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British Journal of Radiology (2006) 79, S2-S15
© 2006 British Institute of Radiology
doi: 10.1259/bjr/41321492
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Full paper

New developments in MRI for target volume delineation in radiotherapy

V S Khoo, FRACR, FRCR, MD1,2 and D L Joon, FRACR3

1 Royal Marsden Hospital, Institute of Cancer Research, Fulham Road, London SW3 6JJ, 2 University of Manchester, Manchester, UK, 3 Austin Health Radiation Oncology Centre, Heidelberg Repatriation Hospital, Victoria, Australia


   Abstract
Top
 Abstract
Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
MRI is being increasingly used in oncology for staging, assessing tumour response and also for treatment planning in radiotherapy. Both conformal and intensity-modulated radiotherapy requires improved means of defining target volumes for treatment planning in order to achieve its intended benefits. MRI can add to the radiotherapy treatment planning (RTP) process by providing excellent and improved characterization of soft tissues compared with CT. Together with its multiplanar capability and increased imaging functionality, these advantages for target volume delineation outweigh its drawbacks of lacking electron density information and potential image distortion. Efficient MR distortion assessment and correction algorithms together with image co-registration and fusion programs can overcome these limitations and permit its use for RTP. MRI developments using new contrast media, such as ultrasmall superparamagnetic iron oxide particles for abnormal lymph node identification, techniques such as dynamic contrast enhanced MRI and diffusion MRI to better characterize tissue and tumour regions as well as ultrafast volumetric or cine MR sequences to define temporal patterns of target and organ at risk deformity and variations in spatial location have all increased the scope and utility of MRI for RTP. Information from these MR developments may permit treatment individualization, strategies of dose escalation and image-guided radiotherapy. These developments will be reviewed to assess their current and potential use for RTP and precision high dose radiotherapy.


   Introduction
Top
 Abstract
 Introduction
MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
The increased sophistication of modern radiotherapy planning techniques such as conformal (CFRT) and intensity-modulated radiotherapy (IMRT) necessitates improved means of defining target volumes for treatment. This is needed to achieve the intended benefits of using CFRT and IMRT. This step remains the most crucial and difficult part of the radiotherapy planning process, otherwise a geographical miss of the tumour or a systematic error will be perpetuated throughout therapy. MRI is being increasingly used in oncology for staging, assessing tumour response and evaluating disease recurrence. As a result of the enhanced imaging properties of MR, it has been estimated to be a more cost effective diagnostic tool in the management of some diseases [1]. Similarly, the improved characterization of soft tissues and visualization of tumour extent using MRI can be used to benefit the radiotherapy treatment planning (RTP) process from delineation of target volumes to determining planning margins and treatment response [2].

There are many current areas of development in MRI. These include developments in hardware technology, such as 3 Tesla machines, and the use of new MR contrast media, such as ultrasmall superparamagnetic iron oxide particles for lymph node evaluation [3]. MR techniques and sequences previously used for research are now becoming available for general use. MR techniques such as dynamic contrast enhanced and diffusion weighted MRI may provide further characterization of tissue and tumour regions [4, 5]. MR sequences such as ultrafast volumetric and 3D cine sequences can offer the opportunity to assess target/organ motion and deformity [6, 7]. Temporal-spatial information gleaned from MRI can then be used for image-guided strategies in radiotherapy delivery. All these features have the potential to increase the scope and utility of MRI for RTP.

It is worthwhile briefly reviewing the background to the use of MRI for RTP in order to understand the rationale and issues with its use. Some methods of utilizing MRI in RTP will be outlined. This article will then discuss the new MRI developments in terms of their current and potential impact in target volume definition for treatment planning with examples of applications at some cancer subsites.


   MRI rationale for RTP
Top
 Abstract
 Introduction
 MRI rationale for RTP
Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
Any additional procedures used for RTP must add value to the planning process. Standard RTP uses CT data. CT images are good at distinguishing between structures that have substantially different X-ray attenuation properties or Hounsfield units, such as between air, tissue and bone. It is more difficult to discriminate between adjoining soft tissue structures using CT if these soft tissue structures possess similar Hounsfield units unless there is a fat, air or bone interface between these structures. The imaging parameters for CT scanning are much more limited compared with the range available with MRI.

In the case of MRI, the contrast from soft tissue structures can be widely varied by extensively manipulating the imaging parameters, which include proton densities and tissue relaxation times (spin-lattice or T1 and spin–spin or T2). This increased flexibility in varying tissue contrast or signal intensities offers much better characterization of soft tissues even when these structures possess very similar X-ray attenuation properties or electron densities. Tumours often have similar electron densities to their neighbouring soft tissues. By using different MRI sequences, better tissue discrimination can be obtained between the extent of tumour with its boundaries of infiltration and the adjacent normal structures. In this manner, MRI provides improved target delineation for RTP. This utility of MRI applies not only to the initial radiotherapy treatment of tumours but also potentially for re-treatments by being able to differentiate between changes due to recurrent cancer or that secondary to post-treatment fibrosis. It can also provide better delineation of organs at risk (OARs) for dose avoidance in RTP.

