotherapy for hepatocellular carcinoma (HCC), we recently revised RECICL for the fourth
time. The revision process this time is in line with the concepts used for the 2009 version but includes relatively
extensive revision of the definition of treatment effect 1
(TE1) and the assessment of overall response.
In Europe, the World Health Organization (WHO) Handbook for Reporting Results of Cancer Treatment in Solid
Tumors (hereinafter the WHO criteria)5 and Response Evaluation Criteria in Solid Tumors (RECIST, version 1.0)6 have
been used conventionally to assess treatment response in
T
HE FIRST VERSION of the Response Evaluation
Criteria in Cancer of the Liver (RECICL) was compiled
in October 1993 and published in a 1994 issue of Kanzo.1
The revised versions of RECICL were subsequently published in Kanzo in 20042 and 20093 and have been used
widely in routine clinical practice. As described in the
2004 RECICL and the version published in Hepatology
Research,4 the basic concepts of RECICL are that it: (i) is
simple and sufficiently applicable in daily clinical practice;
(ii) is internationally acceptable; (iii) is primarily for
locoregional treatments (ethanol injection, microwave
coagulation and radiofrequency ablation [RFA]) and
Correspondence: Dr Masatoshi Kudo, Liver Cancer Study Group of Japan,
Department of Gastroenterology and Hepatology, Kinki University School of
Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
Email: [email protected]
Received 11 March 2015; revision 26 May 2015; accepted 31 May 2015
© 2015 The Japan Society of Hepatology
Key words: hepatocellular carcinoma, Liver Cancer Study Group
of Japan, modified Response Evaluation Criteria in Solid Tumors,
Response Evaluation Criteria in Cancer of the Liver, Response
Evaluation Criteria in Solid Tumors
3
4
M. Kudo et al.
HCC. RECIST 1.0 was simplified further, and version 1.17 is
used widely today. However, the WHO criteria and RECIST
are both inappropriate for the assessment of direct treatment
effects on the target HCC lesion because they use only tumor
size reduction as the criterion for treatment effect and do not
recognize tumor necrosis as a treatment effect even though
the necrosis of HCC is frequently caused by various
locoregional treatments. For example, it has been shown that
pathological necrosis does not correlate with tumor size reduction assessed by the WHO criteria and RECIST after
transarterial chemoembolization (TACE) using lipiodol.8
For this reason, establishing response evaluation criteria that
take into consideration the necrosis of HCC is urgently
needed. In 2010, Lencioni et al. proposed a modified version
of RECIST (mRECIST) that incorporates the necrosis of
tumors as a treatment effect into RECIST 1.0 to make the
appropriate criteria for HCC.9 However, the criteria used to
evaluate necrosis lack accuracy because unidirectional measurements were used. On the other hand, since the 1990s, tumor necrosis has been assessed using bidirectional
measurements to improve the accuracy of treatment response evaluation in RECICL. Therefore, RECICL may
be more specific to HCC. In recent years, treatment
methods for HCC have changed greatly because of the
adoption of molecular-targeted agents. Unlike cytotoxic
anticancer drugs, molecular-targeted agents cause not
only size reduction but also necrosis in tumors due to
their antiangiogenic property. In other words, there is a
greater need to establish proper evaluation criteria for
tumor necrosis. In the 2009 version, the response
evaluation criteria for systemic chemotherapy were
supplemented by RECIST. In this revision, RECICL was
modified to be all-in-one evaluation criteria that are
applicable to all treatment methods by incorporating
the overall evaluation criteria of RECIST. RECICL is
now applicable to extrahepatic lesions and its features
that are specific to HCC remain.
