Original Investigations

Use of Diffusion-Weighted, IntravoxelIncoherent Motion, and DynamicContrast-Enhanced MR Imagingin the Assessment of Responseto Radiotherapy of Lytic Bone

Metastases from Breast Cancer

Michele Gaeta, MD, Caterina Benedetto, MD, Fabio Minutoli, MD, Tommaso D’Angelo, MD,Ernesto Amato, PhD, Silvio Mazziotti, MD, Santi Racchiusa, MD, Enricomaria Mormina, MD,

Alfredo Blandino, MD, Stefano Pergolizzi, MD

Ac

FrScItaMco

ªht

Rationale and Objectives: To investigate the value of diffusion-weighted (DW), perfusion-sensitive, and dynamic contrast-enhanced (DCE)magnetic resonance imaging (MRI) techniques in assessing the response of bonemetastases frombreast cancer to radiotherapy, with partic-

ular emphasis on the role of intravoxel incoherent motion (IVIM)-DW parameters as a potential valuable imaging marker of tumor response.

Materials and Methods: Fifteen women having breast cancer and bone metastases underwent MRI before and after radiotherapy

(3 weeks [time 1], 2 months [time 2], and 4 months [time 3]), consisting of DW, perfusion-sensitive (IVIM), and DCE acquisitions.MR-based DW and perfusion parameters, including water diffusivity (D), perfusion fraction (f), pseudodiffusion (D*), total apparent diffusion

coefficient (ADC-total), fractionated ADCs (ADC-high and ADC-low), and initial area under the gadolinium concentration curve after the first

60 seconds (IAUGC60), were determined. The morphologic MRI findings were also recorded. A one-way repeated measures analysis ofvariance was used to compare the value of MR-based parameters at the different time points.

Results: A significant variation between pretreatment (time 0) and post-treatment (times 1, 2, and 3) was found for ADC-total and D

parameters (P < .001). A statistically significant reductionwas also found for IAUGC60 values between times 0 and 3 (P< .001). A significantchange across the different time points was observed forD* and IAUGC60 parameters (P < .001). On the contrary, there was no statistically

significant change over time for parameters ADC-total, D, f, and IAUGC60 comparing response between each metastasis, that is, the

response to therapy was similar for each metastasis.

Conclusions: DW, IVIM, andDCE-MRI techniques show effectiveness in assessing the response to radiotherapy in bonemetastases frombreast cancer.

Key Words: DW; IVIM; DCE-MRI; bone metastases; radiotherapy.

ªAUR, 2014

Breast cancer accounts for 16% of all cancers in

women, the most common cancer worldwide in

the women after skin cancer. The bone is the most

common site of recurrence of breast cancer, and autopsy

studies showed an incidence of bone metastases of 73% (1).

ad Radiol 2014; -:1–8

om the Section of Radiological Sciences, Department of Biomedicaliences and Morphologic and Functional Imaging, University of Messina,ly (M.G., C.B., F.M., T.D., E.A., S.M., S.R., E.M., A.B., S.P.). Receivedarch 25, 2014; accepted May 20, 2014. Conflicts of interest: None. Addressrrespondence to: C.B. e-mail: cate.benedetto@gmail.com

AUR, 2014tp://dx.doi.org/10.1016/j.acra.2014.05.021

To assess the effectiveness of anticancer therapy, the most

commonly used set of criteria is the Response Evaluation

Criteria in Solid Tumors (RECIST), which focus predomi-

nantly on the physical measurement of solid tumors (2). There

is an increasing awareness that the evaluation of tumor

response to oncologic treatments based solely on anatomic

imaging assessments faces many limitations, and, in particular,

fails in the evaluation of bone metastases (3,4). The limitations

of morphologic-based diagnosis can be successfully addressed

using functional imaging techniques as dynamic contrast-

enhanced (DCE) magnetic resonance imaging (MRI),

diffusion-weighted (DW) MRI, MRI spectroscopy, and posi-

tron emission tomography (PET) (5–7).