An obvious benefit of enhancing the visualization of volumes of interest (VOI) is the increased reliability and consistency of target definition. This will improve both interobserver and intraobserver variability for outlining. This has value for institutional and multicentre trials in radiotherapy where it is important to maintain consistent and accurate target and OAR volumes. Substantial and inappropriate variations in target volumes can impact on trial outcomes, with geographical misses for poorer local control rates or unnecessary inclusion of normal tissue for higher toxicity rates.

MRI can avoid bony and metal artefacts seen with CT. Large thick bony sections attenuate X-rays and reduce the adjacent soft tissue image quality. This can obscure identification of nearby tumours and internal anatomy. MR images are not affected by this. MRI can thus further improve the delineation of both tumour and OAR volumes for RTP in these regions.

Another feature of the increased functionality of MRI is its true multiplanar capability. This ability to image in any oblique plane can reduce the "partial volume" imaging effect that often results from conventional transaxial CT imaging, particularly where the 3D shape of the target is extreme or changes substantially between conventional transaxial CT slices. Para-sagittal or para-coronal views can also permit better understanding of the boundaries of target volumes with the surrounding normal tissues leading to better target volume delineation (GoFigures 1 and 2Go).


Figure 1
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  		Figure 1. A comparison of sagittal views of the pelvis for prostate radiotherapy with(a) CT reconstructed from 2.5 mm slices and (b) MR image obtained in-plane in the same patient. Some of the relevant structures of interest for radiotherapy are labelled on the MR image. These structures are not visualized well enough on CT to provide confident determination of the prostate boundaries for radiotherapy.

 

Figure 2
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  		Figure 2. A comparison of coronal views of the pelvis for prostate radiotherapy with(a) CT reconstructed from 2.5 mm slices and (b) MR image obtained in-plane in the same patient. Definition of the prostate gland boundaries and the adjacent structures is better visualized on MRI than with CT.

 
Furthermore, MRI can provide functional and biological information for tumour regions that may improve target definition and permit new opportunities for novel radiotherapy strategies. Some of the salient features of using MRI for RTP are summarized in Table 1Go. However, it is important to be aware that implicit in the use of MRI for RTP is that oncology clinicians should have the necessary training to comprehend MR images and understand how to use them appropriately for defining VOIs. Thus it is important to undertake suitable supervised training [8]. Even if there is relevant experience, it is still beneficial to liaise closely with local diagnostic colleagues who have MR expertise for the cancer subsite(s) in question. Ideally there should be an oncology team collaboration for the definition of target volumes in radiotherapy similar to the multidisciplinary team arrangement that exists for general cancer management. This approach has been endorsed by national bodies, such as the Royal College of Radiologists in a recent publication [9].


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  		Table 1. Advantages and disadvantages of MRI for radiotherapy planning(RTP)

 
All of these advantages add to the RTP process and outweigh its current drawbacks, which include the lack of electron density information, potential image distortion and specific patient considerations with MR scanners. Some examples of the current impact of using MRI for target volume delineation and some of these issues in using MRI for RTP will be briefly outlined below. A more in-depth review has been published and the reader is advised to peruse this [10].


   Current impact of MRI for treatment planning
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
In many areas of oncology, diagnostic MRI is the gold standard imaging modality for the staging and assessment of cancer patients. This is true for imaging of cerebral and spinal tissues, soft tissue sarcomas and pelvic tumours. Some examples will be highlighted here to illustrate the current status of the added advantage of MRI for target volume delineation in the planning process.

MRI has been used extensively for central nervous system (CNS) radiotherapy. Many investigators have reported quantitative improvements of up to 80% of cases in target volume definition with the addition of MRI to 3D CT based treatment planning [11–13]. Despite the obvious advantage of MRI for target volume definition at this site, there are clear situations where the use of both CT and MRI data is valuable and can provide for more consistent volume delineation than compared with either MRI or CT alone [14]. In a study of base of skull meningiomas, MRI was able to delineate tumour volumes that were present close to the base of skull bones as the X-ray attenuation from these large bones can obscure soft tissue detail using CT alone [15]. However, CT was able to provide information on the extent of bony erosion from tumour that was not available with MRI. In some cases, the individual CT or MR volumes were vastly different, with each modality providing separate but complementary information (Figure 3Go). This supports the use of combined CT and MRI data to provide the optimum target volume delineation. Segmentation algorithms, automated and atlas based, may further aid the delineation process and this methodology is currently being investigated [16, 17]. In many centres providing CFRT and IMRT for CNS tumours, the use of CT-MRI fusion for RTP may now be considered as standard practice. The major thrust of current developments in CNS treatment planning is to integrate the use of functional data for target volume determination [18].


Figure 3
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  		Figure 3. A case from a study of meningiomas of the skull base evaluating the differences between MRI and CT assessment of the clinical target volume(CTV) for radiotherapy. The 3D reconstructed view of the CT-defined CTV (red outlines) and MR-defined CTV (yellow outlines) illustrates the spatial differences in CTV definition by the two different imaging modalities where the MR-defined CTV demonstrates tumour extending laterally along the petrous ridge that was not seen using CT [15].

