Functional Imaging of Colorectal Cancer: Positron Emission Tomography, Magnetic Resonance Imaging, and Computed Tomography

Comprehensive Review

Functional Imaging of Colorectal Cancer: Positron Emission Tomography, Magnetic Resonance Imaging, and Computed Tomography Nikhil Kapse, Vicky Goh Abstract In the past 10 years, overall survival and disease-free survival of patients with colorectal cancer (CRC) has improved substantially because of a combination of factors: (1) more accurate staging as a result of advances in imaging technology; (2) refinements in surgical technique; (3) ‘curative’ metastasectomy for patients with limited metastatic disease; (4) improvements in radiation therapy planning and greater precision of radiation therapy delivery; and (5) increasing chemotherapeutic options, including antiangiogenic and vascular targeting drugs. In this era of ‘personalized medicine,’ the increasingly individualized treatment of patients with CRC has highlighted the need for functional imaging techniques in addition to conventional anatomic-based imaging.This review discusses the contribution of positron emission tomography to the clinical management of CRC. In addition, evolving techniques such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), DCE computed tomography (perfusion CT), diffusion-weighted MRI, and blood oxygenation level–dependent MRI that might have a future role will be covered. Clinical Colorectal Cancer, Vol. 8, No. 2, 77-87, 2009; DOI: 10.3816/CCC.2009.n.013 Keywords: Carcinoembryonic antigen, Radiotracers, Relaxation rate, Transrectal ultrasound

Introduction In recent years, the treatment options available for patients with colorectal cancer (CRC) have expanded both in the primary and in metastatic setting, necessitating accurate assessment of disease status. Imaging has played an important role within the care pathway of patients with CRC but has typically been based on morphology. For example barium enema, computed tomography (CT), or CT colonography has been used for diagnosis; magnetic resonance imaging (MRI), transrectal ultrasound (TRUS), and CT for staging; CT for radiation therapy planning; MRI, TRUS, or CT for therapeutic assessment; and CT or MRI for subsequent surveillance and assessment of disease relapse. Nevertheless, the recent trend toward a personalized approach to treatment has highlighted the need for an alternative to current morphologically based assessment. Functional imaging techniques have the potential to personalize patient treatment in addition to improvThe Paul Strickland Scanner Centre, The Cancer Centre, Mount Vernon Hospital, Northwood, UK

ing assessment of disease extent and patient selection for treatment. There is still a paucity of data for CRC, but it might be possible in the future to tailor a patient’s chemotherapy or to alter treatment at an earlier stage, when an early response is not detected, for example, from a tumor’s metabolic and/or vascular profile. This review focuses on the clinical evaluation of patients with CRC using positron emission tomography (PET). In addition to its more established role in the detection of recurrent CRC, fluorine-18 (18F)2-fluoro-2-deoxy-D-glucose (FDG)-PET might improve initial staging and patient selection for surgery, in particular patients with limited volume metastatic disease suitable for metastasectomy, and provide better and earlier assessment of therapeutic response. Evolving techniques based on other imaging modalities, such as dynamic contrast-enhanced (DCE) MRI and DCE-CT, that act as surrogates for tumor angiogenesis; diffusion-weighted (DWI) MRI, which provides indirect assessment of tumor cellularity; and blood oxygenation level–dependent (BOLD) MRI, which provides indirect assessment of tumor hypoxia will be reviewed also. These techniques remain research-based tools, but emerging evidence of a role in the management of CRC will be explored.

Submitted: May 22, 2008; Revised: Sep 8, 2008; Accepted: Oct 9, 2008

Positron Emission Tomography

Address for correspondence: Vicky Goh, MRCP FRCR, Paul Strickland Scanner Centre Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex HA6 2RN Fax: 44-1923-844-600; e-mail: [email protected]

Positron emission tomography technology uses positron emitting radiotracers to detect and quantify processes on a cellular level in a noninvasive manner. The most commonly used radiotracer in tumor

This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.

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Functional Imaging of CRC Figure 1 Whole-Body FDG-PET/CT Study in an 81-Year-Old Man Showing a FDG-Avid Rectal Tumor

Irinotecan

Inactive Metabolites

Carboxylesterase Topoisomerase I

SN-38 UGT1A1 SN-38G (Inactive)

Figure 2 Whole-Body FDG-PET/CT Study in a 78-Year-Old Woman Illustrating Diffuse Physiologic Bowel FDG Uptake

reduced during imaging by fasting and resting patients before imaging, use of muscle relaxants (eg, benzodiazepines), use of antiperistaltic agents (eg, Buscopan), bladder voiding before imaging, and use of a diuretic (eg, furosemide) to avoid focal ureteric activity. The poor spatial resolution of FDG-PET imaging and its inability to provide anatomic localization has been overcome to a greater extent by the recent development of hybrid PET/CT scanners. Anatomic coregistration of PET with the CT has improved localization of tracer activity and improved sensitivity and specificity over that of PET alone, including detection of small lesions (< 1 cm).1-4 In the assessment of the abdomen and pelvis, PET/CT has added value when compared with PET alone reducing equivocal findings on PET alone by approximately 50%.5 Nevertheless, FDG-PET has limitations in assessing CRC. Tumor detectability is dependent on lesion size, the degree of tracer uptake, background uptake, and imaging resolution. Thus, FDG-PET has a lower sensitivity for small lesions (< 1 cm), where metabolic activity is low.6 Mucinous adenocarcinomas that demonstrate low metabolic activity might result in a false negative study.7 Partial volume averaging and necrotic lesions might also cause false negative studies. Inflammation, for example from radiation therapy or diverticulitis, will produce increased tracer uptake, giving false positive results (Figure 3), especially if morphologic features mimic those of cancer. Incidental physiologic bowel FDG uptake can also mimic that of a tumor, if not the typical diffuse and/or segmental pattern of tracer uptake.8 The mechanism for physiologic bowel uptake is unclear but might relate to muscular peristaltic activity, lymphoid tissue or a high concentration of white blood cells, or cells secreting FDG in the bowel wall.8 Nevertheless, focal increased bowel FDG uptake should not be ignored and further investigated to exclude a premalignant or malignant lesion9,10 if associated with anatomic changes, for example, pericolonic infiltration or a mass lesion.

Diagnosis and Staging of Colorectal Cancer imaging is FDG. This glucose analogue is taken up preferentially by cells that exhibit high glycolytic activity via cell surface glucose transporter proteins. Within the cell, FDG is phosphorylated by hexokinase into glucose-6-phosphate and thus is effectively trapped and unable to participate further in the normal glycolytic pathway. Positron emission from FDG detected by the PET scanner is displayed visually (Figure 1), but tracer uptake can be expressed semiquantitatively as a ‘standardized uptake value’ (SUV), which represents the metabolic activity of the tissue of interest compared with surrounding tissue, corrected for injected dose and patient weight. Uniform tracer distribution in the body would produce an uptake value of 1. Malignant tumors are a principal site for FDG accumulation as a result of upregulation of cell surface glucose transporter proteins, and increased intracellular hexokinase and phosphofructokinase enzyme levels that promote glycolysis. However, glycolysis also occurs in normal tissues; thus, physiologic FDG uptake will be present at many sites, including the heart, skeletal muscle, metabolically active fatty tissue (brown fat), and gastrointestinal tract (eg, esophagus, stomach, cecum; Figure 2). FDG is also filtered by the kidney and excreted and thus will highlight the urinary tract. Physiologic FDG activity may be

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Diagnosis At present, FDG-PET plays no major role in diagnosis of CRC because this is usually confirmed by colonoscopy and biopsy. Nonetheless, previous studies have shown that FDG uptake might occur in premalignant colonic adenomas10 and might potentially aid detection of malignant polyps, especially in cases of failed optical colonoscopy. A sensitivity of 91% and specificity of 100% for polyps > 6 mm can be achieved with integrated FDG-PET/CT colonography (using water as the distending agent)11; however, studies have shown no increase in sensitivity for polyp detection compared with CT colonography alone.11,12