The high incidence of multicentric tumors and of
intrahepatic recurrence and metastasis is a biological feature specific to HCC and not to other types of cancer. Consequently, it is not always appropriate to interpret the
appearance of a new intrahepatic lesion in the untreated
area in the liver as progressive disease (PD). The major
goal of RECICL is that it focuses only on the efficacy of
various treatment methods (locoregional treatments) for
target lesions, and also correlates the treatment effects with
prognosis as much as possible in assessing the overall
response. This is different from RECIST, which is used to
assess the efficacy of one particular therapy. With RECIST,
when current therapy is considered ineffective when PD is
diagnosed, changing to another treatment method may be
© 2015 The Japan Society of Hepatology
Hepatology Research 2016; 46: 3–9
considered. Unlike systemic chemotherapy, treatment by
transcatheter arterial therapy or ablation therapy is not
performed throughout the liver and therefore does not
affect newly developed lesions in untreated areas of the
liver. In other words, when the latter therapies are
repeated for new target lesions, the treatment response
of the new lesions is expected to be the same as that
observed in previous target lesions. Therefore, even if a
new target lesion (i.e. multicentric lesion) appears in a
different area, it should neither represent an indication
for changing the treatment method nor be used to
determine prognosis. This point should be considered
when evaluating treatment response in HCC, and
RECICL provides the evaluation criteria that fully
consider these specific characteristics of HCC.
MAJOR REVISED POINTS IN THE 2015 VERSION
OF RECICL (TABLE 1)
1 Up until the 2009 version of RECICL, tumor enlargement
of 25% or more was defined as TE1 and was treated as
PD. However, a bidirectional enlargement of 25% is
roughly equivalent to a unidirectional enlargement of
11% and is a stricter criterion than the definition of
20% enlargement for PD in RECIST 1.1. This 20% unidirectional enlargement in RECIST 1.1 would be equal to a
44% bidirectional enlargement (1.2 × 1.2 = 1.44 times).
In this revision, we used an enlargement of 50% as the
criterion for TE1 because of its consistency with RECIST
and its usability in clinical settings (Table 2).
2 Up until the 2009 version, lesions subject to evaluation
(target lesions) were intrahepatic lesions, and when
multiple intrahepatic lesions are present, five lesions
from largest to smallest were selected as target lesions.
However, in accordance with RECIST 1.1, two lesions
per organ and a maximum of five lesions in total will
be determined as target lesions in the 2015 version. If
three or more intrahepatic lesions are present, a maximum of three lesions should be counted as target
lesions to comply with the criterion of three or less
lesions that are 3 cm or less in the Milan criteria and
as an indication for ablation therapy.
3 In the 2015 version, it was clearly stated that response to
locoregional treatments should be assessed 1–3 months
after completion of therapy or at the last treatment
if a series of treatments were given. In chemotherapy
(including hepatic arterial infusion), treatment response should be assessed 1–3 months after the first
administration of the anticancer agents. If the therapy
is ongoing, the assessment should be repeated every
1–3 months. The efficacy of radiation therapy is
Hepatology Research 2016; 46: 3–9
RECICL (2015 revised version)
5
Table 1 Differences between Response Evaluation Criteria in Cancer of the Liver (RECICL) 2009 and 2015 versions
RECICL 2009 version
RECICL 2015 version
Target lesions
Intrahepatic lesions only
Maximum of five intrahepatic lesions
Measurement direction
Bidirectional
Assess the cross-sectional area of the
tumor by multiplying the major axis of the
maximum cross-section and the maximum
diameter crossing the major axis at a right
angle. However, the unstained region and
the region of lipiodol accumulation without
washout are regarded as necrotized regions.
Immediately after ablation therapy
One month or more after TACE or hepatic
arterial infusion chemotherapy
Six months or less after radiation therapy
Measurement method
Time for evaluation
Treatment response of target
lesions (treatment effect [TE])
TE4
TE4a
TE4b
TE3
TE2
TE1
Tumor necrosis of 100% or 100% reduction
in tumor size
Necrotized area larger than an original tumor
(enough ablative margin)
Necrotized area similar in size to an original
tumor (insufficient ablative margin)
Tumor necrosis of 50–100% or 50–100%
reduction in tumor size
Effect other than TE3 or TE1
Tumor enlargement of >25% regardless
of necrosis
Intrahepatic and extrahepatic lesions
Two lesions per organ or three lesions
per liver, up to a maximum of five lesions
(same as 2009 version)
(same as 2009 version)
(same as 2009 version)
One to three months after ablation therapy
One to three months after TACE or hepatic
arterial infusion chemotherapy
(same as 2009 version)
(same as 2009 version)
(same as 2009 version)
(same as 2009 version)
(same as 2009 version)
(same as 2009 version)
Tumor enlargement of >50%
(excluding the area of necrosis after treatment)
assessed based on the best treatment response observed
during the 6 months of therapy after treatment initiation.
