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    Guidelines for

    Modern Radiation OncologyPractice

    Vol XIV

    (Part A)

    Published by

    Tata Memorial CentreMumbai

    Editors

    Dr. Umesh Mahantshetty

    Tata Memorial Hospital

    Dr. Santam ChakrabortyAssistant Professor, Radiation Oncology

    Tata Memorial Hospital

    Dr. Shyamkishore ShrivastavaProfessor & Head, Department of Radiation Oncology

    Tata Memorial Hospital

    Professor, Radiation Oncology

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    Tata Memorial Hospital

    Dr. Ernest Borges Road, Parel

    Mumbai 400 012. INDIA.Tel.: +91-22-2417 7000Fax: +91-22-2414 6937Email: [email protected]: http: //tmc.gov.in

    Published by the Tata Memorial Hospital, MumbaiPrinted at the Sundaram Art Printing Press, Mumbai

    2015 Tata Memorial Hospital, MumbaiAll rights reserved.

    Evidence Based Management of Cancers in IndiaVol. XIV

    Three Parts

    Set ISBN: 978-93-82963-06-6

    Guidelines for Modern Radiation Oncology Practice

    Part A ISBN: 978-93-82963-07-3

    Guidelines for Cytogenetic and Molecular Testing inMyeloid MalignanciesPart B ISBN: 978-93-82963-08-0

    Guidelines for Cardio OncologyPart C ISBN: 978-93-82963-09-7

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    Dedicated to

    all our patients at

    The Tata Memorial Hospital

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    Contributors

    Dr. Jai Prakash Agarwal

    Dr. Ashwini BudrukkarDr. Naveen Balaiyya

    Dr. Abhishek Chatterjee

    Dr. Sayan Das

    Dr. Deepak D Deshpande

    Dr. Reena Engineer

    Dr. Lavanya G

    Dr. Tejpal Gupta

    Dr. Rakesh Jalali

    Ms. Swamidas V Jamema

    Dr. Sangeeta Kakoti

    Dr. Chira Ranjan Khadanga

    Dr. Nehal Khanna

    Dr. Rajesh Kinhikar

    Dr. Siddhartha Laskar

    Dr. Sarbani (Ghosh) Laskar

    Dr. Shirley Lewis

    Dr. Umesh MahantshettyDr. Renuka Masodkar

    Dr. Ashwathy Mathew

    Dr. Manu Mathew

    Dr. Vedang Murthy

    Dr. Rima Pathak

    Dr. Abhishek Puri

    Dr. Anupam Rishi

    Dr. Rajiv Sarin

    Dr. Jayant Goda Sastri

    Dr. Supriya Sastri

    Dr. Shyamkishore Shrivastava

    Dr. Monali Swain

    Dr. Anil Tibdewal

    Dr. Bhavin Visariya

    Dr. Tabassum Wadasadawala

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    Contents

    1 Evolution of Newer Radiation Techniques 12 Brain tumors 18

    3 Head and Neck Cancers 724 Thoracic tumors

    Lung 122Oesophagus 170

    5 Breast CancersNewer XRT techniques 195Brachytherapy 251

    6 Gynaecological CancersExternal Radiation 276Brachytherapy 300

    7 Urology CancersProstate Cancer 329Bladder Cancer 356

    8 Gastro-Intestinal Cancers

    Stomach 368Hepato-biliary tumors 376Hepatocellular Cancers 390Biliary Tract Cancers 400Rectum Canal 406Anal Canal 425

    9 Hematolymphoid tumors 432

    10 Pediatric Solid tumors 45311 Bone &Soft Tissue Sarcomas 477

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    Preface

    Practice of Evidence Based Medicine in Oncology allowsthe clinician to make important clinical decisions forimprovement in cancer care. It integrates the bestmedical research evidence with clinical expertise andpatient values.

    Radiation Oncology specialty has evolved from radiumera to the state-of-the-art radiation technology today.In last 2 decades, a revolution in radiation technology

    has lead to a change in Radiation Oncology practicetoday. The Modern Radiation Oncology practicemandates the use of newer imaging modalities,powerful treatment planning algorithms andautomated treatment delivery systems. The state-of-artradiation technologies namely, Intensity ModulatedRadiation Therapy (IMRT), VMAT, Image Based

    Brachytherapy etc. has been implemented in routineclinical practice for past 10-15 years. There is a majorthrust and emphasis on the use of these newer radiationtechniques for better therapeutic ratio in terms of betteroutcomes, minimizing toxicities and better quality oflife. With the advent of newer technology, stereotacticradio-surgery / radiotherapy and hypo-fractionated

    radiation for many cancers is being implemented. Also,these modern radiation techniques have rekindled newavenues for re-irradiation in some sites.

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    This is the 14thVolume on Evidence Based ManagementGuidelines brought out by Tata Memorial Centre

    represents the commitment of our institution toimplement uniform treatment strategies for canceracross India. With an improvement in survival in mostcancers, the emphasis has now shifted toindividualization of treatment and reduction intreatment related toxicities in this era of multi-disciplinary approach. The current volume addresses the

    best available evidence and potential research avenuesfor Modern Radiation Oncology Practice for all cancersites. Each chapter is dedicated to a specific cancer siteand covers evolution of radiation technology to itssuccessful implementation in clinical practice andgeneration of high level of current evidence. It alsoincludes in detail the hurdles in standardization of

    various processes, evidence in terms of clinical outcomeand toxicities, caveats and research avenues for highprecision radiation techniques.

    I hope this volume helps all the oncologists tounderstand and adopt Modern Radiation Oncologytechniques in their routine clinical practice to achieve

    excellent outcomes!

    R A Badwe

    February 2015 Director,

    Mumbai, India Director, Tata Memorial Centre

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    1

    Evolution of High PrecisionRadiation Technology

    IntroductionRadiation therapy (RT) has advanced dramatically andrapidly in the past few decades. From use of multileafcollimators, CT imaging for planning, 3D Conformaltreatment, Intensity modulated treatment (IMRT), Image

    guided treatment (IGRT), the list is endless. These advanceshave lead to innovations in physics dosimetry as well.Effectively it has resulted in precise dose delivery to thetarget and better sparing of critical organs. The goal ofradiotherapy is to deliver maximum possible dose to thetumour whilst sparing normal tissue. Technologicaladvances incorporating new imaging modalities, morepowerful computers and software, and new deliverysystems have helped to achieve this.

    Paradigm Shift from 2D to 3DCRT2D RT using rectangular fields based on plain X-ray imaginghas largely been replaced by 3D radiation therapy based

    on computed tomography (CT) imaging which allowsvolumetric delineation of the tumour and critical organstructures for optimal beam placement and shielding. This

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    lead to more critical definitions of target volumes viz. grosstumour volume (GTV), with a margin for microscopictumour extension called the clinical target volume (CTV),

    and a further margin uncertainties from organ motion andsetup variations called the planning target volume (PTV)etc.

