Prognostic factors and functional imaging in...

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Radiología. 2012;54(1):45---58

www.elsevier.es/rx

UPDATE IN RADIOLOGY

Prognostic factors and functional imaging in rectal cancer�

R. García Figueirasa,∗, P. Caro Domíngueza, R. García Dorregoa, A. Vázquez Martína,A. Gómez Caamanob

a Servicio de Radiodiagnóstico, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela,A Coruna, Spainb Servicio de Oncología Radioterápica, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela,A Coruna, Spain

Received 4 February 2011; accepted 4 May 2011

KEYWORDSRectal cancer;Magnetic resonanceimaging;Functional imaging;Diffusion;Prognostic factors

Abstract The outcome of treatment for rectal cancer in recent years has been improved bydiverse advances in the field of surgery and in neoadjuvant oncologic therapies. Heald’s intro-duction of the concept of the mesorectum as an anatomical unit (total mesorectal excision)in 1982 and the generalization of preoperative radiochemotherapy have improved the prog-nosis in a significant number of patients. Owing to these advances, it has become necessaryfor imaging studies to define a series of prognostic factors for tumors, both before and afterneoadjuvant treatment, to make it possible to tailor treatment for individual patients withrectal tumors.

On the other hand, the advent of functional and molecular imaging techniques has provideda way to study a series of distinctive tumor characteristics in vivo, including the angiogenesis,metabolism, or cellularity of rectal tumors, and these techniques are making a growing contri-bution to the prognosis, staging, treatment planning, and evaluation of the response to therapyin patients with rectal cancer.© 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

PALABRAS CLAVECáncer rectal;

Factores pronósticos e imagen funcional del cáncer de recto

loaded from http://zl.elsevier.es, day 30/04/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Resonanciamagnética;Imagen funcional;

Resumen La evolución del tratamiento de cáncer de recto durante los últimos anos ha estadocondicionada por diversos avances en el campo de la cirugía y terapias oncológicas neoadyu-vantes. La introducción por Heald en 1982 del concepto del mesorrecto como unidad anatómica

Difusión;Factores pronósticos

(escisión mesorrectal total) y la generalización de la radioquimioterapia preoperatoria, handeterminado una mejoría del pronóstico en un número significativo de pacientes. Debido a estosavances, ha surgido la necesidad de que la imagen defina una serie de factores pronósticos del

� Please cite this article as: García Figueiras R, et al. Factores pronósticos e imagen funcional del cáncer de recto.Radiología. 2012;54:45---58.

∗ Corresponding author.E-mail address: [email protected] (R. García Figueiras).

2173-5107/$ – see front matter © 2011 SERAM. Published by Elsevier España, S.L. All rights reserved.

dx.doi.org/10.1016/j.rxeng.2012.05.004

http://www.elsevier.es/rx

mailto:[email protected]

46 R. García Figueiras et al.

tumor, tanto antes como después del tratamiento neoadyuvante, que permitan individualizarel manejo del paciente con neoplasia de recto.

Por otra parte, la irrupción de las técnicas de imagen funcional y molecular permite abrir unavía de estudio in vivo de una serie de características tumorales distintivas como la angiogénesis,el metabolismo o la celularidad en las neoplasias de recto con una aportación creciente en ladeterminación del pronóstico, la estadificación, la planificación terapéutica y la evaluación dela respuesta al tratamiento en pacientes con cáncer de recto.© 2011 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

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Document downloaded from http://zl.elsevier.es, day 30/04/2014. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

ntroduction

olorectal cancer (CRC) is one of the most common malig-ant tumors. In one-third of the cases, CRC is diagnosedn the rectum, and rectal involvement has a worse progno-is due to a higher rate of local recurrence and a higherncidence of metastasis at diagnosis.1

Although surgery is still the fundamental therapeu-ic tool, the management of rectal cancer patients hashanged and is being delivered by a multidisciplinary team.hese multidisciplinary teams tailor individualized treat-ent strategies according to patient and tumor features.2,3

n this setting, imaging studies are no longer exclu-ively reliant on the TNM system to stage rectal canceratients, but also on prognostic factors that were tradition-lly obtained through histopathological analysis. Significantrognostic factors are depth of the intramural/extramuralnvasion, distance from the tumor to the mesorectal margin,nvolvement of lymph nodes, vascularity and peritoneum, asell as involvement of the sphincter complex. The overallssessment of these factors determines both the need foreoadjuvant therapy and the type of surgical technique toe used.4---7

Furthermore, as a result of a greater insight into tumoriology, we now know that neoplasms are very complexnd variable pathologic models, where balance betweenertain processes, such as angiogenesis, tumor cellularity,etabolism, and oxygenation determines the behavior of

hese tumors. Many of these tumor features are currentlyssessed by functional or molecular imaging techniques,8,9

o that diagnostic imaging provides information that poten-ially helps both plan an individualized management ofatients and predict tumor response to the treatment.

