The Value of Magnetic Resonance Imaging for Radiotherapy Planning Piet Dirix, MD, PhD,*,‡ Karin Haustermans, MD, PhD,*,‡ and Vincent Vandecaveye, MD, PhD†,§ The success of highly conformal radiotherapy techniques in the sparing of normal tissues or in dose escalation, or both, relies heavily on excellent imaging. Because of its superior soft tissue contrast, magnetic resonance imaging is increasingly being used in radiotherapy treatment planning. This review discusses the current clinical evidence to support the pivotal role of magnetic resonance imaging in radiation oncology. Semin Radiat Oncol 24:151-159 C 2014 Elsevier Inc. All rights reserved.

Introduction

O

ver the last decades, conformality in radiation therapy (RT) has increased dramatically. With current techniques, the high-dose areas can be sculpted around the target volumes, with steep dose fall-off immediately outside these regions. Obviously, in such a context, accurate disease localization is of critical importance to prevent marginal misses. As it becomes easier to spare important organs at risk (OARs) outside the target volumes, the maximum dose becomes restricted by the presence of dose-limiting structures within the irradiated volume. It has therefore been suggested that dose escalation in areas of increased radioresistance within the tumor should be attempted in an effort to improve locoregional control. Consequently, the concept of “dose painting” on a biological target volume was introduced.1 Clearly, this can only be successfully implemented by detailed imaging of the tumor and its microenvironment. For target volume delineation in the clinical routine, computed tomography (CT) remains the most widely used

*Department of Radiation Oncology, Leuvens Kankerinstituut (LKI), University Hospitals Leuven, Leuven, Belgium. †Department of Radiology, Leuvens Kankerinstituut (LKI), University Hospitals Leuven, Leuven, Belgium. ‡Department of Oncology, KU Leuven, Leuven, Belgium. §Department of Imaging & Pathology, KU Leuven, Leuven, Belgium. Financial support: Karin Haustermans is supported by a grant from the Research Foundation—Flanders (FWO). Address reprint requests to Piet Dirix, MD, PhD, Department of Radiation Oncology, Leuvens Kankerinstituut (LKI), University Hospitals Leuven, Campus Gasthuisberg Herestraat 49, Leuven 3000, Belgium. E-mail: piet. [email protected]

http://dx.doi.org/10.1016/j.semradonc.2014.02.003 1053-4296/& 2014 Elsevier Inc. All rights reserved.

modality. CT is broadly available, has a high spatial resolution and good reproducibility, does not suffer from geometric distortion, and provides intrinsic information on the electronic densities of various tissues—information that is used in dose calculation algorithms. CT allows clear delineation of tumors that border air-filled cavities, fat tissue, or bone. However, CT lacks contrast resolution for differentiation between normal soft tissue structures and tumor extent. Research has shown important intraobserver as well as interobserver variability in CT-based target volume delineation of several solid cancers.2-4 It also provides little biological information and cannot be used for biological target volume delineation. Therefore, radiation oncologists routinely combine data from the planning CT with information from other imaging modalities. [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been extensively studied for RT treatment planning (RTP). The use of FDG-PET, and in particular integrated PET/CT, has potential value in several cancer sites.5 However, the accurate segmentation of an FDG-PET image for tumor delineation is an incompletely resolved issue.6 Probably, inherently low spatial resolution functional imaging such as FDG-PET should not be used as a surrogate for anatomical imaging. Indeed, it seems more promising to use the biological information provided by FGD-PET for dose painting. The major advantages of magnetic resonance imaging (MRI) over CT are primarily superior contrast resolution and better soft tissue differentiation. Other benefits of MRI include the lack of radiation exposure, no need for iodinated contrast agents, and a high flexibility in its performance allowing the adaptation of imaging protocols to the specific needs of the patient as well as easy integration of functional imaging sequences. However, it should be kept in mind that MRI has 151

152 a longer imaging time and a higher susceptibility to motioninduced artifact and geometric distortions. Moreover, the execution of MRI examinations is more complex as sequences need to be tailored to the anatomical region or pathology scanned, making it a more demanding examination to both radiation physicists and physicians as compared with CT.