    Coupled with these developments, the advent of MLCShas given a tool in hands of clinicians and physicists toconform the dose to above target volumes. Many organs

    are relatively sensitive to radiation damage (the spinal cord,salivary glands, lungs, and the eyes are common examples)and must be given special consideration duringradiotherapy treatment planning. Explicit field shaping ofthe beam with MLCs has become possible to reduce theamount of healthy tissue irradiated, and multiple beamsare used to lower the dose absorbed by tissue outside the

    target volume. This form of treatment popularly knownas 3DCRT has been an important landmark in evolution ofprecision therapy.

    IMRTIMRT allows creating irregular-shaped radiation fields thatconform to the target volume whilst simultaneouslyavoiding critical organs. The critical organs are givenconstraints to limit the dose through inverse planning.This requires much advanced computer assisted treatmentplanning systems. IMRT is made possible through:a) inverse planning software and b) computer-controlledintensity-modulation of multiple radiation beams during

    treatment. IMRT can be delivered by linear acceleratorswith static or dynamic multi-leaf collimators ortomotherapy machines using binary MLCs.

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    IMRT has become treatment of choice for almost all sitesand there are many studies, which have establishedsuperiority of IMRT against 3DCRT, mainly due to reduced

    dose to critical organs.

    Treatment planning algorithmsThe smarter and faster algorithms with more capabilitylike auto-contouring, smart segmentation and improveddose calculation have been developed. Algorithms for

    registration to approach towards adaptive radiotherapyand the dose calculation for accurate treatment deliveryare essential and desired features of TPS. The rigidregistration and deformable registrations play an importantrole in 3D and 4D planning. Calculations greatly differ inheterogeneous mediums or density changing zones.TPS algorithms in computing volumetric doses

    commercially available are: pencil beam convolution(Eclipse PBC), analytical anisotropic algorithm (EclipseAAA), AcurosXB (Eclipse AXB), FFT convolution (XiOConvolution), multigrid superposition (XiO Superposition),Collapsed cone convolution (Tomotherapy) and MonteCarlo photon (Monaco MC), etc.

    SRS/SRTStereotactic radiotherapy/radiosurgery treatment aremainly developed for brain cases. It employs small fieldtreatments with high dose per fraction in later case. SRS isused mainly for AVMS with a single fraction high dose oforder of 12-18 Gy. A stereotactic invasive frame is usedfor immobilization. The mechanical precision of themachine is very crucial for accurate delivery of thetreatment. SRT uses non invasive specialised thermoplastic

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    immobilization and is fractionated treatment. The planningsystem commissioning for small fields with miniature MLCsor cones should be very accurate. The margin around PTV

    with MLC is around 1-2 mm and same precision is expectedfrom the machine as well. The DICOM transfer of the planfrom treatment planning system to the machine needsspecial attention from quality assurance point of view.Generally other imaging modalities MRI and Angiographyare used in fusion with CT for better localization.Nowadays, with use of frameless SRS/SRT, IGRT plays animportant role.

    Hypofractionated Radiotherapy/SBRTStereotactic body radiation therapy (SBRT) involves thedelivery of a small/large number of ultra-high doses ofradiation with few fractions (usually 4-8) to a target volume

    using very advanced technology and has emerged as anovel treatment modality for cancer. The role of SBRT ismost important at two cancer stagesin early primarycancer and in oligometastatic disease. This modality hasbeen used in the treatment of early-stage non-small-celllung cancer, prostate cancer, renal-cell carcinoma, livercancer, and in the treatment of oligometastases in the

    lung, liver, and spine. The concept of delivering a singlehigh dose of radiation (as done with the Gamma Knifetechnology for brain malignancies) rather than multiplesmaller doses can be especially useful for patients withpainful cancers metastatic to the spine. Immediate painrelief is the goal and with the newer treatment planningdevices and treatment delivery machines it is possible to

    give a large single dose successfully without damage tothe nearby spinal cord.

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    Image Guided Radiotherapy (IGRT):IGRT is a technique, where, imaging is performed, withinthe treatment room, prior to radiotherapy to improve thegeometric accuracy of the delivery of radiation beam. It isa logical evolution arising from the ability to deliver highlyconformal dose through techniques such as IMRT, hypo-fractionated SRT, and charged particle therapy. Theseconformal techniques would not be as effective if therewere significant uncertainties in daily patient positionverification. The combination of highly conformal dosedistribution, and accurate daily targeting of the tumor leadsto the possibility of dose escalation while reducing thetreatment related morbidity. Geometric and dosimetricbenefits of IGRT have been reported for a variety of diseasesites including the prostate, head and neck , lung andliver.

    Techniques of IGRT: Traditionally surface and skin markswere used to direct the radiation beams, later on portalimaging came into existence. However, with theintroduction of 3D imaging capability, there are a widerange of techniques that are used for IGRT.

    CBCT: The most commonly used IGRT technique is theCone-Beam Computed Tomography (CBCT) through

    onboard kilovoltage systems on the currently availablelinear accelerators. With improvements in flat-paneltechnology, CBCT has been able to provide superior imagequality, and also allows for radiographic or fluoroscopicmonitoring throughout the treatment process. Typically,cone beam CT acquires many projections over the entirevolume of interest in each projection. Using the

    reconstruction algorithms, the 2D projections arereconstructed into a 3D volume analogous to the CTplanning dataset.

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    MVCT:Megavoltage Cone Beam CT is a technique to usemegavoltage beam of accelerator for getting images justbefore treatment. For getting better image however,

    megavoltage energy is reduced for this purpose. It hasbeen used in earlier accelerator models and now used inTomotherapy. 3MV energy is used for getting MV images.

    Ultrasound: US is useful for soft tissue visualizationespecially in breast and prostate cancer patients.

    Optical tracking: Optical tracking entails the use of a

    camera to relay positional information of objects withinits inherent coordinate system by means of a subset ofthe electromagnetic spectrum of wavelengths spanningultra-violet, visible, and infrared light. Optically trackedtools are then used to identify the positions of patientreference set-up points and these are compared to theirlocation within the planning CT coordinate system. Acomputation based on least-squares methodology isperformed using these two sets of coordinates todetermine a treatment couch translation that will result inthe alignment of the patients planned isocenter with thatof the treatment set up.

    MRI based IGRT systems: MRI-guided radiation therapy

    enables clinicians to see a patients internal anatomy inreal-time using continual soft-tissue imaging and allowsthem to keep the radiation beams on target when thetumor moves during treatment.

    Electromagnetic transponders: Electromagnetictransponder serve exactly the same clinical function as CBCT

    or kV X-ray, yet provide for a more temporally continuousanalysis of setup error analogous to that of the optical

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    tracking strategies although it is not an IGRT system perse.

    Correction StrategiesThere are two basic correction strategies used whiledetermining the most beneficial patient position and beamstructure: on-line and off-line correction. Both serve theirpurposes in the clinical setting, and have their own merits.Generally, a combination of the both strategies isemployed. Often, a patient will receive corrections to theirtreatment via on-line strategies during their first radiationsession, and subsequent adjustments off-line during checkfilm rounds.

    On-line: The On-line strategy makes adjustment to patientand beam position during the treatment process, basedon continuously updated information throughout the

    procedure. The on-line approach requires a high-level ofintegration of both software and hardware. The advantageof this strategy is a reduction in both systematic andrandom errors. Gold markers are implanted into theprostate to provide a surrogate position of the gland. Priorto each days treatment, portal imaging system results arereturned.

