09111912154317320.pdf

Cancer Treatment Reviews 35 (2009) 309–321

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevierhealth.com/journals/ctrv

HOT TOPIC

Beyond RECIST: Molecular and functional imaging techniques

for evaluation of response to targeted therapy

I.M.E. Desar a, * , C.M.L. van Herpen a,d , H.W.M. van Laarhoven a,d , J.O. Barentsz b,e ,

W.J.G. Oyen c,f , W.T.A. van der Graaf a,d

a Department of Medical Oncology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

b Department of Radiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

c Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

article info

summary

Article history:

Received 19 August 2008

Received in revised form 21 November 2008

Accepted 3 December 2008

The development of targeted therapies is a major breakthrough in the treatment of cancer. By evoking

necrosis and cavitation, evaluation based on tumour size alone, as is done in the RECIST criteria, is no

longer an adequate method. New molecular and functional imaging techniques are developed. This

review focuses on the use of new imaging modalities for the evaluation of treatment response of pathway

based targeted therapies. First, the basic principles of functional and molecular imaging modalities are

brieﬂy discussed. Thereafter, their clinical application in targeted therapies is correlated to the underlying

biological mechanism. In this way, the best method for response evaluation for a new agent can be

identiﬁed.

Keywords:

Cancer

Targeted therapy

Molecular imaging

Functional imaging

Introduction

tial response (PR) as a reduction of at least 50% of the product of

these two diameters, progressive disease (PD) as an increase of

25% and stable disease as every response between PR and PD. In

2000, new evaluation criteria called RECIST (response evaluation

criteria in solid tumours) criteria were developed, to make tumour

evaluation easier. 2 RECIST is based on the sum of one-dimensional

measurements of the greatest diameter of the tumour and/ or

metastases. CR is deﬁned by the complete absence of disease, PR

is deﬁned as more than 30% decrease of the sum of these largest

diameters, PD as an increase of more than 20% of the sum of the

largest diameters and stable disease as all outcomes in between.

Thus, both methods are based on the assessment of the size of

the tumour or metastases. Although the RECIST criteria have some

limitations, for the evaluation of treatment response of solid tu-

mours to classic cytotoxic chemotherapy, they are widely applied

and well accepted. Several validation studies have been performed

for the classic cytotoxic tumour treatments. 3–8 However, the ques-

tion is whether these criteria are sufﬁcient for the evaluation of re-

sponse to targeted therapies. The effects of the new therapeutic

modalities, such as angiogenesis inhibitors and anti-vascular ther-

apies, are more complex. Necrosis and cavitation without a change

in size are frequently observed. Thus, the effect of targeted therapy

is often underestimated by using tumour size based RECIST evalu-

ation. For example, single-agent treatment with sorafenib 9 and

bevacizumab 10 in metastatic renal cell cancer failed to achieve

signiﬁcant objective response rates according to the RECIST crite-

ria, but did result in a signiﬁcant increase in progression-free

The development of targeted therapies is a major breakthrough

in the treatment of cancer. Targeted therapies are designed to

interfere with speciﬁc aberrant biological pathways involved in

tumourigenesis. This is in contrast with the generalized cytotoxic

effects of standard chemotherapy. Various mechanisms relevant

in carcinogenesis are exploited by targeted therapies, such as angi-

ogenesis, cell growth signalling and apoptosis. Targeted therapy

has found its way in oncology, administered as, e.g. monoclonal

antibodies or tyrosine kinase inhibitors.

When evaluating response of tumours to anticancer treatment,

a reliable and standardised methodology is essential, not only in

clinical research but also in daily patient care. Therefore, more than

25 years ago, the World Health Organisation (WHO) criteria for tu-

mour evaluation were developed, based on tumour mass assess-

ment on CT or MRI. 1 According to these WHO criteria, the size of

the tumour was assessed by two perpendicular diameters. A com-

plete response (CR) was deﬁned as total absence of disease, a par-

* Corresponding author. Tel.: +31 24 3610353; fax: +31 24 3540788.

