Review Article The Role of Imaging in Radiation Therapy ...downloads.hindawi.com/journals/bmri/2014/231090.pdf · surgery, chemotherapy (in earlier times referred to simply as medicine),

Review ArticleThe Role of Imaging in Radiation Therapy Planning PastPresent and Future

Gisele C Pereira1 Melanie Traughber2 and Raymond F Muzic Jr34

1 Department of Radiation Oncology University Hospitals Case Medical Center Case Western Reserve UniversityCleveland OH 44106 USA

2 Philips Healthcare MRTherapy Cleveland OH USA3 Case Center for Imaging Research Case Western Reserve University Cleveland OH USA4Department of Radiology University Hospitals Case Medical Center Case Western Reserve University Cleveland OH 44106 USA

Correspondence should be addressed to Raymond F Muzic Jr raymondmuziccaseedu

Received 19 December 2013 Accepted 17 February 2014 Published 10 April 2014

Academic Editor Tzu-Chen Yen

Copyright copy 2014 Gisele C Pereira et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

The use of ionizing radiation for cancer treatment has undergone extraordinary development during the past hundred years Theadvancement of medical imaging has been critical in helping to achieve this change The invention of computed tomography (CT)was pivotal in the development of treatment planningDespite somedisadvantages CT remains the only three-dimensional imagingmodality used for dose calculation Newer image modalities such as magnetic resonance (MR) imaging and positron emissiontomography (PET) are also used secondarily in the treatment-planning process MR with its better tissue contrast and resolutionthan those of CT improves tumor definition compared with CT planning alone PET also provides metabolic information tosupplement the CT and MR anatomical information With emerging molecular imaging techniques the ability to visualize andcharacterize tumors with regard to their metabolic profile active pathways and genetic markers both across different tumors andwithin individual heterogeneous tumors will inform clinicians regarding the treatment options most likely to benefit a patientand to detect at the earliest time possible if and where a chosen therapy is working In the post-human-genome era multimodalityscanners such as PETCT and PETMR will provide optimal tumor targeting information

1 Introduction to Radiation Therapy

The three most important aspects of cancer treatment aresurgery chemotherapy (in earlier times referred to simplyas medicine) and radiation therapy Of these surgery is theoldest with records discovered by Edwin Smith an AmericanEgyptologist and describing the surgical treatment of cancerin Egypt circa 1600 BC [1] Medicines were also used inancient Egypt at the time of the pharaohs although the useof chemotherapy in cancer was first used in the early 1900s bythe German chemist Paul Ehrlich [2] In contrast radiationtherapy the therapeutic use of ionizing radiation is by far themost recent technique used to treat cancer X-rays a kindof ionizing radiation were discovered in 1895 by WilhelmRoentgen and within months were used to treat tumorsThis use of ionizing radiation has undergone extraordinary

development during the past century As we will discuss theadvancements in medical imaging have been critical to theevolution of modern radiation therapy

In the late nineteenth century three discoveries regardingionizing radiation were instrumental in the development ofradiation therapy

(1) November 8 1895 X-rays discovered by WilhelmConrad Roentgen (1845ndash1923)

(2) March 1 1896 radioactivity discovered by HenriBecquerel (1852ndash1908)

(3) December 26 1898 radium discovered by MadameCurie (Maria Sktodowska) (1867ndash1934)

There are two general classes of radiation therapybrachytherapy and teletherapy ldquoBrachyrdquo a Greek word

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 231090 9 pageshttpdxdoiorg1011552014231090

2 BioMed Research International

Table 1

Acceleratorvoltage

Mean photonenergy Classification

10ndash150 kV 3ndash50 keV Superficial150ndash500 kV 50ndash166 keV Orthovoltage500ndash1000 kV 166ndash333 keV Supervoltagegt1000 kV(1MV)

gt333 keV(033MeV) Megavoltage

means short distance and ldquotelerdquo means long distanceBrachytherapy is treatment performed by placing theradioactive source near or in contact with a tumor that isthe use of intracavitary or intraluminal placement of thetreatment source Conversely teletherapy is treatment withthe radioactive source at a distance from the patienttumorTeletherapy also known as external beam radiation therapymay be classified by the voltage applied to produce X-rayphotons as in Table 1 [3]

The lower energy beams produced by X-ray tubes arewell suited for diagnostic imaging However the use of theselower energy beams is limited in radiation therapy Becausethese beams are highly attenuated that is poorly penetratingthe treatment of deep tumors results in an excessive radiationdose to the skin thus limiting the ability to deliver curativedoses and so are of limited clinical usefulness In order totreat deep tumors while maintaining a lower radiation skindose high-energy beams with greater penetrating power arerequired

High-energy gamma-ray photons are emitted duringradioactive decay of certain radionuclides (X-rays andgamma-rays are both photons and produce the same inter-actions with tissue They differ according to their originGamma-rays originate from the changes between energylevels in the nucleus while X-rays originate from changesbetween energy levels in the electrons orbiting the nucleus)External-beam radiation therapy units may be created bycollimating the gamma-ray emissions from large quantitiesof radioactive material Examples of these units are telera-dium utilizing Radium-226 and emitting gamma-rays withaverage energy of 12MeV telecesium utilizing Cesium-137and emitting gamma-rays with average energy of 066MeVand the Cobalt-60 unit emitting gamma-rays at 117MeV and133MeV All of these units require storage of large amountsof radioactive materials and have associated radiation safetyconcerns including securing thematerials so that they are notused for terrorist activities Therefore the use of radioactivematerials has largely been replaced bymegavoltagemachines