    Off-line:The Off-line strategy determines the best patientposition through accumulated data gathered duringtreatment sessions, almost always initial treatments. Thestrategy requires greater coordination than on-linestrategies. However, the use of off-line strategies doesreduce the risk of systematic error. The risk of random

    error may still persist.

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    Motion Management:Radiotherapy in the presence of intra-fraction organmotion causes blurring of the static dose distribution overthe path of the motion. This displacement results in adeviation between the intended and delivered dosedistributions. The impact of target motion in the thoracicand abdominal regions has been particularly importantdue to the respiratory motion and many organs at risk inthese regions.

    There are various methods to account for respiratorymotion in radiotherapy.

    Slow CT acquisition,

    Inhale and exhale breath-hold CT,

    Four dimensional or respiration-correlated CT.

    Respiratory gating methods:The motion can be managed by means of gated delivery.Respiratory gating involves the administration of radiation,during both imaging and treatment delivery within aparticular portion of the patients breathing cycle. Theposition and width of the gate within a respiratory cycleare determined by monitoring the patients respiratory

    motion, using either an external respiration signal orinternal fiducial markers. Since the beam is notcontinuously delivered, gated procedures are longer thannon-gated procedures.

    Gating using an external respiratory signal

    This device uses external markers for gating the radiationbeam however, it has x-ray imaging capabilities fordetermining the internal anatomy position and for verifying

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    the reproducibility of the internal anatomy duringtreatment.

    Gating using internal fiducial markers:The fiducials are implanted in or near the tumour using apercutaneous or bronchoscopic implanting technique.Fiducial position is tracked in all three dimensions severaltimes a second using a pair of stereotactic kilovoltagex-ray imaging systems in combination with automaticdetection software. When each fiducial is within anacceptable range of the desired (simulation) position forboth stereotactic x-ray cameras, the linear acceleratordelivers radiation.

    Gated IMRT:

    In this method, an arc (conventional gantry system) or

    continuous rotation (ring gantry system) is repeated whilegating the accelerator until the correct number of pulsesis delivered from each beam angle. The couch is stationaryuntil all beam pulses are delivered, then indexed to thenext position. The same technique can also be used withhelical delivery: the treatment helix would need to berepeated until all of the pulses for each angle had been

    delivered. The ability to quickly start and stop gantryrotation or patient breathing irregularity and otheruncertainties are still to be resolved.

    Volumetric Modulated Arc Therapy(VMAT)Despite the obvious benefits of IMRT, there are still somedisadvantages. IMRT plans use a larger number of monitorunits compared with conventional plans leading to an

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    increase in the amount of low dose radiation to the restof the body. The increase in MU and subsequent increasein low dose radiation has led to concerns of increased risk

    of secondary radiation-induced malignancies, which is ofparticular relevance in paediatric patients or patients withlong life expectancies. VMAT is a new radiation techniquethat combines the ability to achieve highly conformal dosedistributions with highly efficient treatment delivery. VMATwas first introduced in 2007 and described as a novelradiation technique that allowed the simultaneousvariation of three parameters during treatment delivery,i.e. gantry rotation speed, treatment aperture shape viamovement of MLC leaves and dose rate. The basic conceptof VMAT is the delivery of radiation from a continuousrotation of the radiation source and allows the patient tobe treated from a full 360 beam angle. The clinical

    worldwide use of VMAT is increasing significantly. Currentlythe majority of published data on VMAT are limited toplanning and feasibility studies, although there is emergingclinical outcome data in several tumour sites.

    Helical Tomotherapy (HT)As a modality for delivering rotational therapy, HT offers

    dosimetric advantages by combining a continuouslyrotating gantry with a binary multileaf collimator. HT,delivers intensity-modulated fan beams in a helical patternusing binary multileaf collimator leaves while the couch istranslated through the gantry. Helical tomotherapy offersthe possibility of treating a variety of casesfrom simpleto complexwith improved target conformality and OAR

    sparing compared with 3D or conventional static field IMRTplans, thereby allowing biologically effective dose

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    escalation. For precise irradiation and possible treatmentadaptation, the fully integrated on-board image-guidancesystem provides online volumetric images of patient

    anatomy using 3.5-MV x-ray beams and the xenoncomputed tomography detectors system.

    CyberKnife:The CyberKnife(CK) system uses the combination of arobotics and image guidance to deliver concentrated and

    accurate beams of radiation to intracranial and extracranialtargets, many of which are inoperable with sub- millimeteraccuracy. The robotic arm is highly flexible, allowing accessto tumors in difficult-to-reach locations. The CyberKnife,unlike other stereotactic radiosurgery systems, is able tolocate and track the position of the tumor without theuse of an invasive stereotactic head frame or stereotactic

    body frame. The system compensates for the patientsrespirations and movement during treatment, constantlyensuring accurate targeting for the delivery of radiationbeams. Unlike conventional SRT techniques, CK treatstumours throughout the body including the head, spine,lungs, prostate, liver, and pancreas. Current data havevalidated that it is a highly efficient radiotherapeutic

    modality for delivery of hypofractionated radiotherapy ina variety of clinical scenarios and sites, especially forpalliation with superior normal tissue sparing. Withavailable evidence, this system offers an invaluable solutionto the treatment of selective tumours/lesions located closeto critical structures, salvage of recurrent and metastaticlesions and potential of treatment of selective early stage

    malignancies like the carcinoma prostate and lung.However, it is still too premature, with insufficient follow

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    up data to advocate it as the treatment of choice in anyset up. There are several radiobiological issues that alsoremain in the gray zone.

    Flattening Filter Free (FFF) beams:Flattening Filter Free (FFF) X-ray beam has been in clinicaluse for quite some time. However, not until recently, theseFFF beams are used in limited, small field sizes, for example,in Tomotherapy and CyberKnife machines, However, FFF

    X-ray beams in conventional linacs have up to 40 X 40 cmfield sizes for both 6 and 10 MV X-rays. For large treatmentfields, the dose uniformity within an irradiated treatmentfield will need to be modulated by MLC movements tocut down the higher beam intensity near the centralportion of the FFF X-ray beam. Thus, larger MUs arerequired compared with a conventional (flattened) X-ray

    beam. Or, MLC movements (IMRT) are now being used toflatten the FFF X-rays to provide dose uniformity withinthose large PTVs. The high dose rates from the FFF X-raysare now being off-set by the larger MUs requirements.Therefore, FFF X-rays can bring clinical advantages overconventional X-rays when used with small field sizes, suchas in SBRT and/or SRS applications. The primary purpose

    of the FFF X-rays is to provide much higher dose ratesavailable for treatments. Commercially available FFF doserates are 1400 MU/minute for 6 MV X-rays and 2400 MU/minutes for 10 MV X-rays. Higher dose rates have definiteclinical benefits in organ motion management. Forexample, larger dose fractions can be delivered in a singlebreath-hold or gated portion of a breathing cycle. In SRS

    or SBRT treatments, large MUs are often required and FFFX-ray beams can deliver these large MUs in much shorter

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    beam-on time. With shorten treatment time, these FFFX-rays improve patient comfort and dose delivery accuracy.FFF X-ray beams may become one of the necessary

    equipment configurations for SBRT and/or SRS treatments,in the future.