Basically, the ultimate goal of rectal cancer (RC) manage-ent would be to implement imaging techniques to obtain

set of morphologic and functional/molecular data relatedo the patient progress (survival, progression-free interval,tc.).10

rognostic factors in rectal cancer

n recent years, the role of presurgical assessment by rec-al cancer imaging has changed significantly. This change
s due to the implementation of total mesorectal excisionTME), to the good outcome after neoadjuvant therapy inelected patients, as well as to the interest in assessingesponse to such therapy. These events have shifted the
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ocus of imaging techniques from the traditional TNM stagingo the evaluation of the abovementioned prognostic fac-ors. These factors enable individualized management ofC patients, characterization of tumor maps, planning ofhe appropriate surgical approach, and decision-making onhe use of neoadjuvant therapy.4,5,11 Assessing all these ele-ents and including them in the radiological report are

rucial tasks for the radiologist. In this respect, the usef structured reports that systematically include these ele-ents seems to enhance RC imaging evaluation by avoiding

bviating key data to be considered for decision-making,y facilitating inter-department information exchange,nd by fostering scientific research12 (on-line reportingorm).

opographic and morphologic tumor mapping

rucial for accurate rectal neoplasm evaluation is thenderstanding of the mesorectal anatomy and its ade-uate imaging assessment, which is part of the informationhat must be provided to the surgeon or radiotherapeu-ic oncologist.13,14 Magnetic resonance (MR) imaging enablesumor mapping by determining the distance to the anal mar-in, endoluminal tumor extension, tumor morphology, andhe involvement of the sphincter complex and the levatoruscles (Fig. 1).4,5,11 All these aspects determine the type ofotential surgical or radiotherapeutic approach, and couldelp set a standard of reference to audit the surgical out-omes. Moreover, some findings of tumor morphology (longr ulcerated tumors and wide involvement of the circum-erence of the rectal lumen) should alert the radiologist tohe possible extramural tumor involvement, even if this isot conspicuous.4 Additionally, the diagnosis of mucinousumor can be suggested in many cases because this typef tumor usually shows large hyperintense areas on T2-eighted sequences (Video 1). The degree of response ofucin-producing tumors to neoadjuvant therapy is normally

ower.Tumors located in the lower third of the rectum must

e considered differently. These are a separate type ofumor because they are associated with a risk of involvementf the surgical circumferential resection margin (CRM) andecause of their tendency to show higher recurrence rates.
his is due to the fact that involvement of the lower thirdeyond the muscularis propria could lead to tumor infiltra-ion into the margins in an ultralow TME or in a conventionalbdominoperineal excision (APE).15 For this reason, these

Prognostic factors and functional imaging in rectal cancer 47

Figure 1 (A and B) MRI tumor mapping of rectal cancer. Sagittal (A) and axial (B) TSE T2-weighted sequences featuring a cT4arectal carcinoma. These images show MRI capacity to accurately yield important data, such as distance to anal verge (1 + 2 distance

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in A), tumor spread to rectal lumen (3), as well as involvement

neoplasms require neoadjuvant therapy in earlier stages(T2), and may require different surgical techniques suchas extralevator/extrasphincteric APE, which resects thesphincter complex, levators, and en-bloc mesorectal exci-sion (Fig. 2).

Depth of mural/extramural tumor invasion andinvolvement of the surgical resection margin

Current preoperative imaging techniques for local rectalcancer staging----i.e. endorectal ultrasonography, computer-ized tomography (CT), and MR----have proved generally oflimited value in the accurate assessment of the ‘T’ stage

tw(m

Figure 2 Anatomy of the lower rectum and anal canal (left) antechniques in these locations (right). The images correspond to a pat(white star). Red line: anterior total mesorectal excision plane. YeFuchsia line: intersphincteric abdominoperineal amputation plane (a

e peritoneal reflection (white arrows).