The first megavoltagemachine used to produce therapeu-tic X-rays was a type of accelerator called the Van de Graaffgenerator It is an electrostatic accelerator which acceleratescharged particles in this case electrons The high-energyelectrons strike a target to create X-rays from 1 to 2MeVin energy Its first clinical use was at Huntington MemorialHospital in Boston when it was installed in 1937

Another type of accelerator used in radiation therapy is abetatron which has a hollow doughnut shape with an alter-nating magnetic field to accelerate electrons These accelera-tors were used specifically for the production of therapeuticelectron beams rather than X-rays Most of these units wereinstalled in European medical centers had electron energiesup to 50MeV and were used to treat deeply located tumors

Van de Graaff generators and betatrons were the precur-sors of linear accelerators or ldquolinacsrdquo Linacs to be used forradiation therapywere developed during and afterWorldWarII and used the high-frequency and high-power microwavesources developed for the manufacture of radar systemsLinacs accelerate charged particles most commonly elec-trons to create therapeutic electron or X-ray beams up to25MeV in energy Electrons achieve acceleration by travelingthrough a high electronic field in a magnetic field that causesthe electrons to take a spiral path of increasing radius X-raysare produced when these accelerated electrons collide with ahigh-atomic-number target In 1953 the first isocentric linacwas installed at the Christie Hospital in Manchester UnitedKingdom and these units continue to be the mainstay ofmodern radiation therapy The chronology of the develop-ment of linear accelerators for radiotherapy use is as follows

1953 first isocentric linac installed United Kingdom1954 first dual-throttle (X-rays and electrons) linac in-

stalled St Bartholomewrsquos Hospital London1973 first dual-photon-energy linac installed Antoni van

Leeuwenkoek Amsterdam1981 introduction of motorized collimators1985 new series of fully computer-controlled linacs estab-

lished thus allowing the development of modernradiotherapy of high complexity

2 Past Introduction of Imaging in RadiationTherapy Planning

Together with the progress of radiation therapy linacs wasthe development of dose calculation and treatment-planningtechniquesThe ability to quantify the delivered dose evolvedfrom simple skin erythema observations in the late 1800s tosingle-point calculations inside the patient in the mid 1900rsquosand to computer-based dose calculations in the late 1960sFinally with the invention of computed tomography (CT)by Cormack and Hounsfield in 1972 three-dimensional (3D)dose calculation became possibleThe use of CT in treatmentplanning allowed several important advances in radiationtherapy and resulted in greater precision in dose distributiondose optimization and patient positioning However one ofthemost important advances CT provided for 3D dose calcu-lation was the precise visualization of the geometric positionsof tumor and normal tissue in a patient The radiation dosecould then be calculated and optimized in order to determinethe best dose distribution in the target (tumor) thus avoidingthe surrounding normal tissue Another advance CT offeredwas the creation of digitally reconstructed radiographs orDRRs (Figure 1) for patient position verification at the timeof treatment using the linac

BioMed Research International 3

Figure 1 Creation of digital reconstructed radiographs or DRRsfrom CT

3 Present What Is Used in Practice Today

Currently radiation therapy linacs are fully controlled bycomputers and with new techniques of dose delivery such asintensity-modulated radiation therapy (IMRT) volumetric-modulated arc therapy (VMAT) and imaged-guided radio-therapy (IGRT) the treatment delivery precision is measuredinmillimeters [4] Amore precisemethod of target definitionis necessary for such precise delivery While CT has revolu-tionized the field of radiation therapy further improvementsin imaging are desirable in which the dose can be deliveredwith yet increased accuracy CT has several limitations suchas suboptimal tissue contrast lack of functional informationand the inability to visualize small groups of cancer cells thatare separated from the gross tumor If we can overcome theselimitations we can further improve the precision of the targetdefinition and provide better patient outcomes [5]

The application of other imaging modalities such asmagnetic resonance (MR) imaging and positron emissiontomography (PET) can provide additional information inorder to more precisely define tumor localization for treat-ment planning using radiation therapy [6ndash8] In particularMR has better soft-tissue contrast than CT and providesbetter visual discrimination between tissue that should betreated and that which should not (Figure 2) [9 10] PETallows the identification of areas of metabolic activity andthus allows the radiation oncologist to escalate the radiationdose for the most aggressively growing tumors or regionstherein [11 12] (Figure 3) Despite its limitations for severalreasonsCT is currently the only 3D imagingmethod acceptedfor treatment planning Most treatment-planning algorithmswere developed specifically for CT as it was the first available3D imaging modality and CT scanners are more commonlyused than MR or PET Furthermore the geometric fidelityof CT is better than that of MR in which distortionsmay occur and as CT generally has shorter acquisitiontimes than MR or PET organtumor motion managementcan be assessed Most importantly with CT it is possibleto identify the mass attenuation coefficient (120583120588 (m2Kg))

or attenuation characteristics for high-energy photons X-rays and gamma-rays as this is critical for precise dosecalculation

Photon interactions with tissue such as photo-electricabsorption Compton scatter and pair production are depen-dent on the atomic number electron density of the tis-sue and photon energy (Figure 4) Therefore to accuratelycalculate the radiation dose the specific mass attenuationfactor for different types of tissue that is heterogeneityencountered by a photon beam must be identified For thisreason the treatment planning dose calculation is still onlypossible using CT Newly developed algorithms such asconvolutionsuperposition and Monte Carlo provide moreaccurate dose calculations by using heterogeneity correction[13]These new algorithms calculate the radiation absorptionand scatter of different tissue densities and apply that tothe dose calculation although this is only possible becausethe tissue density is obtained using a table that relates theHounsfield number to density Four-dimensional CT (4DCT)is another development used to quantify respiratory andorgan motion Normally the 4DCT is applied in thoracicand abdominal sites in which respiratory motion can causeincorrect information regarding the size and position of atumor and critical organs [14]