E-mail addresses: i.desar@aig.umcn.nl (I.M.E. Desar), c.vanherpen@onco.umcn.nl

(C.M.L. van Herpen), h.vanlaarhoven@onco.umcn.nl (H.W.M. van Laarhoven),

J.barentsz@rad.umcn.nl (J.O. Barentsz), w.oyen@nucmed.umcn.nl (W.J.G. Oyen),

w.vandergraaf@onco.umcn.nl (W.T.A. van der Graaf).

d Tel.: +31 24 3610353; fax: +31 24 3540788.

e Tel.: +31 24 3617133; fax: +31 24 36540866.

doi:10.1016/j.ctrv.2008.12.001

Tel.: +31 24 3610972; fax: +31 24 3618942.

310

I.M.E. Desar et al. / Cancer Treatment Reviews 35 (2009) 309–321

survival (PFS), demonstrating its clinical efﬁcacy. A striking exam-

ple underlining the potential of molecular imaging is the use of

positron emission tomography (PET) with [F-18] ﬂuorodeoxyglu-

cose (FDG) in gastrointestinal stromal tumours (GIST) treated with

imatinib, in which FDG–PET responses preceded the anatomical re-

sponse on CT by several weeks. 11 Response on FDG–PET was asso-

ciated with longer PFS. After comparing FDG–PET results and CT

results in patients with GIST treated with imatinib, Choi et al. pro-

posed modiﬁed CT criteria based on both tumour size as tumour

density. PR is deﬁned as a decrease in size of P10% or a decrease

in tumour density (HU: Hounsﬁeld units) of P15% on CT. PD is de-

ﬁned as an increase in tumour size of P10% and no decrease in tu-

mour density as deﬁned in the criteria for PR. 12 The addition of

tumour density makes it possible to assess tumour necrosis. Be-

sides the difﬁculty regarding the lack of volume changes, CT alone

is not able to differentiate between vital tumour tissue or, for

example, ﬁbrotic tissue. Furthermore, metabolic changes can pre-

cede volume changes, which can be detected by different molecu-

lar and functional imaging techniques. Depicting these early

changes can help to choose the right treatment strategy, including

the ability to prevent unnecessary long treatment courses with

their inherent adverse events and, speciﬁcally in the case of expen-

sive targeted therapies, their costs.

To meet the need for better tools to assess the effects of targeted

therapy, several options can be envisioned. Besides the develop-

ment of new criteria for conventional imaging methods, such as

the Choi criteria for GIST, biomarkers and new functional and

molecular imaging technologies are being introduced. Functional

and molecular imaging implies the quantitative measurement of

physiologic (functional) and molecular events in tumours, which

is now possible utilizing non-invasive new imaging modalities,

radiopharmaceuticals and contrast agents. 13

This review focuses on the use of new imaging modalities for

the evaluation of response to treatment with targeted therapies.

First, the basic principles of functional and molecular imaging

modalities are brieﬂy discussed. Thereafter, their clinical applica-

tion in the evaluation of treatments response to targeted therapies

is correlated with the underlying biological mechanism. In this

way, one can more easily identify the best methods for response

evaluation for a group of drugs. When drugs have multiple targets,

the most dominant pathway is chosen. Only human studies are

discussed.

Figure 1. Parameters as deﬁned by Tofts et al.

a standard set of quantity names and symbols. These include: (1)

a volume transfer constant K trans (min 1 ) also known as wash-in

rate, (2) the volume of the extravascular space (EES) per unit vol-

ume of tissue m e and (3) the ﬂux rate constant between EES and

plasma k ep (min 1 ), the wash-out rate. The rate constant is the ra-

tio of the transfer constant to the EES (k ep = K trans / m e ). Lower values

of k ep or K trans can indicate (1) lower perfusion, (2) lower perme-

ability and/or (3) a smaller blood vessel surface area ( Fig. 1 ).

DCE-MRI has been shown to have diagnostic value in various

tumours and correlates with therapy effect of standard chemother-

apy and radiotherapy.

