Transcript mRECIST - Epatoncologia.it

Assessment of treatment response for
Hepatocellular Carcinoma (HCC)
Guidelines for evaluating response to treatment
in solid tumours have evolved
WHO
RECIST
mRECIST for HCC
Handbook for
reporting results of
cancer treatment1
Response
Evaluation Criteria In
Solid Tumors4
Proposed modifications to
RECISTv1.1 for assessing
response in HCC6,7
1979
2000
1992
2001
2008
2009
2010
2012
mWHO
EASL criteria
RECIST v1.1
mRECIST
Modified WHO
criteria2,3
Conclusions from the
Barcelona 2000 EASL
conference5
Revised RECIST
guidelines8
EASL-EORTC
HCC guideline9
EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors;
WHO, World Health Organisation.
1. WHO 1979. Available at: http://whqlibdoc.who.int/offset/WHO_OFFSET_48.pdf; 2. Green S, et al. Invest New Drugs 1992;10:239-53; 3. P. Therasse
Ann Oncol (2002) 13(suppl 4): 127-129 ; 4. Therasse P, et al. J Natl Cancer Inst 2000;92:205-16; 5. Bruix J, et al. J Hepatol 2001;35:421-30; 6. Llovet JM, et al. J Natl Cancer
Inst 2008;100:698-791; 7. Lencioni R, et al. Semin Liver Dis 2010;30:52-60; 8. Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47; 9. EASL-EORTC Guidelines. J Hepatology
2012;56:908-43
RECIST criteria key limitations

Designed primarily for evaluating cytotoxic drugs1
• Molecular-targeted or loco-regional therapies can be effective by
causing tumour necrosis2

Measure of antitumour activity based on tumour shrinkage alone1
• Changes in tumour vasculature, metabolism or diffusion
characteristics not assessed3

Tumour necrosis, however, does not always lead to reductions in lesion
size1,2,4-6
Assessment of efficacy of molecular-targeted or loco-regional
therapies based solely on changes in tumour size can be misleading1
1. Llovet JM, et al. J Natl Cancer Inst 2008;100:698-791; 2. Lencioni R, et al. Semin Liver Dis 2010;30:52-60; 3. van Persijn van Meerten EL, et al. Eur Radiol
2010;20:1456-67; 4. Abou Alfa G, et al. J Clin Oncol 2006;24:4293-300; 5. Choi H, et al. J Clin Oncol 2007;25:1753-9; 6. Bruix J, et al. J Hepatol 2001;35:421-30
RECIST criteria key limitations
In 2000, a panel of experts on HCC of the European Association for the
study of the Liver (EASL) amended RECIST criteria.
According to the amended criteria the optimal method to assess
treatment response is to estimate reduction in viable tumor area using
contrast-enhanced radiologic imaging.
AASLD practice guideline on the management of HCC (2005):
treatment response evaluation should take into account the induction of
intratumoral necrotic areas in estimating the decrease in tumor load, and
not just a reduction in overall tumor size.
Lencioni R et al. Seminars in liver disease 2010; 30 (1): 52-60
Many targeted agents improve survival, but are
associated with low response rates according to RECIST
Agent
Tumour type
Objective response
(RECIST)
Survival
benefit
NSCLC
9% (PR)
Yes
Sorafenib2
HCC
2% (PR)
Yes
Temsirolimus3
RCC
8,6% (OR)
Yes
Erlotinib1
NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; CRC, colorectal cancer.
1. Shepherd FA, et al. N Engl J Med 2005;353:123-132; 2. Llovet J, et al. New Engl J Med 2008; 3. Hudes G, et al. N Engl J Med 2007;356:2271-81.
Targeted agents can induce tumour necrosis,
but not necessarily tumour shrinkage
Representative CT scanS from a single patient included in a phase II study of
137 patients with inoperable HCC treated with sorafenib
Reponse by
mWHO
Volume (cm3)
Baseline
Follow-up 1
(8 weeks)
Follow-up 2
(16 weeks)
295
341
285
2
53
51
% necrosis
Tumour size increase
CT, computed tomography
1. Abou Alfa G, et al. J Clin Oncol 2006;24:4293-300
Treatment efficacy assessment
• The endpoint in cancer research is overall survival.
• Tumor response and time to progression have been considered pivotal
for surrogate assessment of efficacy.
• Tumor response was initially measured according to the World Health
Organization (WHO) criteria, and afterwards according to the Response
Evaluation Criteria in Solid Tumors (RECIST) guideline.
• WHO and RECIST define standard measurement methods for
converting radiology image observations into a quantitative and
statistically tractable framework for measuring the response of tumor size
to therapy.
• Target lesions are measured using:
• the bilinear product approach (WHO) or
• single linear summation (RECIST)
Lencioni R et al. Seminars in liver disease 2010; 30 (1): 52-60
Taking tumour necrosis into account:
EASL criteria