 
Head and neck anatomy is complex and the extent of the infiltrating tumour can be difficult to define. MRI can assist in delineation of radiotherapy volumes here. It is useful for defining (1) longitudinal tumour infiltration along the upper aero-digestive tract and adjacent fascial planes, e.g. pre-vertebral fascia, (2) tumour infiltration of soft tissue structures and tissue planes such as the pterygoids and tongue (Figure 4Go), (3) the extent of perineural infiltration and intracranial extension, e.g. nasopharyngeal tumours and (4) nodal metastases. This situation is best illustrated by nasopharyngeal tumours where the use of multimodality imaging with MRI can change disease staging in about 50% of cases impacting on RTP [19, 20]. In a study of over 250 patients, up to 40% of intracranial infiltration detected on MRI was missed by CT [21]. Segmentation algorithms for MRI are being developed to help in target volume delineation based on the contrast enhancement ratio of T1 weighted images and signal intensity of T2 weighted images, and this methodology may further assist the RTP process [22].


Figure 4
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  		Figure 4. A case of a base of tongue cancer imaged with(a) CT and (b) MRI showing a large mass on the left side of the oropharynx involving the base of tongue and the left tonsillar fossa with invasion of the left parapharyngeal space. The base of tongue mass extends past the midline. These features are better visualized using MRI than CT.

 
In the pelvis, MRI has provided improved target delineation for urological, gynaecological and gastrointestinal cancers. For prostate cancer, MRI can provide better internal organ assessment than CT for disease extent, capsular and seminal vesicle involvement [23–25]. MRI can overcome some of the limitations of CT definition of prostate treatment volumes (GoFigures 1 and 2Go). MRI, particularly using sagittal views, can be useful in defining the prostatic apex and distinguishing between the boundaries of the prostate with the base of the bladder and the anterior wall of the rectum [26, 27]. The prostatic capsule, which cannot be distinguished from adjacent normal tissue on CT, can be seen as a thin rim of low signal intensity on T2 weighted MRI thereby permitting boundary definition (Figure 5Go). Comparative MRI-CT planning studies using MRI-defined prostate volumes as the gold standard have reported that CT-defined prostate volumes tend to overestimate the planning volume by as much as 27–43% due to the soft tissue uncertainty in CT delineation [28–31]. In our prospective study of 105 men with prostate cancer, we found that MRI-CT fusion for RTP can often up-stage the disease extent by clarifying extracapsular spread, seminal vesicle involvement and early adjacent organ invasion that resulted in substantial changes to the target volumes in 29% of cases [32]. In a retrospective review of 199 patients treated with radiotherapy, a comparable upstaging effect of MRI was seen in 52% [33]. For post-prostatectomy patients, a visible mass was noted within the operative bed using MRI in 50% of cases, that was not seen using CT [32]. This improved ability to delineate prostate and seminal vesicles can also reduce interobserver and intraobserver variation. MRI can also be useful where the internal pelvic anatomy has been substantially altered due to previous extensive surgery such as abdominal-perineal resections [34]. It can also aid delineation of adjacent normal tissue structures such as rectal wall, recto-vesicle fascia of Denonvillier, urogenital diaphragm, penile bulb, periprostatic venous plexus, neurovascular bundle, levator ani and anal sphincters. The use of MR-based prostate planning volumes can result in more appropriate treatment volumes, leading to better shaping of the treatment fields that can reduce the risk of treatment related complications to important normal structures such as the rectum and penile bulb [35].


Figure 5
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  		Figure 5. A comparison of transaxial co-registered views of the pelvis for prostate radiotherapy with (a) CT and (b) MR in the same patient. The boundaries of the prostate are better visualized using MR than with CT, notably the anterior rectal wall/recto-vesical fasia and prostate capsule.

 
In addition, co-registered CT/MRI has also been used for permanent and high dose rate prostate brachytherapy to better define target volumes, reduce delineation uncertainty for RTP and to guide needle insertion compared with other imaging methods used such as ultrasound or CT [36, 37]. This is particularly important for post-implant dosimetry where the prostate gland delineation may be more difficult following the implant procedure and where CT assessments may be hampered by its poor intrinsic tissue contrast and seed induced artefact [38, 39]. MR-CT fusion has also been found to be beneficial for brachytherapy in other tumour sites such as head and neck, sarcomas and gynaecology [40]. In cervical brachytherapy, the use of MRI has been strongly supported by the Gynaecological GEC-ESTRO Working Group [41].