1

GAETA ET AL Academic Radiology, Vol -, No -, - 2014

Of note, DCE-MRI and DW-MRI became objects of

utmost interest owing to their potential of providing informa-

tion on tumor blood supply and cellular changes as response to

treatment (8–10). Particularly, the apparent diffusion

coefficient (ADC) has proven to be a reliable predictor of

response to tumor treatment. To our knowledge, the value

of intravoxel incoherent motion (IVIM) imaging has not

been clinically investigated so far (11–13). The IVIM theory

presumes the presence of two diffusion components: true

diffusion component related to Brownian motion of water

molecules and perfusion component related to blood

microcirculation in the capillary network (11,12).

The aim of our study was to investigate the value of DW,

perfusion-sensitive, and DCE-MRI techniques in assessing

the response of bone metastases from breast cancer to radio-

therapy, with particular emphasis on the role of IVIM as a

potential valuable imaging marker of tumor response.

MATERIALS AND METHODS

The Institutional Review Board approved this study.

Informed consent was obtained from each patient.

Subjects

Twenty-five women (mean age, 73 years; range, 67–84 years)

with breast cancer and bonemetastaseswere recruited to partic-

ipate in this prospective study betweenAugust 2012 and August

2013. Diagnosis of bone metastasis was made on the basis of

clinical history, 99mTc-methylene diphosphonate bone scintig-

raphy, PET scan, and/or bone marrow biopsy. We studied only

purely lytic metastases to avoid interference because of the pres-

ence of calcium in sclerotic and mixed metastases. Study inclu-

sion criteria were (1) the presence of pure lytic bone metastases

of the iliac bone and/or upper femurs as demonstrated on

computed tomography (CT) and (2) the presence of pain or

risk of fracture indicating the need to perform radiotherapy

of the lesions. The exclusion criteria were (1) contraindications

to MR and/or to gadolinium-based contrast agents (n = 2) and

(2) inability to lie on the MR table (n = 2).

In the remaining 21 patients, radiotherapy was started imme-

diately after the firstMRI examination. Each patient underwent

the following radiotherapy regimen: five sessions of 4 Gywith a

total dose of 20Gy in aweek. In three patients two pelvic and/or

femoral lesions were treated simultaneously. After radiotherapy,

the patients underwent an MRI follow-up protocol with MRI

examination obtained3weeks, 2months, and4months after the

starting of radiotherapy. Six patientswere unable to complete the

scheduled follow-up. The remaining 15 patients with a total of

16 treated metastases constituted the final study population.

The clinical response to treatment was evaluated at multiple

time points, namely 3 weeks, 2 months, and 4 months after the

starting of radiotherapy.We used the Visual Analog Scale (VAS)

for pain evaluation in which the pain intensity varies from ‘‘no

pain’’ (score 0) to ‘‘worst imaginable pain’’ (score 100) (14).

Of note, at the start of radiotherapy, eight patients had a

VAS score of 5–6 and seven patients a VAS score of 7–10; at

2

time 1 follow-up, pain score of 0–2 was reported in five

patients and 3–4 in 10 patients. At time 2, pain score was

0–2 in seven patients and 3–4 in eight patients. Finally, at

time 3, pain score of 0–2 was reported in eight patients and

3–4 in seven patients. For all the cases, a reduction in analgesic

and opioid intake was observed.

Magnetic Resonance Imaging

All MRI examinations were performed with a 1.5-Twhole-

body imaging system (Achieva; Philips Medical Systems,

Best, the Netherlands). A SENSE XL Torso coil with 16

elements was used in all the patients. SENSE is a Philips spe-

cific scan technique used for optimal coil performance. The

SENSE principle relies on the multiple coil elements in the

XL Torso Coil simultaneously receiving a reduced field of

view image. SENSE reconstruction combines and unfolds

the individual coil images.

In each patient, the region from the subtrochanteric regions

up to the iliac crests was scanned using the following acquisi-

tion protocol:

1. Axial fast-short tau inversion recovery (fast-STIR): 4000/

50/140 (repetition time (TR) in milliseconds/echo time

(TE) in milliseconds/inversion time in milliseconds), slice

thickness 6 mm, and matrix 314 � 314.