Staging Magnetic resonance imaging, TRUS, and CT are established techniques for staging primary CRC. In order to determine if a rectal cancer is resectable, the relationship of the primary tumor and mesorectal nodes to the potential circumferential resection margin is an important piece of information that has to be taken into account in addition to the tumor-node-metastasis (TNM) staging classification. MRI is used widely because it provides such information: a recent prospective European multicenter study

Nikhil Kapse, Vicky Goh Figure 3 Whole-Body FDG-PET/CT Study in a 70-Year-Old Man Demonstrating FDG Uptake in the Sigmoid Colon Related to Underlying Diverticular Disease

has demonstrated an accuracy of 87% and specificity of 92% in predicting a clear circumferential resection margin.13 TRUS has a role in staging small early tumors (T1 N0 or T2 N0; < 3 cm; within 8 cm of anal verge) because it provides excellent depiction of the rectal wall layers and is more sensitive than CT or MRI for perirectal tissue invasion (90% versus 79% and 82%, respectively, in a meta-analysis).14 Body CT is performed also to complete staging of distant metastases. For colon cancer, body CT is usually performed as the sole imaging investigation. However, accurate nodal staging remains a challenge for these imaging modalities: accuracies varying from 62% to 83% have been reported for TRUS, whereas accuracies varying from 39% to 95% have been reported for MRI.14 Fluorodeoxyglucose PET can contribute to staging because its sensitivity for metastatic disease is such that it will prevent futile surgery in cases of advanced metastatic disease (Figure 4), provide a baseline study for further neoadjuvant or adjuvant treatment, and guide the decision for metastasectomy in patients with limitedvolume metastatic disease at initial presentation. Several small studies have suggested that FDG-PET is superior to ultrasound15 and CT15,16 for staging, particularly for metastatic disease, although one did not find FDG-PET to be superior to CT.17 As with other imaging modalities, nodal staging remains problematic. In early FDG-PET studies, Abdel-Nabi et al reported a sensitivity of 29% only for positive nodes.16 False negative nodes occurred because of their small size, whereas false positive nodes occurred because of physiologic activity. Nodal staging has improved with FDG-PET/CT. A more recently published study of FDG-PET/CT performed in conjunction with pelvic MRI, TRUS, and CT in 47 patients with low rectal cancer showed PET/CT altered staging in 10 patients (21%)—upstaging 7 of 10 patients and downstaging 3 of 10 patients.18 PET/CT was able to demonstrate nodal involvement in 5 patients not noted on conventional imaging and to exclude nodal involvement in 2 patients with enlarged nodes on CT.18 Likewise a study comparing FDG-PET/ CT and whole-body MR in colon cancer found that FDG-PET/CT was superior to whole-body MRI for nodal staging identifying 15/20 node positive cases versus 10/20 using MRI.19 More recently, FDG-PET/CT colonography (using water as the distending agent) for staging CRC has been investigated.20-22 These studies have shown that FDG-PET/CT colonography is

feasible in the clinical setting. An initial study by Veit-Haibach et al demonstrated 18 colonic tumor sites in 14 patients.20 PET/CT colonography did miss a 5-mm polyp, but this was subsequently found to be a benign tubular adenoma.20 In terms of TNM staging, PET/CT colonography appeared to be equivalent to CT plus PET but was better than CT alone for T staging. There was no improvement in N staging, especially when a size cutoff of 7 mm rather than 10 mm was used for abnormal nodes on CT.21 Despite its superior sensitivity for metastatic disease and its ability to alter clinical management in up to 36% of CRC cases,15,17,23,24 FDG-PET has not been incorporated routinely into the staging pathway to date, reflecting available health service resources and lack of cost-benefit data.

Assessment of Metastatic Relapse and Suitability for Resection Surveillance after surgery is usually undertaken using serum carcinoembryonic antigen (CEA), colonoscopy, and contrast-enhanced CT.25 Contrast-enhanced CT is also the first-line investigation in patients suspected of metastatic relapse in the presence of a rising CEA level. However, FDG-PET has an established role in this scenario when conventional imaging is deemed ‘normal.’ FDG-PET is able to differentiate equivocal findings on conventional imaging and is a sensitive tool with a positive predictive value of 89% and a negative predictive value of 100% (Figure 5).26 A meta-analysis of 11 studies found FDG-PET had an overall sensitivity of 97% and specificity of 76% in the detection of recurrent CRC, leading to a change in the management in 29% of cases.27 Compared with conventional imaging for detecting local recurrence and hepatic metastatic disease, FDG-PET had a higher sensitivity and specificity (87% and 68%, respectively) compared with CT (66% and 59%, respectively).7,28-30 Fluorodeoxyglucose PET is becoming increasingly established in the diagnostic workup for patients planned for surgical resection of limited metastatic disease (‘metastasectomy’), and is complementary to CT (which remains the ‘first-line’ imaging investigation) and contrast-enhanced liver MRI (usually performed with liver-specific contrast agents when liver resection is planned). Approximately 25% of patients who develop metastases following ‘curative’ surgery are potentially suitable for metastasectomy. However, up to 75% of these patients will relapse despite further surgery unless imaging accuracy

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Functional Imaging of CRC Figure 4 Whole-Body FDG-PET/CT Study in a 44-Year-Old Man Showing FDG-Avid Colorectal Liver Metastases

Figure 5 Whole-Body FDG-PET/CT Study in a 56-Year-Old Woman Presenting with Rising Tumor Marker (Carcinoembryonic Antigen) Showing FDG-Avid Recurrent Disease in the Right Paracolic Gutter

is further improved. Studies have shown that PET or PET/CT is superior to CT alone and CT portography31 in the detection of liver metastases.31-33 A meta-analysis of imaging of CRC liver metastases found a sensitivity of 94.6% on a per-patient basis for FDG-PET compared with 64.7% for helical CT, 75.8% for 1.5T noncontrast MRI though sensitivity on a per-lesion basis was comparable with gadolinium and superparamagnetic iron oxide–enhanced MRI.33 However, its advantage is its greater accuracy for extrahepatic disease, with an accuracy of 92% compared with 71% with CT.31 Thus, FDG-PET might prevent unnecessary surgery for patients with undetected nodal disease or more widespread metastatic disease.34 It might alter management in up to 30% of patients, predominantly through its sensitivity for extrahepatic disease.35-37

Therapeutic Assessment Response to Chemotherapy and Chemoradiation Fluorodeoxyglucose PET provides information on tumor cell viability following treatment. A metabolic response to treatment might occur before any structurally detectable change, eg, tumor