    Brachytherapy:The brachytherapy has evolved tremendously over past fewdecades. In earlier days Radium needles/tubes were used

    for implanting in tumour and the doses were calculatedby various systems like Manchester, Paris. Stockholmderived from rich clinical experience and which were usedto deliver specified dose to the tumour fairly accurately inabsence of planning systems and any mode of visualizationof Implants & dose distributions. Later with developmentof various manual and after-loaded applicators and

    different Radium substitutes like Cs-137, Co-60, Ir-192large potential of brachytherapy were evident. High DoseRate (HDR) remote after-loading coupled with advancesin treatment planning systems has ensured well definedprotocols and methods for brachytherapy dose analysis.Recently use of imaging techniques for 3-D data acquisitionfor brachytherapy application, contouring and treatment

    planning has made significant contribution for precisebrachytherapy dose delivery.

    Conventional Simulator radiographs had been basic toolsfor TPS to input brachytherapy applicator & source data.Recently CT-Simulator has been used to input theapplicator data and 3-D reconstruction through direct

    images transfer by DICOM network. The CT & MRI arealso being used for contouring various volumes like target& clinical organs which coupled with 3-D planning

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    algorithms gives direct doses to critical organs with volumeanalysis. In case of intracavitary application MRI gives bettervisualization of soft tissue so that we can more clearly see

    the critical organs like bladder & rectum.

    American Brachytherapy Society (ABS) Image guidedBrachytherapy working group (IGBWG) have providedguidelines in reporting the image based brachytherapy,which recommends the prescription of dose to a volumerather than a point. Later GEC ESTRO published guidelines

    for the practice and reporting of image based ICA, whichhas been widely accepted so that a unified approach isformed among the users of image based brachytherapy.

    Hadron TherapyThe new and exciting development is use hadrons such asprotons and heavy ions (carbon) for radiotherapy. Proton

    beam therapy has the advantage that the proton beamgives up its maximum energy at end of its range in a smallarea known as the Bragg peak. This has advantages interms of normal tissue sparing, better dose homogeneity.The narrow brag peak is broadened by spreading it byvarying the energy of the beam to form a Spread OutBragg Peak (SOBP), which covers the target. The Carbonions have advantage of greater Relative BiologicalEffectiveness (RBE), which is very important characteristics.Intensity modulated proton therapy (IMPT) allows for themodulation of the fluence and the position of the Braggpeak, permitting three-dimensional dose distributions. Soit allows for the delivery of very high doses of radiation to

    the tumor with minimal side effects.

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    Dosimetry and Quality AssuranceThe advances in physics dosimetry include, advancesoftwares in radiation field analyzers, detector arrays (ionchamber based and diode based), in-vivo dosimetrysystems (diodes, MOSFETs, Gel dosimeters, opticallystimulated luminescence dosimeters (OSLD) etc). Thedevelopments in film dosimetry led to more recent andinstant readout from the Radiochromic films, which doesnot need development. Electronic portal imaging has

    played its important role in IGRT and dosimetry as well.EPID based dosimetry is used for patient specific dosimetryin IMRT and volumetric modulated arcs.

    In view of conforming targets and precise dose deliverypatient dose verification has assumed greater importance.There are several national and international organizationsplaying pivotal roles in patient dose verification. In UnitedStates, Radiologic Physics Center (RPC, USA) and RegionalCalibration Laboratories (RCLs) provides phantoms andTLDs with a benchmark case plan for advanced treatment-delivery techniques to be delivered at hospital end andcompare with standard. Advanced Technology IntegrationCommittee (ATIC) and American Association of Physicists

    in Medicine (AAPM) assist in standardizing the dosimetryprotocols through task group reports. Radiation TherapyOncology Group (RTOG) formulates clinical protocols fornewer treatment modalities and delivery techniques.EQUAL-ESTRO in Europe also issues certificate afterintercomparison for particular clinical projects.International Atomic Energy Agency (IAEA) conducts the

    inter-institutional thermo-luminescent dosimeter (TLD)comparison in order to facilitate the comparisons oftreatment protocols for better patient care. Bhabha Atomic

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    Research Center (BARC) in India is working towards thesame goal and conducts TLD intercomparison in thecountry.

    References:1. Purdie TG, Bissonnette JP, Franks K, et al. Cone-beam

    computed tomography for on-line image guidanceof lung stereotactic radiotherapy: localization,verification, and intrafraction tumor position. Int J

    Radiat Oncol Biol Phys 2007;68:243252.2. ICRU Repoat No. 50. Prescribing, recording and

    reporting photon beam therapy In: Landberg T.,Chavaudra J., Dobbs J., Hanks G., Johansson K.,Mooller T., Purdy J. editors. International Commissionon Radiation Units and Measurements, 1993.

    3. Lei Xing, Brian Thorndyke, Eduard Schreibmann,

    et.al. Overview of image-guided radiation therapy.Medical Dosimetry, Volume 31, Issue 2, Summer2006, Pages 91112

    4. Richard Potter, Christine Haie-Meder, Erik VanLimbergen et al. Recommendations fromgynaecolgical (GYN) GEC ESTRO working group (II):

    concepts and terms in 3D image based treatmentplanning in cervix cancer brachytherapy-3D dosevolume parameters and aspects of 3D image basedanatomy, radiation physics, radiobiology.Radiotherapy and Oncology, 78: 62-67, 2006.

    5. Followill DS, Kry SF, Qin L, Lowenstein J, Molineu A,Alvarez P, Aguirre JF, Ibbott GS.The Radiological Physics

    Centers standard dataset for small field size outputfactors. J Appl Clin Med Phys. 2012 Aug 8;13(5):3962.

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    Erratum in: J Appl Clin Med Phys. 2014;15(2):4757.PMID:22955664

    6. Fanning B.CBCTthe justification process, auditand review of the recent literature. J Ir Dent Assoc.2011 Oct-Nov;57(5):256-61. Review. PMID:22165476

    7. Glide-Hurst CK, Chetty Improving radiotherapyplanning, delivery accuracy, and normal tissue sparingusing cutting edge technologies. IJ. J Thorac Dis. 2014

    Apr;6(4):303-18. Review. PMID:246887758. Jaffray D, Kupelian P, Djemil T, Macklis RM. Review of

    image-guided radiation therapy. Expert Rev AnticancerTher. 2007 ;7:89-103.

    9. Teoh M1, Clark CH, Wood K, Whitaker S, Nisbet A.Volumetric modulated arc therapy: a review of currentliterature and clinical use in practice. See comment inPubMed Commons belowBr J Radiol. 2011 ;84:967-96.

    10. Sahani G, Sharma SD, Dash Sharma PK, DeshpandeDD, Negi PS, Sathianarayanan VK, et al. Acceptancecriteria for flattening filter-free photon beam fromstandard medical electron linear accelerator: AERB task

    group recommendations. J Med Phys 2014;39:206-11.