Diffusion weighted imaging

Diffusion weighted MRI (DWI or DW-MRI) is a unique MRI

alone technique that depicts image contrast that is related to the

thermal motion of water molecules. In biologic tissues the move-

ment of water molecules is restricted because their motion is mod-

iﬁed and limited by interactions with cell membranes and

macromolecules. There is an inverse correlation between the de-

gree of restriction of motion of the water and the tissue cellularity

and integrity of cell membranes. 19–22 This means that in a tumour

with high cellularity, the motion of water molecules is more re-

stricted. On the other hand, when a tumour has a high glandular

component or has signiﬁcant necrosis, there is less restriction of

motion. The apparent diffusion coefﬁcient (ADC; unit mm 2 /s) is

the quantitative parameter used for the assessment of tissue diffu-

sion. The word ‘‘apparent” in this notation is being used to indicate

that diffusion in tissues is not free. A low ADC reﬂects restricted

diffusion. In general, treatments inducing apoptosis (e.g. chemo-

therapy) results in increased ADC values due to cell swelling, tu-

mour lysis and necrosis. 23 Statistically signiﬁcant increases in

ADC values can be seen within a few days. However, the duration

of raised ADC values tends to be short because tissue dehydration

following cell death subsequently decreases ADC value 24 this is un-

like K trans changes which are persistently reduced following suc-

cessful therapy.

Molecular and functional imaging techniques

Magnetic resonance imaging (MRI)

MRI is a non-invasive imaging technique, which makes use of

strong magnetic ﬁelds. It has a good depth penetration and is able

to provide high-resolution anatomical information, without radia-

tion safety issues. By using speciﬁc MR techniques functional infor-

mation on tumour perfusion, 14 vascular permeability, 15 vascular

volume and ﬂow, extracellular space tortuosity 14 and hypoxia 16

can be obtained.

Dynamic contrast enhanced MRI

Dynamic contrast enhanced MRI (DCE-MRI) is performed after

injection of a contrast agent. Usually the low molecular weight

contrast agents (e.g. gadopentetate dimeglumine, Gd-DTPA) are

used. MR sequences can be designed to be sensitive to the vascular

phase of contrast medium delivery, so-called T2 methods. From

these images data on tissue perfusion and blood volume can be ex-

tracted. By using sequences sensitive to the presence of contrast

medium in the extravascular extracellular space, so-called T1

methods, information on microvessel perfusion, permeability and

extracellular leakage space is obtained. 17 Tofts et al. 18 described

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) provides chemical

information about tissue metabolites. 25 Just like MRI MRS makes

use of the properties of certain nuclear isotopes (e.g. hydrogen 1

( 1 H), phosphorus 31 ( 31 P), ﬂuorine 19 ( 19 F), carbon 13 ( 13 C), deute-

rium ( 2 H), tritium ( 3 H) or sodium 23 ( 23 Na)). When placed in a

strong magnetic ﬁeld these nuclei start to resonate at a speciﬁc fre-

quency, which can be measured by MRS. The application of such a

strong magnetic ﬁeld induces electronic currents in atoms and

molecules producing further small magnetic ﬁelds. The size of

these small ﬁelds depends on the (electronic) environment of the

speciﬁc nucleus. Different chemical environments give rise to sig-

I.M.E. Desar et al. / Cancer Treatment Reviews 35 (2009) 309–321

311

nals at different frequencies. Thus, a MR spectrum is a kind of

molecular ﬁngerprint and may contain many resonance frequen-

cies or peaks, one for each chemically distinguishable site or group

in a given metabolite or for speciﬁc sites in a variety of metabolites.

and an inefﬁcient metabolism, which is the molecular basis for

FDG-positive cancer lesions on PET scans. However, high glucose

metabolism is not speciﬁc for cancer. Normal organs, such as the

brain, 26 and in some patients the heart 27 accumulate FDG, as do

activated white blood cells in inﬂammatory lesions. 28 Besides the

use of FDG–PET for characterizing, staging and restaging of tu-

mours, the application of FDG–PET as a prognostic marker and an

(early) predictor of therapy response after conventional chemo-

therapy was evaluated. Review of these data is beyond the scope

of this study. Excellent reviews have been published before (e.g.