MRI Basics The basic requirements for signal generation with MRI are (1) the presence of a strong static magnetic field (B0) aligning the protons to the longitudinal direction of the magnetic field and resulting in a net magnetization (M), (2) a superimposed radiofrequency (RF) pulse causing the net magnetization of protons to rotate away from the longitudinal direction, and (3) a realignment of the net magnetization with the direction of B0 when the RF pulse is turned off. The latter is called recovery or relaxation, and it is during this recovery that the electromagnetic signal is generated.7 Overall, 3 forms of relaxation can be measured: (1) T1 recovery or longitudinal relaxation; (2) T2 decay or transverse relaxation; and (3) T2* decay, which is a decrease of the transverse magnetization because of magnetic field inhomogeneities. Image contrast at T1-weighted images is generated because tissues with different T1 values will show longitudinal relaxation at different rates, whereas image contrast at T2-weighted images is generated as tissues with different T2 values will dephase at different rates. Consequently, differences in T1, T2, and proton density (PD) are pivotal for creating differences in MRI tissue contrast. This explains the complex relation between images and tissue characteristics on MRI compared with CT, where contrast merely depends on atomic number and electron density. The most important clinical implication of this interaction is that differences in T1 relaxation and T2 relaxation usually do not reliably allow for tissue differentiation on their own. Consequently, sets of images need to be produced with various T1 and T2 weighting, contrast enhancement, and functional sequences to allow true tissue characterization. In practice, sequences are designed to give images that are weighted according to a particular relaxation time (ie, T1, T2, or PD). The correct implementation of 2 parameters, that is, echo time and repetition time, is key to obtaining image contrast. T1-weighted imaging is most beneficial for depicting anatomy but has low sensitivity for depicting disease entities unless paramagnetic contrast agents are administered. Typically, at T1-weighted imaging, fluid appears dark and fat appears bright. At T2-weighted images fluid appears bright and fat shows varying degrees of brightness. T2-weighted images best depict disease sites as most pathologic processes show higher water content compared with the surrounding tissue, appearing bright on T2-weighted images. However, it should be noted that the information provided by T2 weighting is often nonspecific as the T2 signal is affected by many other parameters such as lesion vascularity and cellularity. PD images aim to have no contrast from either T1 or T2 relaxation,

P. Dirix, K. Haustermans and V. Vandecaveye and signal contrast relates purely to differences in PD between different tissues. PD images depict both disease entities and anatomy and usually allow higher spatial resolution than T1or T2-weighted imaging. Currently, application of PD MRI for disease characterization is limited. There are 2 basic MRI pulse sequences: spin echo (SE) and gradient echo (GRE). All other types of sequences are derived from these basic pulse sequences by adding different parameters.8 MR pulse sequences can be performed in 2-dimensional (2D), meaning that 1 section at a time is acquired, or in 3D, when a volume or multiple acquisitions are taken at 1 time. In SE sequences, a 901 excitation RF pulse flips the net magnetization in the transverse plane, whereas a 1801 pulse rephases the spinning nuclei until they are realigned with the direction of the B0 field. Owing to this mechanism, basic SE sequences are slow and more prone to movement artifacting. As an advantage, SE sequences allow high spatial resolution and are relatively robust to artifacting caused by field inhomogeneities and susceptibility. The most important derivate sequences of the basic SE sequence that are relevant for RTP include the following: (1) The fast or turbo SE (TSE) sequence, for which the 901 pulse is followed by multiple 1801 refocusing pulses. This sequence is preferred over the SE sequence owing to substantially reduced scanning time. (2) TSE sequences with an inversion-recovery prepulse, including fluid-attenuation inversion recovery (FLAIR) and short tau inversion recovery (STIR). The STIR prepulse sequences cancel out the signal from fat and are frequently used for the detection of bone marrow changes including edema or metastases, liver lesions, or lymph node metastases. FLAIR cancels out the signal from fluid and is mostly used for brain imaging. A GRE sequence consists of small-angle RF pulses applied in rapid succession (short repetition time). GRE imaging uses a reversal of the magnetic field gradients rather than a 1801 RF pulse to refocus spins. Consequently, the sequence allows very short acquisition times and is therefore less prone to movement artifacting. As a trade-off, GRE sequences usually have lower spatial resolution and are more prone to artifacting owing to field inhomogeneities and susceptibility. Important applications of GRE imaging include the detection of brain hemorrhage, cerebral perfusion imaging, blood oxygenation level–dependent imaging for mapping of brain function and, potentially, assessment of tumor hypoxia. Moreover, the GRE sequence is used as a base for 3D breath-hold T1-weighted imaging. This is mainly used for fast contrast-enhanced imaging of moving organs such as the liver or pancreas or when multiphase contrast-enhanced imaging is required. Diffusion-weighted imaging (DWI) characterizes tissues by probing differences in the random mobility of water molecules related to tissue cellularity and cellular membrane integrity.9 A DWI sequence is repeated with increasing strength of diffusion sensitization of the magnetic gradients, categorized by b values between 0 and 1000 s/mm2. Crucially, high b values allow perceiving water molecule movements at the cellular level. The signal decay with increasing b value can be quantified using the apparent diffusion coefficient (ADC). Tissue with a relatively increased cellular density (eg, tumor) will typically be bright on