The primary disadvantage of CT for treatment planningis the low tissue contrast which can result in the tumordefinition varying significantly from physician to physician[15] Other imaging modalities such as MR and PET mayhelp in the tumor definition due to their improved soft-tissuecontrast and functional information [16 17] Therefore incontemporary radiation therapy practice MR and PET areoften used to complement CT for tumor delineation andnormal tissue identification although only CT is used fordose calculationTherefore the ability to accurately coregisterthese various image sets is one of the most powerful tools forradiation therapy planning

31 MR Paul Lauterbur at the State University of New YorkUSA and Peter Mansfield at the University of NottinghamEngland independently produced the first NMR image nowcalled MR in the 1970s Their invention had a profoundimpact on medical imaging and they shared the 2003 NobelPrize in Physiology or Medicine

MR is a powerful diagnostic tool Compared to CTimaging MR has several advantages such as greater intrinsicsoft-tissue contrast and resolution than CT and nonionizingradiation as it uses radiofrequency waves for signal gen-eration In many clinical specialties such as orthopedicsneurology and neurosurgery as well as for various anatomiesand pathologies including pelvic organs and tumors soft-tissue visualization is used for diagnosis Therefore MR isthe preferred imaging modality for many diagnostic imagingapplications Despite the wide use of MR for diagnosticimaging in radiation therapy treatment planning MR is stilla secondary image modality due to its image artifacts lack oftissue density information and relatively small field of view(FOV)


(a) (b)

(c) (d)

Figure 2 Differences in the soft-tissue contrast from four images (a) is a T2-weighted MR image (b) is a T1-weighted MR image (c) is aT1-weighted MR image with contrast and (d) is a CT image The ROIs shown above are eyes (purple and light green colors) optical nerves(green and yellow colors) brain stem (teal color) gross tumor (pink color) and clinical target (yellow color) which extend from the grosstumor by a few millimeters with the intent of treating the subclinical microscopic extension of disease

MR systems available only five years ago were less suc-cessful due to issues rendering them unsuitable for RT plan-ning However improvements in MR hardware and softwaredesign have allowed MR imaging to become part of the RTplanning workflow [18ndash21] Protocols generated specificallyfor the purpose of RT planning rely on fundamentally robusthigh-resolution contrast-consistent large FOV acquisitionscompared to the variety of sequences that may be used indiagnostic imaging This effort has helped to increase the useof MR in RT planning although still only as a secondaryimaging set

Two significant issues keep MR relegated to a secondaryrole that is the lack of electron-density information derivedfrom MR images and the potential error in its geomet-ric accuracy Regarding electron density therapy planningentails estimating the radiation dose which depends on themanner and degree to which the radiation interacts withand deposits energy in the tissue This occurs primarily dueto Compton events in which the incident high-energy X-rays interact with outer shell electrons in the tissue Theinteraction probability is proportional to electron density

on which the CT but not the MR signal depends AlthoughMR cannot directly image tissue density there are severalstudies showing the potential to calculate the radiation doseand even generate DRRs based solely on MR data (Figure 5)[18 20 21] A common approach is to assign a bulk density totheMR image using an atlas-based electron-densitymappingmethod [20 22] This remains an active area of research andnew methods may be forthcoming

Regarding the geometric accuracy MR images mayappear spatially warped so that the location of somethingappearing in the image differs from its actual physicallocation This could be caused for example by distortions inthe magnetic gradient fields With MR the spatial location isencoded by the spin frequency of protons which depends onthe localmagnetic-field strengthMagnetic gradients are usedto vary the field strength in a spatially dependent mannerSpatial warping then results with aberrations in field strengththat can be caused by residual error in system calibrationsand by the presence of materials such as dental implantsprostheses and even due to transitions between materials forexample between tissue and air


Table 2 Sources of MR distortion correction and method for assessment

Level of distortion Distortion source Distortion correction Assessment ofresidual distortion

System Gradient nonlinearity Gradient coil design (HW)Model-based corrections (SW)

Geometric fidelity phantoms andassessment tools

Static field (B0)inhomogeneity Magnet design and static-field shims (HW) B0-field map in phantoms

PatientStatic-field (B0)inhomogeneity

Gradient-shim coils (HW)Patient-specific B0 field correction (SW) B0-field map in the patient

Transmit-field (B1)inhomogeneity

Multiple RF transmit channels (HW)Patient-specific B1 field correction (SW) B1-field map in the patient

Sequence Gradient switching(eddy currents)

Gradient preemphasis (HWSW)Protocols with low gradient slew rates (SW) Visual inspection

R

A

L

P

121mm56

(a)

R

A

L

P

121mm56

(b)

A

P

121mmCT 56PT 56

(c)

Figure 3 PETprovides the ability to differentiate areas of neoplastichyper-metabolic activity within surrounding normal tissue where(a) is the CT image (b) is the PET and (c) is the fused PETCT Allof the images show the gross tumor delineated from the PET imagein teal color