4 Although the evaluation criteria for overall treatment
response were supplemented by RECIST in the RECICL
2009 version, we developed new evaluation criteria in
line with RECIST 1.1 for the 2015 version. For new
lesions that developed after ablation therapy or
transarterial chemoembolization, it is important to describe whether the new lesion is (i) inside or (ii) outside
the previously treated area to make the information
useful in future revisions of the current criteria.
FULL TEXT OF RESPONSE EVALUATION
CRITERIA IN CANCER OF THE LIVER
Subjects
S
UBJECTS ARE PATIENTS who are treated for the
primary lesion and for recurrence. As a rule, contrastenhanced computed tomography (CT) is performed to
assess treatment response in RECICL, the principle targets
in the assessment should be clearly visualized on the
images, and should be hypervascular in intrahepatic and
extrahepatic lesions.
Among all measurable lesions, two lesions per organ
and a maximum of five lesions in total are defined as target
lesions. If there are three or more lesions in the liver, three
nodules should be included in the target lesions. The area
of individual target lesions is calculated by multiplying
the length of the major axis by the maximum diameter
crossing the major axis at a right angle, and the sum of
the areas in all target lesions is used as the baseline area.
All the remaining lesions are regarded as non-target lesions.
Detailed description
Description of past medical history
1 Methods and date when the definitive diagnosis of HCC was
made.
© 2015 The Japan Society of Hepatology
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Hepatology Research 2016; 46: 3–9
M. Kudo et al.
Table 2 Assessment of direct treatment effect on target lesions
Treatment effect (TE)
TE4
Tumor necrosis of 100% or 100%
reduction in tumor size
TE4a: necrotized area larger than the
original tumor (sufficient ablative margin)
TE4b: necrotized area similar in size to the
original tumor (insufficient ablative margin)
TE3
Tumor necrosis of 50–100% or 50–100%
reduction in tumor size
TE2
Effect other than TE3 or TE1
TE1
Tumor enlargement of ≥50% (excluding
the area of necrosis after treatment)
A unidirectional enlargement of 20%, which is defined as progressive
disease in RECIST 1.1, is equivalent to a bidirectional enlargement of
44% (1.2 × 1.2 = 1.44 times). Therefore, in the new version, the enlargement of a tumor by 50% is defined as TE1 to be consistent with
internationally accepted criteria, RECIST and to be easy to use in the
clinical setting.
2 Previous treatment modality (as described in “Description of treatment modalities”).
3 Dates of initiation and completion of previous treatment.
4 Methods and date when recurrence was diagnosed.
Descriptions of HCC at the time of treatment initiation
In accordance with the sixth edition of the General Rules for
the Clinical and Pathological Study of Primary Liver Cancer
(edited by Liver Cancer Study Group of Japan),10 the
descriptions should include the following items:
1 Tumor location.
2 Tumor size, number and vascular invasion. The tumor
size is presented as the major axis and maximum diameter crossing the major axis at a right angle.
3 Macroscopic classification.
4 Tumor stage (tumor–node–metastasis [TNM]). Even for
tumors that are only assessable by imaging, TNM staging should be described similar to surgical findings
and those of the resected specimen.
5 Histological classification or differentiation.
Description of treatment modalities
1 Treatment names: transarterial therapy (hepatic arterial
infusion chemotherapy, transarterial embolization
[TAE], and transarterial chemoembolization [TACE],
and local ablation treatments such as percutaneous
© 2015 The Japan Society of Hepatology
ethanol injection, microwave coagulation, and radiofrequency ablation [RFA]); radiation therapy; and systemic chemotherapy (including molecular targeted
therapy)
2 Treatment details: for treatments using drugs, the
name of the drugs* (anticancer drugs, lipiodol, etc.),
route of administration, treatment interval, dose, total
number of administrations, and total dose should be
described. For other treatment methods, the details
should be described appropriately. When the treatment is discontinued, the reason for discontinuation
and the presence or absence of adverse effects should
be described.