For rectal cancer radiotherapy, traditional planning relies on visualizing a filling defect using rectal contrast with the treatment fields usually placed according to bony landmarks, but rectal contrast does not define the circumferential thickness of the tumour and bony landmarks do not accurately define the anterior margin as governed by the rectal lymphatic drainage and mesorectum. CT planning can improve delineation of the rectal tumour by providing visualization of the increased thickness of the rectal wall and provide better definition of the lymphatic region by depicting the vascular structures, visible lymph nodes and boundaries of the mesorectum [42]. However, inaccuracies in the CT definition of tumour may occur because of poor contrast between faeces and tumour, partial volume effects due to the curves/valves of Houston in the rectum and imaging of the horizontal sigmoid. Infiltration into the anus can also be difficult to assess in a low rectal tumour unless there is an obvious mass effect (Figure 6Go). MRI can avoid these CT identification issues and better define the depth of invasion through the rectal wall [43]. MRI can provide visualization similar to endorectal ultrasound investigations, but ultrasound data cannot be imported into treatment planning systems. MRI can aid the CT based RTP process by defining the longitudinal spread of the cancer superiorly and inferiorly, as well as the extent of infiltration of the mesorectum [44]. It may also provide better assessment of early invasion into local adjacent structures such the bladder, prostate or seminal vesicles in men, and vagina and uterus in women, in addition to anal sphincter infiltration in both [45–47]. This better estimation of the gross tumour volume may permit strategies of anal sphincter sparing, tumour boosting and dose escalation with or without concurrent chemotherapy.


Figure 6
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  		Figure 6. Co-registered (a) CT and (b) MRI scans showing a rectal cancer in the lower rectum extending to the anorectal junction with invasion of the left posterolateral wall. This is easily seen on the T2 weighted MRI scan as a hyperintense signal region that is not visible on CT.

 

   MRI issues and schemas for treatment planning
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
A comprehensive step-by-step guide and methodology review for the integration of MR into treatment planning systems is outside the remit of this article. However, it is worthwhile to outline briefly some of the relevant issues faced when using MR images for RTP and some of the available methods used.

In RTP, geometrically accurate images are needed for precision radiotherapy and electron density information is required to take into account tissue inhomogeneities when calculating dose distributions. CT data provide the necessary information for both these requirements. MRI suffers from a lack of electron density information and potential spatial image distortion. As a result, MR images cannot be imported alone into RTP systems to readily create and plan three-dimensional (3D) radiotherapy.

Unlike CT images where the Hounsfield units can be directly related to electron density values, the signal intensities in MR images do not have such a relationship. If MR images are to be used alone for RTP, then X-ray attenuation coefficients have to be manually assigned to all regions within the MR image in order to allow dosimetry calculations. In some regions, such as in the brain where the internal tissue is more homogeneous and the skull can be easily segmented, this may be easily achieved by assuming an homogeneous attenuation value within the skull vault. On MR images, investigators have calculated that doses were within 2% of those calculated using CT data [48]. Similar work has been recently performed in the pelvis for prostate radiotherapy with 2–3% between CT-based and MR-based dose calculations [49]. Other investigators noted dosimetry discrepancies that were >2% compared with CT dosimetry for the pelvis if bone and water CT number bulk-assigned values were not assigned to MR images [50]. Simple methods of CT density value assignments may more difficult to implement if the anatomy is varied or complex such as in the head and neck regions or thorax/abdominal regions.

An alternative method is to integrate MR images with CT data. This requires bringing the MR data into spatial 3D alignment with planning CT data or image registration. Then the different image modalities can be "fused" so that a common image set is produced with both sets of imaging information available for clinical interrogation. This method is favoured as the data can be transferred and implemented within a treatment planning system and provides for optimum evaluation of the imaging information to create the most appropriate VOI for RTP. The methodology for image co-registration and image fusion is considered by Kessler in this issue.

MR image distortion
Before image co-registration can occur, it is important to ensure that the MR data are suitable. MR image distortion is one potential concern. MR image distortions can be grouped into two main categories; system-related and object-induced. An illustration of these distortion effects is shown in Figure 7Go.


Figure 7
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  		Figure 7. An illustration of various forms of distortion in MRI using a phantom consisting of a coplanar array of water-filled tubes embedded within in a circular solid plastic (PMMA) block. System distortion effects are seen in the apparent curvature of the tubes at A and their disappearance at B, which was due to warping distortion of the imaging plane. Magnetic susceptibility differences due to the presence of the plastic support block at C give rise to object-induced distortions in the form of discontinuities at the point where each tube enters the support block [10]. (Reproduced with permission from Elsevier).

 
System-related distortions are due to the imperfections of the magnet, its operating system and imaging sequences. The effects of magnet field inhomogeneity, gradient field non-linearities and eddy currents can contribute to system-related image distortion. In general, the effects of system related distortion are smallest at the centre of the magnet and worsen with increasing distance from the magnet centre. The distortion magnitude is largest at the periphery of the field-of-view (FOV).

Object-induced distortion arises when any object (i.e. the patient) is placed within a magnetic field. This type of distortion results from magnetic susceptibility and chemical shift effects. Different body tissues have different magnetic susceptibilities and susceptibility artefacts can be pronounced at different tissue boundaries, such as between air cavities and soft tissues. Chemical shift effects result from the different behaviour of protons in fat and tissue. Fat protons "precess" at a slower rate than water protons and this can result in a chemical shift effect where the positions of fat/water protons are shifted from their true spatial locations.