depth of mural infiltration and minimal extramural spreadn the mesorectum).16 However, it is argued that the primaryim of imaging techniques for rectal cancer determina-ion is not ‘T’ stage assessment, but to arrange groups ofatients according to how they will be managed. In thisegard, depth of extramural spread seems to predict theisk of local recurrence more accurately than the ‘T’ stageoes. There is a body of research studies that advocate forhis type of group management and provide evidence ofhe behavioral inhomogeneity of T3 tumors. Accordingly, T2
umors with extensive involvement of the muscularis propiaould have the same prognosis as T3 tumors with minimal
2 mm) extramural spread. Similarly, T3 tumors with extra-ural invasion <5 mm would have a much higher disease-free

d visualization of the excision plane with different surgicalient with a lower rectum tumor invading the sphincter complexllow line: extra-levator abdominoperineal amputation plane.daptation from Shihab et al.15).


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Figure 3 Circumferential resection margin. Mucinous rectaltumor. Axial T2-weighted image and b-value (=1000) diffu-sion sequence (detail from the image) showing tumor mucin incontact with mesorectal fascia (arrows) all around its contour.Tm

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urvival rate (85%) than those with extramural invasion5 mm (53%).17 Apart from this, some authors hypothe-ize that preoperative neoadjuvant therapy would hardlye of any benefit to patients with tumors with extramuralpread <5 mm.18

The TME technique (a surgical technique in which theheoretical dissection plane is on the mesorectal fasciaurrounding the mesorectal fat, together with the lym-hatic system and rectal vessels as well as the rectumtself) shows how crucial the assessment of the preopera-ive state of the circumferential resection margin (CRM)19

s. A positive CRM is associated with high local and dis-ant recurrence rates,19 since virtually all patients with CRMnvolvement (tumor cells within 1 mm of the CRM) afterhemoradiotherapy present with tumor recurrence with aigh risk of distant metastasis.10 Wibe et al. report localecurrence rates of 22% in patients with positive CRM andf 5% in patients with negative CRM after TME.20 For thiseason, one of the main goals of assessment of and ther-py planning for RC patients is to obtain a tumor-free CRMt surgery.21---26

However, the mesorectal fascia should not be mistakenor the CRM (a margin that is defined postoperatively)lthough on MRI mesorectal fascia is taken as the the-retical reference margin. For this reason, a margint risk at imaging can be interpreted as a histolog-cal tumor-free CRM (R0) or a CRM with microscopicR1) or macroscopic (R2) invasion. Distance between theumor and the mesorectal fascia would be the primaryocal prognostic factor in RC. It should not be for-otten, however, that this distance must be measuredhere the tumor has extended beyond the muscularisropria, which means that T1 and T2 tumors would beegarded as not having margins at risk (except for the analanal).4,11

Determination of the possible CRM involvement on MRIs variable. However, as a general rule, a CRM is consid-red to be involved when the primary tumor, a malignantymph node, a venous or lymphatic invasion, and/or a tumoreposit are located at a distance ≤1 mm (Fig. 3). Because ofts wide coverage and high spatial resolution, MRI has estab-ished itself as the modality of choice to predict tumor-freeRM (92% sensitivity).11,23---26

xtramural vascular invasion

lthough the term EVI (extramural vascular invasion) haseen used to designate both vascular and lymphatic inva-ion in CRC, vascular invasion normally refers to venousnvasion extending outside the muscularis propria. EVI isound in approximately 30% of cases,27 and is associ-ted with poorer survival, with locally advanced tumors,ith a high risk of metastatic disease, with high likeli-ood of tumor-positive mesorectal nodes, and with CRMositivity at surgery.28 MRI is the only imaging tech-ique that provides appropriate EVI assessment (Fig. 4A,
ideo 2). Smith et al. provide a number of featuresuggestive of EVI, mainly vascular thickening in the vicin-ty of the tumor and heterogeneous intravascular signalntensity.29,30
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his means that there is risk of tumor invasion 360◦ around theesorectal margin.

nvolvement of the peritoneal surfacend adjacent organs

RI has good sensitivity for diagnosis of tumors invadingrgans or adjacent structures (T4a) or a peritoneal sur-ace (T4b).6,11 Evaluation of RC by MRI must always involvessessment of the peritoneal reflection, which is a peri-oneal surface that attaches in a v-shaped manner onto thenterior wall of the upper third of the rectum. Involvementf the peritoneal reflection suggests risk of peritoneal seed-ng (Fig. 4B and C; Video 3).