[29,30] ).

One of the challenges of using FDG–PET in clinical studies and

daily practice is the need for standardization and validated re-

sponse criteria. In 1999, the EORTC proposed a set of criteria to

determine PET response. In 2006, a workshop of the National Can-

cer Institute made recommendations to develop a standard FDG–

PET protocol for NCI-sponsored clinical trials to assess treatment

efﬁcacy. In these recommendations was stated that there is no

one best methodology for obtaining or analyzing FDG–PET scans,

nor is there one agreed-on standard for judging the signiﬁcance

of a response seen on FDG–PET. The timing of the post treatment

imaging was recommended two weeks after the end of a speciﬁc

chemotherapy cycle, although the exact timing could depend on

the frequency and duration of therapy. 31 An ENASCO working

group is now working on the revision of these standardised re-

sponse criteria for FDG–PET in solid tumours. Driven by nation-

wide multicenter trials, a Dutch multidisciplinary group developed

extensive recommendations for further standardization of PET

acquisition and processing (Boellaard et al., EJNMMI 2008, Epub

ahead of print). Recently, an International Harmonization Project

(IHP) was convened to discuss standardization of clinical trial

parameters in lymphoma. 32 It was considered adequate to rely

on visual assessment alone for interpreting PET ﬁndings as positive

or negative when assessing response after therapy in lymphoma. In

solid tumours, however, only visual assessment is insufﬁcient. At

present a wide range of quantitative criteria based on SUVs has

been proposed. The most often applied SUV reduction of 35% for

a minor response and 60% for a major response seem reasonable.

These criteria should also allow to combine the metabolic changes

with volumetric changes, as can be obtained with a integrated

FDG–PET-CT. Validated and generally accepted quantitative crite-

ria to assess metabolic response using SUV are urgently required.

This is the only way to make sure that future evaluations of (tar-

geted) therapy by FDG–PET will be reproducible and validated.

In summary, FDG–PET has proven to be an important improve-

ment in cancer imaging including its use for the evaluation of

treatment response to conventional chemotherapy. Its role in the

evaluation of targeted therapy is less clear. Available human data

will be discussed in the pathway based imaging section.

Computed tomography (CT)

Contrast enhanced CT is the most commonly used imaging

technique in oncology, as is it widely available, fast and conve-

nient. It provides a high anatomical resolution and by using the

Hounsﬁeld units (HU) it gives information about tissue density.

However, it lacks the ability to provide biochemical and physiolog-

ical information.

Dynamic contrast enhanced perfusion CT

Dynamic contrast enhanced CT (CTP) is also called functional

CT, dynamic CT or perfusion CT. CTP can provide information about

blood ﬂow, blood volume, capillary permeability and micro vessel

density. After an intravenous bolus of conventional iodinated con-

trast, a series of images is performed. There is a linear relation be-

tween the concentration of contrast agent and the attenuation

numbers (expressed in HU). The used parameter is the standard-

ised perfusion value (SPV), deﬁned as the ratio of tumour perfusion

to whole body perfusion.

Radionuclide imaging

PET and single-photon emission computed tomography (SPECT)

are both radionuclide imaging techniques. PET is based on a unique

feature of positron emitting radionuclides: upon annihilation of a

positron with an electron two 512 keV gamma rays are emitted

with an angle of 180. A ring of detectors is used to detect these

gamma rays, allowing three-dimensional image reconstruction.

Standard acquisition protocols provide whole body images, which

allow convenient quantiﬁcation of all visualized lesions, expressed

as standardised uptake values (SUV). More advanced, dynamic

imaging allows absolute quantization of tracer uptake and kinetics

over time. PET-CT enables the assessment of molecular character-

istics as depicted by PET with anatomical structures on CT. Cur-

rently, efforts are being made to construct combined PET–MRI

scanners to further enhance the potential of multimodality

imaging.

For PET, a wide variety of radiopharmaceuticals are available,

encompassing speciﬁc molecular features of tumours and normal

tissues, e.g. metabolism (FDG), proliferation (FLT), amino acid up-

take and protein synthesis (e.g. FET), hypoxia (e.g. F-MISO), perfu-

sion and blood volume ( 15 O-water, 11 C-carbon monoxide).