2. Axial T1-weighted dual-echo fast field echo (FFE): TR

300 milliseconds, TE 2.3/4.6 milliseconds, flip angle

80�, slice thickness 6 mm, and matrix 280 � 225.

3. Axial DW: TR 1880 milliseconds, TE 73 milliseconds,

slice thickness 6 mm, matrix 124 � 124, b values of 0,

20, 40, 80, 100, 300, 600, and 1000 s/mm2 with spectral

presaturation inversion recovery fat saturation.

4. Dynamic gadolinium-enhanced examinations were

performed with a three-dimensional FFE spectral attenu-

ated inversion recovery, T1-weighted high-resolution

isotropic volume examination sequence using the

following parameters: 4.4/2.2 (TR in milliseconds/TE

in milliseconds), a 10� flip angle, matrix 180 � 180, and

acquisition time 4–6 seconds.

An automated power injector (Mallinckrodt, Hazelwood,

MO) was used to inject a bolus of 0.2 mL of gadoterate meglu-

mine (Dotarem;LaboratoireGuerbet,Aulnay-sous-Bois, France)

per kilogram of body weight through a catheter inserted into an

antecubital vein at a rate of 3mL/s, followed by a 30-mL saline at

the same flow rate. The sequences were started when half the

contrast medium had been injected and were repeated 40 times.

After the dynamic-enhanced examination, an axial delayed-

enhanced T1-weighted turbo spin echo (TSE) with spectral

presaturation inversion recovery fat saturation was acquired

with the following parameters: TR 560 milliseconds, TE

20 milliseconds, slice thickness 6 mm, and matrix 380 � 300.

The sequence parameters are detailed in Table 1.

Imaging after Processing and Data Analysis

A radiologist, with 15 years of experience in MRI, manually

placed regions of interest on each bone metastasis. Fast-STIR

TABLE1.SequenceParameters

UsedforMagneticResonanceStudies

Sequence

Acquisition

Plane

RepetitionTim

e(m

illiseconds)/

EchoTim

e(m

illiseconds)/Flip

Angle

(degrees)

No.ofSignals

Acquired

EPI

Factor

No.ofb

Values

Turbo

Factor

Matrix

Paralle

l

Imaging

Factor

Section

Thickness

(mm)

Contrast

Material

Injection

Fast-STIR

Axial

4000/50/N

A

IT(m

illiseconds)=140

2NA

NA

30

314�

314

1.5

6NO

T1-w

eighteddual-echoFFE

Axial

300/2.3–4

.6/80

5NA

NA

NA

280�

225

1.7

6NO

Diffusion-w

eightedSPIR

fat

saturation

Axial

1880/73/N

A4

53

8*

NA

124�

124

26

NO

3DFFE-S

PAIR-e-THRIVE

Axial-coronal

4.4/2.2/10

1NA

NA

NA

180�

180

22

YESy

T1-w

eightedturbospin-echo-

SPIR

fatsaturation

Axial

560/20/N

A3

NA

NA

10

380�

380

NA

6YES

3D,three-dim

ensional;e-THRIVE,T

1-w

eightedhigh-resolutionisotropicvolumeexamination;F

FE,fastfield

echo;IT,inversiontime;N

A,n

otapplicable;SPAIR,spectralattenuatedinversion

recovery;SPIR,spectralpresaturationinversionrecovery;STIR,shorttauinversionrecovery;EPI,echoplanarim

aging.

*Eightbvalues:

0,20,40,80,100,300,600,and1000s/m

m2.

y e-THRIVEsequenceswere

startedwhenhalfthecontrastmedium

hadbeeninjectedandwere

repeated40times.

Academic Radiology, Vol -, No -, - 2014 MRI ASSESSMENT OF RESPONSE TO RADIOTHERAPY

and precontrast T1-weightedMR images were used as a refer-

ence to determine tumor areas on the corresponding DWand

DCE images. During the regions of interest placement (mean

size, 4.3 mm2; range, 1.4–7.4 mm2), care was taken to encom-

pass as much of the tumor as possible.