2001 EASL Panel of HCC Experts conclusions:1
• Measurement of tumour load by simple bidimensional
determinations of diameter is not accurate enough, since tumour
necrosis due to treatment is not taken into account
• Extensive tumour necrosis may not be paralleled by a reduction in
diameter of the lesion
• Estimation of the reduction in viable tumour volume (recognized by
non-enhanced areas by spiral CT) should be considered the
optimal method to assess the local response to treatment
Definition
Viable tumor:
uptake of contrast agent in the arterial phase of dynamic
computed tomography (CT) or magnetic resonance
imaging (MRI). 2
1. Bruix J, et al. J Hepatol 2001;35:421-30; 2. Lencioni R, et al. Semin Liver Dis 2010;30:52-60
Taking tumour necrosis into account:
EASL criteria
• Tumour necrosis previously not considered
• Tumour necrosis ≠ reduction in tumour diameter
• Spiral CT optimal to assess viable tumour volume
EASL criteria
[change in enhancement
(viable volume)]
1. Bruix J, et al. J Hepatol 2001;35:421-30; 2. Riaz A, et al. J Hepatol 2011; 54: 695–704;
RECIST criteria
(change in size)
Taking tumour necrosis into account:
EASL criteria
Application of EASL panel recommendations to WHO criteria:
CR
No viable lesions
PR
50% decrease vs baseline in sum of viable areas
SD
Neither PR or PD criteria met
PD
25% increase vs smallest sum on study of viable area
or new lesions
1. Bruix J, et al. J Hepatol 2001;35:421-30; 2. Spira D et al. Academic Radiol 2011;18:89-96
EASL criteria better reflect the therapeutic
benefit of loco-regional therapy in HCC

Comparison of two patient cohorts selected from
prospective studies at the same centre assessing DEB-TACE
(n=24) or PEI/RFA (n=31)1
Treatment
DEB-TACE
PEI/RFA
Response
criteria
Response (%)
CR
PR
SD
PD
Overall
RECIST
0
50
29
21
50
EASL
29
46
4
21
75
RECIST
0
0
61
39
0
EASL
74
13
3
10
87
Evaluation of response should incorporate reduction in
viable tumour burden
DEB-TACE, drug-eluting bead transarterial chemoembolization; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
1 Forner A, et al. Cancer 2009;115:616-23.
Taking tumour necrosis into account:
AASLD recommendations

An AASLD expert panel on trial design1 suggested the following
changes to those initially proposed by the EASL Panel of HCC
Experts:2
• Measurements by change in the sum of diameters of viable target
lesions (contrast enhancement in the arterial phase)
• Uniform image acquisition parameters, quality control, and
independent blinded multi-reader assessment to be used

The 2010 update of the AASLD Practice Guidelines for the
management of HCC state:3
• Evaluation of treatment response should take into account intratumoural necrotic areas in estimating the decrease in tumour load
• For the investigation of small nodules in patients at risk of HCC, a
multidetector CT scan for arterial hypervascularity and venous or
delayed phase is recommended
AASLD, American Association for the Study of Liver Diseases
1. Llovet JM, et al. J Natl Cancer Inst 2008;100:698-791; 2. Bruix J, et al. J Hepatol 2001;35:421–30; 3. Bruix J & Shermann M. Hepatology 2010. Available at:
http://www.aasld.org/practiceguidelines
Taking tumour necrosis into account:
EASL-EORTC recommendations

Assessment of response in HCC should be based on
mRECISTcriteria (recommendation 2B)
•