To mitigate these effects one can use acquisitionsequences that are less sensitive to magnetic field inaccura-cies Table 2 shows the types of MR distortion correctionand assessment As mentioned above current MR systemshave hardware and software solutions available that optimizethe geometric fidelity Improved gradient linearity static-field homogeneity and patient-induced inhomogeneitycompensation have brought MR greater acceptance for RT

001 01 1 10 100

Relat

ive p

roba

bilit

y (

)

Photon energy (MeV)

Muscle

ComptonPhotoelectricPair prod

100

80

60

40

20

0

Figure 4 Probability of photon interaction (Compton Photoelec-tric and Pair Production) in muscle

planning Quality assurance tools to test various sourcesof image distortion can also be used to characterize theseimprovements on both a daily and a patient-by-patientbasis These advancements have increased the use of MRsystems in radiation oncology clinical departments and haveencouraged further development of MR-guided treatmentsolutions including several projects intended to integrateMRimaging during external-beam radiation therapy [23ndash25]

32 PET PET entails imaging the biodistribution of aradiolabeled compound selected based on its biochemicalbehavior Most commonly 2-[18F]fluoro-2-deoxy-D-glucose(FDG) a glucose analog is used and is transported into cellsphosphorylated and then trapped intracellularly Differingfrom CT and conventional MR which show morphologyFDG-PET shows metabolically active tissue As such PETcan be used to refine the target volume or to provide a doseboost to themostmetabolically active tumors or areas therein[16] PET can also be used to monitor tumor response while


Figure 5 DRRs based solely on MR data

noting that metabolic changes would precede changes intumor shape and size [17]

While FDG is the most commonly used PET radio-pharmaceutical others may also be useful for radiationtherapy For example some radiopharmaceuticals such as64Cu-diacetyl-bis(N4-methylthiosemicarbazone) commonlycalled 64Cu-ATSM and 18F-fluoromisonidazole commonlycalled 18F-FMISO have been designed to demonstratehypoxia and as hypoxia is associated with radiation resis-tance such areas may be targeted for additional radiationdosage [26] 31015840-[18F]fluoro-31015840-deoxythymidine18F-FLT hasbeen developed as a marker of cellular proliferation and isused to assess the response to radiation therapy [27] It hasthe potential to be an earlier indicator than FDG as radiationcauses an inflammatory response that necessitates a delaybetween therapy and follow-up FDG-PET imaging [28]

Regardless of the radiotracer used determining its spatiallocation is essential for radiation therapy planning In thisregard image registration and fusion that is the ability todetermine corresponding spatial locations in two or moreimage volumes and to visualize the result as a superposition-ing of images is a very useful technology In the 1990s imageregistration and fusion were achieved by scanning a patienton two different scanners and then analyzing the data usinga combination of computer software and human guidanceto rotate and translate one of the two image volumes untilit best matches the other It is also possible to stretch orwarp the image volumes to account for further differencesin patient position and orientation although it is less usedand more prone to error than rigid-body transformationssuch as rotation and translation Therefore the advent ofmultimodality scanners beginning around the year 2000with combined PET-CT [29 30] was a seminal advance forthe use of imaging in radiation therapy planning as patientswould be placed in the same position for both PET andCT In fact this change was so significant that the sale ofPET scanners lacking CT absolutely disappeared within a fewyears Motivated by the success of PET-CT other combinedinstruments have beenmade with PET-MRbeing the newestand have the greatest number of technical challenges owing

to the difficulty of operating PET detectors in the strongmagnetic field of MR [31 32] Despite these and otherchallenges it is exciting that MR offers soft-tissue contrastthat is not possible with CT and that facilitates for examplevisualization of prostate and head and neck cancer (Figure 6)

33 Image Registration and Fusion The ability to fuse andcoregister the three main types of oncologic imaging tech-niques that is CT MR and PET became available forradiation oncology planning in the early 1990s due to theimprovement of the software algorithms used to registerand fuse multimodality imaging datasets Registration is theability to align the same points from different images Inmedical applications these points are the same anatomicalregions of the body such as bone and organs for the samepatient Fusion is the ability to display different types ofregistered images anatomically overlain on one another ina single composite image [33] Fusion provides the bestinformation for each image that is geometric definition andtissue density from the CT image soft-tissue contrast fromthe MR image and metabolic information from the PETimage The combined information reduces the uncertaintyregarding the tumor definition for geometric localization aswell as determining the size and spread of the disease Byimproving the accuracy of the target definition image fusioncan potentially improve the treatment outcome and decreasecomplications as less normal tissue is irradiated

Currently most radiation treatment planning systemssupport image registration and fusion There are severalfusion algorithms The most common is geometrical trans-formation (rigid and nonrigid) that can be point-basedintensity-based or based on the mechanical properties of thetissue [34] Registration algorithms are very complex and cancreate undesirable image artifacts thus causing errors in thetumor and normal tissue localization To minimize potentialissues using software-based registration it is desirable toposition patients as similarly as possible and to use thesoftware to refine the result This can be achieved by usingimmobilization devices as well as using flat tables for diagnos-tic imaging equipment and which match the geometry of the


(a) (b)

Figure 6 Axial-view images of a patient using a combined PETMR scannerTheupper rows showPET images of FDGactivity correspondingto glucose metabolism The middle rows show MR images acquired using a T1-weighted fat saturation sequence The lower rows show thefused images The PET images show elevated FDG uptake indicating cancer in (a) the tongue base and (b) the epiglottis

treatment couch As a patientrsquos body may still move betweenand during the image set acquisitions a 3-dimensionalregistration is necessary Keeping the patient immobilized inthe image set will produce smaller corrections for the fusionalgorithm thus causing fewer registration errors Currentlythe process of fusing multiple image techniques in radiationoncology is labor-intensive and requires manual verificationof the quality of the registration by qualified experts [35]Automation of this process will depend on improvementsin the algorithms as well as better metrics for accuracyverification