The ADC-IVIM parameters were calculated on a voxel-by-

voxel basis and averaged. ADC-IVIM parameter maps were

also generated (15). Themarkers used to evaluate any treatment

response included the signal intensity at different b values, the

water diffusivity (D), the perfusion fraction (f), the pseudo-

diffusion (D*), the total ADC (ADC-total), the fractionated

ADCs (ADC-high and ADC-low), and the perfusion ADC

(ADC-perf = ADC-low to ADC-high) (15).

DCE-MRI data, which also evaluate the permeability and

perfusion ofmetastases, were calculated using a semiquantitative

method, analyzing the initial area under the gadolinium con-

centration curve after the first 60 seconds (IAUGC60) (8–10).

The analysis of all bone metastases was performed both

before (time 0) and 3 weeks (time 1), 2 months (time 2),

and 4 months (time 3) after the beginning of radiotherapy.

Changes in perfusion and diffusion were assessed.

In addition, two independent readers, with 10 and 5 years

of experience in MRI, were asked to independently evaluate

morphologic MR images (fast-STIR, axial T1-weighted

dual-echo FFE, and delayed-enhanced T1-weighted TSE

sequences) (16,17). They were unaware of the patient

treatment response and all clinical data except patient age.

For each patient, all baseline and post-treatment MR images

were analyzed on workstations in two separate sessions, with

a 2-week interval to assess the ability of morphologic MR

images in detecting the response of metastases to radiotherapy

in early phases. The response was classified as present, absent,

or indeterminate.

Finally, 6 months after the beginning of radiotherapy the

same radiologists evaluated the response of treated lesions by

CTusing modified criteria for the detection of bone response

developed at The University of Texas MD Anderson Cancer

Center (MDA criteria), to obtain a standard of reference for

comparison to our IVIM and perfusion data (2,3).

IVIM Magnetic Resonance Imaging

In 1986, Le Bihan et al. introduced the principles of IVIM

used to quantitatively assess the microscopic translational

motions that occur in each image voxel at MRI. Using

IVIM-based DW imaging (DWI), it is possible to estimate tis-

sue diffusivity and tissue microcapillary perfusion using multi-

ple b values (11,12).

In our study, the following equation was used to express the

relationship between signal intensities and b values:

Sb

S0

¼ ð1� f Þexpð�bDÞ þ f exp½ � bðDþD�Þ�; (1)

where f represents the perfusion fraction, in particular the

contribution of blood microcirculation and microscopic

3

Figure 1. (a)Bonemetastasis of the rightiliac bone (arrow). ADC-high map ob-

tained before radiotherapy (time 0) shows

amean ADC value of 1.1� 2� 10�3 mm2/

s. (b) ADC-high map obtained 4 monthsafter the beginning of the radiotherapy

(time 3) shows an evident increase in the

signal of the lesion (arrow). ADC values

are 1.9 � 2 � 10�3 mm2/s, suggestingtumor cell death. ADC, apparent diffusion

coefficient.

GAETA ET AL Academic Radiology, Vol -, No -, - 2014

flow to signal decay (18), D the pure diffusion coefficient (ie,

slow component of diffusion), and D* the pseudodiffusion

coefficient (ie, fast component of diffusion); S0 and Sb are

signal intensities at b = 0 and b = 20, 40, 80, 100, 300, 600,

or 1000 s/mm2, respectively.

We determined f, D, and D* values by fitting experimental

data by means of a Levenberg-Marquardt algorithm (19). The

IVIM parameters (f, D, and D*) for each tumor were

expressed as means of those obtained from all the tumor areas

analyzed.

Figure 2. Signal attenuation curves obtained bymeans of intravoxel

incoherent motion biexponential analysis show behavior of metasta-

ses before and after radiotherapy, with significant increases in D

values at time 1 (3 weeks after the beginning of radiotherapy), time2 (2months after the beginning of radiotherapy), and time 3 (4months

after the beginning of radiotherapy), lowering signal intensity on high

b value. RT, radiotherapy.