*Chemotherapeutic agents, any agent directly injected
into the tumor to induce necrosis such as ethanol,
and/or embolization material used in transarterial
chemoembolization should be described.
3 Dates of initiation and completion or termination of
each treatment.
Assessment of direct treatment effect on the
target lesion
1 To assess the treatment effect on the target nodule, the
tumor-necrotizing effect or the rate of tumor size
reduction are calculated based on the size reduction or
disappearance of arterial enhancement of the nodule
on dynamic contrast-enhanced CT. In the assessment,
the findings of dynamic magnetic resonance imaging
(MRI) or contrast-enhanced ultrasonography (US) can
substitute the findings of dynamic contrast-enhanced CT.
2 The necrotizing effect is assessed by diagnostic
imaging. The percent ratio of the necrotized area to the
cross-sectional area of the tumor should be calculated.*
*When various cross-sections are obtained for a single
tumor, the total sum of the necrotic areas should be
used; however, when the maximum cross-section represents the entire findings of the tumor, assessment could
be based on the maximum cross-sectional area.
3 The size reduction rate is calculated using the equation
below after calculating the size by multiplying the major
axis of the maximum cross-section by the maximum
diameter crossing the major axis at a right angle:
Size reduction rate ¼ ð½size before treatment
½size after treatmentÞ=
ðsize before treatmentÞ100
4 Target nodule treatment response (treatment effect [TE]).
Effects on individual lesions are categorized into four categories based on tumor size reduction observed within a
Hepatology Research 2016; 46: 3–9
predetermined period* after initiation of treatment or the
maximum tumor-necrotizing effect.** As shown in Table 2, TE4 is equivalent to a complete response (CR)
and is defined as 100% tumor-necrotizing effect or
100% tumor size reduction. TE3 is equivalent to partial
response (PR) and defined as 50–100% tumornecrotizing effect or 50–100% tumor size reduction.
TE2 is regarded as stable disease (SD) if the effect is neither PR nor PD. TE1 corresponds to PD with an increase
in tumor size of 50% or more,*** excluding the area of
treatment-induced necrosis.
*Treatment effects are assessed 1–3 months after local ablation treatments (percutaneous ethanol injection, microwave coagulation and RFA), hepatic
arterial infusion chemotherapy with or without
lipiodol, TAE, TACE or systemic chemotherapy.
When a series of treatments are performed, the effects
should be also assessed 1–3 months after completion
of the last treatment. The effect of radiation therapy is
assessed using the best response observed during the
6 months after treatment initiation.
**For local ablation treatments, when the nonstained, low-density area is wider across the entire
circumference than the low-density area in the late
phase of pretreatment CT scan (sufficient ablative
margin), the lesion is regarded as 100% necrotized
(TE4a). Although the ideal sufficient ablative margin
is more than 5 mm from an edge around the tumor,
presence of a smaller sized non-stained area of
5 mm can be regarded as a sufficient margin in this
criteria. The disappearance of hypervascularity alone
with the lack of a wider non-stained region compared
with the low-density area on CT scan is judged as
TE4b (insufficient ablative margin). The effect of
TAE or TACE is judged as 100% tumor-necrotizing
effect (TE4) when the following findings are present:
(i) complete tumor disappearance; (ii) lack of tumor
hypervascularity on contrast-enhanced CT; (iii)
strongly dense lipiodol accumulations; or (iv)
shrinkage of lipiodol-accumulated areas across the
lesion when lipiodol is used. The effect of radiation
therapy is also evaluated using the criteria for necrotizing effects when tumor necrosis is observed.
***Up until the 2009 version of RECICL, tumor enlargement of 25% or more was defined as TE1 and
was treated as PD. However, a bidirectional enlargement of 25% is roughly equivalent to a unidirectional enlargement of 11%, and is stricter than the
PD criterion of 20% enlargement in RECIST 1.1. To
ensure consistency with RECIST 1.1, a unidirectional
enlargement of 20% will be equivalent to a
RECICL (2015 revised version)
7
bidirectional enlargement of 44% (1.2 × 1.2 = 1.44
times). Therefore, in the 2015 version of RECICL, a
50% enlargement in tumor size is used as the criterion for TE1 because treatment is continued in most
patients with PD based on RECIST and because of
the usability in clinical settings.