4 Future Considerations

The primary goal of treatment planning is to preciselycalculate the radiation dose to the tumor in order to improvethe outcome and reduce toxicity The future of imaging inradiation therapy treatment planning is promising and otheradvances will contribute to better target definition Higherresolution imaging will be developed for all of the modalitiesdiscussed Specifically higher definition PET-CT scannersand high magnetic field MR have the ability to improvethe visualization of tumors even to the level of microscopicdisease extension [6]

Emerging algorithms for image fusion [33] will be moreaccurate and will allow an automated fusion process andverification These new algorithms will make the tumorlocalization in the several types of images more precise andless time-consuming

As previously mentioned several solutions have beenintroduced in order to allow MR-based simulation andplanning to become a reality This may ultimately lead tothe elimination of CT in radiation therapy and which hasbeen the foundation of treatment planning during the pastfour decades This has far-reaching implications includinglower overall cost and reduced X-ray exposure Howeveranother issue that has slowed the adoption ofMRby radiation

oncology is the lack of staff training for MR imaging andexplaining the use of MR for treatment planning duringtraditional professional education

Once MR systems are readily available for imagingpatients undergoing radiation treatment the opportunity toassess their response to treatment and to adapt the treatmentplan for improved patient outcomes is likely [36ndash41] Thenumber and types of functional measurements which can bedetermined using MR imaging are multiple Table 3 showssome of the basic functional imaging types that have shownpromise in predicting the clinical outcomes for various tumortypes

41 ldquoOmicsrdquo and the Future Several investigators are attempt-ing to apply the field of ldquoomicsrdquo to tailor individual treatmentfor a better outcome in cancer therapy through the expressionof genes proteins and metabolites In radiation therapyldquoomicsrdquo may be able to predict the treatment responsethrough immunohistochemical markers DNA microarraygene signatures and nucleotide polymorphisms [42] Identi-fying biomarkers that can predict the sensitivity or resistanceof tumors to radiation therapy is another promising area ofongoing research [43]

The advances in omics imaging for radiation treatmentplanning will include molecular imaging such as the newMR sequences described in Table 3 functional imaging aswell as the development and application of new PET tracerssuch as 18F-FLT 64Cu-ATSM and 18F-FMISO that can betteridentify regions of hypoxia oxygen metabolism microscopicdisease and high metabolism inside the tumor [27] Tumorgenetic and radiobiological factors will guide individualizedradiation therapy with better target delineation avoidance ofnormal tissue dose escalation dose fractionation and betterprediction of treatment response [44] The semiquantitativestandardized uptake value (SUV) with different radiotracersfor different tumor histologies will be able to predict thetumor heterogeneity based on metabolism The SUV can


Table 3 Basic MR functional imaging types that have shown promise in predicting outcomes for various tumor types

Type of measurement Functional imaging method Known as What is measured

Perfusion

Dynamic contrast enhanced DCE permeability Gadolinium-inducedshortening of T1

Dynamicsusceptibility contrast DSC Gadolinium-induced

shortening of T2lowast

Arterial spin labeling ASLIntrinsic contrast

enhancement generated frommagnetization of arterial blood

Diffusion Diffusion weighting imaging DWIGradient-induced

sensitization of moleculardiffusion

Metabolic function Spectroscopy MRSI Chemical composition basedon resonant frequency

Oxygenation Bold-level oxygendependent BOLD fMRI T2lowast differences in oxy- and

deoxyhemoglobin

identify more aggressive (metabolically active) or radioresis-tant (hypoxic) areas within a tumor and allow these areas tobe treated with higher radiation doses (dose painting) [44]

In the omics era therapy may be personally optimizedbased on pathologic and genetic characterization of tumorsin order to target the relevant treatment pathways whileminimizing undesirable side effects [45] In both the past andpresent detailed characterization requires biopsy Howeverbiopsy is invasive and only provides a snapshot of a subsetof the cells of interest As tumors are often heterogeneousthere may be multiple regions in a tumor each with its owngenetic profile Tumors may be near nerves or other criticalstructures that make needle placement unacceptably riskyMolecular imaging has the promise to overcome these pitfallswhile providing key insight regarding the tumor geneticsactive pathways and sensitivity to radiation all as a spatialmap which can be used to target a constellation of tumorsand even regions within tumors [46]

In conclusion the future of image-guided treatmentplanning is boundless and with continuous innovations thatwill ultimately lead to higher cure rates and less treatment-associated toxicity

Conflict of Interests

The authors declare that they have no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors thank David Mansur MD for review of thepaper and Bonnie Hami MA (USA) for her editorialassistance in the preparation of the paper

References

[1] R E Pollock and D L Morton ldquoPrinciples of surgical oncol-ogyrdquo in Cancer Medicine D W Kufe and R E Pollock Eds BC Decker Hamilton Ontario Canada 2000

[2] V T de Vita Jr and E Chu ldquoA history of cancer chemotherapyrdquoCancer Research vol 68 no 21 pp 8643ndash8653 2008

[3] F M Khan ldquoClinical radiation generatorsrdquo in The Physics ofRadiation Therapy Lippincott Williams amp Wilkins Philadel-phia Pa USA 2010