The value of MRI for RT planning

153

high b-value images and dark on the ADC map, whereas tissue with a relatively decreased cellular density (most benign tissues, inflammation, and necrosis) will be dark on high bvalue images and bright on the ADC map. Dynamic contrast-enhanced (DCE) MRI consists of repetitive T1-weighted imaging with high temporal resolution over a predefined lesion before and during the injection of a gadolinium contrast agent.10 Quantitative analysis of DCEMRI can be done by the volume transfer constant (Ktrans) and rate constant (kep). These parameters hold the advantage that their information can be linked to the underlying biological processes of tumor vasculature such as permeability surface area and flow. Proton (1H) MR spectroscopy imaging provides metabolic information about tissues by displaying the relative concentrations of chemical compounds.11 Normal tissue generally contains high levels of citrate. In the presence of cancer, the citrate level is often diminished because of a conversion from a citrate-producing to a citrate-oxidating metabolism. The choline level is elevated owing to a high phospholipid cell membrane turnover in the proliferating malignant tissue. Hence, the method for depicting tumors is based on an increased choline-citrate ratio. Because the creatine peak is very close to the choline peak in the spectral trace, the 2 may be inseparable; therefore, the ratio of choline and creatine to citrate is used for spectral analysis in clinical routine.

Clinical Implementation Diagnostic MRI aims to detect and characterize suspect lesions, as well as perform local, regional, and, if required, distant staging. For this purpose, diagnostic MRI needs a combination of sequences including plain, contrast-enhanced, and often diffusion-weighted sequences to achieve this goal. Usually relatively large field of views are required for which larger-

surface receiver coils are mandatory. As diagnostic MRI examinations are generally time consuming, the patient is usually positioned in the most comfortable way, as this enhances cooperation with the examination and reduces the risk of artifacts related to movement. As such, diagnostic MRI is different from MRI for RTP where preferably short examinations should be performed focusing on the target lesion(s), only using the sequences that can best depict the tumor for target delineation.12 A proposal of preferred MRI sequences for RT target delineation, based on clinical experience rather than evidence, is formulated in Table 1.

Brain Tumors MRI is firmly established as the superior imaging modality for diagnostic purposes when assessing cranial lesions. MRI provides better visualization of tumor and normal tissues (eg, optic chiasm and cochlea) than CT, and significantly reduces intraobserver as well as interobserver variability in target delineation of brain tumors.13,14 Malignant gliomas are typically hypointense on T1-TSE images and enhance heterogeneously following gadolinium contrast infusion. The gadolinium-enhancing lesion reflects regions where there has been a breakdown of the blood-brain barrier. However, this may not be a reliable indicator of active tumor owing to the presence of nonenhancing tumor tissue or contrast-enhancing necrosis. Ideally, T2-TSE or FLAIR information, or both, should also be taken into account to estimate microscopic extension, especially if a low-grade component is suspected.15 With FLAIR sequences, the signal of fluid is suppressed, improving lesion delineation at the border of cerebrospinal fluid containing ventricles and sulci. In diffusion tensor (DTI) MRI, diffusion gradients are applied in several different directions and the dominant direction of diffusion within each voxel is determined, in addition to its magnitude, and is quantified as fractional

Table 1 Proposal of Preferred MRI Sequences for Radiotherapy Target Delineation Tumor Site