Furthermore, the recently introduced use of positron emitting

radionuclides for labelling of monoclonal antibodies (immunoPET),

peptides and other receptor-targeting compounds, has broadened

the horizon for mechanistic studies.

SPECT involves the use of radionuclides that emit single gamma

rays. In contrast to PET, SPECT generally has lower sensitivity and

quantiﬁcation of SPECT is more challenging. Several biological

compounds such as antibodies and peptides can readily be labelled

with single photon-emitting radionuclides, such as indium-111,

radioiodine and Tc-99m.

Fluoro- L -thymidine PET (FLT-PET)

The thymidine analogue FLT accumulates in proliferating tis-

sues. FLT is transported across cell membranes by nucleoside

transporter proteins. Once intracellular, FLT is phosphorylated by

thymidine kinase I. Similarly to FDG, the phosphorylated FLT is

trapped intracellularly, but is not further incorporated into DNA.

Thereby, FLT-PET uptake is a marker for proliferation.

FDG–PET

FDG is by far the most commonly used radiopharmaceutical for

PET. FDG is transported into the cell by glucose transporters,

mainly glucose transporter-1 (GLUT-1). Thereafter, FDG is phos-

phorylated. As FDG-6-phosphate is not further metabolized it is

as such irreversibly trapped inside the cell. Thus, FDG uptake on

PET reﬂects the metabolic activity of cells. Cancer cells are known

to have higher rates of glucose uptake, due to increased demand

F-MISO-PET

This tracer has been used to image tissue hypoxia in human tu-

mours. F-MISO accumulates in tissue by binding macromolecules

when pO 2 < 10 mm Hg. F-MISO is only sensitive to hypoxia in via-

ble cells, not in necrosis.

In lung tumours, F-MISO was able to monitor the changing hy-

poxia during radiotherapy. 33

In head and neck cancer, 34 F-MISO

312

I.M.E. Desar et al. / Cancer Treatment Reviews 35 (2009) 309–321

uptake was correlated to poor outcome to chemotherapy and

radiotherapy.

DCE-MRI parameters (namely K ep and K trans ) was observed, indi-

cating a drop in tumour blood volume and/or perfusion and/or

permeability. However, these changes were not signiﬁcantly cor-

related to clinical response in most cancers except perhaps renal

cell cancer. 41–43 Targeted therapies directed to VEGFR or down

stream signalling have also been evaluated by DCE-MRI. Unfortu-

nately, different MRI protocols and different methods for quanti-

ﬁcation have been used. Overall, in most studies dose dependent

decreases in tumour blood perfusion, or tumour blood ﬂow are

found, even in phase I studies when the tumour microvasculature

would be expected relatively resistant. Although changes in DCE-

MRI parameters can occur as early as 24 h after initiation of the

therapy, such changes are not always reliable for all anti-VEGF

therapies because of the transient phenomenon of vascular nor-

malization when regional increases in blood ﬂow can be detected

– this is not always observed. ( Table 1 ) Since vascular normaliza-

tion is of short duration, vascular collapse using anti-VEGF strat-

egies is most reliably detected after two weeks. From the two

registered multi kinase VEGFR inhibitors, sorafenib and sunitinib,

sorafenib is most extensively evaluated by molecular and func-

tional imaging techniques. In total more than 220 patients, in

nine studies 44–52 were treated with sorafenib (some of them com-

bined with bevacizumab 44 ). Four studies showed decreases in

DCE-MRI parameters corresponding with clinical treatment out-

come. 44–47 Remarkably, in the combined sorafenib–bevacizumab

study, no signiﬁcant changes were found at ﬁrst evaluation of sin-

gle-agent therapy (4 weeks after start of treatment) while after

the following combination therapy in the same patients DCE-

MRI parameters, especially K trans , decreased. 44 Suninitib has not

been evaluated by DCE-MRI so far. Of the other VEGFR inhibitors,

vatalanib, semaxanib and cediranib, have been most intensive

evaluated by DCE-MRI. Vatalanib and cediranib showed decreases

in DCE-MRI parameters as early as 2 days after start of treatment.