In order to utilize MR images for RTP, these image distortions must be evaluated, minimized, and/or corrected especially if they are to be co-registered with CT, otherwise a systematic error will be incorporated into the treatment plan. There are many methods to deal with MR image distortion, but the primary task is to quantify the presence and extent of any distortion. This methodology has been previously described in detail [51–54]. This system provides for evaluation and correction of both system-related and object-induced distortions, but can also facilitate quality assurance programs. It is important to ensure that the same MR scanner and imaging sequence used for mapping is also used for patient imaging.

System-related distortion is best quantified and mapped using a phantom (linearity test object) with a known array of markers in 3D to provide spatial assessments of the whole imaging volume used for RTP. A reference frame with imbedded markers provides another set of marker positions that covers the periphery of the imaging volume. The linearity test object or the patient is housed within this reference frame. A separate set of markers placed on the patient's surface provides assessment of object-induced effects. In brief, the positions of all markers are mapped within the imaging volume using a dedicated automated algorithm. The use of read-out gradient reversal imaging and post-processing image corrections can account for object-induced effects. Distortional shifts of up to 5 mm can be corrected [51–54]. Other correction methods have also been developed and can reduce distortions by a factor of two [55]. Site specific phantoms have also been created with air cavities to assess the use of MRI for lung RTP [56].

Other MR considerations
It is important to review the image protocols to be used and to evaluate those sequences which can offer the best combination of image quality/resolution and minimal image distortion. These sequences will differ depending on the anatomical site being imaged and treated. As previously mentioned, the effect of distortion is least within the centre of the magnet and VOI for RTP should be imaged within this zone whenever possible. If larger FOVs are used, the central region of imaging may be extracted and this region can then be co-registered with CT data to aid target volume definition. In determining imaging protocols for multi-modality image co-registration, attention must be paid to some of the issues listed below to optimize the appropriate imaging acquisition parameters.

  1. What is the appropriate sequence to be used for the cancer type and anatomical region? For example, will it be T1, T2 weighted or a hybrid sequence, standard or ultra-fast acquisition, gated or volumetric, and contrast or not? This will depend on what imaging information is needed by the clinician.
  2. What is the optimal FOV and relevant imaging volume?
  3. What is the resolution needed?
  4. What is the appropriate imaging slice orientation, slice thickness and slice gaps?
  5. Is there a need for multislice and/or non-coplanar image reconstruction or oblique plane imaging?
  6. What is the influence of various body coils or internal body MR probes on the MR images for co-registration?
  7. What is the appropriate quality assurance program to ensure reliability of image quality and data transfer?

Any MRI for RTP should also mimic the CT planning procedures such as scanning the patient in the treatment position with a flat bed insert, using the same but MR compatible immobilization devices where specified, providing the same instructions to the patient, e.g. full or empty bladder, and minimizing internal organ motion by breath held procedures, bowel relaxants or reducing the scanning time whenever indicated and possible. Ideally the MRI scans should be timed as close as possible to the CT planning scans.


   New developments in MRI
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
Developments in MR hardware
3 T MRI scanners
The field strengths of MRI scanners have been increasing since their initial development from 0.5 T (Tesla) scanners to 1 T and now 1.5 T and 3 T. The advantages of increasing the field strength are several-fold. The quality of the MR image is related to the signal obtained relative to any imaging deficiencies using the MR scanner, such as machine imperfections and object/patient induced errors. This relationship is termed the signal-to-noise ratio (SNR). The image quality or resolution increases when the signal is strengthened and the noise lowered. The SNR approximately increases in a linear manner with field strength. In simplistic terms, higher field strengths would permit higher resolution images with improved tissue contrast that can lead to better tissue diagnosis and definition of tumour volumes for RTP. The image acquisition time may also be reduced and this can potentially minimize motion artefacts. With these advantages, the development and use of 3 T MRI machines may become more commonplace as they can further improve the image quality using external phased array coils. In prostate MRI, the image quality from external phased array coils using 3 T are comparable with endorectal coils at 1.5 T [57] and in some cases exceeding them [58]. This provides more imaging options and avoids the internal deformation that occurs with endorectal coils that may limit its use for RTP. These 3 T machines can also benefit the application of functional MRI and MR spectroscopy (MRS) by providing better resolution for assessed metabolites that can define tumour regions, e.g. for brain [59] and prostate radiotherapy [60]. The latter subject is covered in more detail by Payne and Leach in this issue.

There are several issues associated with 3 T MR scanners that may limit their use for RTP. Amongst these is the exacerbation of magnetic susceptibility effects, doubling of the chemical shift effect, patient safety and engineering challenges. Currently, the clinical role of these 3 T scanners including their utility for RTP remains to be defined.

Magnetic susceptibility effects.
Higher field strengths can exacerbate the magnetic susceptibility artefacts, particularly at borders of different structures; for example, at tissue/bone/air boundaries, such as in the head and neck regions [61]. These effects can lead to increased signal intensities that can cause misdiagnosis using contrast studies unless pre- and post-contrast views are used for appropriate comparison. This effect can potentially result in misidentification of abnormal areas leading to erroneous volumes for RTP.