[4] T Bortfeld and R Jeraj ldquoThe physical basis and future ofradiation therapyrdquo British Journal of Radiology vol 84 no 1002pp 485ndash498 2011

[5] D Vordermark ldquoTen years of progress in radiation oncologyrdquoBMC Cancer vol 11 article 503 2011

[6] W Schlegel ldquoIf you canrsquot see it you can miss it the role ofbiomedical imaging in radiation oncologyrdquo Radiation Protec-tion Dosimetry vol 139 no 1ndash3 pp 321ndash326 2010

[7] P H Ahn and M K Garg ldquoPositron emission tomogra-phycomputed tomography for target delineation in head andneck cancersrdquo Seminars in Nuclear Medicine vol 38 no 2 pp141ndash148 2008

[8] D Mak J Corry E Lau D Rischin and R J Hicks ldquoRole ofFDG-PETCT in staging and follow-up of head and neck squa-mous cell carcinomardquo Quarterly Journal of Nuclear Medicineand Molecular Imaging vol 55 no 5 pp 487ndash499 2011

[9] D R Simpson J D Lawson S K Nath B S Rose A J Mundtand L K Mell ldquoUtilization of advanced imaging technologiesfor target delineation in radiation oncologyrdquo Journal of theAmerican College of Radiology vol 6 no 12 pp 876ndash883 2009

[10] E Glatstein A S Lichter and B A Fraass ldquoThe imagingrevolution and radiation oncology use of CT ultrasoundand NMR for localization treatment planning and treatmentdeliveryrdquo International Journal of Radiation Oncology BiologyPhysics vol 11 no 2 pp 299ndash314 1985

[11] A-L Grosu M Piert W A Weber et al ldquoPositron emissiontomography for radiation treatment planningrdquo Strahlentherapieund Onkologie vol 181 no 8 pp 483ndash499 2005

[12] K U Hunter and A Eisbruch ldquoAdvances in imaging targetdelineationrdquo Cancer Journal vol 17 no 3 pp 151ndash154 2011

[13] N Papanikolaou J J Battista A L Boyer et al ldquoTissueinhomogeneity corrections for megavoltage photon beamsrdquo inReport of Task Group 65 pp 1ndash142 American Association ofPhysics in Medicine 2004

[14] P Keall ldquo4-dimensional computed tomography imaging andtreatment planningrdquo Seminars in Radiation Oncology vol 14no 1 pp 81ndash90 2004


[15] R J H M Steenbakkers J C Duppen I Fitton et al ldquoReduc-tion of observer variation using matched CT-PET for lungcancer delineation a three-dimensional analysisrdquo InternationalJournal of Radiation Oncology Biology Physics vol 64 no 2 pp435ndash448 2006

[16] J Li and Y Xiao ldquoApplication of FDG-PETCT in radiationoncologyrdquo Frontiers in Oncology vol 3 pp 1ndash6 2013

[17] V Gregoire K Haustermans X Geets S Roels and MLonneux ldquoPET-based treatment planning in radiotherapy anew standardrdquo Journal of Nuclear Medicine vol 48 no 1 pp68Sndash77S 2007

[18] E M Kerkhof J M Balter K Vineberg and BW RaaymakersldquoTreatment plan adaptation forMRI-guided radiotherapy usingsolely MRI data a CT-based simulation studyrdquo Physics inMedicine and Biology vol 55 no 16 pp N433ndashN440 2010

[19] K LMaletz R D Ennis J Ostenson A Pevsner A Kagen andI Wernick ldquoComparison of CT andMR-CT fusion for prostatepost-implant dosimetryrdquo International Journal of RadiationOncology Biology Physics vol 82 no 5 pp 1912ndash1917 2012

[20] J A Dowling J Lambert J Parker et al ldquoAn atlas-based elec-tron density mapping method for magnetic resonance imaging(MRI)mdashalone treatment planning and adaptive MRI-basedprostate radiation therapyrdquo International Journal of RadiationOncology Biology Physics vol 83 no 1 pp e5ndashe11 2012

[21] M Kapanen J Collan A Beule T Seppala K Saarilahti andM Tenhunen ldquoCommissioning of MRI-only based treatmentplanning procedure for external beam radiotherapy of prostaterdquoMagnetic Resonance inMedicine vol 70 no 1 pp 127ndash135 2013

[22] J H Jonsson M G Karlsson M Karlsson and T NyholmldquoTreatment planning using MRI data an analysis of the dosecalculation accuracy for different treatment regionsrdquo RadiationOncology vol 5 no 1 article 62 2010

[23] B G Fallone B Murray S Rathee et al ldquoFirst MR imagesobtained during megavoltage photon irradiation from a proto-type integrated linac-MR systemrdquo Medical Physics vol 36 no6 pp 2084ndash2088 2009

[24] B W Raaymakers J J W Lagendijk J Overweg et alldquoIntegrating a 15 TMRI scanner with a 6MV accelerator proofof conceptrdquo Physics in Medicine and Biology vol 54 no 12 ppN229ndashN237 2009

[25] J Dempsey ldquoWE-E-ValA-06 a real-time MRI guided externalbeam radiotherapy delivery systemrdquoMedical Physics vol 33 no6 pp 2254ndash2254 2006

[26] M M Clausen ldquoDose escalation to high-risk sub-volumesbased on non-invasive imaging of hypoxia and glycolyticactivity in canine solid tumors a feasibility studyrdquo RadiationOncology vol 8 article 262 2013