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    BRAIN TUMORS

    Introduction to Radiation therapy (RT) inNeuro-Oncology:Earch year 18,000 new brain tumor cases are registeredin India, accounting for 5% of all cancer cases in thecountry(1).Recent advances in imaging modalities likeMagnetic Resonance Imaging (MRI), Magnetic Resonance

    Spectroscopy (MRS), Perfusion, Bio-imaging andsimultaneous improvement in surgical techniques,radiation therapy delivery techniques as well as discoveryof better chemotherapeutic drugs have led to improvementin overall survival in these tumors. Brain tumors are broadlyclassified into paediatric and adult tumors since prognosisand management is different for these two groups. Till

    the last decade adult high grade gliomas (HGM) wereconsidered to have poor clinical outcome. However, theoutcomes are now improving (2,3)not only due to theabove advances in the multimodal treatment approachesbut also due to the incorporation of molecular profiling inthe treatment algorithm(4).

    Most paediatric brain tumors are low grade with goodlocal control and overall survival rates(5). Treating paediatrictumors with good prognosis is especially challenging where

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    the long term treatment related toxicities can bediscouraging. Modern radiotherapy technology is focusedat achieving optimal therapeutic gain (6).

    Surgery remains the mainstay of treatment for primarybrain tumors. However, adjuvant radiotherapy plays acrucial role in improving local control, progression freesurvival and overall survival rates for most intermediate tohigh grade tumors. Following maximal safe resection,adjuvant radiotherapy is indicated in all high-grade primary

    brain tumors. Following complete excision of benigntumors, like pituitary adenoma, Grade I meningiomas, lowgrade gliomas (LGM) etc., currently, there is no evidencefor benefit with adjuvant radiotherapy. However, adjuvantradiotherapy is indicated for macroscopic residual tumor,recurrence or progression. For tumors in the eloquentcortex where only a partial excision or biopsy is possible,

    radical radiotherapy improves outcome.With increasing overall survival (OS) there are concernsregarding treatment related morbidity, which includesneuropsychological impairment, endocrine dysfunction,growth retardation, risk of second malignancy andcerebrovascular events that can be attributed to both

    treatment and tumour effects. Although the exact role ofradiotherapy in the causation of these sequelae is not yetcompletely understood, it is fair to assume thatradiotherapy is at least partly responsible. Irradiated volumeis higher with conventional treatment portals whichpotentially causes increased morbidity. Combinedapproach of surgery and early chemotherapy, to delay or

    avoid Radiotherapy (RT), reduction in RT doses withconcurrent chemotherapy have been tried in very youngchildren with mixed outcomes (5). Possibility of reducing

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    volume of normal tissue irradiation with advance RTtechniques have gained popularity due to their potentialto save critical normal structures without compromising

    tumor control thereby reducing the long term sequelae (6)

    Evolution of radiotherapy techniques inNeuro Oncology

    What is the need for changing radiotherapytechnique from 2D to 3D?

    Two dimensional RT has been practised since the timewhen x-rays were discovered and put to use in thecancer therapy. It is still being extensively used inmajority of the centres across the world. However,with the evolution in both imaging and radiotherapytechnology, there is a shift in practise from 2D RT to3D-CRT.

    3-Dimensional Conformal techniques (3DCRT/IMRT)are capable of precisely targeting tumors whileavoiding normal structures. 3D planning and accuratedelivery of radiation dose to the target volume isimportant for CNS tumours as it has been shown toreduce late complications in long term survivors.

    Requirements for radiotherapy planning anddelivery in brain tumours:

    Positioning and Immobilization:

    Immobilization devices have two fundamentalroles: to provide a reliable means ofreproducibility of the patient position during the

    course of treatment and to immobilize thepatient during treatment to reduce motion.Proper positioning and good immobilization is

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    an essential prerequisite for precisionradiotherapy for brain tumours in order toachieve maximum benefit. Proper positioning

    with different head support systems are requiredfor brain tumour radiotherapy delivery. For e.g,Pituitary tumours, tumours in the frontal lobeand temporal lobe are treated with full flexionof the neck. Tumours in the high parietal region,posterior fossa are treated with neutral neckposition.

    Study from TMH between neck rest(NR) only andneck rest with flexion(NRF) showed that errorswere significantly higher in the AP direction withNRF when compared to NR-only (11).

    For craniospinal irradiation (CSI) pts werepreviously treated in prone position with

    thermoplastic moulds to immobilize head andneck. At present, with advanced techniques ofradiation delivery (IG-IMRT), supine position isused as there is no difference in target coverage,dose homogeneity and doses to OARs whencompaired with Vs prone position(12).

    Target volume delineation by incorporation offunctional imaging:

    11C Methionine positron emission tomography(MET-PET) has an improved specificity andsensitivity for high-grade gliomas (9, 13).

    Ga-DOTA TOC PET/CT shows increased sensitivityin cranial meningioma when compared with

    CE-MRI (14) and now this has been utilized intarget volume delineation for RT planning.

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    MET PET/MRI fusion demonstrates tumor infiltra-tion better as compared to MRI shows greyareas(15).

    Radiation necrosis can be better differentiatedfrom actual tumor progression with a higheraccuracy(13).

    Lee et al has shown association between highareas of uptake and local failure (16).

    Dose constraints:

    Lt Temporal lobe 13 % of the volume shouldreceive less than 43.2 Gy (17).

    Hippocampus: Dmedian

    < 7.8 Gy, D100% < 10Gy and D

    max< 15.3 Gy (18)

    The Quantitative Analysis of Normal Tissue Effectsin the Clinic (QUANTEC) review has given

    exhaustive normal tissue dose/volume toleranceguidelines

    Brainstem: Max dose should not go beyond54 Gy & 1% volume

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    setup uncertainty. The determination of the setupuncertainty prior to the initiation of radiation playsan important role in the treatment of CNS

    malignancies. Daily setup variation may be underrecognized and may have an adverse impact,including target under dose and normal structuresreceiving a higher dose than anticipated.

    Dose to critical structures can be affected bypatient motion during treatment and risk

    volumes based on patient motion arerecommended to accurately ascertain the doseadministered to normal tissues (19).

    Setup margin can be reduced using dailylocalization based on cone beam CT and it furtherhelps in reducing normal tissue exposure toradiation (20).

    Evidence about the efficacy of ModernRadiation Therapy Practice (General)

    Early toxicity: -

    RT is very well tolerated with modern conformal RTfor both localized fields and large fields such as CSI.

    Also concurrent chemo RT quite feasible in routinepractice with minimal interruption in radiotherapy.

    Modern conformal RT also gives an opportunity toplan and deliver full RT doses in standard fractionationeven in elderly patient population with moderatePS(ECOG2/3). This was not so much possible in 2Dera with cobalt 60 or in the era where WBRT wascommonly practiced.

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    Use of modern conformal techniques and precisionRT either with conventional IMRT or Tomotherapy inpatients with large field RT like CSI can be treated

    with minimum interruptions or the need for growthfactors/platelets support.

    Recent preliminary experiences in ultra high-precisionRT techniques of helical Tomotherapy and particletherapy have shown promise in further minimizingearly RT induced toxicties. Many of the patients need

    minimal or no dose of corticosteroids during RT formost of the gliomas and other benign brain tumours(21, 22).