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shrinkage. FDG-PET may also distinguish between active disease and scar tissue.38 A metabolic response to chemotherapy might correlate with later Response Evaluation Criteria in Solid Tumors response on CT.39-41 In the neoadjuvant setting, serial FDG-PET might aid treatment planning, for example, the appropriate length of neoadjuvant chemotherapy for metastatic disease to maximize response before planned surgical resection or lead to a change in chemotherapeutic agent in tumors showing no metabolic response. Small studies of FDG-PET in advanced CRC have shown that FDGPET can demonstrate a decrease in tumor glucose metabolism with chemotherapy and might be predictive of outcome.42-46 In rectal cancer, sequential FDG-PET following neoadjuvant chemoradiation might also predict response47,48 and be an independent prognostic predictor of disease-free survival49 and 5-year overall survival (91% vs. 72% in PET-negative versus PET-positive studies 6 weeks after completion of treatment).50 However, not all studies have been concordant. For example, a study using FDG-PET/CT in 30 patients with locally advanced rectal cancer undergoing preoperative chemoradiation 7 weeks after completion of treatment only had a sensitivity of 45% and accuracy of 53% compared with histopathologic response.51 The use of FDG-PET to assess therapeutic response is a complex task.44 The National Cancer Institute has published protocols to standardize methods for obtaining and analyzing FDG-PET across multicenter clinical trials.52 Similarly, the European Organization for Research and Treatment of Cancer has published criteria for FDG-PET–determined metabolic response.53 However, the optimal scheduling of FDG-PET in CRC is unclear. A confounding increase in FDG uptake, a ‘flare’ phenomenon, has been reported in responding lesions shortly after initiation of chemotherapy. False positive studies might also occur with radiation therapy because of inflammation or regenerating tissue. Data from squamous esophageal cancer54 and adenocarcinomas of the gastroesophageal junction,55 examining the changes in SUV at different time points after commencement of chemoradiation and chemotherapy, respectively, 14 days and preoperatively after completion of therapy have demonstrated that SUV change varies depending on when the FDG-PET study is performed. This suggests that different SUV criteria might have to be applied depending on the scheduling of the FDG-PET study to the treatment concerned. Published CRC studies have also applied different approaches to assess therapeutic response, using either a semiquantitative approach (SUV) or a kinetic approach to measuring FDG uptake over time. Findlay et al45 used lesion:background ratios to predict response to chemotherapy in CRC patients with hepatic metastases 4-5 weeks after commencing therapy. Dimitrkopoulou-Strauss et al46 combined kinetic modeling with semiquantitative (SUV) data from dynamic FDG-PET examinations to classify patients with metastatic CRC further into short- and long-term survival groups, correctly in 77.8%. Similarly, De Gues-Oei et al compared quantitative Patlak analysis of glucose uptake with SUV in patients with advanced CRC undergoing chemotherapy and found that both methods were capable of predicting outcome (overall survival and progression-free survival).42 The ‘better’ approach remains debated—whereas others have favored a quantitative approach,46 some have suggested that SUV is sufficient.42

Nikhil Kapse, Vicky Goh Table 1 Fluorodeoxyglucose Positron Emission Tomography in the Management of Colorectal Cancer

Diagnosis

Staging/Re-staging

Current Practice

Role for FDG-PET Currently?

Colonoscopy and biopsy

No

Small number of studies only Early data from PET/CT colonography – possible future role in diagnosis/staging?

Rectal: MRI ± TRUS; CT Colon: CT

Yes

Established role in staging patients planned for metastasectomy Changes in management reported in up to 59% of cases

CT ± MRI

Yes

Established role in localization of disease in cases of elevated CEA and ‘normal’ or equivocal conventional imaging

Rectal: MRI ± CT Colon: CT

Possible

Evolving role in the context of therapeutic assessment, particularly in the neoadjuvant setting

CT

No

Small number of studies only; possible future role

No

Small number of studies only; future role dependent on availability and cost-benefit analysis

Assessment of Disease Recurrence Therapeutic Response Radiation Therapy Planning Surveillance

Colonoscopy, serum CEA, CT

Comment

Figure 6 Dynamic Contrast-Enhanced Magnetic Resonance Imaging Study in a 77-Year-Old Man with Rectal Cancer: T2-Weighted, Ktrans and Ve Parametric Maps Are Shown (Left to Right)

Abbreviation: Ve = Volume extravascular-extracellular space

Response to Chemotherapy and Chemoradiation Fluorodeoxyglucose PET can also be used to assess residual disease following completion of local ablative therapy. Following local ablative treatment of CRC hepatic metastases, eg, transarterial chemoembolization (TACE), radiofrequency ablation (RFA), or cryoablation, FDG-PET might better depict treatment response than conventional imaging32 and might allow localization of recurrent tumor to better target a biopsy or to guide repeat RFA.56 Similarly, FDG-PET/CT might provide more accurate and earlier assessment of therapy response after intra-arterial administration of Yttrium-90 (90Y) microspheres to unresectable liver metastases when compared with CT.57 A prospective study of patients with CRC hepatic metastases demonstrated FDG-PET as an accurate indicator of treatment response to 90Y-microsphere treatment, correlating with a decrease in CEA, unlike CT or MRI.58

Radiation Therapy Planning Fluorodeoxyglucose PET allows delineation of biologically active tissue. Fusion of this functional information with anatomic information from CT or MRI can be used to refine radiation treatment planning to a ‘biologic target volume,’ allowing greater sparing of surrounding healthy tissue and potentially reducing geographic misses. The utility of integrating FDG-PET/CT into treatment

planning has been explored in tumors such as non–small-cell lung cancer (NSCLC)59-61 and head and neck cancers,62 but few studies have been published of rectal cancer. In a study of automated PET image-guided radiation treatment planning for rectal cancer, Ciernik et al63 found that the pathologic tumor extent could exceed that of a CT-derived treatment volume. Positron emission tomography could thus reduce the risk of a geographic miss. In another study of rectal cancer, clarification of active tumor tissue with PET/CT altered target volume definition by 25% for the gross tumor volume (GTV) and 4% for clinical tumor volume (CTV); the PET/CT–defined GTV and CTV was greater than that defined by CT.64

Other Positron Emission Tomography Radiotracers A number of radiotracers are currently undergoing investigation particularly in the context of clinical trials of new drugs that target specific molecular processes. These include tracers that reflect cellular proliferation (18F-3-deoxy-3-fluorothymidine [18F-FLT]), hypoxia (18F-fluoroimidazole [18F-FMISO]), and perfusion (150-labeled water). 18F-FLT, a stable thymidine analogue, is phosphorylated by thymidine kinase and trapped in cells as part of DNA synthesis,65 thus providing a noninvasive measure of cellular proliferation. 18F-FLT uptake has been correlated with histologic measures of proliferation

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Functional Imaging of CRC Figure 7 Perfusion Computed Tomography Study in a 77-Year-Old Man with Rectal Cancer

Blood flow (left) and blood volume (right) parametric maps are shown superimposed on the morphologic image.

Table 2 Typical Imaging Parameters for DCE-MRI and Perfusion Computed Tomography Studies Based on Our Practice T1W DCE-MRI 2D/3D

T2*W DCE-MRI 2D

MDCT Single Level (2D)

Contrast

0.5 mmol/mL gadolinium

0.5 mmol/mL gadolinium

> 300 mg/mL iodine

Dose

0.1 mmol/kg

q0.2 mmol/kg

0.5 mL/kg

Imaging Parameter

Typical volume

10-15 mL

25-35 mL

40 mL

Injection rate

3 mL/s bolus

4-6 mL/s bolus

3-5 mL/s bolus

Acquisition Type

Single level

Single level

Single level

30 mm

30 mm

125 mm

5-12 s for 5-7 minutes

1-2 s for 1-2 minutes

1 s for 1-2 minutes

Increase/large

Decrease/small

Increase/small

General kinetic model

Central volume theorem

Distributed parameter model

Transfer constants, leakage space

Relative BF, BV, MTT

BF, BV, MTT, PS

Coverage Data Sampling Signal Change/ Magnitude of Effect Kinetic Modeling Parameter Typically Measured

Abbreviations: BF = blood flow; BV = blood volume; MTT = mean transit time; PS = permeability surface area product

(Ki-67), for example in lung nodules.66 In general, FLT uptake is lower than FDG; therefore, it is a poorer tracer for detection of malignancy, but it appears to be more specific. In CRC, it has comparable sensitivity to 18F-FDG for primary tumor assessment but poorer sensitivity for hepatic metastases due to high background liver uptake.67 It might demonstrate a response to neoadjuvant chemotherapy68: imaging performed 2 weeks after initiation of chemoradiation and 4 weeks post treatment demonstrated a reduction in FLT uptake at both time points. However, in this small study, the degree of change in FLT uptake did not correlate with histopathologic tumor regression. Given current data, it is unlikely that 18FFLT will play a major clinical role in the evaluation of CRC. 18F-FMISO might be used to provide in vivo mapping of hypoxia, because it shows high accumulation in hypoxic tissue (where it is bound intracellularly) with little or no uptake in normally oxygenated tissue. Hypoxic or anoxic tumor areas arise as a result of an imbalance between supply and consumption of oxygen. It is a contributor to radiation therapy and chemotherapy resistance. It is an important selective variable in the clonal evolution of tumors, promoting oncogenic mutations, cell survival, and more aggressive behavior and thus plays an important part in the