Subsite

Sequence

References

Brain

–

Postgadolinium T1-TSE or SPGR T2-TSE FLAIR-TSE DTI for anisotropic margins DTI for OAR delineation

13,14 13-15 15 16,17 16,18,19

Head and neck

Base of skull

Postgadolinium T1-TSE T2-TSE with fat suppression Postgadolinium T1-TSE T2-TSE with fat suppression DWI for nodal staging

20-22,25 20-22,25 25-28 25-28 31-39 (Table 2)

Pharyngolaryngeal

Breast cancer

–

T1-TSE 3D T1-GRE

51 52-54

Rectal cancer

–

T2-TSE STIR T1- and T2-TSE

55,57-61 58

Prostate cancer

–

T2-TSE DWI, MRSI, and DCE-MRI

68-73 75-79

Abbreviation: MRSI, MR spectroscopy imaging.

154 anisotropy. Thus, DTI gives information on the structure of tissues and is most commonly known for its use in delineating and evaluating the integrity of neural tracts.16 It has been suggested that migrating cancer cells follow the paths of least resistance as determined from DTI, and that anisotropic margins, based on DTI in each individual patient, could be used to reduce unnecessary irradiation of normal brain tissue and at the same time improve disease control.17 Similarly, white matter fiber pathways (eg, pyramidal tract or optic radiation) could be spared from receiving high doses of radiation if successfully imaged with DTI.18,19

Head and Neck Cancer MRI should be considered as the standard imaging technique for nasopharyngeal cancer (NPC). Chung et al20 looked at the effect of adding MRI to CT for RTP in 258 patients with NPC. They found that 40% of the patients had intracranial infiltration, detected on contrast-enhanced T1-weighted MRI (especially in the coronal sections) through cavernous sinus invasion and dural thickening or enhancement, but missed on CT. MRI also showed an exceptional capacity to identify subtle bony invasion, diagnosed as high signal intensity of cortex, marrow replacement by tumor, and contrast enhancement in bone, but underestimated on CT. Comparable results were observed by Emami et al,21 who found that MRI-based NPC targets were 74% larger than CT-based delineations and were more irregularly shaped. In 38% of patients, MRI was helpful in visualizing intracranial extension of tumor that was not seen on CT. Rasch et al22 showed increased interobserver agreement, from 36-64 surface % (P ¼ 0.003) for target volume delineation in 10 patients with NPC. For sinonasal cancer, MRI facilitates the evaluation of dural or intracranial tumor spread, orbital invasion, and perineural tumor spread. The presence of Z 2 mm of dural thickening, loss of hypointense zone, and nodular dural enhancement are highly predictive for the presence of dural invasion. Moreover, a defect of the orbital bone of the periorbita and invasion of the orbital fat, an important feature of sinonasal cancer, can be superiorly detected on MRI. The periorbita shows hypointensity on T2-weighted images compared with the high-intensity tumor. On contrast-enhanced T1-weighted images, the periorbita shows less enhancement than the tumor. Consequently, the presence of the tumor through or beyond the periorbita can be easily detected on MRI, especially on coronal images, although it is generally impossible to differentiate the periorbita from the tumor on CT. There are no prospective data comparing CT with MRI for RT planning, but it is clear that MRI-guided IMRT has significantly improved results compared with CT-based planning.23,24 The incremental value of MRI for RTP in other subsites of the head and neck is more controversial. Comparative data to CT are scarce, and it is unclear if MRI can significantly reduce intraobserver or interobserver variability in target volume delineation. An obvious advantage of MRI is that it is not degraded by the presence of dental fillings, which can confound delineation of oropharyngeal and oral cavity tumors on CT images.25