    Even large field RT like CSI- Minimum need to interruptRT or need for growth factors/platelets

    50 pts of various histologies treated with vertebralbody sparing Proton CSI reported low incidence of

    haematological and GI toxicity. 5 pts developed grade 2 anorexia and 3 pts developed grade 3cytopenias (22). This incidence is lower as comparedto conventional CSI technique.

    In a retrospective review of acute toxicity of 40 ptstreated with conventional CSI and Proton CSI, Proton

    CSI resulted in a significant reduction in weight loss,grade II nausea and vomiting, oesophagitis, fewerfalls in blood counts (23).

    Fatigue during radiation therapy is an important issuewhich affects the quality of life of patients.

    Compared to photon, fatigue is reduced with protonand carbon ion (24).

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    Scalp sparing RT (Hair Loss) :

    Roberge et al has shown in a dosimetric studyusing IMRT that scalp sparing EBRT is feasible inbrain tumours (25).

    With the evolution of radiation deliverytechniques like VMAT and helical tomotherapyscalp sparing IMRT is achievable (26, 27).

    Late Toxicity-

    Quality of life: 62 children of posterior fossa brain tumors

    treated with conventional therapy and/orchemotherapy were evaluated for QOL at amedian follow up of 5.2 yrs showed a correlationbetween persistent hydrocephalus and largeventricular size to be significantly associated with

    reduction in QOL (28). In a longitudinal phase II prospective trial using

    proton beam therapy for LGG showed nochanges in QOL assessment over time (29).

    Neurocognition:

    Neurocognition is an important end point for

    evaluation and formulation of treatment strategiesin brain tumours. The morbidity of neurocognitivedeficits is experienced with varying severity by all braintumor patients, but their impact is diluted in highgrade brain tumor with poor survival. Patients withlow grade gliomas or benign brain tumors have agood overall survival and hence risk associated with

    treatment related long term toxicities need to beweighed against the benefit. Neurocognitive Function

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    (NCF) impairment is experienced due to a variety offactors like the tumor itself, location of the tumor,presenting symptoms like seizures, control of seizures

    with anti- epileptic medication, surgical treatment andits outcome on seizures, radiotherapy; its total dose,fraction size, treatment volumes and technique (30).

    Neurocognitive morbidity could be expressed indiverse forms like lack of attention, executivefunctioning, processing speed, working memory and

    they collectively contribute to declines in intellectualand academic abilities as reported by Linda et al in agroup of 65 patients of LGG (31). Not all patientswith brain tumors and especially children, with similardiagnoses and treatment, have identicalneurocognitive outcomes. Reliable predictive markersthat indicate poor outcomes need to be recognizedand a risk-adapted strategy, to preserve neuro-cognitive function and QOL must be adopted.

    Radiotherapy has shown to affect all the domains ofNCF. There are studies that have evaluated the impactof early adjuvant RT Vs delayed RT (at progression)after maximal safe resection in LGGs, the results differ.

    However most studies conclude that the decision ofwhether or not to irradiate should be individualizedand that whenever indicated early low dose RT isrecommended (32). Many studies have consistentlyshowed the impact of volume of irradiation on NCFdecline and hence it becomes important to use

    modern RT techniques to spare as much normal brainwherever possible (10). A new ongoing randomizedcontrolled trial ACNS 0331 is evaluating the impact

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    of reducing the treatment volume in CSI formedulloblastoma.

    A study by Raber et al suggested that the memorycomponent of NCF was affected by radiation tohippocampus (33). Subsequently many studiessuggested that avoiding high doses to hippocampuswhen delivering whole brain radiation was possibleusing IMRT and that delayed recall was better in thesepatients. Further prospective studies are needed to

    establish the dose constraints for hippocampus forwhole brain and partial brain radiation.

    Evidence for factors affecting neurocognition:

    WBRT: In a study of acute lymphoblasticleukaemia pts who received prophylactic cranialirradiation to dose of 24 Gy or 18 Gy, demonstra-ted that pts who have received 18 Gy were

    significantly better in FSIQ, Verbal IQ andPerformance IQ than 24 Gy and at same levelsas controls (34, 35)

    In a multicentric phase III randomized controlledtrial of 1-3 brain metastasis treated by surgery/radiosurgery was randomized between WBRT

    30Gy/10# and observation. HRQOL scores wereworse in WBRT as compared to observation. Thedifference between scores was more in earlyfollow up period (36).

    Focal RT photons: Use of radiotherapy carries asignificant risk for intelligence and informationprocessing in a study of 50 pts treated with

    conventional radiotherapy (37). Conformalradiation therapy preserved neurocognition scoreas compared to conventional RT(38).

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    Focal Proton therapy: 31 pts were prospectivelyfollowed up after proton therapy, mean FSIQ atBL and FU are 107 and 101, mean BL and FU

    VIQ 110 and 109, PIQ 106 and 102. Processingspeed dropped from 99.5 at BL to 85.2 at FU(p = 0.002)(39).

    CSI: Neuropsychological evaluation of 31 pts ofPF were retrospectively reviewed and showed thatlong term impairment occurred in most patents.

    Significant correlation between the full-scale IQscore (FSIQ) and the CSI dose was demonstrated.Also marked drop in verbal comprehension scoreswas noted in children who had received thehigher dose (40).

    Dose per fraction: Higher dose per fraction sizeof > 2Gy has detrimental effect on neuro-

    cognition(41), however even with 2 Gy/#neurocognitive effects were seen (31)

    Age: Young age at diagnosis of medulloblastomais the most significant predictor of worseoutcome despite reduction in dose and volume(42,43).

    Radiation volumes: In a study of 88 pts oflocalized ependymoma, total brain volume andsupratentorial brain volume significantlycorrelated with IQ (42).

    Surgical complications: Young high risk childrenof MB with posterior fossa syndrome have higherand earlier onset of neuro cognition (43,44).

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    Hippocampal sparing:

    Selective avoidance of hippocampus to avoid radiationinduced cognitive decline This is currently being tested ina prospective fashion for patients with good prognosis inbrain metastases.

    In a phase II (RTOG 0933)clinical trial of hippocampalsparing treated with WBRT to dose of 30 Gy/10#,LINAC based IMRT and IMRT tomotherapy plans weregenerated and demonstrated that target coverage

    and homogeneity was acceptable for both techniques.Helical tomotherapy spared the hippocampus, witha median and maximum dose of 5.5 Gy & 12.8 Gyrespectively while LINAC-based IMRT spared thehippocampus, with a median and maximum dose of7.8 Gy &15.3 Gy. Hippocampus volume was on anaverage 2% of planned brain volume (18).

    However, there is no current recommendation forsparing in gliomas since it has not been tested in anyclinical trial; it can be problematic if the glioma isclose to hippocampal structure. Therefore there is astrong case for inclusion of low grade gliomas.

    Study investigating the role of treatment margins,

    hippocampal avoidance and proton therapy inreducing neurocognitive deficits in 17 paediatricpatients of MB, showed that largest risk reductionwas with hippocampus sparing proton therapy andsmallest boost margin. Based on this studyhippocampus avoidance was best with proton therapyas compared to 3D CRT and IMRT(45).