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development of metastatic disease. Hypoxia also upregulates the angiogenic pathway via hypoxia inducible factor–induced expression of vascular endothelial growth factor (VEGF).69 Studies have shown the value of 18F-FMISO PET in head and neck cancer and NSCLC as a prognosticator70 and for therapeutic assessment,71 but there have been few studies of CRC. For example, a phase I study of oxaliplatin combined with infusional 5-FU and concomitant radiation therapy found detectable hypoxia in 4 of 6 colorectal tumors imaged with 18F-FMISO.72 15O-water is a freely diffusible radiotracer that acts as a marker of perfusion. It has the potential to be used in clinical trials to monitor changes in blood flow in response to chemotherapy or antiangiogenic agents such as bevacizumab.73 However, it has a short half-life (T1/2 = 2 minutes), limiting widespread clinical application. To date, there have been no studies in human CRC. Other radiotracers such as copper-64 (⁶⁴Cu)–DOTAPEGE[c(RGDyK)]2 and 18F-Galacto-RGD, which bind to the AvB3 integrin and provide assessment of angiogenesis, and iodine-124–labeled or 18F-labeled annexin and ⁶⁴Cu-labeled streptavidin that provide assessment of apoptosis, have shown promise in animal studies but have yet to show utility in humans.

Nikhil Kapse, Vicky Goh Summary

Figure 8 DWI-MRI Study in a 71-Year-Old Man with Rectal Cancer

At present, FDG-PET has an established role in staging patients with CRC planned for surgical resection of metastases, and in the localization of disease relapse, particularly in patients with elevated CEA levels, where ‘conventional’ imaging has been deemed ‘normal’ or equivocal (Table 1).74 In these areas, FDG-PET improves management, prevents pointless surgery and might lead to better outcome. There is increasing interest in FDG-PET beyond this in the assessment of residual masses posttreatment, eg, radiation therapy, RFA; in the assessment of early tumor response to neoadjuvant chemotherapy or chemoradiation; in prediction of response; in radiation therapy planning; and in tumor surveillance.

Other Imaging More recently there has been a trend toward the development of functional imaging using conventional imaging modalities—MRI and CT. These modalities are already used widely in oncology for diagnosis, staging, therapeutic assessment, and surveillance based on morphology. Thus, the ability to combine morphologic with functional information is an attractive proposal. These techniques remain predominantly research tools and include techniques that assess tumor angiogenesis (DCE-MRI or perfusion CT), tumor cellularity (DWI-MRI), and tumor hypoxia (BOLD-MRI).

Assessment of Tumor Angiogenesis Kinetic modeling of dynamic contrast enhancement at MRI or CT provides functional information of the underlying tumor vasculature and tumor angiogenesis (Figures 6 and 7). Both semiquantitative and quantitative parameters can be obtained using these techniques and have been correlated with histologic measures of angiogenesis in a variety of cancers including lung, renal, and colorectal cancer,75-78 although some MRI and CT studies have reported no correlation.79,80 These techniques have been shown to have a role in therapeutic assessment, for example, evaluating antivascular drug effect in early-phase clinical trials.81-84 To date, these research-based techniques have not been integrated into general clinical use but might have potential, for example, as a prognostic tool at tumor staging.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Contrast medium kinetics differ between normal tissue and tumor such that kinetic modeling of a bolus injection of lowmolecular-weight (< 1 kDa) gadolinium-based paramagnetic MRI contrast medium can be used for tumor evaluation. Different MRI sequences might be performed to investigate the tumor vasculature. T1-weighted sequences are sensitive to contrast in the extravascularextracellular space. After contrast medium injection, signal intensity increases over time as contrast medium diffuses from the intravascular into the extravascular-extracellular space. Provided the relationship between signal intensity and gadolinium concentration can be defined (as this is typically nonlinear, with an amplification effect), the rate of contrast medium extraction (transfer constant; Ktrans), fractional extracellular leakage space (Ve), and rate of contrast return from the extravascular-extracellular space to the intravascular space

T2-weighted and apparent diffusion coefficient (ADC) maps shown before (top row) and after chemoradiation (bottom row). The tumor demonstrates low ADC values on the baseline study; ADC increases following chemoradiation.

(rate constant; Kep) can be estimated using kinetic modeling. Ktrans reflects both plasma flow and permeability-surface area product, and is heterogeneously distributed in primary and metastatic CRC. At regions where the permeability surface area product is high compared with flow, such as at the peripheral highly angiogenic rims of tumors, Ktrans estimates are dominated by plasma flow. At regions where permeability is low compared with flow, usually within the tumor center, Ktrans predominantly reflects permeability surface area product. This parameter has been shown to be reproducible and has been recommended as an appropriate vascular parameter for study in phase I antiangiogenesis drug trials.85,86 In tumors where the vasculature is highly permeable, this parameter predominantly reflects plasma flow rather than permeability surface area product. T2*-weighted sequences are sensitive to the susceptibility effects of intravascular contrast medium. A reduction in signal intensity occurs initially after contrast administration with a subsequent recovery in signal intensity as T1 effects overrule T2* effects. Mean transit time, relative blood flow, and relative blood volume can be estimated from the G-variate fitted signal intensity-time graphs. Typical acquisition parameters are illustrated in Table 2.

Perfusion Computed Tomography Like DCE-MRI, DCE-CT techniques, also known as perfusion CT, exploit the differences in contrast medium kinetics between normal and tumor tissue. The relationship between CT contrast medium concentration and CT enhancement is linear; thus, quantification of vascular parameters is more straightforward than MRI. Kinetic modeling of the change in contrast enhancement over time following contrast medium injection allows blood flow, blood volume, and permeability surface area product to be estimated directly. Its clinical application is facilitated by the availability of FDA-approved commercial software on standard CT workstations. Typical acquisition parameters are illustrated in Table 2. CT technology has advanced such that large tissue volumes can be assessed up to 12.5 cm with single-level tech-

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Functional Imaging of Colorectal Cancer Figure 9 BOLD-MRI Study in a 68-Year-Old Man with Rectal Cancer: T2-Weighted, Proton Density, and R2* Maps are Shown

Table 3 Comparison of the Different Functional Imaging Modalities Modality Comparator Tumor Property Assessed

DWI-MRI

BOLD-MRI

Tumor angiogenesis

Tumor angiogenesis

Tumor cellularity

Hypoxic blood volume

No

No

DCE-MRI

Tumor metabolism FDG

Gadolinium-based contrast agent

Iodinated contrast agent

SUV or kinetic analysis of FDG uptake

Ktrans, Kep, Ve Relative BF, BV, MTT

BF, BV, PS

ADC

R2*

SUVmean: 3-15 SUVmax: 5-40

Ktrans: 0.28-1.8 min−1 PI: 7-10 mL/min/100 g

BF: 60-73 mL/min/100 g BV: 3-6 mL/min PS: 13-18 mL/min/100 g

ADC: 0.5-1.2 × 103 mm2/s

R2*: 20-37.9/s

Tracer Injection Required Parameter Assessed

DCE-CT

FDG-PET

Typical Range for Primary Current role: Staging

Yes

No

No

No

No

Therapeutic assessment

Yes

Yes

Yes

Yes

No

Surveillance

No

No

No

No

No

Abbreviations: ADC = apparent diffusion coefficient; BF = flow; BV = blood volume; Kep = rate constant; Ktrans = transfer constant; PS = permeability surface area product; R2* = relaxation constant; SUV = standardized uptake value; Ve = volume extravascular-extracellular space

niques on the latest 256-detector row scanners, and up to 25 cm with helical techniques.

