Assessment of Diffusion-weighted Magnetic Resonance (MR) Imaging to Predict Chemotherapy Outcome in Liver Metastases and Hepatocellular Carcinoma (HCC)
In R patients an increase of the mean diameter of the neoplastic cells should be present
from the first week of CHT with a consequent reduction of the ADC-value. Then, the ADC-value
should increase after 2-3 weeks due to the reduction of the cellular volume and to the
increase of the membrane permeability. In NR patients, these biochemical changes should not
be present with a consequent constant ADC-value before/after CHT. Our multicentre study will
allow the recruitment of a higher number of patients vs. previous studies. Moreover,
presently the outcome of CHT in liver metastases is evaluated only after 2-3 cycles of CHT
according to the RECIST (Response-Evaluation-Criteria-In-Solid-Tumors) and then merely on a
dimensional basis. Anyway, frequently liver metastases in R patients, can not show any
significant dimensional change, while they present several biochemical/metabolic changes,
not included in the RECIST, but probably detectable by DW-MRI.
The principal objective of the study is the early assessment of CHT outcome in liver
metastases and advanced hepatocellular carcinoma (HCC). Patients with liver metastasis will
be stratified as R and NR on the basis of the contrast-enhanced CT examination performed 20
days after the beginning of the second cycle of CHT; patients with HCC undergoing therapy
with Sorafenib will be stratified as R and NR on the basis of the contrast-enhanced CT
examination performed 90 days after the beginning of the therapy. The ADC-values obtained
before and after the first CHT cycle will be compared between each patient category to
assess the grade of agreement between the dimensional and functional parameters. Moreover,
the investigators' aim is to assess whether those liver metastases or HCCs presenting a
lower ADC-value before CHT are actually more responsive to CHT in comparison to liver
metastases and HCCs presenting a higher ADC-value.
Secondary objectives: to propose some additional functional criteria to the RECIST 1.1 and
mRECIST (for HCC) criteria based on water diffusion and biochemical changes of the
neoplastic cells. As a further objective it is possible to hypothesize a different response
to CHT of the different tumor histotypes detectable from the different ADC changes induced
- of age, compliant, patients enrolled for CHT, without major contraindications to the MR
- non-confluent liver metastases, from every primary carcinoma histotype
biopsy/surgical-proven, without intralesional necrosis/calcification involving >30% of
- multiple confluent hepatocellular carcinomas, histotype biopsy/surgical-proven in
prevision of treatment with Sorafenib;
- at least one marker lesion allowing reproducible ADC measurements, i.e. placed at the
level of the lower right liver segments;
- detection/enrolment by contrast-enhanced CT before CHT that allow to define the lesion
size or the gross parenchymal involvement (if HCC).
Each patient will sign an informed consent, after the procedure will be completely
For the metastasis: three diameter of each marker lesion will be measured, and the
mean/minimal/maximal ADC±standard deviation will be quantified by region-of-interests (ROIs)
placed within the lesion avoiding lesion margins and the necrotic/intratumoral calcification
areas. All measurements will be repeated for three times even at the level of the adjacent
liver parenchyma (within 3 cm from the lesion margins, keeping a ROI diameter >2 cm).
Consequently, the absolute values (s/mm2) of ADC, and the ADC percentages vs. the adjacent
liver parenchyma measured at the different times will be compared.
For HCC: three diameter of gross parenchymal involvement will be measured, and the
mean/minimal/maximal ADC±standard deviation will be quantified by large region-of-interests
(ROIs) placed within the liver lobe containing the involvement. All measurements will be
repeated for three times even at the level of the adjacent normal liver parenchyma (within 3
cm from the lesion margins, keeping a ROI diameter >2 cm). Consequently, the absolute values
(s/mm2) of ADC, and the ADC percentages vs. the adjacent liver parenchyma measured at the
different times will be compared.
For metastasis: patients will be scanned by DW-MRI and contrast-enhanced CT before the
beginning of CHT (Time 0). The time between the initial MRI and contrast-enhanced CT should
not be superior to one week. MRI examination will be repeated within one week (Time 1) and
20 days from the beginning of the first cycle of CHT (Time 2), and 20 days from the
beginning of the second cycle of CHT (Time 3).
For HCC: patients will be scanned by DW-MRI and contrast-enhanced CT before the beginning of
CHT (Time 0). The time between the initial MRI and contrast-enhanced CT should not be
superior to one week. MRI examination will be repeated after 30 days (Time 1), 60 days and
90 days (Time 3) from the beginning of the CHT.
Contrast-enhanced CT will be performed contemporarily or within one week after the last MRI
Contrast-enhanced CT examination will be performed according to an established protocol by
using a 16/64-row equipment according to the centre involved, contrast bolus-track
technology, slice- thickness reconstruction of 3 mm, before/after ev. injection of iodinated
contrast agent (3 mL/s), during arterial/portal phase.