Statistical Analysis

A one-way repeated measures analysis of variance (ANOVA)

was conducted to compare the value of each parameter at the

different time points. A ‘‘mixed between-within subjects

ANOVA’’ was then used to analyze the change and an inter-

action effect between D* and IAUGC60 across the time

points. This analysis is an extension of the one-way repeated

measures design mixed with a two-way ANOVA.

The Cohen kappa statistic was used to assess the interob-

server agreement. The guidelines of Landis and Koch (20)

were followed to interpret kappa values: 0.00–0.20, poor

agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate

agreement; 0.61–0.80, good agreement; and 0.81–1.00,

almost perfect agreement.

Differences were considered significant if the P value was

<.05 (21). All statistical analyses were performed using a

statistical software program (SPSS, version 15; SPSS, Inc,

Chicago, IL).

RESULTS

A significant effect between pretreatment examinations (time

0) and each of the post-treatment examinations (times 1, 2,

and 3) was found for ADC-total and D parameters

(Figs 1 and 2) (P < .001). A statistically significant reduction

was also found for IAUGC60 values between times 0 and 3

(Fig 3) (P < .001). On the other hand, a statistically significant

increase for IAUGC60 values was found at time 1 in compar-

ison to time 0 (P < .001).

In 11 lesions,D* was significantly reduced at time 3 (Fig 4);

however, D* calculated as average value of all the lesions was

not significantly reduced between the different times. In addi-

tion, no significant longitudinal variation for f parameter was

4

found at the different times. A significant change across the

different time points for D* and IAUGC60 parameters was

observed (P < .001). A statistically significant interaction

effect denoted a changeover time for these parameters

(P < .001). By comparison, there was no significant difference

in response between different metastases for parameters

ADC-total, D, f, and IAUGC60.

For all lesions, the two readers defined the early tumor

response to treatment evaluated on morphologic images as

indeterminate, with an almost perfect agreement (k = 1.00)

(Fig 5).

On the contrary, the response to treatment at 6 months was

evaluated as complete in 12 patients and partial in three pa-

tients according to MDA criteria (Fig 6).

DISCUSSION

In this study, we sought to determine the value of MR-based

perfusion and diffusion imaging characteristics of bone metas-

tases of breast cancer both before and after radiotherapy

(4,22). In addition, we also compared these results to those

obtained by using the IVIM model.

Figure 3. (a) Coronal maximum intensityprojection (MIP) reconstruction of the arte-

rial phase of gadolinium-enhanced dy-

namic examination, performed at time

0 (before radiotherapy), demonstrates theintense arterial enhancement of the un-

treated right iliac metastasis (arrows). (b)Coronal MIP reconstruction of the arterial

phase of gadolinium-enhanced dynamicexamination, performed at time 3

(4 months after the beginning of radio-

therapy), depicts the disappearance ofthe pathologic arterial enhancement of

the lesion.

Figure 4. (a) Perfusion map obtained at

time 0 (before radiotherapy) shows high

signal intensity of the right iliac bonemetastasis (arrow) (ADC-low to ADC-

high = 2.7 � 2 � 10�3 mm2/s). (b) Fourmonths after the beginning of radiotherapy(time 3), the signal intensity of the metas-

tasis (arrow) is clearly reduced (ADC-low

to ADC-high = 2.0 � 3 � 10�3 mm2/s).

This finding is in accordance with reducedperfusion demonstrated by gadolinium-

enhanced dynamic examination (see Fig

3b). ADC, apparent diffusion coefficient.

Figure 5. (a) The right iliac bone metas-tasis (arrow) is well visible on the axial

fast-STIR image obtained before radio-

therapy (time 0). (b) Four months after

the beginning of radiotherapy (time 3), onaxial fast-STIR image, the lesion (arrow)

shows the same signal intensity and

extension than before radiotherapy. Aslight edema of the gluteal muscles (E) is

related to after radiotherapy myopathy.

STIR, short tau inversion recovery.