Potential Clinical Applications In CRC, DCE-MRI and perfusion CT have predominantly been used for therapeutic assessment to date.81-84,87,88 In phase I drug trials, these imaging techniques have been used as biomarkers of antiangiogenic drug action81,83,84: for example, a reduction in primary rectal cancer perfusion and blood volume has been shown to occur in rectal cancer after bevacizumab, correlating with a decrease in microvessel density.81 However, the relationship between imaging changes in phase I studies and efficacy endpoints of phase III studies has been complex. Observed imaging vascular changes induced by antiangiogenic drugs imaging might not reflect eventual outcome. As an example, PTK787/ZK 222584 (valatinib); a multiple VEGF receptor inhibitor, showed early promise in CRC. In phase I studies, DCE-MRI demonstrated an antivascular effect within 33 hours of a single drug dose, with a mean decrease in the bidirectional transfer constant, Ki, of 43% noted in liver metastases. Higher drug doses (> 1000 mg) resulted in a greater decrease in Ki that was sustained at day 28.83 However, definitive efficacy trials in CRC (CONFIRM-1/2) were ultimately disappointing. In terms of prediction of treatment response, some studies have suggested that

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DCE-MRI and perfusion CT estimates of perfusion might predict for chemoradiation response in rectal cancer. However, numbers have been small (ranging from 9 to 19), and results conflicting with some studies showing higher baseline perfusion as a predictor of good response88,89 whereas others have indicated that higher baseline perfusion is a marker of poor response.87,90 In the context of diagnosis and staging, perfusion CT has shown promise.91 Early data suggest it might have a role in the distinction of colon cancers in patients with coexistent diverticular disease, where simple morphologic characteristics have proven difficult to interpret.92 It might also have a role in detecting early hepatic metastatic disease before detectable morphologic change, through differences in hepatic vascularity.93,94 Primary tumor perfusion might also predict for the subsequent development of metastatic disease.95 However, these findings have yet to be substantiated by further studies. DCE-MRI has also shown promise in evaluating recurrent disease96-98 by its potential ability to distinguish between malignant and benign tissue.99 These techniques have yet to be integrated widely into clinical practice.

Assessment of Tumor Cellularity The motion of water molecules in the body can be explored by DWI-MRI. In the body, the movement of water molecules is

Nikhil Kapse, Vicky Goh restricted by interaction with cell membranes and macromolecules. The higher the cellular density and the greater the presence of lipophilic cell membranes, the more restricted water motion is. Conversely, the lower the cellular density, or where the cell membrane has been breached, the less restricted diffusion will be, as water molecules will be able to move more freely about the extravascularextracellular space and from the extravascular-extracellular space into the intravascular space. This can be exploited to provide indirect assessment of tumor cellularity. In practice, the DWI signal is derived from the motion of water molecules within the extravascular-extracellular space, intracellular space, and intravascular space. The relative contribution of each space will vary from tissue to tissue, but clearly in any unit time, diffusion will be greatest in the intravascular space given blood flow. Thus, in highly vascular tumors, intravascular water diffusion will account for a significant proportion of the DWI signal. The Stejskal and Tanner approach to DWI is the basis of many sequences in clinical use today.100 Motion of the water molecules is detected as a reduction in signal intensity. The sensitivity to water motion can be altered by changing ‘b values,’ which predominantly reflect the amplitude of gradients applied during MRI. Water molecules with a large degree of motion will show signal attenuation at low ‘b values,’ whereas slow-moving molecules will show only gradual signal attenuation with increasing ‘b values.’ A qualitative or quantitative approach may be taken to DWI-MRI. The disadvantage of using a qualitative approach (ie, visual assessment of the relative attenuation of signal intensity) for tumor detection, tumor characterization, and therapeutic response is that tissue T2 relaxation time also affects DWI signal intensity. Thus, an area with a long T2 relaxation time might remain of high signal and be mistaken for an area of restricted diffusion, an effect known as ‘T2 shine through.’ Quantitative analysis by plotting the logarithm of the relative signal intensity (y-axis) versus b value (x-axis) allows calculation of the apparent diffusion coefficient (ADC) from the slope of the fitted line. Flow insensitive ADC values (fitting of high b values only, eg, b values > 150 s/mm2) might provide a more accurate estimate of the tumor microenvironment by minimizing the intravascular contribution. Areas of restricted diffusion show low ADC values. In CRC, DWI-MRI has been explored predominantly in the context of therapeutic assessment, where DWI-MRI appears to have a role in the prediction of response. DWI-MRI of rectal cancer has shown changes in ADC with chemoradiation (Figure 8).101,102 Tumors with a high initial ADC might predict for a poor response.101 DWI-MRI of colorectal hepatic metastases undergoing chemotherapy has shown a high initial ADC to be a predictor of a poor response to chemotherapy.103,104 To date, there are few studies of tumor detection to support a role for DWI-MRI as a single technique in this context. Two studies have assessed whether DWI-MRI may be used for primary rectal tumor detection. In one study, good sensitivity and specificity (87%-90% and 100%, respectively) were achieved for CRC ranging in size from 2 cm to 7 cm105; however, in another study, there were 7/20 false positive studies (in the control group), resulting in a lower specificity of 65%.106 A study has explored if DWI-MRI has a role in improving detection of hepatic metastases:

when combined with mangafodipir trisodium contrast-enhanced liver MRI, diagnostic accuracy improved compared with either technique alone.107 Further work is still required. An area where DWI-MRI is showing promise is in the detection and characterization of lymph nodes. Although MRI using lymphotropic contrast agents has shown promise in colorectal108 and other cancers, including prostate, gynecologic, and breast,109-111 these agents are not licensed for use in Europe. DWI-MRI in cervical and uterine cancers112 and NSCLC113,114 can improve detection and characterization of lymph nodes, which is promising for its application in CRC, although specific CRC data have yet to be published. Nevertheless, the ease with which DWI-MRI can be incorporated into the clinical workflow with little patient perturbation has already facilitated clinical acceptance, and clinical uptake will no doubt increase further as supporting data come through.

Assessment of Tumor Hypoxic Blood Volume Blood oxygenation level–dependent MRI or intrinsic susceptibility-weighted MRI is a research technique sensitive to paramagnetic deoxyhemoglobin within red blood cells in perfused vessels and in adjacent surrounding tissue. Deoxyhemoglobin increases the transverse relaxation rate of water in blood (R2*); thus, BOLDMRI might provide information of red cell delivery and the level of blood oxygenation (Figure 9). Studies have shown that R2* alters with vasomodulation using carbogen (95% C02; 5% 02) inhalation and is correlated with tissue p02115, but there have been few studies of human tumors. Although an initial feasibility study of 15 patients with primary CRC showed BOLD-MRI was possible, R2* did not correlate with histologic markers of hypoxia.79 To date, no studies have examined its role in staging, its feasibility for radiation therapy planning or therapeutic assessment. Thus, at present, this technique remains very much a research tool with no immediate clinical application in CRC. A major limitation for the application of BOLD-MRI in clinical practice is that carbogen vasomodulation is challenging (up to 35% of patients will not tolerate it), p02 is not assessed directly (the relationship between R2* and tissue p02 is nonlinear), and the signal to noise ratio is low. Furthermore tissue perfusion is required in order for BOLD-MRI to inform on oxygenation status; thus, chronic hypoxia is less likely to be reflected by BOLD-MRI.