5 When multiple intrahepatic lesions are present, the
treatment effect on target nodules is assessed individually for up to a maximum of three lesions.
Overall evaluation of treatment response
1 From the perspective of intrahepatic and extrahepatic treatment effects and the duration of treatment effects, overall
treatment response is assessed based on the four-grade
system using CR, PR, SD and PD, as shown in Table 3.
2 To use this method to predict the prognosis, TE is
determined and recorded at 1–3 months after treatment
initiation to assess overall response. However, the effect
of radiation therapy is assessed based on the maximum
effect observed within 6 months of treatment initiation.
3 Definition of new lesions. In dynamic CT, dynamic MRI
(including gadoxetic acid-enhanced magnetic resonance
imaging [Gd-EOB-MRI]) and Sonazoid-enhanced US,
new intrahepatic lesions are typically observed as
hypervascularity in the early phase and washout in the
late phase (low-intense nodules on Gd-EOB-MRI hepatocyte phase images or Kupffer defect on Sonazoidenhanced US images). As a rule, new intrahepatic lesions
should be nodules of 10 mm or more. When a new
intrahepatic lesion appears after ablation therapy or
TACE, it is important to determine whether the
location is inside or outside the previously treated area.
Extrahepatic lesions should be nodules of 10 mm or
more, and lymph nodes with a minor axis of 15 mm
or more are regarded as lymph node metastasis.
Table 3 Overall response (evaluation based on the maximum
response obtained over a period of 1–3 months or within 6 months
in case of radiation therapy)
Target lesions
Non-target
lesions
TE4
TE4
TE3
TE2
TE1
Any
Any
TE4
TE3, TE2
Non-TE1
Non-TE1
Any
TE1
Any
New
lesions
Overall
response
No
No
No
No
Yes or no
Yes or no
Yes
CR
PR
PR
SD
PD
PD
PD
CR, complete response; PD, progressive disease; PR, partial response;
SD, stable disease; TE, treatment effect.
© 2015 The Japan Society of Hepatology
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Hepatology Research 2016; 46: 3–9
M. Kudo et al.
Table 4 Reference table for the assessment of treatment effect in liver cancer
AFP, α-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive fraction of AFP; CR, complete response; DCP, des-γ-carboxyprothrombin; PD, progressive disease; PIVKA-II, protein induced by vitamin K absence/antagonist-II; PR, partial response; SD, stable disease.
Detailed criteria
Necrotizing effects are assessed in accordance with the response evaluation criteria for the treatment of a target
nodule.
© 2015 The Japan Society of Hepatology
1 The presence of a non-enhancing area corresponding
to the original nodule after treatment on dynamic
contrast-enhanced CT using an i.v. bolus injection
is regarded as a necrotizing effect. Such non-stained,
low-density areas are enhanced less intensely than
Hepatology Research 2016; 46: 3–9
the surrounding liver parenchyma in the early and
late phases.* In other words, the CT attenuation value
of a non-stained, low-density area does not change
due to contrast enhancement.
***The early phase of contrast-enhanced CT using a
bolus injection represents the hepatic arterial dominant phase, whereas the late phase represents the
equilibrium phase.
2 When lipiodol is used, the presence of a region retaining
lipiodol homogeneously and densely in the tumor on
CT images taken 1 month after therapy is regarded
as a necrotizing area. Contrast-enhanced MRI or
contrast-enhanced US can be used as an alternative.
3 The lowest levels of three tumor markers (α-fetopro-
tein [AFP], protein induced by vitamin K absence/
antagonist-II and Lens culinaris agglutinin-reactive
fraction of AFP) within 3 months (6 months in the
case of radiation therapy) described in the sixth
revised edition of the General Rules for the Clinical
and Pathological Study of Primary Liver Cancer10
should be recorded as reference values for the overall
response evaluation (Table 4).
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© 2015 The Japan Society of Hepatology