Use of changes in serum levels of biomarkers such as AFP levels is
under investigation
Dynamic CT or MRI are recommended tools to assess response
one month after resection, loco-regional or systemic therapies
(recommendation 1A)
•
•
Follow-up strategies for detection of recurrence include one imaging
technique every 3 months to complete at least two years. Afterwards,
regular ultrasound is recommended every 6 months.
Assessment of time to progression is recommended with CT and/or
MRI every 6-8 weeks based on the modification of the RECIST criteria
during the first year, and every six months thereafter
EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma J Hepatology 2012;56:908-43
Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf
Taking tumour necrosis into account:
mRECIST for HCC
In mRECIST for HCC, tumor response is a result of the combined assessment of target lesions
and non target lesions
EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma J Hepatology 2012;56:908-43
Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf
RECIST vs mRECIST in HCC Patients Treated with
TAE / DEB-TACE
mRECIST
RECIST
p = 0.63
p = 0.009
83 eligible patients (at baseline 69 CPA; 13CPB;1 not documented);
There was a median of 30 days (range, 1–123) between the date of the baseline scan and the
embolisation procedure and 64 days (range, 18–129) between the embolisation and assessment scan.
Adapted from Gillmore R et al. J Hepatol 2011;55:1309-1316
Non–responders vs responders to TACE
according to mRECIST criteria
Overall responses
A
Target lesion responses
B
Kaplan–Meier curves were generated to compare survival rates between responders and non-responders
according to mRECIST radiological assessment methods.
Assessments were also defined according to overall responses (A) and target lesion responses (B)
Adapted from Gillmore R et al. J Hepatol 2011;55:1309-1316
Indipendent prognostic factor for survival in
TACE treated patients
The overall responses measured with mRECIST criteria
between 2 and 3 months after the first TACE are
independently associated with survival
Adapted from Gillmore R et al. J Hepatol 2011;55:1309-1316
Which Response Criteria Best Help to Predict
Survival after TACE in HCC Patients?
Size criteria
Enhancement
criteria
Adapted from Shim JH et al. Radiology 2012;262:708-718
Which Response Criteria Best Help to Predict
Survival after TACE in HCC Patients?
Adapted from Shim JH et al. Radiology 2012;262:708-718;
Which Response Criteria Best Help to Predict
Survival after TACE in HCC Patients?
Survival of 332 BCLC stage B
patients, as determined with EASL
criteria. Data were stratified into
four response categories.
Adapted from Shim JH et al. Radiology 2012;262:708-718;
Which Response Criteria Best Help to Predict
Survival after TACE in HCC Patients?
* Numbers in parentheses are the 95% CIs
Survival of 332 BCLC stage B
patients, as determined with
mRECIST criteria. Data were
stratified into four response
categories.
Adapted from Shim JH et al. Radiology 2012;262:708-718;
Sorafenib: how to evaluate efficacy

Antiangiogenic drugs
• response rate by RECIST criteria is very low: 2% in SHARP, 3.3% in
Asia–Pacific
• however, mRECIST criteria - as adapted by EASL - which reflect
changes in tumor vascularization may be a much more appropriate
criteria to measure response
RECIST
Lencioni R, Llovet JM. Semin Liver Dis. 2010;30:52‐60.
mRECIST
Sorafenib: how to evaluate efficacy
Baseline
RECIST
After treatment
Evaluation according to RECIST
and mRECIST of a voluminous
lesion with central necrosis before
treatment and discontinuous
peripheral enhancement after
treatment with sorafenib.
(A,B) RECIST measurement of the
lesion (arrows) before (A) and after
treatment (B).
(C,D) mRECIST measurement of
the same lesion before (C) and
after treatment (D).
mRECIST
mRECIST measurements were not
taken at the same level as RECIST
measurements to ensure that the
greatest dimension of continuous
enhancement was measured.
For patients with HCC who are receiving antiangiogenic drugs, mRECIST should be used for the
standard assessment of treatment efficacy
Edeline J, et al. Cancer. 2012 Jan 1;118(1):147-56
Sorafenib: how to evaluate efficacy
■ Retrospective analysis of 53 patients who received sorafenib for advanced HCC
•
Patients have undergone a 4-phase CT scan before treatment and repeatedly thereafter
•
mRECIST were evaluated and compared with RECIST 1.1
■ Results :
RECIST
mRECIST
OR: 2%
SD: 79%
PD: 19%
OR: 23%
SD: 57%
PD: 21%
•
Patients with an OR according to mRECIST had a longer OS than nonresponding with SD
or PD (median OS, 18 months and 8 months, respectively; P = 0,013)
•
In the 42 patients with SD according to RECIST, OS differed depending on tumor
response according to mRECIST
•
Median OS for patients who achieved an OR (n = 11), SD (n = 29), and PD (n = 2) was
17, 10 and 4 months, respectively (P = 0,016).
For patients with HCC who are receiving antiangiogenic drugs, mRECIST should be used for
the standard assessment of treatment efficacy
Edeline J, et al. Cancer. 2012 Jan 1;118(1):147-56
EASL may more accurately reflect tumour
burden in HCC than RECIST

Prospective study of 38 patients with advanced HCC receiving
sorafenib (18% BCLC-B; 82% BCLC-C)

22 evaluable patients assessed by CT scan

Overall, progression significantly less frequent by EASL criteria
than by RECIST criteria (p=0.006)
Response criteria
Response (%)
CR
PR
SD
PD
RECIST
0
9
62
29
EASL
0
43
38
19
BCLC, Barcelona Clinic Liver Cancer; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Iavarone M, et al. AASLD 2009 Abstract #936
mRECIST may reflect response to sorafenib in
HCC more accurately than RECIST