Conclusion In recent years, the adoption of a more aggressive surgical approach to the management of CRC (including metastasectomy with curative intent) and the licensing of novel drugs for use in combination with standard chemotherapy have highlighted the need for a multimodality anatomic–functional imaging approach to achieve optimal tumor evaluation. FDG-PET is now an established technique for the staging and restaging of patients with metastatic disease, in particular, to localize sites of relapse and to aid surgical planning. There is increasing interest in FDG-PET in therapeutic assessment because the information it provides could enable treatment to be altered at an earlier stage than conventional imaging or allow a patient’s treatment to be more tailored to tumor biology. There is also interest in radia-

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Functional Imaging of Colorectal Cancer tion therapy planning, where more accurate planning volumes might be achieved, and in tumor surveillance. Other functional methods such as DWI-MRI, DCE-MRI, and CT are emerging as useful clinical tools (Table 3). DWI-MRI is showing promise in lymph node detection and characterization and in therapeutic assessment, whereas DCE-MRI and CT have an emerging role in assessment of antivascular drug therapy.

Disclosures The authors report no relevant conflicts of interest.

References 1. Antoch G, Saoudi N, Kuehl H, et al. Accuracy of whole-body dual-modality Fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol 2004; 22:4357-68. 2. Bar-Shalom R, Yefremov N, Guralnik L, et al. Clinical performance of PET/CT in evaluation of cancer: additional value for diagnostic imaging and patient management. J Nucl Med 2003; 44:1200-9. 3. Hany TF, Steinert HC, Goerres GW, et al. PET diagnostic accuracy: improvement with in-line PET-CT system: initial results. Radiology 2002; 225:575-81. 4. Park IJ, Kim HC, Yu CS, et al. Efficacy of PET/CT in the accurate evaluation of primary colorectal carcinoma. Eur J Surg Oncol 2006; 32:941-7. 5. Cohade C, Osman M, Leal J, et al. Direct comparison of (18)F-FDG PET and PET/CT in patients with colorectal carcinoma. J Nucl Med 2003; 44:1797-803. 6. Esteves FP, Schuster DM, Halkar RK. Gastrointestinal tract malignancies and positron emission tomography: an overview. Semin Nucl Med 2006; 36:169-81. 7. Whiteford MH, Whiteford HM, Yee LF, et al. Usefulness of FDG-PET scan in the assessment of suspected metastatic or recurrent adenocarcinoma of the colon and rectum. Dis Colon Rectum 2000; 43:759-67. 8. Gutman F, Alberini J, Wartski M, et al. Incidental colonic focal lesions detected by FDG PET/CT. AJR Am J Roentgenol 2005; 185:495-500. 9. Kamel EM, Thumshirn M, Truninger K, et al. Significance of incidental 18F-FDG accumulations in the gastrointestinal tract in PET/CT: correlation with endoscopic and histopathologic results. J Nucl Med 2004; 45:1804-10. 10. Yasuda S, Fujii H, Nakahara T, et al. 18F-FDG PET detection of colonic adenomas. J Nucl Med 2001; 42:989-92. 11. Mainenti PP, Salvatore B, D’Antonio D, et al. PET/CT colonography in patients with colorectal polyps: a feasibility study. Eur J Nucl Med Mol Imaging 2007; 34:1594-603. 12. Gollub MJ, Akhurst T, Markowitz AJ, et al. Combined CT colonography and 18FFDG PET of colon polyps:potential technique for selective detection of cancer and precancerous lesions. AJR Am J Roentgenol 2007; 188:130-8. 13. Mercury study group. Diagnostic accuracy of preoperative magnetic resonance imaging in predicting curative resection of rectal cancer: prospective observational study. BMJ 2006; 333:779-84. 14. Bipat S, Glas AS, Slors FJM, et al. Rectal cancer:Local staging and assessment of lymph node involvement with endoluminal US, CT and MR imaging-a metaanalysis. Radiology 2004; 232:773-83. 15. Kantorova I, Lipska L, Belohlavek O, et al. Routine (18)F-FDG PET preoperative staging of colorectal cancer: comparison with conventional staging and its impact on treatment decision making. J Nucl Med 2003; 44:1784-8. 16. Abdel-Nabi H, Doerr RJ, Lamonica DM, et al. Staging of primary colorectal carcinomas with fluorine-18 fluorodeoxyglucose whole-body PET: correlation with histopathologic and CT findings. Radiology 1998; 206:755-60. 17. Furukawa H, Ikuma H, Seki A, et al. Positron emission tomography scanning is not superior to whole body multidetector helical computed tomography in the preoperative staging of colorectal cancer. Gut 2006; 55:1007-11. 18. Gearhart SL, Frassica D, Rosen R, et al. Improved staging with pretreatment positron emission tomography/computed tomography in low rectal cancer. Ann Surg Oncol 2006; 13:397-404. 19. Squillaci E, Manenti G, Mancino S, et al. Staging of colon cancer: whole body MRI vs whole body PET-CT-initial clinical experience. Abdom Imaging 2008; 33:676-88. 20. Veit P, Kuhle C, Beyer T, et al. Whole body positron emission tomography/computed tomography (PET/CT) tumour staging with integrated PET/CT colonography: technical feasibility and first experiences in patients with colorectal cancer. Gut 2006; 55:68-73. 21. Veit-Haibach P, Kuehle CA, Beyer T, et al. Diagnostic accuracy of colorectal cancer staging with whole body PET/CT colonography. JAMA 2006; 296:2590-600. 22. Kinner S, Antoch G, Bockish A, et al. Whole-body PET/CT-colonography: a possible new concept for colorectal cancer staging. Abdom Imaging 2007; 32:606-12. 23. Park IJ, Kim HC, Yu CS, et al. Efficacy of PET/CT in the accurate evaluation of primary colorectal carcinoma. Eur J Surg Oncol 2006; 32:941-7. 24. Gambhir SS, Czernin J, Schwimmer J, et al. A tabulated summary of the FDG PET literature. J Nucl Med 2001; 42:1S-93S. 25. Rodriguez-Moranta F, Salo J, Arcusa A, et al. Postoperative surveillance in patients with colorectal cancer who have undergone curative resection: a prospective, multicenter, randomized, controlled trial. J Clin Oncol 2006; 24:386-93.