Academic Radiology, Vol -, No -, - 2014 MRI ASSESSMENT OF RESPONSE TO RADIOTHERAPY

The results of our study showed a significant response toD

and ADC-total parameters. This response was likely related

to necrosis or cellular lysis because of radiotherapy, which

leads to increases in tissue water diffusivity (D), thus

lowering signal intensity on high b value images with corre-

sponding increases in ADC values (23). Because cell death in

response to treatment precedes changes in lesion size,

changes in DW-MRI may act as an effective, early biomarker

of response to radiotherapy (24,25), therefore overcoming

the limitations of RECIST for response of bone metastases

to treatment.

In our study, we extended our evaluations also to ADC-

high, ADC-low, and ADC-perf (26,27). The increase in

ADC-high values after radiotherapy can be related to changes

in cellularity induced by radiotherapy, thereby resulting in

higher values of D. The ADC-low, which was calculated

using low b values (0–100 s/mm2) and dominated by

perfusion component of the total tissue diffusivity, revealed

no significant differences in bone metastases before and after

radiotherapy. The ADC-perf (calculated as ADC low- ADC

high) showed a decrease after radiotherapy, likely reflecting

a reduction in perfusion.

The pseudodiffusion coefficient (D*) is considered propor-

tional to the mean capillary segment length and average blood

velocity. In particular, in 11 of 16 lesions (68%),D* was signif-

icantly reduced at time 3. These results showed that DW-MRI

measurements are sensitive to tissue perfusion, and the tech-

nique could thus be potentially used to provide assessment

of the microcirculatory perfusion of tissues, in addition to

measuring tissue diffusivity.

Interestingly, although D* after radiotherapy was signifi-

cantly reduced in 68% of the treated metastases, the vascular

volume fraction f showed no change before and after treat-

ment. As yet, it is challenging to provide a definite explanation

for these apparent discrepancies, considering that blood vol-

ume to bone metastasis is clearly reduced as IAUGC60

5

Figure 6. (a) Lytic bone metastasis of the

right iliac bone (arrow) is well visible on the

axial computed tomography (CT) imagebefore radiotherapy (time 0). (b)Sixmonths

after the beginning of radiotherapy (time 3),

on axial CT image, the right iliac bone

metastasis (arrow) shows a scleroticconversion.

GAETA ET AL Academic Radiology, Vol -, No -, - 2014

demonstrated. It is conceivable that D* and f values may

reflect distinct perfusion properties. A similar effect was

recently reported by Luciani et al. (18) in the clinical setting

of liver cirrhosis. In fact, the f value may correlate with the

amount of normal angiogenesis with intact vessels in terms

of basement membrane thickness and pericyte coverage.

Therefore, it may represent an indicator of preserved vascular

permeability (28). It could be argued that the microcapillary

perfusion is affected by tumor hypoxia. In a recent study

focusing on prostate cancer, ADC-low values were lower in

high-risk than in low-risk prostate cancers probably because

of hypoxia than in more aggressive tumor might reduce tumor

perfusion (29).

On the basis of the results of our study, one may advocate

that the use of IVIM perfusion parameters (f) is not useful to

assess the response of bone metastasis from breast cancer after

radiotherapy. Notably, in all patients the DCE MR perfusion

evaluation using IAUGC60 calculation showed a statistically

significant reduction between times 0 and 3, with decreases

in the rate and magnitude of enhancement, indicating success-

ful treatment results.

DCE-MRI is able to provide functional tumor informa-

tion, such as vascular permeability, vessel density, and perfu-

sion (6,30–32). Interestingly, our results showed a

statistically significant increase for IAUGC60 at time 1 in

comparison to time 0; after 3 weeks from the beginning of

radiotherapy, the perfusion parameters showed an increase in

blood flow in all metastases, which well correlates with the

hypervascularization induced by endothelial growth factors

as an early response to radiotherapic treatment (24).

On the contrary, no statistically significant correlation be-

tween semiquantitative perfusion values (IAUGC60) and

microperfusion values of D* was found. This is in line with

the published literature in which only a few studies about

brain and renal circulation showed a significant agreement be-

tween IVIM and DCE MR perfusion (33,34).