34 of 39 patients with advanced HCC were evaluable for
therapeutic effects of sorafenib treatment by MDCT imaging with
contrast medium
Mean age was 70.2 years, HCC stage III (n=7), IVa (n=13), and IVb
(n=14)
Overall response to therapy was evaluated using both RECIST
(v1.1) and mRECIST before therapy initiation and 4-6 weeks after
therapy initiation
Response criteria
Response (%)
CR
PR
SD
PD
RECIST
0
2.9
67.6
29.4
mRECIST
0
35.3
41.2
23.5
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Kuzuya T, et al. AASLD 2010 Abstract #1781.
EASL and mRECIST may more accurately reflect
tumour burden in HCC than RECIST v1.1
 Retrospective analysis of 25 patients with inoperable HCC treated with sorafenib
Response criteria
Response (%)
CR
PR
SD
PD
RECIST v1.1
4
0
72
24
EASL
4
24
52
20
mRECIST for HCC
4
44
36
16
MRI images from patient with PD by RECIST v1.1 and PR by EASL and mRECIST
Baseline
MRI, magnetic resonance imaging
Spira D, et al. Academic Radiol 2011;18:89-96
After 5 weeks of sorafenib treatment
Long arrows, viable tumour; Short arrows and red circles, necrotic areas
Survival of HCC patients treated with sorafenib.
Association with radiologic response
OS according to mRECIST
Responders
Non-responders
Median OS of patients with mRECIST OR
(18.2 months, 95% CI 15.4–20.9) was significantly
better than patients with SD or PD (7.7 months, 95%
CI 6.3–9.0; P=0.013)
OR=objective response
Edeline J, et al. Cancer. 2012 Jan 1;118(1):147-56
OS according to mRECIST in
42 patients with SD according to RECIST
Responders
SD
PD
In the 42 patients with RECIST SD, median OS
differed depending on mRECIST:
17.1 months (OR, n=11), 9.7 months (SD, n=29) and
3.7 months (PD, n=2)
Survival of HCC patients treated with sorafenib.
Usefulness of AFP ratio and mRECIST combination
OS according to AFP ratio
OS according to mRECIST,
Child-Pugh, AFP ratio
AFP ratio≤1 at 8weeks
AFP ratio≥1 at 8weeks
*
OS of patients with AFP ratio≤1 at 8 weeks from the start of
the treatment was significantly better than patients with AFP
ratio>1 (P=0.002)
Median OS of patients with a predictor score of 3 (24 months,
P=0.001) was significantly better than patients with score of 0
(3 months), 1 (5 months) and 2 (21 months)
The combination of mRECIST and AFP ratio is useful for the assessment of prognosis
of patients with advanced HCC treated with sorafenib.
* : score was calculated as sum of the response by mRECIST (PD:0, CR or PR of SD:1), Child-Pugh score (B:0, A:1) and AFP ratio at 8 weeks from the start of the treatment
(>1:0, ≤1:1)
Kawaoka T, et al. Oncology 2012;83:192–200
Survival of HCC patients treated with sorafenib.
Usefulness of AFP response
OS according to RECIST
In 82 patients with DC or PD examined for
baseline and follow-up CT, median OS was not
significantly different (DC=10.1 and PD=7.5
months, P=0.823)
OS according to AFP response
In 32 patients with 20% AFP decrease ( AFP OR),
median OS was significantly better (13.3 months,
P=0,022) than in 53 AFP non-responder patients
(8,2 months)
AFP response is an independent surrogate end point for survival that should be consider
in conjunction with radiologic response evaluation.
OR=objective response
Personeni N, et al. Journal of Hepatology. 2012 ;57:101-07
Survival of HCC patients treated with sorafenib.
Usefulness of AFP response
Overall survival
Progression Free Survival
Patients (n=19) with an early AFP level 20% higher than the baseline value had shorter OS and PFS than
the other patients (OS, 6.9 vs. 18.3 months; P=0.0002; OS rate at 1 year, 20.3 vs. 55.8%; PFS, 1.4 vs. 4.2
months; P=0.0006; PFS rate at 1 year, 7 vs. 23%).
Early increase in AFP of more than 20% within 4 weeks after the initiation of sorafenib
treatment predicts subsequent disease progression.
Nakazawa T, et al. Journal of Hepatology. 2012 ;57:101-07
Considerations for future application of
mRECIST and serum biomarkers

The proposed mRECIST assessment is expected to provide a reliable
method for assessing tumor response in HCC 1

Requirement for adequate skills and expertise – education and trainin 1

Hardware requires standardization to ensure reproducibility and reliable
comparisons, e.g.: 1
• optimization of image acquisition protocols
• uniform image acquisition parameters
• rigorous quality control
• blinded assessments

The use of changes in serum levels of biomarkers (i.e. AFP levels) for
the assessment of response in HCC is under investigation 2
1. Lencioni R, Llovet JM. Semin Liver Dis. 2010;30:52‐60. 2 EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma J Hepatology 2012;56:908-43
Available on: http://www.easl.eu/assets/application/files/d38c7689f123edf_file.pdf