86

| Clinical Colorectal Cancer

April 2009

26. Flanagan FL, Dehdashti F, Ogunbiyi OA, et al. Utility of FDG-PET for investigating unexplained plasma CEA elevation in patients with colorectal cancer. Ann Surg 1998; 227:319-23. 27. Huebner RH, Park KC, Shepherd JE, et al. A meta-analysis of the literature for whole-body FDG PET detection of recurrent colorectal cancer. J Nucl Med 2000; 41:1177-89. 28. Delbeke D, Vitola JV, Sandler MP, et al. Staging recurrent metastatic colorectal carcinoma with PET. J Nucl Med 1997; 38:1196-201. 29. Valk PE, Abella-Columna E, Haseman MK, et al. Wholebody PET imaging with [18F]fluorodeoxyglucose in management of recurrent colorectal cancer. Arch Surg 1999; 134:503-11. 30. Kostakoglu L, Agress H, Goldsmith S. Clinical role of FDG PET in evaluation of cancer patients. Radiographics 2003; 23:315-40. 31. Delbeke D, Martin WH. PET and PET-CT for evaluation of colorectal carcinoma. Semin Nucl Med 2004; 32:209-23. 32. Long-Bang C, Jin-Long T, Hai-Zhu S, et al. 18F-DG PET/CT in detection of recurrence and metastasis of colorectal cancer. World J Gastroenterol 2007; 13:5025-9. 33. Bipat S, van Leeuwen MS, Comans EF, et al. Colorectal liver metastases: CT, MR imaging, and PET for diagnosis—meta-analysis. Radiology 2005; 237:123-31. 34. Lai DT, Fulham M, Stephen MS, et al. The role of whole-body positron emission tomography with [18F]fluorodeoxyglucose in identifying operable colorectal cancer metastases to the liver. Arch Surg 1996; 131:703-7. 35. Selzner M, Hany TF, Wildbrett P, et al. Does the novel PET/CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg 2004; 240:1027-34; discussion, 1035-6. 36. Truant S, Huglo D, Hebbar M, et al. Prospective evaluation of the impact of [18F]fluoro-2-deoxy-D-glucose positron emission tomography of resectable colorectal liver metastases. Br J Surg 2005; 92:362-9. 37. Wiering B, Krabbe PF, Jager GJ, et al. The impact of fluor-18-deoxyglucosepositron emission tomography in the management of colorectal liver metastases. Cancer 2005; 104:2658-70. 38. Ito K, Kato T, Tadokoro M, et al. Recurrent rectal cancer and scar: differentiation with PET and MR imaging. Radiology 1992; 182:549-52. 39. Herbertson RA, Lee ST, Tebbutt N, et al. The expanding role of PET technology in the management of patients with colorectal cancer. Ann Oncol 2007; 18:1774-81. 40. Ell PJ. The contribution of PET/CT to improved patient management. Br J Radiol 2006; 79:32-6. 41. Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl J Med 2006; 354:496-507. 42. De Gues-Oei LF, Van Laarhoven HW, Visser EP. Chemotherapy response evaluation with FDG-PET in patients with colorectal cancer. Ann Oncol 2008; 19:348-52. 43. de Geus-Oei LF, Wiering B, Krabbe PF, et al. FDG-PET for prediction of survival of patients with metastatic colorectal carcinoma. Ann Oncol 2006; 17:1650-5. 44. Metser U. 18F-FDG PET in evaluating patients treated for metastatic colorectal cancer: can we predict prognosis? J Nucl Med 2004; 45:1428-30. 45. Findlay M, Young H, Cunningham D, et al. Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil. J Clin Oncol 1996; 14:700-8. 46. Dimitrakopoulou-Strauss A, Strauss LG, Burger C, et al. Prognostic aspects of 18F-FDG PET kinetics in patients with metastatic colorectal carcinoma receiving FOLFOX chemotherapy. J Nucl Med 2004; 45:1480-7. 47. Konski A, Hoffman J, Sigurdson E, et al. Can molecular imaging predict response to preoperative chemoradiation in patients with rectal cancer? A Fox Chase Cancer Center prospective experience. Semin Oncol 2005; 32:S63-7. 48. Capirci C, Rampin L, Erba PA, et al. Sequential FDG-PET/CT reliably predicts response of locally advanced rectal cancer to neo-adjuvant chemo-radiation therapy. Eur J Nucl Med Mol Imaging 2007; 34:1583-93. 49. Kalff V, Duong C, Drummond EG, et al. Findings on 18F-FDG PET scans after neo-adjuvant chemoradiation provides prognostic stratification in patients with locally advanced rectal carcinoma subsequently treated by radical surgery. J Nucl Med 2006; 47:14-22. 50. Capirci C, Rubello D, Chierichetti F, et al. Long term prognostic value of 18FFDG PET in patients with locally advanced rectal cancer previously treated with neoadjuvant chemoradiotherapy. AJR Am J Roentgenol 2006; 187:W202-8. 51. Kristiansen C, Loft A, Berthelsen AK, et al. PET/CT and histopathologic response to preoperative chemoradiation therapy in locally advanced rectal cancer. Dis Colon Rectum 2008; 51:21-5. 52. Shankar LK, Hoffman JM, Bacharach S, et al. Consensus recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute trials. J Nucl Med 2006; 47:1059-66. 53. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer 1999; 35:1773-82. 54. Wieder HA, Brucher BL, Zimmermann F, et al. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol 2004; 22:900-8. 55. Wieder HA, Ott K, Lordick F, et al. Prediction of tumor response by FDG-PET: comparison of the accuracy of single and sequential studies in patients with adenocarcinoma of the esophagagastric junction. Eur J Nucl Med Mol Imaging 2007; 34:1925-32. 56. Barker DW, Zagoria RJ, Morton KA, et al. Evaluation of liver metastases after radiofrequency ablation: utility of 18F-FDG PET and PET/CT. AJR Am J

Nikhil Kapse, Vicky Goh Roentgenol 2005; 184:1096-102. 57. Bienert M, McCook B, Carr B, et al. 90Y microsphere treatment of unresectable liver metastases: changes in 18F-FDG uptake and tumour size on PET/CT. Eur J Nucl Med Mol Imaging 2005; 32:778-87. 58. Wong CO, Salem R, Raman S, et al. Evaluating 90Y-glass microsphere treatment response of unresectable colorectal liver metastases by [18F]FDG PET: a comparison with CT or MRI. Eur J Nucl Med 2002; 29:815-20. 59. Gondi V, Bradley K, Minesh M, et al. Impact of hybrid fluorodeoxyglucose positron emission tomography/computed tomography on radiotherapy planning in esophageal and non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2007; 67:187-95. 60. Grills IS, Yan D, Black QC, et al. Clinical implications of defining gross tumor volume with combination of 18FDG-positron emission tomography in non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2007; 67:187-95. 61. Ashamalla H, Rafla S, Parikh K, et al. The contribution of integrated PET/CT on the evolving definition of treatment volumes in radiation treatment planning in lung cancer. Int J Radiat Oncol Biol Phys 2005; 63:1016-23. 62. Ashamalla H, Guirgius A, Bieniek E, et al. The impact of positron emission tomography/computed tomography in edge delineation of gross tumour volume for head and neck cancer. Int J Radiat Oncol Biol Phys 2007; 68:388-95. 63. Ciernik IF, Huser M, Burger C, et al. Automated functional image guided radiatiob treatment planning for rectal cancer. Int J Radiat Oncol Biol Phys 2005; 62:893-900. 64. Bassi MC, Turri L, Sacchetti G, et al. FDG-PET/CT imaging for staging and target volume delineation in preoperative conformal radiotherapy of rectal cancer. Int J Radiat Oncol Biol Phys 2008; 70:1423-6. 65. Groves AM, Win T, Ben Haim S, et al. Non-[18F]FDG PET in clinical oncology. Lancet Oncol 2007; 8:822-30. 66. Buck AK, Hetzel M, Schirrmeister H, et al. Clinical relevance of imaging proliferative activity in lung nodules. Eur J Nucl Med Mol Imaging 2005; 32:525-33. 67. Francis DL, Freeman A, Visvikis D, et al. In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography. Gut 2003; 52:1602-6. 68. Wieder HA, Geinitz H, Rosenberg R, et al. PET imaging with [18F]3`-flurothymidine for prediction of response to neoadjuvant treatment in patients with rectal cancer. Eur J Nucl Med Mol Imaging 2007; 34:878-83. 69. Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia initiated angiogenesis. Nature 1992; 359:843-5. 70. Eschmann SM, Paulsen F, Reimold M, et al. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med 2005; 46:253-60. 71. Hicks RJ, Rischkin D, Fisher R, et al. Utility of FMISO PET in advanced head and neck cancer treated with chemoradiation incorporating an hypoxia-targeting chemotherapy agent. Eur J Nucl Med Mol Imaging 2005; 32:1384-91. 72. Loi S, Ngan SY, Hicks RJ, et al. Oxaliplatin combined with infusional 5-FU and concomitant radiotherapy in inoperable and metastatic rectal cancer: a phase I trial. Br J Cancer 2005; 92:655-61. 73. Laking GR, West C, Buckley DL, et al. Imaging vascular physiology to monitor cancer treatment. Crit Rev Oncol Hematol 2006; 58:95-113. 74. Fletcher JW, Djulbegovic B, Soares HP, et al. Recommendations on the use of FDG-PET in oncology. J Nucl Med 2008; 49:480-508. 75. Tuncbilek N, Karakas HM, Altaner S. Dynamic MRI in indirect estimation of microvessel density, histologic grade, and prognosis in colorectal adenocarcinomas. Abdom Imaging 2004; 29:166-72. 76. Tateishi U, Kusumoto M, Nishihara H, et al. Contrast enhanced dynamic computed tomography for the evaluation of angiogenesis in patients with lung carcinoma. Cancer 2002; 95:835-42. 77. Wang JH, Min PQ, Wang PJ, et al. Dynamic CT evaluation of tumor vascularity in renal cell carcinoma. AJR Am J Roentgenol 2006; 186:1423-30. 78. Goh V, Halligan S, Daley F, et al. Quantitative assessment of colorectal tumor vascularity using MDCT: do tumor perfusion measurements reflect angiogenesis? Radiology, in press. 79. Atkin G, Taylor NJ, Daley FM, et al. Dynamic contrast enhanced magnetic resonance imaging is a poor measure of colorectal cancer angiogenesis. Br J Surg 2006; 93:992-1000. 80. Li ZP, Meng QF, Sun CH, et al. Tumor angiogenesis and dynamic CT in colorectal carcinoma: radiologic-pathologic correlation. World J Gastroenterol 2005; 11:1287-91. 81. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10:145-7. 82. Meijerink MR, Van Cruijsen H, Hoekman K, et al. The use of perfusion CT for the evaluation of therapy combining AZD2171 with gefitinib in cancer patients. Eur Radiol 2007; 17:1700-13. 83. Morgan B, Thomas AL, Drevs J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 2003; 21:3955-64. 84. Koukourakis MI, Mavanis I, Kouklakis G, et al. Early antivascular effects of bevacizumab anti-VEGF monoclonal antibody on colorectal carcinomas assessed with functional CT imaging. Am J Clin Oncol 2007; 30:315-8. 85. Leach MO, Brindle KM, Evelhoch JL, et al. The assessment of anti-angiogenic and antivascular therapies in early stage clinical trials using magnetic resonance imaging: issues and recommendations. Br J Cancer 2005; 92:1599-610.