odal involvement

odal involvement is another independent negative prog-ostic factor for RC patients’ survival and local recurrence.areful consideration of possible pathways of spread isequired. In this regard, it should be taken into accounthat lower rectum tumors have a greater tendency to invadeelvic extramesorectal nodes, which are the only pathwaysor lymphatic spread in up to 6% of these tumors.31

Nodal staging by imaging techniques is highly limitedhen relying on the criterion of size in the short axis.32

rown et al. found that 55% of positive nodes are less than mm in diameter and that 15% of nodes <5 mm are positivemean size 3.8 mm).33

A number of research studies report on series that assess
orphologic criteria (irrespective of nodal size) to deter-ine the nonmalignant or malignant nature of lymph nodes.rown et al. and Kim et al.33,34 suggest border contour andignal intensity as criteria for evaluation. Unfortunately,


Figure 4 (A---C) Magnetic resonance imaging of prognostic factors. Different samples of rectal neoplasms showing several negativeprognostic factors (arrows). (A) Extramural vascular invasion with extensive tumor involvement of vessels near a large rectal tumor.(B) Invasion of the peritoneal reflection. (C) Tumor invading the right seminal vesicle (arrow).

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the promising outcomes could not be reproduced in laterstudies. Recent studies suggest that diffusion-weighted MRI(DW-MRI) could help in nodal characterization prior to andfollowing neoadjuvant therapy.35 New contrast media couldalso be an alternative option. The use of ultrasmall particlesof iron oxide (USPIO) could be of value for characterizationof nodal involvement by combining morphologic and func-tional criteria (USPIO uptake). Unfortunately, the use ofparticles of iron oxide has not been approved for clinical use,and its use requires training for suitable evaluation.36 Apartfrom this, vascular contrast media could help in determin-ing the nature of lymph nodes. Beets-Tan et al. found thatvascular contrast agents only enhance the vessels of normaltissues and normal nodes. However, this outcome must betaken with caution because of the low number of patientsenrolled in this study.37

Imaging-based decision algorithms

Different studies provide data advocating for a change of pri-orities in RC imaging evaluation. On the one hand, surgeryalone could be curative for T1 and T2 tumors as well asfor some early-stage T3 tumors, with a low local recur-rence rate with TME and tumor-free resection margins.38

For other tumors, in contrast, preoperative chemo- andradiation therapy has shown clear benefits, such as tumorsize reduction, possibility of sphincter complex preserva-tion at surgery, decrease of recurrence rate (10.1% of localrecurrence with TME and 1% of local recurrence with TMEplus radiotherapy), and most importantly, overall survivalimprovement.39---42

Based on these data and taking into consideration thepreviously assessed factors, three main patient groups canbe set up that require a different clinical management3,4

(Table 1):

1. Patients with a good prognosis that do not require neoad-juvant therapy (T1---T2 N0 tumors).

2. Patients with tumors that require a standard pattern ofneoadjuvant therapy (mainly T3 tumors).

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. Patients with tumors that require a neoadjuvant ther-apy with intensified radiation therapy: T4 tumors ortumors threatening or invading the mesorectal fascia(Fig. 5A---C).

Differences between institutions arise when certainatients are classified:

. Some authors include T3a and T3b tumors in the groupwith the best prognosis.23

. Brown et al. include T3a---b tumors with nodal involve-ment (N1) and no compromised CRM in the group thatcan only be treated with surgery,43 whereas the Dutchauthors regard nodal involvement as a clear indicationfor neoadjuvant chemoradiotherapy (CRT).44

. EVI signs would mean risk of systemic involve-ment, requiring neoadjuvant therapy and adjuvantchemotherapy.45

unctional---molecular imaging in RC

ancer has a number of distinctive features that determinets behavior such as self-sufficiency in growth signals, insen-itivity to growth-inhibitory (antigrowth) signals, evasionf apoptosis, sustained angiogenesis, limitless replicativeotential, and neighboring tissue invasion and metastasis.46

natomic evaluation and evaluation of the prognosticactors discussed enable the decision-making for patientreatment. However, evaluation of this type entails a lim-ted tumor approach. Specific assessment of the distinctiveumor features in RC could allow a more individualizedatient management; a more accurate definition of key ele-ents of this management; to establish patient prognosis or

he response to the different therapies.47,48 In this regard,ome molecular and functional imaging techniques couldomplement current morphologic evaluation, which wouldnable the analysis of the following key tumor features8,9

Table 2): angiogenesis (perfusion CT or dynamic MRI), cel-ularity (diffusion MRI), and cellular metabolism (PET). Apartrom this, many of the specific tumor features have becomehe target of novel oncologic therapies for CRC treatment,


Table 1 Imaging-based therapeutic strategy in rectal cancer. Image findings define patient groups with different management.