All MR examinations will be carried out using the following 1.5-T units:
- Gyroscan ACS NT Intera Release 12 (Philips, Eindhoven, The Netherlands) (Trieste and
Florence), gradient strength, 30 mT/m; slew rate, 120 T/m/s; six-channel phased array
- Magnetom Avanto (Siemens, Erlangen, Germany) (Treviso and Napoli), gradient strength,
45 mT/m; slew rate, 200 T/m/s; 2 phased-array coils with 18 elements. The different MR
equipments employed by the different centers will be calibrated by a dedicated phantom.
The phased array multicoil will be adequately positioned to cover the upper abdomen of the
subject lying in a supine position, the arms extended over the head to avoid artifacts.
Patients, fasting from 4 hours, will be instructed to maintain a constant respiration depth,
even with the possibility to use exogenous oxygen delivery to avoid deep respiration. All
acquisitions will be obtained by single-shot sequence to obtain immediately/automatically
The protocol included the following acquisitions:
1. T2-weighted half-Fourier single-shot turbo spin-echo (HASTE) free-breath sequence;
transverse/coronal plane; TR/TE, 810/80 ms; echo-train length, 69; slice number, 40;
slice thickness, 5 mm; intersection gap, 10%; field of view, 300-420 mm; effective
matrix size, 256 x 165; number signal averages (NSA), 1; total acquisition time, 2-3
2. T1-weighted 2D gradient echo in/out phase breath-hold sequence; transverse plane;
TR/TE, 231-121/ 14.6-2.3 ms; slice thickness, 5 mm; slice number, 24; intersection
gap,10%; flip angle, 80°; sense factor, 1.5; field of view, 300-420 mm; effective
matrix size, 256 x 165; NSA, 1; total acquisition time, 18 s;
3. D-weighted echo-planar imaging (EPI) single-shot free-breath sequences will be acquired
on transverse plane with variable EPI factor and the following parameters. Fat
suppression will be obtained by spectral pre-saturation inversion recovery. Isotropic
motion probing gradients will be applied for each DwI acquisition and for each b-value
will be obtained images and corresponding ADC map.
The investigators presently define as R those patients who show a reduction of the liver
metastasis or HCC diameter ≥30% on contrast-enhanced CT at three weeks after the beginning
of the second CHT cycle; if not, it was considered NR. Changes in tumor size after treatment
were calculated by using the formula % Vend =(VB -Vend)/VBx100, where VB was lesion size
before treatment (maximum transverse diameter) and Vend was lesion size 20 days after the
On the basis of the dimensional reduction of liver metastases and parenchymal involvement
(for HCC) on contrast-enhanced CT on Time 3 vs. Time 0 scan, each patient will be classified
as R or NR according to the RECIST and mRECIST criteria. Afterwards, on the basis of the
ADC-values measured during the different MR examinations, the inter/intra-individual
ADC-values will be compared to the results of contrast-enhanced CT to assess the relation
between reduction of the liver metastasis diameter and:
- increase of the ADC-value on Time 3 (after the end of CHT);
- reduction of the ADC-value on Time 1 (very early assessment);
- increase of the ADC-value on Time 2 (early assessment); and to assess whether the
lesions with the highest pre-treatment ADC-value present also the highest dimensional
reduction and the highest ADC-value at the end of CHT; In each center each evaluation
will be performed three times by two blinded observers (all trained how to place the
ROI by an inter-centre conference) to assess the reproducibility of all measurements.
The observers who will assess the MR images will be different from the observers
assessing the CT images and will not be aware about the size changes after CHT. The
investigators will perform data mathematical fitting on multi-b DW-MRI data sets to
calculate the true diffusion and the perfusion fraction.
Statistical analysis will employ linear regression analysis to assess the association
between the ADC-value changes and the CHT outcome.
The transferability of the results of the present study to the clinical practice will be
possible after the achievement of the primary objective, corresponding to the possibility of
stratifying patients as R and NR to CHT through DW-MRI just after one week of treatment
and/or with the pre-treatment ADC assessment. Nowadays, it is necessary to wait 20-30 days
after the end of the second or third CHT cycle to know the individual outcome of CHT. This
determines 2-3 months of ineffective therapy with consequent avoidable pain for the patients
related to drug administration, and unusable costs. The possibility to know the response of
each patient to CHT well in advance will allow avoiding vain drug administration to patients
who could attempt a different treatment or drug combinations reducing treatment costs.
The clinical transferability of the present study will be performed after the achievement of
one or both the secondary objectives, corresponding to the identification of functional
criteria based on water diffusion and biochemical features of the neoplastic cells which can
be proposed as additional or alternative criteria to the RECIST 1.1 and mRECIST, and to the
identification of a different response to CHT of different tumor histotypes. If only one of
these objectives will be reached this study will achieve an important result, allowing a
more correct assessment of individual response to CHT.
Time Perspective: Prospective
Apparent Diffusion Coefficient (ADC) value changes of the lesion during chemotherapy.
Linear regression analysis to assess the association between the ADC-value changes and the CHT outcome.
For metastasis: 2-4-8 weeks after CHT; for HCC: 30-60-90 days after CHT.
Stefano Colagrande, MD
University of Florence
Italy: Ethics Committee