P. Dirix, K. Haustermans and V. Vandecaveye Regarding oropharyngeal tumors, MRI could significantly improve the delineation of the primary tumor, which is usually selectively boosted. The group from the Royal Marsden Hospital used flexible surface coils to obtain high-quality MRI scans in the treatment position in 8 patients with a base of tongue tumor.26 The mean primary tumor volume was larger on MRI (22.2 vs 9.5 cm3, P ¼ 0.05) than on CT. The volume overlap index between MRI and CT for the primary tumor was 0.34, suggesting that MRI depicts parts of the primary tumor not detected by CT. MRI volumes for brainstem and spinal cord were significantly smaller owing to improved organ definition. In addition, parotid gland delineation was significantly improved on MRI, with a potential effect on the prevention of permanent xerostomia. The optimum MRI protocol for parotid imaging would involve fat-suppressive sequences or T2-weighted imaging. Regarding laryngeal and hypopharyngeal tumors, Geets et al27 did not observe any clinical advantage of MRI over CT for target volume delineation. The same group has compared preoperative primary tumor delineation based on CT, MRI, and FDG-PET with the surgical specimen in 9 patients who underwent laryngectomy.28 Although all imaging techniques overestimated the tumor volume, FDG-PET appeared to be the most accurate modality. It should be noted, however, that substantial parts of the surgical specimen (on average 10% on CT, 9% on MRI, and 13% on FDG-PET) were missed on each modality. Obviously, accurate nodal staging of head and neck cancer (HNC) is equally important, as underestimation of nodal involvement could lead to regional recurrences, while the elective irradiation of at-risk nodal levels complicates the sparing of OAR. For lymph node delineation, both CT and anatomical MRI depend on morphologic criteria: (1) any level II node 41.5 cm or any levels I, III, IV, V, or retropharyngeal node 41.0 cm in greatest diameter; (2) any node with internal central or peripheral attenuation suggestive of necrosis; (3) extracapsular extension; and (4) obliteration of fat or perivascular soft tissue planes.29 Although this leads to acceptable specificity, sensitivity is generally low, suggesting that metastasis in smaller lymph nodes are missed on conventional imaging because of the use of such arbitrary criteria.30 DWI measures the restricted water diffusion due to tumoral deposits in metastatic lymph nodes and holds exceptional promise in the detection of lymph node metastases in HNC. Metastatic lymph nodes have consistently been described to have a significantly lower ADC compared with benign lymph nodes. A pilot study from our group on the use of DWI found a sensitivity of 84% and a specificity of 94% per lymph node in surgically treated patients.31 The technique appeared especially robust in the detection of subcentimeter lymph nodes, with a sensitivity of 76% compared with 7% for conventional CT and MRI. These results have been confirmed by several other groups, as shown in Table 2.32-38 A planning study compared DWI-based vs CT-based target volume delineation to pathology and found that agreement between imaging results and pathology findings was significantly stronger for DWI (k ¼ 0.97) than for conventional imaging (k ¼ 0.56; P ¼ 0.019).39 DWI allowed to very closely

The value of MRI for RT planning

155

Table 2 Overview of Trials Examining the Potential of DWI for Detection of Lymph Node Involvement in Head and Neck Cancer Study Wang et al32 Sumi et al35 Abdel Razek et al34 Sumi et al35 Vandecaveye et al31 de Bondt et al36 Holzapfel et al37 Perrone et al38

Lesion size Mean ADC Nþ, Mean ADC N, P Value Threshold Sensitivity Specificity (cm) ( 103 mm2/s) ( 103 mm2/s) ( 103 mm2/s) (%) (%) 41.0 41.0 0.9-1.5

1.13 ⫾ 0.43 0.41 ⫾ 0.11 1.09 ⫾ 0.11

1.56 ⫾ 0.51 0.30 ⫾ 0.06 1.64 ⫾ 0.16

0.002 o0.01 o0.04

1.22 0.4 1.38

84 52 98

91 97 88

41.0 0.4-1.5

1.17 ⫾ 0.45 0.85 ⫾ 0.27

0.63 ⫾ 0.10 1.19 ⫾ 0.22

o0.001 o0.0001

0.74 0.94

86 84

94 94

0.5-3.0

0.85 ⫾ 0.19

1.2 ⫾ 0.24

o0.05

1.0

92

84

41.0

0.78 ⫾ 0.09

1.24 ⫾ 0.16

o0.05

1.02

100

87

NA

0.85

1.45

o0.01

1.03

100

93

Abbreviation: NA, not available.