Chemical shift effect.
The chemical shift effect (see above) is doubled using 3 T field strengths. This effect causes misregistration of fat and water tissues and will hinder the definition of radiotherapy volumes when co-registered with planning CT images. However, this aspect may be of considerable use in MRS as it can increase the resolution of identifying tissue metabolites. This may permit improved and more reliable localization of tumour regions for boosting, such as the use of MRS citrate-choline assessment in prostate cancer. It is also very useful for brain and MR angiography assessments because of the longer, more variable T1 relaxation time.

Patient safety.
There may be patient safety concerns as the energy deposited using 3 T scanners may be up to 4 times that of 1.5 machines. This may be a factor when using fast or intensive pulse sequences. Potential problems may be reduced by appropriately modifying the pulse sequences and/or reducing the volume of tissue being imaged.

Machine factors.
3 T scanners are still not commonplace and are substantially more expensive than 1.5 T machines. There are also engineering issues that include the use of higher gradient systems and increased shielding, as well as smaller scanner bores. These may restrict the size of the patient scanned and also increase the potential for patient claustrophobia.

MR simulators
Open and low field MR scanners can act as radiotherapy simulators providing a radiotherapy environment similar to CT simulation for RTP. Other advantages include the lower cost of these machines, greater T1 image contrast, reduced vessel flow/ghosting artefacts and the opportunity to use patient immobilization devices that were previously restricted by size with conventional MR scanners. Although open low field MR scanners may have larger system-related distortions which can be compensated for, object-induced distortions are substantially less due to the lower magnetic field strength [40, 62]. Individual MR sequences may be longer using low field MRI and provide more opportunity for internal organ motion, but appropriate selection of sequences can reduce the scanning required. One limitation of MR simulation is that there is inadequate image detail of bony structures from MR to automatically create digitally reconstructed radiographs needed for treatment verification. Software to delineate bone regions can overcome this issue.

The lower SNR may limit diagnostic quality images, but good quality images have been obtained using low field 0.2 T MRI in regions of interest such as the prostate [63]. A recent study of 243 patients revealed that open low field MR simulation provided adequate images for RTP in up to 95% of cases [40]. The greater target volume delineation from MRI led to RTP improvements in up to 33% of lung cases and 40% of prostate cases. MR simulation can better delineate erectile soft tissues to permit dose sparing of these structures by IMRT [64].


   Developments in MR sequences
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 
Manipulation of the relaxation times of protons in tissues provides the two basic T1 and T2 weighted MR sequences. Whilst this provides superior imaging of soft tissues, the imaging parameters can also be manipulated to benefit RTP by providing ultrafast imaging, volumetric sequences and cine-mode acquisition. These sequences can be used to provide information on target motion, OAR displacement to modify planning margins for RTP and to initiate image-guided radiotherapy strategies.

A series of ultrafast imaging can be obtained by sequences such as echoplanar imaging. Evaluation of the position of OARs and tumours that are influenced by respiration or other internal organ activity during irradiation can be performed and modelled. MRI can provide better delineation of internal soft tissue structures such as between myocardium and ventricular space compared with CT for heart dose–volume assessment by breath hold for left breast radiotherapy [65] or ultrafast acquisitions can be performed with normal respiration to assess the impact of irradiation compared with other treatment image-guided strategies. Ultrafast acquisitions may also be used to obtain gated images to model organ and/or target motion for RTP [6].

Sequential volumetric and cine-mode acquisitions can greatly aid image-guided radiotherapy strategies by providing data for the implementation of appropriate site-specific planning margins for both the target and OARs. Cine MRI can evaluate intrathoracic tumour mobility for patient individualization of treatment margins [66] and determination of the efficacy of free-breathing gating techniques for lung radiotherapy [67]. Cine MR has been used to assess intrafraction motion in prostate cancer [7, 68]. This intrafraction information can be used not only to determine internal margin size for RTP but also to estimate the degree of organ deformation that may occur during radiotherapy [69]. This issue of target volume deformation is also currently being investigated for bladder cancers in an image-guided program (POLO or Predictive Organ LOcalization) whereby cine MR studies are obtained to assess the temporal-spatial changes of the bladder as it fills during radiotherapy and the degree of tumour deformation that can occur during this period [70].

Ultrafast, volumetric and cine MRI can provide non-invasive means to evaluate not only variability in target volume positioning during radiotherapy but also the temporal variation in target volume deformation that may occur interfractionally and intrafractionally. These are pertinent issues that currently limit precision radiotherapy and justify the development of image-guided radiotherapy.


   Developments in MR contrast agents
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
Developments in MR techniques
 Summary
 References
 
Local-regional control is an important issue in radiotherapy treatment for many cancers. Adequate dose to involved lymph nodes can increase the probability of local control and this may translate into improved survival. Reducing dose appropriately to uninvolved local-regional nodal regions can substantially lower the probability of radiation related side-effects and also allow combination with systemic chemotherapy or radiosensitizers to be better tolerated or permit dose intensification. However, the determination of pathological lymph nodes is poor using current imaging techniques and surgery remains the gold standard in establishing the lymph node status.