In case of vatalanib, this decrease was dose dependent and corre-

lated with clinical outcome. 53–56 However, vatalanib was unsuc-

cessful in phase III combination studies indicating that apparent

success as a single agent in early phase clinical studies may not

translate into ultimate clinical efﬁcacy. The DCE-MRI results for

semaxanib in four studies are conﬂicting ( Table 1 ). For the other

VEGF/PDGF pathway agents only single DCE-MRI studies with

limited numbers of patients have been published. Disparate re-

sults with VEGF/PDGF inhibition on DCE-MRI maybe due to

antagonistic effects of anti-permeability due to VEGF inhibition

and pro-permeability effects of PDGF inhibition. This indicates

that anti-angiogenic therapies do not always result in reductions

of blood ﬂow in the short term and that DCE-MRI kinetic re-

sponse relationships are not universally strong across all tissue

sites for all drugs.

CTP showed a decrease in tumour perfusion and blood volume

7–12 days of start of treatment with bevacizumab. 57,58 These stud-

ies did not correlate imaging ﬁndings to clinical outcome. In ad-

vanced carcinoids on stable octreotide doses, patients were

randomly assigned to bevacizumab or peg-IFN- a 2b. CTP showed

a signiﬁcant decrease in tumour blood ﬂow, respectively, 2 days

and 18 weeks after start of bevacizumab compared to interferon.

Only the day 2 CTP results of bevacizumab were related to a longer

PFS. 59 Cediranib, 60,61 SU6668, 62 sorafenib and sunitinib 63 have also

been studied by CTP and showed a drop in tumour blood ﬂow and

tumour blood volume. The decrease in tumour blood ﬂow was

predictive for treatment response in case of sorafenib and sunitinib

treatment. 63

Only four studies used ultrasound for the evaluation of treat-

ment response. The observed decrease in vascular density in pa-

tients treated with semaxanib did not correlate with clinical

outcome, 64 while responders to sorafenib as assessed by DCE-US

proved to have a better PFS. 48 Similar DCE-US results were found

15 O-water-PET

15 O is able to bind to hydrogen or carbogen, thereby providing

two important tracers: 15 O-water and C 15 O. 15 O-water-PET allows

determination of blood ﬂow perfusable tissue fraction, and volume

of distribution with high spatial resolution.

Radiolabeled receptor-targeting ligands

Several radiopharmaceuticals have been developed for PET and

SPECT imaging of receptor and antigen expression on tumour cells.

Aims of these techniques are for example to monitor VEGF expres-

sion or to evaluate the tumour response to drugs as bevacizumab 35

and anti-angiogenic drugs. Examples are 123 I-VEGF and 111 In-hnTf-

VEGF (drug target: VEGFRs), 111 In-trastuzumab (drug target:

HER2), 111 In-EGF (drug target EGFRs), 18 F-ﬂuoro-oestradiol and

radiolabelled somatostatin analogues. 36,37

Ultrasound (US)

Ultrasound uses waves to visualize body organs and blood-ﬂow

velocity, based upon the fact that the speed of sound through tis-

sue varies with tissue density and that the accompanying echoes

can reveal these differences. The Doppler technique makes it pos-

sible to assess blood ﬂow. US is frequently used in the oncologic

clinical practice.

Dynamic contrast enhanced US

US contrast agents, such as microbubbles, nanoparticles or per-

ﬂuorcarbon gas, alter wave absorption and reﬂection. This en-

hances the intensity of the signals bouncing back from the

tissues. This provides morphologic and physiologic information,

without biochemical information.

Molecular and function imaging for response evaluation to

targeted therapy

Several molecular and functional imaging techniques have been

used for the evaluation of targeted therapy. Frequently, this has

been done within phase I or early phase II trials. As a result, num-

bers of patients are low, while the diseases and treatment or imag-

ing protocols are heterogeneous. Here we summarize the literature

on this.