[27] B J Allen E Bezak and L GMarcu ldquoQuoVadis radiotherapyTechnological advances and the rising problems in cancermanagementrdquo BioMed Research International vol 2013 ArticleID 749203 9 pages 2013

[28] S Chandrasekaran ldquo18F-fluorothymidine-pet imaging of glio-blastomamultiforme effects of radaition therapy on radiotraceruptake and molecular biomarker patternsrdquoThe Scientific WorldJournal vol 2013 Article ID 796029 12 pages 2013

[29] T Beyer D W Townsend T Brun et al ldquoA combined PETCTscanner for clinical oncologyrdquo Journal of Nuclear Medicine vol41 no 8 pp 1369ndash1379 2000

[30] DThorwarth X Geets andM Paiusco ldquoPhysical radiotherapytreatment planning based on functional PETCT datardquo Radio-therapy and Oncology vol 96 no 3 pp 317ndash324 2010

[31] H Herzog and J van den Hoff ldquoCombined PETMR systemsan overview and comparison of currently available optionsrdquoQuarterly Journal of Nuclear Medicine and Molecular Imagingvol 56 no 3 pp 247ndash267 2012

[32] B J Pichler M S Judenhofer and C Pfannenberg ldquoMulti-modal imaging approaches PETCT and PETMRIrdquoHandbookof Experimental Pharmacology no 185 pp 109ndash132 2008

[33] A Ardeshir Goshtasby and S Nikolov ldquoImage fusion advancesin the state of the artrdquo Information Fusion vol 8 no 2 pp 114ndash118 2007

[34] J M Fitzpatrick D L G Hill and C R Maurer ldquoImageregistrationrdquo in Handbook of Medical Imaging M Sonka andJ M Fitzpatrick Eds SPIE Press 2009

[35] M L Kessler ldquoImage registration and data fusion in radiationtherapyrdquo British Journal of Radiology vol 79 pp S99ndashS1082006

[36] B A Moffat T L Chenevert T S Lawrence et al ldquoFunctionaldiffusion map a noninvasive MRI biomarker for early strat-ification of clinical brain tumor responserdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 102 no 15 pp 5524ndash5529 2005

[37] JM Lupo E Essock-Burns A M Molinaro et al ldquoUsingsusceptibility-weighted imaging to determine response to com-bined anti-angiogenic cytotoxic and radiation therapy inpatients with glioblastoma multiformerdquo Neuro-Oncology vol15 no 4 pp 480ndash489 2013

[38] Y Cao ldquoThe promise of dynamic contrast-enhanced imaging inradiation therapyrdquo Seminars in Radiation Oncology vol 21 no2 pp 147ndash156 2011

[39] A R Padhani and K A Miles ldquoMultiparametric imaging oftumor response to therapyrdquo Radiology vol 256 no 2 pp 348ndash364 2010

[40] A R Padhani G Liu D Mu-Koh et al ldquoDiffusion-weightedmagnetic resonance imaging as a cancer biomarker consensusand recommendationsrdquo Neoplasia vol 11 no 2 pp 102ndash1252009

[41] J E Bayouth T L Casavant M M Graham M Sonka MMuruganandham and J M Buatti ldquoImage-based biomarkersin clinical practicerdquo Seminars in Radiation Oncology vol 21 no2 pp 157ndash166 2011

[42] S M Bentzen ldquoFrom cellular to high-throughput predictiveassays in radiation oncology challenges and opportunitiesrdquoSeminars in Radiation Oncology vol 18 no 2 pp 75ndash88 2008

[43] C H Chung S Wong K K Ang et al ldquoStrategic plans topromote head and neck cancer translational research withinthe radiation therapy oncology group a report from the trans-lational research programrdquo International Journal of RadiationOncology Biology Physics vol 69 no 2 pp S67ndashS78 2007

[44] A Basu ldquoThe scope and potencials of functional radionuclideimaging towards advancing personalizedmedicine in oncologyemphasis on PET-CTrdquo Discovery Medicine vol 13 no 68 pp65ndash73 2012

[45] H Schoder and S C Ong ldquoRole of positron emission tomogra-phy in radiation oncologyrdquo Seminars in Nuclear Medicine vol38 no 2 pp 119ndash128 2008

[46] S A Amundson M Bittner and A J Fornace Jr ldquoFunctionalgenomics as a window on radiation stress signalingrdquoOncogenevol 22 no 37 pp 5828ndash5833 2003

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



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OphthalmologyJournal of


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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1

Acceleratorvoltage

Mean photonenergy Classification

10ndash150 kV 3ndash50 keV Superficial150ndash500 kV 50ndash166 keV Orthovoltage500ndash1000 kV 166ndash333 keV Supervoltagegt1000 kV(1MV)

gt333 keV(033MeV) Megavoltage

means short distance and ldquotelerdquo means long distanceBrachytherapy is treatment performed by placing theradioactive source near or in contact with a tumor that isthe use of intracavitary or intraluminal placement of thetreatment source Conversely teletherapy is treatment withthe radioactive source at a distance from the patienttumorTeletherapy also known as external beam radiation therapymay be classified by the voltage applied to produce X-rayphotons as in Table 1 [3]

The lower energy beams produced by X-ray tubes arewell suited for diagnostic imaging However the use of theselower energy beams is limited in radiation therapy Becausethese beams are highly attenuated that is poorly penetratingthe treatment of deep tumors results in an excessive radiationdose to the skin thus limiting the ability to deliver curativedoses and so are of limited clinical usefulness In order totreat deep tumors while maintaining a lower radiation skindose high-energy beams with greater penetrating power arerequired