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    Endocrine dysfunction:

    Irradiation to HPA axis during craniospinalirradiation can cause GH, ACTH and TSHdeficiencies which leads to morbidity that needsprolonged hormonal replacement therapy (46).

    Risk of hypothyroidism was similar in both 23.4Gy and 36 Gy of CSI in MB. Young age andchemotherapy correlated with higher incidenceof hypothyroidism (47).

    Merchant et al has shown endocrinopathies werepresent even before conformal radiation therapy(GH-24%) and 10 yr cumulative incidence of GH,thyroid hormone, ACTH and GnRH analogreplacement were 50%, 64%, 19.2% and 34.2%respectively(10).

    In a retrospective review of 24 pts of uncured

    cushings disease treated with CRT, 15 patientsunderwent remission, none of the patients hadrecurrence. New onset endocrine deficiencieswere seen in 8 (40%) patients (48).

    Ototoxicity :

    In a prospective observational study of 23 pts of

    medulloblastoma, the rate of high-gradeototoxicity was low (5%) and the sensitivity tolow frequencies was preserved. These ptsreceived cisplatin to mean cumulative dose of303mg/sq.m (49).

    Increased dose to cochlea was significantlyassociated with increasing ototoxicity and PF orTB boost with 3D CRT and IMRT technique canreduced the dose to cochlea and reduced theincidence of grade 3 or 4 ototoxicity.

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    In a prospective study of 60 patients treated withproton therapy, median dose to the cochlea was29.5 CGE (Standard Risk) and 41.6 CGE (High

    Risk). POG Grade 3 or 4 hearing deficit at baseline and follow up (mean 2.6 years) were 4.8%ears and 16.7% ears, respectively (39).

    Radiation Necrosis: 236 medulloblastoma pts werereviewed for the incidence of necrosis and after amedian follow up of 56 months, cumulative incidence

    of necrosis at 5 yrs was 3.7% 1.3% and 4.4% 1.5% for infratentorial tumor location. Volume ofinfratentorial brain receiving > 50Gy was predictiveof necrosis (50).

    Second Malignancy:

    Packer et al reported estimated cumulative 10-year incidence rate of secondary malignancies

    of 4.2% (1.9%6.5%) in MB after a medianfollow up of 5.8 years after diagnosis in whichmajority were CNS tumours (5).

    The use of proton radiation therapy was notassociated with a significantly increased risk ofsecondary malignancies compared with photon

    therapy (51). Role of modern radiation delivery techniques for Re-

    irradiation:

    In a retrospective study of 18 pts of recurrentependymoma who received reirradiation withconformal therapy (Radiosurgery and IMRT) todose of 54 Gy (focal/CSI), median durationbetween first and second radiation was 2.2 years.3yr OS rate was significantly better in reirradiated

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    Vs non-reirradiated (81% Vs 7%). Time to secondprogression after reirradiation was significantlylonger than time to first progression(52).

    In a single series of 172 pts of recurrent gliomafrom Germany, fractionated stereotacticreirradiation was given after a median durationof 48 months for LGG to a median dose of 30Gy. Median survival was 22 months for LGG afterreirradiation(53).

    38 pts of ependymoma who relapsed after amedian time of 16 months treated withreirradiation using different techniques(SRS, Focalconformal RT & CSI) experience local tumorcontrol however remain at risk of metastasis (54).

    Proton: Reirradiation for malignant brain tumorshas been tried with acceptable clinical outcomes

    and toxicity (55). SRS: In a retrospective review of 87 consecutive

    pts of recurrent high grade gliomas treated withradiosurgery. Dose of 18 Gy was delivered atmargins. Median survival after reirradiation was10 months (56).

    In a single institutional prospective study cohortof 114 pts of recurrent glioma treated with SRSusing Gamma Knife to a dose of 16 Gy prescribedto 50% isodose line. Median survival from timeof SRS was 26 months and 13 months for Gr IIIand Gr IVgliomas respectively (57).

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    Modern radiation therapy practices w.r.tto specific Brain Tumours

    Adult Low grade Glioma (Grade I/II,Oligoastrocytoma, Oligodendroglioma)

    Although the role of RT is established in low gradegliomas, its timing is quite debatable. Since thesurvival in these patients is long, there is high chanceof development of late toxicities. Hence the role ofconformal techniques such as 3D CRT and IMRT isessential to reduce late toxicities for e.g.neurocognition. However there are no randomizedtrials to compare the role of different conformaltechniques in terms of clinical outcome or late toxicity.

    Clinical outcome

    In a multicentric randomized controlled trial of

    adult LGG pts (EORTC 22845) between no RT Vsupfront RT (54Gy/30# arm),no significantdifference was seen in overall survival in boththe arms, however, progression free survival andseizure control was better in the upfront RTarm (58).

    In a randomized controlled trial of adult LGG ptsbetween 45Gy Vs 59.4Gy (EORTC 22844) treatedwith conventional/conformal techniques, nodifference in PFS (47% Vs 50%) and OS (58% Vs59%) was found after a median follow up of 74months (59).

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    Paediatric Low Grade Gliomas (PilocyticAstrocytoma, Ganglioglioma, DNET, PXA)

    Clinical Outcome:

    In a phase II trial of 78 paediatric pts treatedwith 3D-CRT using 1 cm CTV margin and MRIguidance demonstrated 87 % and 74% EFS rateand OS rate of 98.5 % and 96 % at 5 and 10 yrrespectively(60).

    Recent retrospective series of 39 paediatric pts

    treated with IMRT after resection or atprogression reported 8 yr PFS and OS rate of 78.2and 93.7 % respectively. This study used differentCTV margins to GTV and found CTV of 5 mm issufficient enough for achieving good outcomes.

    In a prospective study of 50 pts of LGG treatedwith SCRT at Dana Farber Cancer Institute, OSrate of 97.8 % & 82 % and PFS rate of 82.5 % &65 % at 5 yr and 8 yr respectively were reported(62).

    143 pts of grade II astrocytoma received FSRTand after a median follow up of 44 months, anactuarial OS rate of 58% and 50% at 5 and 8

    years respectively and improvement in QOL (KPSscore) for 53% of pts were reported (63).

    15 pts of optic pathway glioma reported byCombs et al shows PFS rate of 92% and 72%and OS rate of 100% and 90% respectively (64).

    In a single arm prospective trial of proton therapy

    of 20 pts, potential treatment toxicity andprogression-free survival was evaluated. After a

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    median follow up of 5.1 yrs intellectualfunctioning remained stable over time. No overalldecline in cognitive functioning was seen over

    time. The PFS rate at 3 years was 85%, but itdropped to 40% at 5 years (29).

    Late Toxicity:

    Merchant et al studied 78 pts using conformaltherapy and has shown that cognition waspreserved without compromising overall survival

    rate. Significant improvement in childs behaviorscore and visual auditory learning were seen.Decline in spelling scores was the only domainwhich had statistical significance. Patientsyounger than 5 yrs had greatest decline incognition (10).