Perfusion parameters obtained with DW-MRI could be

different from perfusion parameters measured using intra-

vascular tracers (eg, contrast medium) because the latter

method is influenced by tissue uptake or removal of the

injected tracer (35).

6

To date, there are no universally accepted methods for

assessing tumor response in skeletal metastases. Response is

estimated by a combination of imaging tests, serum and urine

biochemical markers, and clinical evaluations (36).

Bone scintigraphy, plain radiographs, or cross-sectional im-

aging, such as CT or MRI remains the commonest imaging

methods used to characterize and follow up bone marrow

metastases.

Unfortunately, bone scintigraphy suffers from poor spatial

resolution and limited diagnostic specificity; moreover, it may

be unsuitable for the therapy assessment of predominantly lytic

metastases without an associated osteoblastic response (36).

CT scans are also limited in their ability to assess therapy

response of bony disease. RECIST (v 1.1) criteria do allow

individual osteolytic or mixed osteolytic/osteoblastic metasta-

ses to be measured but diffuse disease and osteoblastic bone

metastases are considered as nonmeasurable. Moreover, CT

is not sensitive to early response (4).

There are a number of MRI methods that can evaluate the

bone for metastasis detection and response assessment. How-

ever, morphologic MRI sequences as T1 weighted, T2

weighted, and fast-STIR are not sensitive in the early phase

of response (37).

DWI and DCE-MRI techniques are emerging as accurate

bone marrow assessment tools for detection and therapy

monitoring of bone metastases and myeloma. The major ad-

vantages of DWI include the fact that no ionizing radiation is

administered and no injection of isotopes or any contrast

medium is necessary (38–40).

Limitations of our study must be acknowledged. The first

limitation is that fairly small cohort represents the foremost

criticism of our research. However, our sample could be

considered representative of a subtype of breast cancer bone

metastases (purely lytic) that is more rare than the mixed

lytic-sclerotic type.

A second limitation attains to the standard of reference in

evaluating the response of bone metastases because multiple

biopsies obviously cannot be obtained. Response criteria spe-

cific to bone metastases have been developed at The Univer-

sity of Texas MD Anderson Cancer Center (MDA criteria)

and can be used to assess therapeutic response in numerous

Academic Radiology, Vol -, No -, - 2014 MRI ASSESSMENT OF RESPONSE TO RADIOTHERAPY

types of bone metastases. Recently developed PET Response

Criteria in Solid Tumors allow response to be measured in the

absence of anatomic change through the assessment of meta-

bolic activity; however, PET examination is expensive

(41,42). We used the recently modified MDA criteria and

clinical response as a standard of reference to compare our

data (3).

A third limitation is the use of semiquantitative parameters

(IAUGC60) for the evaluation of T1-weighted gadolinium-

enhanced perfusion examinations. Semiquantitative parameters

may not accurately reflect contrast agent concentration in the

tissue of interest and can be influenced by the contrast agent in-

jection procedure, the scanner settings (including the pulse

sequence, gain, and scaling factors), and target position in the

image. The relationship between IAUGC60 and underlying

physiology is complex and not completely clarified (43,44).

On the other hand, IAUGC60, calculated from the area

under the contrast agent concentration curve up to a

specified cutoff time (60 seconds), has the advantage of being

relatively straightforward to acquire. In addition, it does not

require any curve-fitting or knowledge of an accurate physio-

logical model, and for this reason it is more robust than other

parameters, which can be vulnerable to fit failures in the case

of highly vascular regions, very poorly perfused regions, or

physiological motion; therefore, it has been recommended as

a practical substitute for K trans in clinical studies (45).

CONCLUSIONS

The results of our study indicate that MR functional imaging

techniques, such as DW-MRI, IVIM, and DCE-MRI are

effective tools in assessing the response to radiotherapy. To

be specific, although the f factor showed a limited value, other

parameters such as D*, ADC, and the IVIM diffusion param-

eter (D) seem very promising because they may evaluate

change in tumor viability and vascularity also in the early

phase of response to radiotherapy.

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