VEGFR/PDGFR pathway

VEGF and its receptors play a pivotal role in both normal and

pathological malignant angiogenesis. Activation of the VEGFR

pathway leads to endothelial cell activation, proliferation and sur-

vival, degradation of the basement membrane which is necessary

for endothelial cell migration and invasion, increased vascular per-

meability and mobilization of endothelial progenitor cells (EPCs)

from the bone marrow into the peripheral circulation. 38 VEGF is

expressed in response to hypoxia, oncogenes or cytokines. The

VEGFR pathway is considered to be the most important and best

explored pathway in angiogenesis of tumours. The platelet derived

growth factor receptor (PDGFR) pathway is also important for angi-

ogenesis. However, the exact mechanism remains to be eluci-

dated. 39 PDGF is important for the recruitment of pericytes,

which are required for microvessel stability. 40

DCE-MRI is the most frequently used functional imaging tech-

nique for the evaluation of this pathway. Usually as a pharmaco-

dynamic biomarker in early phase, single-agent studies. After

start of VEGF antibody therapy, i.e. bevacizumab, a decrease of

I.M.E. Desar et al. / Cancer Treatment Reviews 35 (2009) 309–321

313

Table 1

VEGFR/PDGFR.

Reference Drug

Target

Tumour

Technique n Result

[98]

Axitinib

VEGFR, PDGFR, KIT Solid cancer DCE-MRI 17 Decrease in K trans and AUC on day 2, inversely proportional to axitinib

exposure

[99]

ABT869

VEGFR, PDGFR, FLT-3 Solid cancer DCE-MRI 15 Permeability-surface area product and distributed parameters model shows

better correlation with drug exposure than K trans

[42]

Bevacizumab

(+chemotherapy)

VEGF

Breast cancer DCE-MRI 18 Decrease in K trans , k ep and v e after 3, 12, 21 weeks. No correlation with

response

[41]

Bevacizumab

(+chemotherapy)

VEGF

Breast cancer DCE-MRI 19 Decrease in K trans , k ep and AUC

[100]

Bevacizumab

(+chemotherapy)

VEGF

GBM

DCE-MRI 20 Changes in K trans value were highly correlated with the % decline in tumour

volume after 1 cycle but not correlated to treatment outcome

[58]

Bevacizumab

VEGF

CRC

CTP

12 Decrease in HU values and perfusion score

[59]

Bevacizumab

VEGF

carcinoid

CTP

12 Signiﬁcant decrease in tumour blood ﬂow after 2 days and after 18 weeks of

treatment compared to IFN- a control group

[65]

Bevacizumab

VEGF

HCC

DCE-US

42 Decrease in AUC, peak intensity, AUC wash in and out. DCE-US on day 3 and 8

predicts the treatment response after 4 months

[57]

Bevacizumab (+

radiotherapy)

VEGF

Rectal cancer CTP, FDG–

PET

6 Decrease in tumour blood perfusion and blood volume. Decreased FDG

uptake after 6 weeks

[69]

Bevacizumab

(+chemotherapy)

VEGF

GBM

FLT-PET

19 Metabolic response in 47%, predictive for overall survival

[68]

Bevacizumab

(+chemotherapy)

VEGF

GBM

FDG–PET 35 6/35 patients completed one year treatment who had a hypometabolic FDG–

PET result

[66]

Bevacizumab

(+chemotherapy)

VEGF

CRC

FDG–PET 7 Better correlation with pathologic response for FDG–PET compared to CT

[67]

Bevacizumab

(+chemotherapy)

VEGF

Liver

metastasis of

CRC

FDG–PET-

11 Decrease in median SUV max from 8 (baseline) to 4 (after 1 cycle). Decrease of

SUV max in responder group >50% compared to baseline

[101]

BIBF 1120

VEGFR, PDGFR, FGFR Hepatic

metastasis of

solid cancer

DCE-MRI 7 Median decrease of 15% in hepatic perfusion index after 28 days

[102]

CDP860

PDGFR

CRC, ovarian

cancer

DCE-MRI 8 No effects on iAUC and K trans . In 3/8 patients increased vascularised tumour

volume on day 1

[103]