High-energy gamma-ray photons are emitted duringradioactive decay of certain radionuclides (X-rays andgamma-rays are both photons and produce the same inter-actions with tissue They differ according to their originGamma-rays originate from the changes between energylevels in the nucleus while X-rays originate from changesbetween energy levels in the electrons orbiting the nucleus)External-beam radiation therapy units may be created bycollimating the gamma-ray emissions from large quantitiesof radioactive material Examples of these units are telera-dium utilizing Radium-226 and emitting gamma-rays withaverage energy of 12MeV telecesium utilizing Cesium-137and emitting gamma-rays with average energy of 066MeVand the Cobalt-60 unit emitting gamma-rays at 117MeV and133MeV All of these units require storage of large amountsof radioactive materials and have associated radiation safetyconcerns including securing thematerials so that they are notused for terrorist activities Therefore the use of radioactivematerials has largely been replaced bymegavoltagemachines

The first megavoltagemachine used to produce therapeu-tic X-rays was a type of accelerator called the Van de Graaffgenerator It is an electrostatic accelerator which acceleratescharged particles in this case electrons The high-energyelectrons strike a target to create X-rays from 1 to 2MeVin energy Its first clinical use was at Huntington MemorialHospital in Boston when it was installed in 1937

Another type of accelerator used in radiation therapy is abetatron which has a hollow doughnut shape with an alter-nating magnetic field to accelerate electrons These accelera-tors were used specifically for the production of therapeuticelectron beams rather than X-rays Most of these units wereinstalled in European medical centers had electron energiesup to 50MeV and were used to treat deeply located tumors

Van de Graaff generators and betatrons were the precur-sors of linear accelerators or ldquolinacsrdquo Linacs to be used forradiation therapywere developed during and afterWorldWarII and used the high-frequency and high-power microwavesources developed for the manufacture of radar systemsLinacs accelerate charged particles most commonly elec-trons to create therapeutic electron or X-ray beams up to25MeV in energy Electrons achieve acceleration by travelingthrough a high electronic field in a magnetic field that causesthe electrons to take a spiral path of increasing radius X-raysare produced when these accelerated electrons collide with ahigh-atomic-number target In 1953 the first isocentric linacwas installed at the Christie Hospital in Manchester UnitedKingdom and these units continue to be the mainstay ofmodern radiation therapy The chronology of the develop-ment of linear accelerators for radiotherapy use is as follows

1953 first isocentric linac installed United Kingdom1954 first dual-throttle (X-rays and electrons) linac in-

stalled St Bartholomewrsquos Hospital London1973 first dual-photon-energy linac installed Antoni van

Leeuwenkoek Amsterdam1981 introduction of motorized collimators1985 new series of fully computer-controlled linacs estab-

lished thus allowing the development of modernradiotherapy of high complexity

2 Past Introduction of Imaging in RadiationTherapy Planning

Together with the progress of radiation therapy linacs wasthe development of dose calculation and treatment-planningtechniquesThe ability to quantify the delivered dose evolvedfrom simple skin erythema observations in the late 1800s tosingle-point calculations inside the patient in the mid 1900rsquosand to computer-based dose calculations in the late 1960sFinally with the invention of computed tomography (CT)by Cormack and Hounsfield in 1972 three-dimensional (3D)dose calculation became possibleThe use of CT in treatmentplanning allowed several important advances in radiationtherapy and resulted in greater precision in dose distributiondose optimization and patient positioning However one ofthemost important advances CT provided for 3D dose calcu-lation was the precise visualization of the geometric positionsof tumor and normal tissue in a patient The radiation dosecould then be calculated and optimized in order to determinethe best dose distribution in the target (tumor) thus avoidingthe surrounding normal tissue Another advance CT offeredwas the creation of digitally reconstructed radiographs orDRRs (Figure 1) for patient position verification at the timeof treatment using the linac












(a) (b)

(c) (d)


















R

A

L

P

121mm56

(a)

R

A

L

P

121mm56

(b)

A

P

121mmCT 56PT 56

(c)



001 01 1 10 100

Relat

ive p

roba

bilit

y (

)

Photon energy (MeV)

Muscle


100

80

60

40

20

0













(a) (b)














Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























(a) (b)

(c) (d)


















R

A

L

P

121mm56

(a)

R

A

L

P

121mm56

(b)

A

P

121mmCT 56PT 56

(c)



001 01 1 10 100

Relat

ive p

roba

bilit

y (

)

Photon energy (MeV)

Muscle


100

80

60

40

20

0













(a) (b)














Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(a) (b)

(c) (d)


















R

A

L

P

121mm56

(a)

R

A

L

P

121mm56

(b)

A

P

121mmCT 56PT 56

(c)



001 01 1 10 100

Relat

ive p

roba

bilit

y (

)

Photon energy (MeV)

Muscle


100

80

60

40

20

0













(a) (b)














Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























R

A

L

P

121mm56

(a)

R

A

L

P

121mm56

(b)

A

P

121mmCT 56PT 56

(c)



001 01 1 10 100

Relat

ive p

roba

bilit

y (

)

Photon energy (MeV)

Muscle


100

80

60

40

20

0













(a) (b)














Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























(a) (b)














Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(a) (b)














Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Perfusion










deoxyhemoglobin






Acknowledgments


References





















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article The Role of Imaging in Radiation Therapy ...downloads.hindawi.com/journals/bmri/2014/231090.pdf · surgery, chemotherapy (in earlier times referred to simply as medicine),