Prognosis Image findings Approach

Group with positiveprognostic factors

T1, T2 (except forlower third), T3aand T3b

Surgery

N(−)EVI(−)Free CRM

Group with negativeprognostic factors

T2 in lower third Chemoradiotherapyprior to surgeryT3c and T3d

N(+)EVI (+)Free CRM

Group with mesorectalmargin at risk

Invaded CRMor CRM at risk

Chemoradiotherapywith dose titrationprior to surgeryT4a and T4b

Note: EVI(+) adjuvant chemotherapy required.EVI: extramural vascular invasion; CRM: circumferential resection margin; N: metastatic node involvement.

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nvolving the development of new drugs inhibiting tumorrowth factors, such as the vascular endothelial growth fac-or (VEGF), the epidermal growth factor receptor (EGFR),nd vascular disrupters.49 This fact would further reinforcehe significance of and need for imaging evaluation.

ngiogenesis: Perfusion CT and dynamic MR

eo-angiogenesis development, a process regulated by cer-ain mediators, such as VEGF, is key to tumor growth and

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Table 2 Functional---molecular imaging techniques in RC.

Functional imagingtechnique

Biological properties on which theimages are based

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Perfusion-CT Contrast medium uptake rate intissues which is influenced byperfusion, vessel density, and vesselpermeability

----

Dynamic MRI Contrast medium uptakein tissues

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Diffusion MRI Brownian motion of water -c

PET Glucose metabolism -v

GLUT-1: type 1 glucose transporter; PET: positron emission tomography

etastasis. Until recently, research in angiogenesis focusedn histologic aspects, involving assessment of parametersuch as microvessel density. However, tumor vessels have

number of features different from those characteriz-ng normal vessels, which could provide us with specificnformation about tumor vessels. These features are spa-
ial heterogeneity and chaotic structure, high permeability,nd multiple arterio-venous shunts.50 Compared with nor-al tissue, tumor tissue generally involves an increase in
ascularization with a rapid enhancement peak, followed

uantitative parametersr biomarkers

Physiopathologic datafeatured

Blood flow -Vascular densityBlood volume -Vessel permeabilityMean transit time -Perfusion pressurePermeability surface -Tumor grade

Area under theadolinium curve

-Vascular density

Transfer constantsktrans, kep)

-Vessel permeability

Leakage space fractionve)

-Perfusion

Plasma volume (vp)Apparent diffusionoefficient (ADC)

-Cell density, cellmembrane integrity,extracellular spacetortuosity, nodeformation, necrosis

Standardized uptakealue (SUV)

-Increased expression ofGLUT-1 and hexokinase IIactivity

.

Prognostic factors and functional imaging in rectal cancer

Figure 5 (A---C) Imaging-based radiotherapy planning. (A)Fusion of an axial TSE T2-weighted image and a false colormap derived from a high-b-value (b = 800) diffusion image,acquired in the same plane. Fusion shows tumor implanted atthe five o’clock position in contact with the mesorectal fascia(arrow). (B) Planning of imaging-based radiotherapy showingthe increase in dose (60 Gy instead of 50, area in red) in themesorectal margin at risk. (C) The postneoadjuvant fusion studyshows partial tumor response with an increase in distance to themesorectal margin, suggesting a possible free margin, whichwas confirmed at surgery (R0).

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y early contrast washout. Additionally, the apparent rolehat angiogenesis plays in tumor growth has opened upn avenue towards the development of new drugs thatnhibit tumor angiogenesis. Both angiogenesis and responseo antiangiogenic or antivascular drugs have clear imag-ng applications.51 Technical advancement has promoted theevelopment of new imaging techniques, such as perfusionT and dynamic MRI, that enable the study of angeogene-is in RC tumors in a non-invasive manner.8,9,47,48,50,52 Apartrom a mere qualitative assessment (morphology of uptakeurves), both techniques provide quantitative evaluation ofumor angiogenesis based on mathematical analysis models,hich yield information about a set of physiological param-ters, such as blood flow, blood volume, mean fluid transitime, and transfer coefficient (ktrans).50,52 There are someifferences between perfusion CT and dynamic MRI. CT stud-es assess the contrast medium attenuation of X-rays inhe vascular and extravascular space over the course ofhe study, with a direct relation between contrast concen-ration and density (Fig. 6 and Video 4). Quantificationy dynamic MRI is more challenging because there is noirect relation between MRI signal intensity and contrastoncentration.47,48,52