Cediranib

VEGFR, PDGFR, c-KIT Solid cancer DCE-MRI 32 Reduction in iAUC60, less on day 2 compared to day 28 and 56

[104]

Cediranib

VEGFR, PDGFR, c-KIT Prostate cancer DCE-MRI 10 Decrease in K trans and k ep , consistent with response

[105]

Cediranib

VEGFR, PDGFR, c-KIT GBM

DCE-MRI,

DWI

16 Decrease in K trans and ADC, starting on day 1

[60]

Cediranib

VEGFR, PDGFR, c-KIT Solid cancer CTP

6 Reduction in perfusion and permeability surface product

[61]

Cediranib and

Gefetinib

VEGFR, PDGFR, c-

KIT, EGFR-1

Solid cancer CTP

13 Initial decrease in perfusion.

[43]

HuMV833

VEGF

Solid cancer DCE-MRI,

HuMV833-

PET

20 Decrease in k ﬁrst pass after 48 h. No changes in HuMV833-PET

[106]

IMC-1C11

VEGFR

CRC

DCE-MRI 11 Decrease in K in and EF after 4 weeks

[107]

Semaxanib

VEGFR, PDGFR, KIT Solid cancer DCE-MRI 17 No signiﬁcant changes in K trans and v e

[108]

Semaxanib

VEGFR, PDGFR, KIT Solid cancer DCE-MRI 11 Increase in k ep , wide variations

[109]

Semaxanib

VEGFR, PDGFR, KIT Melanoma

DCE-MRI 5 Decrease in tumour perfusion

[110]

Semaxanib

VEGFR, PDGFR, KIT Solid cancer DCE-MRI 11 Decrease in AUC60, AUC90 and AMX

[111]

Semaxanib

VEGFR, PDGFR, KIT NSCLC

DCE-MRI 35 Signiﬁcant reduction in K trans of 35–38% after 2 and 28 days. No signiﬁcant

correlation with clinical outcome

[112]

Semaxanib

VEGFR, PDGFR, KIT RCC

FDG–PET,

H 2 15 O-PET

5 No consistent ﬁndings

[64]

Semaxanib

VEGFR, PDGFR, KIT Head and neck

cancer

Power

doppler US

7 Decrease in vascular density, not corresponding with clinical outcome

[113]

Semaxanib

VEGFR, PDGFR, KIT CRC

DCE-US

2 Reduced tumour perfusion in stable disease, increased tumour perfusion in

progressive disease

[45]

Sorafenib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

DCE-MRI 16 Decline in K trans and v e . High K trans at baseline and percentage decline of K trans

correlated with time to progression

[114]

Sorafenib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

DCE-MRI 48 iAUC90 and K trans are markers for progression. High variability. Changes in

DCE-MRI parameters were not predictive for PFS

[47]

Sorafenib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

DCE-MRI 17 Decrease in K trans . Association between PFS-baseline K trans and percentage

K trans decline

[48]

Sorafenib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

DCE-US

9 4/9 good responders, correlated with better PFS

[49]

Sorafenib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

FDG–PET-

10 Decrease in mean glucose uptake after 1 month

[50]

Sorafenib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

HCC

FDG–PET 6 Early dynamic changes in FDG uptake seem to be predictive for clinical

outcome

[44]

Sorafenib and

bevacizumab

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT,

VEGF

Solid cancer DCE-MRI,

FDG–PET

38 Reduction of tumour vessel permeability and blood ﬂow in patients with

stable disease or minor regression. No signiﬁcant changes in PET-SUV

[51]

Sorafenib,

sunitinib,

interferon or

placebo

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

CTP

44 26/44 patients with sorafenib or sunitinib. In these patients signiﬁcant drop

in tumour blood ﬂow and tumour blood volume after 6 weeks. Tumour blood

ﬂow predictive for response

[52]

Sorafenib or

sunitinib

Raf-1, B-raf, VEGFR,

PDGFR, FLT-3, C-KIT

RCC

DCE-US

36 DCE-US at day 15 is able to predict efﬁcacy at 3 months and correlated to PFS

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