approach the “true” nodal clinical target volume, as based on pathology. Obviously, no imaging technique to date permits the complete sparing of at-risk, clinically negative nodal levels from prophylactic radiation. However, as functional imaging becomes increasingly able to detect very small tumor deposits in lymph nodes, the question arises whether disease too small for combined imaging may not be effectively treated with deescalated doses.40 DWI has also been extensively studied as a biomarker for response to definitive chemoradiotherapy (CRT) of HNC. Kim et al41 performed DWI before, 1 week during, and approximately 2 weeks after CRT, and correlated ADC measurements with outcome data. They found that patients who responded favorably had significantly lower pretreatment ADC values than partial or nonresponders. Furthermore, they found that normalized ADC values after the first week of treatment had the highest accuracy for separating complete responders vs partial or nonresponders. Probably, this increase in ADC correlates with the histologic presence of apoptosis, necrosis, and fibrosis and thus loss of tumoral structural integrity. In a similar study by our group, DWI was performed before treatment as well as 2 and 4 weeks into CRT.42 The absence of an ADC increase corresponded to lesions that would not disappear or would recur after treatment. This absent ADC increase is probably related to diffusion restriction in the dense microstructure of persistent tumor. In a follow-up study, we found that the difference in ADC (ΔADC) between baseline and a new scan 3 weeks after CRT showed a positive predictive value of 89% and a negative predictive value of 100% for response.43 These results have been confirmed by other prospective studies.44,45 Development of DCE-MRI mainly focused on prediction and early assessment of treatment response. A recent study, investigating pretreatment DCE-MRI in patients with HNC undergoing CRT or surgery, showed that the intratumoral distribution of Ktrans was the strongest predictor of outcome.46 Similarly, Kim et al47 showed that pretreatment Ktrans was significantly higher in patients with complete response compared with patients with only partial response at 6 months after concomitant CRT.

Apparently, DWI as well as DCE-MRI can identify physiological changes within the first weeks of treatment that are correlated with long-term clinical outcome.48 From a radiation oncology point of view, if DWI or DCE-MRI or both have the ability to identify poor responders and can indicate the regions within the tumor that will be the focal point of locoregional failure, they provide both the motive and the opportunity to “paint” a higher dose on these areas in an effort to improve locoregional control.49

Breast Cancer Whole-breast RT, followed by an external or brachytherapy boost of the surgical bed, is an integral part of breastconserving treatment. Intraobserver and especially interobserver variation in the delineation of breast target volume on CT scans can be rather large.50 Giezen et al51 performed a prospective study on 15 patients with breast cancer, scanned in supine position. In their analysis, interobserver variability was identical between CT and MRI, but the MRI-based wholebreast volumes extended significantly further in the cranial direction. Because most patients present with a tumor in the upper quadrants, the authors hypothesized that the use of MRI might have a clinical benefit for a lot of patients. However, it should be noted that results with CT-based whole-breast RT are excellent. Delineation of the boost volume is probably more relevant, especially with the current drive toward partial-breast irradiation (PBI) in selected patients. Kirby et al52 found that addition of MRI data to CT or clip data resulted in tumor bed volumes that were discordant with those delineated based on CT or clips data alone. However, resulting clinical and planning target volumes were sufficiently concordant that coverage of CT- or clips-based tangential PBI fields was satisfactory in most cases. Giezen et al53 also found that MRI adds little additional information to CT. MRI does picture in more detail the interfaces of axillary seromas (if present) with their surroundings and their relationship to the surgical bed. The largest prospective trial (n ¼ 70) to date was performed by Jolicoeur et al54 who found that volumes obtained on MRI

P. Dirix, K. Haustermans and V. Vandecaveye

156 were between 30% and 40% smaller than those derived from CT images. A highly significant interobserver variability in the delineation of the surgical bed on CT was demonstrated (P o 0.0001). This interobserver variability disappeared when the MRI data were used (P ¼ 0.44). Consequently, it seems reasonable to consider the use of MRI for PBI.