In RC angiogenesis evaluation, correlation betweenunctional imaging parameters and angiogenic markersmicrovessel density, VEGF, and CD31 expression) variesetween studies.53---55

Functional---imaging studies of RC have proved to beotentially useful for diagnosis, staging, and patient prog-osis. Accordingly, perfusion CT has proved to be valido differentiate CRC from normal bowel wall and fromenign pathology (such as acute diverticulitis) by yieldinglearly different values in different functional parameters.56

oreover, perfusion-based studies could help in predictingatient prognosis since tumors with high perfusion valuesblood flow or ktrans) seem to better respond to neoad-uvant chemoradiotherapy57,58----despite the low number ofatients in these studies and their sometimes contra-ictory data.59 Perfusion CT could also play a role inetecting occult hepatic metastases, since the presence oficrometastasis is likely to alter hepatic perfusion patterns

ignificantly.Another interesting issue is the assessment of response

o the treatment. Both perfusion CT and dynamic MRI showhanges in their values as a response to chemoradiotherapyFig. 7 and Video 4).52,58,59 Both techniques seem to enable arompt evaluation of tumor response to antiangiogenic andntivascular drugs, showing a decrease in tumor perfusionalues in responders to such drugs.60

ellularity: Diffusion-weighted MRI sequences

iffusion-weighted MRI (DW-MRI) is an emergent techniqueor oncologic imaging. DW-MRI displays contrast imagesy tracking the differences in motion of water moleculesn different media. DW-MRI provides biological informa-ion about different factors, such as cell density, the
ucleus---cytoplasm relationship in cells, extracellular spaceortuosity, the integrity of cell membranes, tissue orga-izational characteristics (e.g. gland formation in tissue),nd tissue perfusion.61,62 The restriction grade of water


Figure 6 Perfusion-CT. Perfusion-CT involves sequential acquisition of images with high temporal resolution and a coverage thatis dependent on the CT number of rows (4 cm in a scanner with 64 rows of detectors). Subsequently, in the workstation, a specificsoftware programme generates intensity change curves of the lesion over time, and yields quantitative maps featuring differentp e) am

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iffusion is inversely related to cell density and thentegrity of cell membranes. Water molecule motion isore restricted in tissues with high cellularity and intactembranes (e.g. tumor tissue) than in areas with lower

ellularity or abnormal membranes.Another advantage of diffusion MRI is that it can be

uantitatively analyzed based on calculation of the appar-nt diffusion coefficient (ADC) value. Tumors generally showow ADC values, whereas normal tissues and benign lesions
sually show higher values. Validity of ADC for tumor char-cterization is reinforced by the fact that a number ofmportant biological features, such as tumor proliferation
mwa

igure 7 (A---C). Perfusion-CT of RC hepatic metastasis and respf blood volume with a 50% transparent color map (B). These imagesion, which shows a marked peripheral neo-angiogenic component.anti-VEGF), the image shows a positive response of this lesion, whi

ccording to an analysis model, which varies depending on the

ndex, tumor grade, and presence of necrosis or apoptosis,orrelate with ADC.63

In RC, diffusion-weighted imaging has proved to be useful technique for CRC detection,64 tumor volumeelimitation (Fig. 8 and Video 5), and distant tumortaging, with detection and characterization of hepaticocal lesions. Diffusion-weighted imaging could also pre-ict response to chemoradiotherapy with ADC values lowerhan pretreatment values in responsive primary tumors and
etastases.65,66 This could be explained because tumorsith high ADC values usually show necrosis, which is associ-ted with poor response to the treatment.
onse to therapy. Acquisition images (A) and parametric mapes were acquired in a perfusion study of a hepatic metastatic

(C) Ten days following administration of an antiangiogenic drugch no longer shows the previously marked ring enhancement.


Figure 8 Cancer versus colitis. Sagittal CT reconstruction and in axial TSE T2-weighted sequences in a CRC patient show diffusethickening of the sigma and of the rectosigmoid junction, but they do not enable to delimitate the extension of the tumor. TheADC map (right) helps to define the tumor (white arrows), which shows a marked hypointensity representing diffusion restriction.