The difficulty in using simple size criteria alone to assess evidence of subclinical tumour involvement is well known. Up to 20% of normal size lymph nodes can be positive for microscopic disease whilst up to 30% of enlarged lymph nodes may only show inflammation. The likelihood of pathological nodal involvement increases with higher stage of disease. Furthermore, in MRI the signal intensity and degree of contrast enhancement between benign and malignant lymph nodes is not reliable enough to provide satisfactory discrimination.

Ultrasmall superparamagnetic iron oxide particles (USPIO)
USPIO particles have recently been reported to be suitable as contrast agents for the identification of and discrimination between normal and abnormal lymph nodes.

USPIO particles are injected and taken up by macrophages and transported via the lymphatic system to the lymph nodes. In the reticuloendothelial tissues of normal lymph nodes, these macrophage ingested USPIO particles produce a reduction in signal intensity within the node due to the negative enhancement from the iron oxide particles. This lowering of signal intensity when scanned 24–26 h following administration can then be compared with the pre-USPIO scan. An example of this negative enhancement seen in normal lymph nodes is shown in Figure 8Go. In diseased nodes that are replaced by tumour, these USPIO particles within macrophages are prevented from occupying the node by the tumour and thus the signal intensity from pathologically involved nodes is preserved.


Figure 8
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  		Figure 8. A case example of the use of ultrasmall paramagnetic iron oxide(USPIO) in MRI to evaluate pelvic lymph nodes in a man with prostate cancer. In this case, the lymph nodes (thick arrow) pre-USPIO (a) returned a negative MR signal following USPIO administration (thin arrow (b)) indicating normal lymph node architecture. This was later confirmed on lymph node sampling.

 
Recent assessments using USPIO have reported a high sensitivity and specificity of up to 90% in cases with small volume tumour nodal involvement [3, 71]. If future studies confirm that this method of detecting early nodal involvement is reliable then the benefits for RTP are immense. This method using 3D sequences can provide visualization of lymph nodes along blood vessels and allow for mapping of lymph nodes according to surgical templates. This will optimize current target volume delineation for lymph nodes. There are many tumour regions where CT defined nodal volumes have only just superseded traditionally designed nodal volumes that are based on regional and bony landmarks. Inadequate nodal coverage can either compromise local control or unnecessarily irradiate normal structures [72, 73].

The use of USPIO imaging can permit individualization of treatment fields. It can substantially influence local-regional volumes currently being prophylactically treated or permit dose escalation for involved lymph nodes. The treatment of head and neck tumours exemplifies this management challenge. USPIO imaging has been used for head and neck planning of surgery [71]. It can also complement the current recommendations for CT defined nodal volumes for head and neck radiotherapy [74]. It is important to note that whilst USPIO methods provide an advance in identification of pathological lymph nodes, it remains a morphological method and hence has its limitations. The threshold size for detecting pathological involvement may be 2–3 mm in a 5–10 mm node and false positives may occur if there is fibrosis or fatty replacement of the nodes [75]. It may be combined with other imaging methods such as PET to further increase its sensitivity and specificity.


   Developments in MR techniques
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
Summary
 References
 
One of the well recognized advantages of MRI is its greater functionality in characterizing tissues. With this ability, MR may provide better knowledge of tumour extent through pathophysiology or tumour response compared with simple morphological assessments. This additional information on active tumour regions may be exploited in radiotherapy for the determination of boost volumes, dose escalation, combined therapy with chemotherapy or radiosensitizers, or to select prospective non-responders during a course of radiotherapy for more aggressive treatment.

Cancer growth is usually accompanied by vascular extension and growth in order to meet the nutritional demands of rapid tumour expansion. These tumour features of vascular angiogenesis and increased cellular growth are exploited by MR techniques such as MR diffusion and dynamic contrast enhanced MRI. These MR techniques have been available in the research domain for some time and are therefore technically not new developments. However, they are included here as they are not part of standard practice and their role in clinical management is still being assessed.

Dynamic contrast-enhanced MRI
Dynamic contrast enhanced MRI (dcMRI) is a technique which exploits the vascular dynamics inherent in new blood vessel proliferation (neo-angiogenesis) and abnormal vasculature associated with tumour growth. Using fast MR sequences timed to capture the sequential changes in vascular perfusion following injection of low-molecular weight contrast agents, the perfusion or enhancement of the examined tissues and/or organ can be characterized. Time dependent enhancement curves can be subsequently produced. These (qualitative) enhancement curves from different nominated regions of interest (ROI) within the tissues can then be compared and assessed. Different tissue enhancement curves can be recognized for normal, tumour and irradiated tissues [4]. In this manner, ROI exhibiting appropriate enhancement tumour curves can be selected or delineated for radiotherapy targeting or tumour boosting.

The phases of the low-molecular weight contrast agents as they pass through the vascular system and tissues can be assessed by different MR sequences. T2 weighted sequences are more sensitive to the vascular phase and thus better display tissue perfusion and blood volume effects [76]. T1 weighted sequences are better at detecting the contrast agents in the extravascular to extracellular space and thus demonstrate microvessel perfusion, permeability and extracellular leakage effects [76]. They can be selected to provide different clinical assessments such as differentiating between benign or normal tissues, localizing active tumour regions and predicting and monitoring tumour response. T2 methods have been reported to be better suited for evaluating brain tumours, particularly gliomas [77], whereas T1 methods have been used more widely in breast, musculoskeletal, gynaecological and urological cancers [78–81].