Rectal Cancer MRI is generally considered the gold standard for staging rectal cancer, and diagnostic MRI data are usually available to aid the delineation of the target volume.55 For RTP, the patient is ideally scanned in the RT position, which is usually prone, in a bellyboard, to limit radiation exposure of the small bowel. Nowadays, MRI-compatible bellyboards are available from different vendors. There are 3 layers of the rectal wall defined on MRI, which are best depicted on T2-weighted images: an inner hyperintense layer corresponding to the mucosa and submucosa, an intermediate hypointense layer corresponding to the muscularis propria, and an outer hyperintense layer that consists of the mesorectal fat. The mesorectal fascia is an important landmark for evaluating the local extent of disease and is characterized as a thin low-signal-intensity structure on T2weighted imaging. The mesorectal fascia also represents the circumferential resection margin, a term denoting the plane of surgery during total mesorectal excision. In general, rectal tumors are minimally hyperintense on T2weighted imaging relative to the adjacent bowel wall. This is why a positive contrast agent can help when distending the rectum, as it allows for better delineation of the mass. Rectal cancers typically demonstrate avid enhancement after contrast administration and demonstrate restricted diffusion on DWI. STIR images highlight the contrast between the high signal in tumors and low signal in fat-suppressed normal tissue. As in most solid cancers, nodal staging based on morphologic criteria is difficult, as some small lymph nodes can be positive while enlarged ones can be reactive. Using 5 mm (any axis) as a cutoff has proven to provide a sensitivity of 66% and a specificity of 76% to predict malignant involvement.56 Currently, because of lack of an established ADC cutoff value, DWI, although helpful in detecting lymph nodes, cannot accurately differentiate benign nodal hyperplasia from metastatic lymph nodes. There is considerable evidence to suggest that MRI should be preferred over CT for target volume delineation in rectal cancer, especially when the tumor receives a higher dose than the elective regions. O'Neill et al57 reviewed imaging and planning data for patients with locally advanced low rectal cancer. They found that tumor volumes defined on MRI were smaller, shorter, and further from the anal sphincter than CTbased volumes, which could lead to a reduction in dose to OARs and facilitate dose escalation. Tan et al58 compared volumetric and spatial relationships of the primary tumor derived from the planning CT and the staging MRI. They found that CT-based tumor coverage was especially inadequate for tumors with anal or sigmoid invasion, and advocate the use of MRI in those instances. Buijsen et al59 compared primary

tumor delineation on CT, diagnostic MRI, and PET-CT with pathology. They found that CT-based measurements did not show a valuable correlation with pathology. MR-based measurements, however, correlated significantly (P o 0.001). Automatic PET/CT-based measurements provided the best correlation with pathology. Braendengen et al60 compared tumor volumes on CT, diagnostic MRI, and PET-CT in 77 patients with advanced rectal cancer. They found that the median volume on MRI was larger than on PET/CT (111 vs 87 cm3, P o 0.001). In a study from our group, MRI and FDG-PET scans were acquired before, during, and after neoadjuvant CRT in 45 patients with rectal cancer.61 In general, MRI showed larger target volumes than FDG-PET. There was an approximately 50% mismatch between the PETand the MRI-based volumes at baseline and during concomitant CRT. Although there is limited evidence that functional MRI techniques improve tumor staging or delineation, DWI especially has been extensively studied for neoadjuvant CRT response assessment. Generally, lower pretreatment ADC values are predictive for better response to RCT compared with tumors with high ADC values.62-65 A possible explanation is that tumors with high pretreatment ADC values are likely to be more necrotic than those with low ADC values. Necrotic tumors may be associated with poor tissue perfusion, an acidic microenvironment, and a low oxygen concentration, leading to a higher resistance to treatment. In DWI scans during and after CRT, an ADC increase can be observed in responding lesions, whereas nonresponding lesions usually have ADC values comparable to baseline.62-65 These results are comparable to what was observed in HNC, and suggest that DWI might be useful for prediction and early assessment of pathologic response to preoperative RCT, with higher accuracy than volumetric measurements. Clearly, DWI should be included in any protocol testing the role of definitive CRT for rectal cancer.