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In contrast, the colitis area posterior to the tumor shows hyper

DW-MRI proves to be valuable for lymph node detec-tion, and could be an alternative technique to assess theirinvolvement.35

Assessment of response to treatment is, however, one ofthe main fields of application of DW-MRI. Expected changesvary depending on the treatment modality. Accordingly,response to a radio- and/or chemotherapy is associatedwith an early rise of ADC values, a rise that lasts longerwith radiotherapy (due to persistent edema). In contrast,response to antiangiogenic drugs would lead to transientreductions of ADC values, which would be secondary toflow reduction, cellular edema, and reduced extracellularspace63 (Table 3).

Metabolism: Positron emission tomography (PET)

PET enables to detect and quantify cellular processes ina non-invasive manner using radiotracers. In clinical prac-tice, the main radiotracer is [(18)F]2-fluoro-2-deoxyglucose(FDG). Malignant tumors generally tend to have anincreased cellular metabolism, together with an increasedrate of glucose transport membrane proteins and anincreased activity of hexokinase and phosphofructokinase,which prompt intracellular glycolysis. This results in anincreased accumulation of FDG. Poor spatial resolutionof PET can hinder tumor diagnosis with this technique.For this reason, modern PET/CT scanners have provedto be more useful, since they enable co-registration of
not only functional---metabolic but also anatomical infor-mation. PET/CT shows advantages in diagnosis, staging,treatment planning, follow-up, detection of CRC recur-rence and metastasis, and patient prognosis.48,67,68 PET/CT
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sity on the ACD map.

ould also change RC management plan in a signifi-ant number of patients because these techniques enablehe detection of unknown metastatic disease and thehange of preoperative radiotherapy field according to thendings.48,67,68

Nevertheless, the application of PET to RC treatment isot without limitations. Small tumors (<1 cm) or mucinousumors usually have a low metabolic activity, and togetherith some necrotic tumors can prompt false-negatives. Inontrast, inflammatory processes or bowel physiologic activ-ty can prompt false-positives.48,67,68

PET could enable to define biologically active tissueVideo 6), which is a big advantage when it comes toetermining RC response to neoadjuvant therapy. However,everal studies have reported contradictory data concerninghe value of PET imaging when determining such response.etastatic CRC treatment can currently rely on different

herapeutic strategies with the incorporation of biologi-al therapies, particularly those involving agents that blockGFR signaling, a well-known factor of tumor development.ew studies have been published that assess response tohese drugs. However, the use of positron emission tomogra-hy FDG or fluorothymidine (a radiotracer that would help inhe study of cellular proliferation) in the assessment of dif-erent tumor types could enable early evaluation of responseo these drugs.69 This fact could facilitate the application ofET FDG to CRC treatment.

ther functional/molecular techniques

he development of different MRI sequences (BOLD andpectroscopic), new PET radiotracers, and other imaging


Figure 9 (A---D) MRI multiparametric capacity. Neoplasm of the middle third of the rectum assessed with different MRI sequences.Fusion of sagittal TSE T2-weighted image and a false color map derived from a high-b-value diffusion image acquired in the sameplane (A), parametric map of blood flow acquired with a perfusion sequence (B), spectroscopic image (C) showing a fat peakin the tumor and ADC map with a histogram featuring the ADC values in the tumor (D). These different MRI sequences enable toe llular(

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valuate different tumor elements, such as morphology (T2), cespectroscopy), using one single technique.

echniques has significantly enhanced the analysis capacitysing imaging techniques of different tumor processes andumor environment. Some of these processes are hypoxia,ellular proliferation, apoptosis, and cellular metabolism.8,9

he clinical utility of all these techniques in RC is stillo be defined,47 since most of them are not of commonlinical use, and require complex implementation. Nev-rtheless, they could enable a more comprehensive andpecific characterization of the biological features of rectaleoplasms.

ultiparametric imaging: The forthcomingaradigm

he possibility to obtain quantifiable parameters with dif-erent molecular and functional imaging techniques is arucial advance in imaging evaluation in oncology. How-ver, recent studies suggest that combining the informationrawn from these different techniques would help in bet-er understanding tumor biology.70---72 In this sense, current
echnological advances enable to obtain multiple datarom one single imaging technique or by combining severalodalities, which provide different data on the tumor. In
he imaging study of RC, MRI alone would yield different

ptca

ity (diffusion), angiogenesis (perfusion), and tumor metabolism

arameters providing information about morphology andrognostic factors (high-resolution turbo-spin-echo (TSE)2-weighted sequences), cellularity (diffusion), angiogen-sis (perfusion), and tumor metabolism (spectroscopy)Fig. 9A---C). The data reported by Goh et al.73 seem toeinforce the usefulness of combining different imagingechniques (PET and perfusion CT) in order to obtain assess-ent of a wide variety of parameters. The joint assessment

f tumor perfusion and tumor metabolism analysis in RCould enable detection of tumors at risk of metastatic

pread by identifying a mismatch between both factorsFig. 10A---F). Similarly, Willet et al. reported a similar out-ome in the response to bevacizumab administration alonen metastatic CRC74 after noting a significant decrease inngiogenesis and a poor decrease in tumor metabolism eval-ated by PET.