These dcMRI methods have been used to detect tumour recurrence in previously irradiated breast [78] and prostate cancer sites [79, 82] as well as to predict response to radiotherapy in head and neck [83], rectal [80] and cervical cancers [81]. These methods can also be used to assess the nature of lymph nodes where pathologically involved nodes may possess appropriate tumour enhancement patterns on their signal intensity time curves. One limitation is that this technique can only assess a specific region and not all nodal sites.

Diffusion weighted MRI
Diffusion weighted MRI (dwMRI) attempts to assess the diffusion capacity of tissue. This methodology relies on the tumour regions having increased cellular density due to tumour proliferation and therefore results in a reduction of diffusion of water molecules through this abnormal region. Apparent diffusion coefficient (ADC) maps can be generated from different spatial regions of interest. A lower ADC is more likely to contain tumour than a high ADC. Early studies suggest that dwMRI may help distinguish between malignant and benign lesions in the brain [5], but dwMRI studies in other cancer types such as soft tissue sarcomas were not found to be as helpful due to substantial overlap in ADC values [84].

The use of dwMRI tumour defined areas may permit the assessment of tumour response during a course of therapy and regions of poor response may be selected for radiotherapy boosting. Preliminary dwMRI studies in rectal cancer treated using chemoradiation suggest that ADC values may provide indicators of tumour response [85, 86]. This can then be used to optimize treatment strategies during therapy or to initiate adjuvant therapy for the individual patient.

Diffusion tensor imaging
Diffusion tensor MRI (DTI) is a technique that can demonstrate white matter abnormalities based on cerebral tissue anisotrophy (a measure of tissue disorganization) and provide information on brain tumour involvement on white matter tracts. Investigators using DTI suggest that this method may be useful for assessing white matter infiltration by occult tumour [87]. A recent study reported that DTI recorded larger white matter tract abnormalities than seen on T2 weighted images in 10 out of 13 high-grade gliomas and previously unrecognized contralateral involvement in 4 of these cases [87]. A further planning study suggested that treatment volumes may be optimized using DTI by reducing the PTV compared with CT planning alone and thus provide the opportunity of dose escalation whilst maintaining tissue tolerances [88]. If these findings are confirmed then this information will aid RTP and also provide prognostic information if the extent of invasion is a determinant of disease outcome.

Magnetoencephalography and DTI can also be used in RTP to limit doses to relevant functional regions of the cerebrum or white tracts to reduce specific radiation-induced neurological dysfunction for each patient case to permit plan individualization [89]. DTI methods may offer complementary information to other imaging techniques including PET that are being used for target volume delineation in brain RTP.


   Summary
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
References
 
The superior characterization of soft tissues and visualization of tumour extent from MRI can benefit RTP by improving target volume delineation and assessment of planning margins in many cancer subtypes in sites such as the brain, spinal cord, soft tissues of the head and neck, trunk and limbs. In the past decade there have been many advances in MRI technology that can further aid the definition of volumes for both external beam radiotherapy and brachytherapy.

Open and low field MR simulators can provide easier integration of MR for RTP by its lower cost, facilitating the use of patient immobilization devices and providing fewer image artefacts and less distortion. USPIO contrast agents can evaluate pathological lymph nodes for treatment. Ultrafast volumetric and cine mode sequences can provide temporal assessment of target volume deformity and positioning for image guided radiotherapy.

3 T scanners can provide higher resolution images for better tissue definition and can also benefit MRS applications. MR techniques using dcMR, dwMR and DTI can further assess target volumes with improved and complementary morphological, functional and biological data that can provide the opportunity to nominate biological target volumes and the potential to gauge treatment response. These techniques may also be combined with PET to further increase diagnostic sensitivity and specificity.

This better estimation of target volumes may permit treatment individualization, organ sparing or functional avoidance, strategies of boosting and dose escalation with or without concurrent chemotherapy. All these new advances can increase the scope of MRI in radiotherapy, but currently their role and utility for RTP remains to be defined. However, just as important is the need for specific training for oncologists to understand how to utilize MR images for RTP. There must be close collaboration between diagnostic radiologists, physicists, radiographers and oncologists in order to effectively harness the benefits of MRI for radiotherapy. Ideally, this should be through a dedicated oncology team approach.


   Acknowledgments
 
We are grateful to Dr M Wada, Austin Health Radiation Oncology Centre, for providing the images demonstrating the base of tongue cancer case.

Received for publication August 9, 2005. Revision received January 6, 2006. Accepted for publication March 10, 2006.


   References
Top
 Abstract
 Introduction
 MRI rationale for RTP
 Current impact of MRI...
 MRI issues and schemas...
 New developments in MRI
 Developments in MR sequences
 Developments in MR contrast...
 Developments in MR techniques
 Summary
 References
 

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