Prostate Cancer Although the routine use of MRI in the primary diagnosis and staging of prostate cancer is still being debated, its benefits for RTP are well recognized. Pelvic scans can be acquired in the RT position using a flat tabletop and a posterior RF coil placed underneath it.66 At the moment, the entire prostate gland is delineated, as prostate cancer is usually multifocal. Several authors have indicated that CT consistently overestimates the prostate volume and that MRI is more reliable than CT for RTP.67-69 Villeirs et al70 have shown that the use of MRI in combination with CT improves the accuracy of prostate gland as well as OAR delineation, with decreased interobserver variability. It should be noted that delineation of the prostatic apex is particularly difficult on CT. MRI can more reliably show the boundary between the high-signal-intensity peripheral zone tissue and the low-signal-intensity levator ani muscle, rectum, distal urethral sphincter, and fibrous tissue in the urogenital diaphragm.71 Steenbakkers et al72 studied the influence of MRI- vs CT-based prostate delineation using multiple

The value of MRI for RT planning observers on the dose to the prostate and OAR. They found that the dose delivered to the rectal wall and bulb of the penis was significantly reduced with plans based on MRI data, allowing a dose escalation of 2.0-7.0 Gy for the same rectal wall dose. Obviously, MRI is also very useful in the case of a hip prosthesis, which leads to scatter on CT images.73 The development of high-precision radiation delivery techniques has paved the way for focal boost RT in prostate cancer. As whole-gland dose escalation is limited owing to a high probability of normal tissue complications, escalating the radiation dose only to the macroscopic tumor nodule (s) seems logical.74 DCE-MRI, DWI, and MR spectroscopy imaging have all been investigated for tumor detection in prostate cancer. However, it seems unlikely that one imaging modality will be able to adequately detect all tumor targets. This is illustrated by the increasing number of studies in which multiparametric MRI is being explored.75-78 A study by our own group combined T2weighted MRI with DWI and DCE-MRI for accurate localization of intraprostatic tumor nodules, with whole-mount histopathology as the gold standard, in 75 surgical patients.79 DWI had the highest sensitivity for tumor localization (31% vs 27% vs 45% for T2, DCE, and DWI, respectively; P o 0.005). Significantly higher sensitivity values were obtained for the combination of T2, DCE, and DWI as compared with each modality alone or any combination of 2 modalities. They also found that tumor volume can most accurately be assessed by means of DWI (r ¼ 0.75; P o 0.0001). Several prospective focal boost trials have been initiated, all using (multiparametric) MRI to define the intraprostatic boost volume, for example, the European Focal Lesion Ablative Microboost in Prostate Cancer (NCT01168479), the North-American Hypofractionated External Beam Image–Guided Highly Targeted Radiotherapy (NCT01411332), and the Canadian TARGET (NCT01802242) trials. The precise role of pelvic RT in prostate cancer treatment remains controversial. The development of more accurate imaging methods for detection of lymph node metastases will allow the selection of patients for lymph node irradiation and will also improve the radiation treatment itself, by reducing the chance of geographic miss and enabling the delivery of a high dose to small positive lymph nodes.80 Our group recently investigated 11C-choline PET-CT and DWI in 36 surgical patients, node negative on CT but with a high estimated risk of lymph node involvement.81 Indeed, almost half of the patients (47%) harbored regional disease, missed on conventional imaging. Disappointingly, sensitivity was extremely low for both investigational techniques (9.4% and 18.8%, respectively), confirming the substantial difficulty of reliably detecting lymph node disease through imaging alone. Recently, MR lymphography (MRL) has been suggested as a novel nodal staging method in prostate cancer. The contrast agent used with this technique consists of ultrasmall super paramagnetic iron oxide particles, such as ferumoxtran-10, which disrupt the magnetic field and result in signal loss. When these particles are injected intravenously, they are transported by macrophages to normal lymph node tissue.

157 Therefore, normal functioning lymph nodes appear black on MRI 24-36 hours after administration of ultrasmall super paramagnetic iron oxide. In metastatic nodes, however, the signal intensity remains unchanged because of the absence of iron particles. The high sensitivity (82%) and negative predictive value (96%) of MRL in a large multi-institutional randomized trials seems promising, suggesting that patients with a negative MRL have a risk of 4% or less of harboring lymph node metastases.82 However, MRL has not yet found its way into routine practice, and in most countries, it has not even received approval for clinical use.

Conclusion Highly conformal RT can only achieve maximal tumor control with minimal toxicity when high-resolution imaging is used for treatment planning. With CT, large interobserver and intraobserver variations have been reported in the delineation of most solid tumors, potentially leading to marginal misses or suboptimal organ sparing or both. MRI, with specific sequences for particular tumor sites, is more consistent and, when compared with pathology, more accurate. MRI also allows functional imaging, useful for dose painting and early response assessment.

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