86. Evelhoch JL, Garwood M, Vigneron D, et al. Expanding the use of magnetic resonance in the assessment of tumor response to therapy: workshop report. Cancer Res 2005; 65:7041-4. 87. Sahani D, Kalva SP, Hamberg LM, et al. Assessing tumor perfusion and treatment response in rectal cancer with multisection CT: initial observations. Radiology 2005; 234:785-92. 88. Bellomi M, Petralia G, Sonzogni A, et al. CT perfusion for the monitoring of neoadjuvant chemoradiation therapy in rectal carcinoma. Radiology 2007; 244:486-93. 89. George ML, Dzik-Jurasz AS, Padhani AR, et al. Non invasive methods of assessing angiogenesis and their value in predicting response to treatment in colorectal cancer. Br J Surg 2001; 88:1628-36. 90. DeVries AF, Griebel J, Kremser C, et al. Tumor microcirculation evaluated by dynamic contrast enhanced magnetic resonance imaging predicts therapy outcome for primary rectal carcinoma. Cancer Res 2001; 61:2513-6. 91. Goh V, Padhani AR, Rasheed S. Imaging colorectal cancer angiogenesis. Lancet Oncol 2007; 8:245-55. 92. Goh V, Halligan S, Taylor SA, et al. Differentiating between diverticulitis and colorectal cancer: quantitative CT perfusion measurements versus morphologic criteria – initial experience. Radiology 2007; 242:456-62. 93. Miles KA, Leggett DA, Kelley BB, et al. In vivo assessment of neovascularisation of liver metastases using perfusion CT. Br J Radiol 1998; 71:276-81. 94. Leggett DA, Kelley BB, Bunce IH, et al. Colorectal cancer: diagnostic potential of CT measurements of hepatic perfusion and implications for contrast enhancement protocols. Radiology 1997; 205:716-20. 95. Goh V, Halligan S, Wellsted DM, et al. Can perfusion CT assessment of primary colorectal adenocarcinoma blood flow at staging predict for subsequent metastatic disease? A pilot study. Eur Radiol 2009; 19:79-89. 96. Muller-Schimpfle M, Brix G, Layer G, et al. Recurrent rectal cancer: diagnosis with dynamic MR imaging. Radiology 1993; 189:881-9. 97. Dicle O, Obuz F, Cakmakci H. Differentiation of recurrent rectal cancer and scarring with dynamic MR imaging. Br J Radiol 1999; 72:1155-9. 98. Torricelli P, Pecchi A, Luppi G, et al. Gadolinium-enhanced MRI with dynamic evaluation in diagnosing the local recurrence of rectal cancer. Abdom Imaging 2003; 28:19-27. 99. Rudisch A, Kremser C, Judmaier W, et al. Dynamic contrast enhanced magnetic resonance imaging: a non-invasive method to evaluate significant differences between malignant and normal tissue. Eur J Radiol 2005; 53:514-9. 100. Stejskal EO, Tanner JE. Spin diffusion measurements: spin echo in the presence of a time dependent field gradient. J Chem Phys 1965; 42:288-92. 101. DeVries AF. Kremser C, Hein PA, et al. Tumor microcirculation and diffusion predict therapy outcome for primary rectal carcinoma. Int J Radiat Oncol Biol Phys 2003; 56:958-65. 102. Dzik-Jurasz A, Domenig C, George M, et al. Diffusion MRI for prediction of response to chemoradiation. Lancet 2002; 360:307-8. 103. Koh DM, Scurr E, Collins DJ, et al. Predicting response of colorectal hepatic metastasis: value of pretreatment apparent diffusion coefficients. AJR Am J Roentgenol 2007; 188:1001-8. 104. Cui Y, Zhang XP, Sun YS, et al. Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases. Radiology 2008; 248:894-900. 105. Hosonuma T, Tozaki M, Ichiba N, et al. Clinical usefulness of diffusion-weighted imaging using low and high b-values to detect rectal cancer. Magn Reson Med Sci 2006; 5:173-7. 106. Ichikawa T, Erturk SM, Motosugi U, et al. High B-value diffusion weighted MRI in colorectal cancer. AJR Am J Roentgenol 2006; 187:181-4. 107. Koh DM, Brown G, Riddell AM, et al. Detection of colorectal hepatic metastases using MnDPDP MR imaging and diffusion-weighted imaging (DWI) alone and in combination. Eur Radiol 2008; 18:903-10. 108. Koh DM, Brown G, Temple L, et al. Rectal cancer: mesorectal lymph nodes at MR imaging with USPIO versus histopathologic findings–initial observations. Radiology 2004; 231:91-9. 109. Harisinghani M, Barentsz J, Hahn PF, et al. Non-invasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003; 348:2491-9. 110. Rockall AG, Sohaib SA, Harisinghani M, et al. Diagnostic performance of nanoparticle-enhanced magnetic resonance imaging in the diagnosis of lymph node metastases in patients with endometrial and cervical cancer. J Clin Oncol 2005; 23:2813-21. 111. Harada T, Tanigawa N, Matsuka M, et al. Evaluation of lymph node metastases of breast cancer using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. Eur J Radiol 2007; 63:401-7. 112. Lin G, Ho KC, Wang JJ, et al. Detection of lymph node metastasis in cervical and uterine cancers by diffusion-weighted magnetic resonance imaging at 3T. J Magn Reson Imaging 2008; 28:128-35. 113. Hasegawa L, Boiselle PM, Kuwabara K, et al. Mediastinal lymph nodes in patients with non-small cell lung cancer: preliminary experience with diffusionweighted MR imaging. J Thorac Imaging 2008; 23:157-61. 114. Nomori H, Mori T, Ikeda K, et al. Diffusion weighted magnetic resonance imaging can be used in place of positron emission tomography for N staging of non-small cell lung cancer with fewer false-positive results. J Thorac Cardiovasc Surg 2008; 135:816-22. 115. Taylor NJ, Baddeley H, Goodchild KA, et al. BOLD-MRI of human tumor oxygenation during carbogen breathing. J Magn Reson Imaging 2001; 14:156-63.

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