Finally, one of the central aspects of the study ofC is response to neoadjuvant therapy. When determin-

ng the grade of tumor response, conventional imagingechniques seem to yield a limited evaluation, which
oorly correlates with the pathologic findings.75 Inhis regard, functional/molecular imaging techniques,ombining different parameters, could be a betterlternative.


Figure 10 (A---F) Multiparametric study of a cT3N2 RC based on the MRI findings. Fusion images of a TSE T2-weighted image anda false color map derived from a high-b-value diffusion image (A and D), PET image (B and E), and perfusion-CT parametric mapof blood volume, acquired in pre- (A---C) and postchemoradiotherapy (D and E). These image show a partial tumor response withrelative decrease of lesion volume, restricted diffusion, and diminished glucose metabolism (pre-therapy SUV = 20 and post-therapySUV = 5), as well as poor blood volume change. The surgical sample confirmed a pT3N2 tumor with poor grade of histologic response(Dworak’s grade IV tumor regression).

Table 3 Functional---molecular imaging techniques and tumor response to therapies in colorectal cancer. Biological effect ofthe different therapies and its evaluation with functional---molecular imaging techniques.

Therapy type Biological effect Imaging techniques Change of parameter

Radiotherapy Cell death, edema,inflammation and vasculardisruption

Perfusion-CT Tumor perfusiondecrease

Dynamic MRI ADC increaseDiffusion MRI SUV decreasePET

Chemotherapy Cell death Perfusion-CT Tumor perfusiondecrease

Dynamic MRI General short-term ADCincrease

Diffusion MRI SUV decreasePET

Antiangiogenic drugs(anti-VEGF)

Vascular normalization Perfusion-CT Marked tumor perfusiondecrease Rapid buttransient ADC decrease

Marked decrease in permeability Dynamic MRI Poor SUV variationDiffusion MRIPET

Anti-EGFR Multiple effects, butinhibition of tumorproliferation

PET SUV decreasePerfusion-CT Poor tumor perfusion

decrease in other tumorsDynamic MRI Possible ADC increase

(no clinical experiencereported)

Diffusion MRI

ADC: apparent diffusion coefficient; EGFR: epidermal growth factor receptor; PET: positron emission tomography; SUV: standardized


uptake value; VEGF: vascular endothelial growth factor.

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onclusion

maging techniques play a pivotal role in the strategiesor management of RC patients. Of these techniques, MRIs currently the modality of choice because of its capac-ty to perform local staging, since it enables evaluation ofnatomic aspects and prognostic factors that are key tohoosing the appropriate surgical approach and determin-ng the need for neoadjuvant treatment. Functional andolecular imaging techniques, able to detect physiologic

nd cellular processes, seem to open up the doors to a morendividualized patient management and a more adequatevaluation of the novel oncologic therapies.

uthorship

Responsible for the integrity of the study: RGF, PCD andAGC.Conception of the study: RGF and AGC.Design: RGF and AGC.Data acquisition: RGF, PCD, RGD, AVM and AGC.Analysis and interpretation of data: RGF, PCD, RGD, AVMand AGC.Bibliographic search: RGF, PCD, RGD, AVM and AGC.Writing: RGF, PCD and AGC.Critical review of the manuscript and intellectually rele-vant contributions: RGF, PCD, RGD, AVM and AGC.Approval of the final version: RGF, PCD, RGD, AVM and AGC.

onflict of interest

he authors declare not having any conflict of interest.

unding

his work has been performed under the auspices ofhe SERAM-INDUSTRIA: 05 RGF INVESTIGACION SERAM 2009rant: ‘‘Multiparametric functional imaging in advanced rec-al cancer’’.

ppendix. Supplementary data

upplementary data associated with this article can beound, in the online version, at doi:10.1016/j.rxeng.012.05.004.

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