    In the same above study, cumulative incidence

    of GH replacement and hearing loss at 10 yr was48.9% and < 6%, however 24% of pts had GHsecretion abnormality before CRT.

    In a prospective study of 32 children treated withprotons, it was observed that all the children hadpreserved Full Scale Intelligent Quotient without

    compromising PFS and OS.However, it wasobserved that a subgroup of children

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    Embryonal Tumours (MB, PNET, Germ CellTumour)

    Dosimetric data:

    Sharma et al compared dosimetrically CSI plansof 3DCRT, IMRT-LA and IMRT- Tomo and showedthat all plans achieved comparable DHI for PTVbrain and PTV spine, IMRT Tomo achieved thehighest mean DHI of 0.96. The IMRT Tomo planwas superior in terms of reduction of maximum,

    mean and integral doses to almost all organs atrisk (OARs) except low dose volume to OARs (66).

    Dosimetrically proton beam when comparedwith IMRT gives greatest reduction of dose to allnon-target areas at all dose levels (67,68).

    Gupta et al studied translational displacementof skull, upper spine and lower spine whilematching MVCT with planning CT ontomotherapy for 33 pts and suggested thatsmaller set-up margins maybe appropriate whileusing daily image-guidance with an onlinecorrection protocol as compared to marginsderived from strooms formula (69).

    Clinical Outcome: In a phase III trial of 421 pts of average risk

    disease delivered CSI to dose of 23.4Gy/13#followed by posterior fossa boost to dose of 32.4Gy/18 # to a dose per fraction of 1.8 Gy/day for5#/week. 10 yr EFS and OS were 75.8 % and81.3% respectively (5).

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    Hyperfractionated Radiation Therapy (HFRT):

    In a phase II trial, Carrie et al showed after amedian follow-up of 77.7 months, 6-year OS andEFS rates of 78% and 75% respectively withoutchemotherapy. Annual full scale IQ decline was2 points over a 6-year period (70). Similarly,Gupta et al after a median follow up of 33months showed, 3-year relapse-free survival andoverall survival of 83.5% and 83.2%, respectively.

    Cognitive functions tested for all domains werepreserved at 2 years post completion of HFRTwith no decline over time (7).

    In a phase I/II study of 15 non metastatic ptstreated with HFRT and adjuvant chemotherapy,95% PFS was demonstrated after a medianfollow up of 6.5 yrs (71).

    Hyperfractionated Accelerated Radiation therapy(HART):

    In a feasibility study of 34 metastaticmedulloblastoma pts, CSI was given to dose of39.68 Gy/32#/ twice daily with minimum of 8 hrinterval between 2 fraction followed by 22.32 Gy

    boost to the whole posterior fossa and 9.92 Gymetastatic boosts. Dose per fraction is 1.24 Gy.Median duration of HART was 34 days (range3138). 3 yr EFS and OS rate of 59% and 71%respectively was achieved after a median followup of 4.5 years (72).

    In another study of metastatic medulloblastoma

    of 33 pts pretreated with chemotherapy and thenwith hyperfractionation to dose of 39Gy/30# @

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    1.3Gy/# b.d followed by posterior fossa boostup to 60 Gy (1.5Gy/# b.d). Eight pts relapsedafter a median of 12 months and EFS, PFS and

    OS at 5 yrs were 70%, 72%, and 73%respectively(73).

    IMRT in Medulloblastoma

    Dosimetric data

    IMRT for CSI gives better dose homogeneity in thecraniospinal field. Moreover, the use of tomotherapy basedIMRT can abrogate the requirement of field junction shifts.There are no randomized studies comparing 2D RT vs IMRTfor CSI although there are small prospective dosimetricstudies showing excellent homogeneity in the craniospinalregion (74).

    Clinical Outcome

    There are no trials which have studied the clinical impactof IMRT in CSI. However, numerous prospective studieshave tried to investigate the role of tumour bed IMRT.These studies did not report any reduction in OS .Moreovernone of the studies have reported any increase in localfailure rates in the boost volumes (75).

    Protons in MedulloblastomaProtons for CSI is used only in limited centers whichhave protons facility.In view of its physical attributes,protons can give homogenous dose distribution withexcellent sparing of normal tissues.

    In a phase II prospective trial of 60

    medulloblastoma pts treated with proton RT. TheOS and PFS for the entire group is 87% and 81%.

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    3 yr OS and PFS for Standard risk was 90% and83% and for HR is 82% and 76% respectively(39).

    Jeminez et al reported outcome data of 15 ptstreated with proton and after a median followup of 39 months, 13 out of 15 were alive andfree of recurrence, one pt died of local failureand one from non-disease related. 13% patientsdeveloped grade 3 ototoxicity requiring hearingaids and 20% had grade 2 neuro-

    endocrinopathy. The IQ index remained stableduring follow-up testing in comparison tobaseline evaluation(76).

    Toxicity data:

    Conformal therapy in craniospinal irradiation usingIMRT either by conventional linacs or by tomotherapyhas led to reduction in radiation induced

    complications. Jose et al in a cohort of 18 pts treated with

    Tomotherapy based IMRT did not report anyincidence of radiation pneumonitis even after amedian follow up of 16.5 months (21).

    Huang et al retrospectively evaluated Pure Tone

    Audiometry of 113 pts treated with eitherconventional RT or IMRT. The reported incidenceof grade 3 or 4 hearing loss was 13 % in IMRTgroup compared to 64% in the conventional RTgroup.

    Ependymoma

    Dosimetry data: In a prospective study of 17 pts of ependymoma,

    dosimetric comparison was done between IMRT

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    with photons, 3D CRT with protons and IMRTwith protons. All normal structures doses wereless with protons when compared with photons

    and IMPT further reduced doses to moststructures. Target volume coverage wascomparable with all 3 techniques (77).

    Clinical Outcome:

    There are no randomized trials comparingdifferent techniques of radiation in

    ependymomas, however 3D CRT and IMRT haveshown improved overall survival and reducedlocal recurrences (60,78,79).

    A Phase II trial of 153 paediatric pts of localizedependymoma treated with conformal radiationtherapy showed a 7 yr LC, EFS and OS rate of83.7%, 69% and 81% after a median follow up

    of 5.3 years. Mean scores of all neurocognitiveoutcomes were stable when tested at or beyond24 months (60,78).

    In a retrospective study of 70 pts with localizedependymoma treated with proton therapy, 3 yearLC, PFS and OS rate was 83 %, 76 % and 95 %

    respectively. Mean Intelligence score and overalladaptive skills remained stable and few ptsdevelop hormonal dysfunction (80).

    Toxicity:

    A cohort of 123 patients treated with 3D CRT orIMRT at St jude hospital were assessed for IQand adaptive functioning till 5 yrs post treatment.Stable IQ and adaptive functioning was foundfor entire study period (81).

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    Hyper fractionation for Ependymoma

    Hyperfractionation with or withoutchemotherapy has also been tried to improvelocal control in a study of 63 consecutive children.5 yr OS and PFS for entire cohort was 75% &56% and 82% & 65% for those who receivedHFRT. This strategy did not improve local controlcompared to historical series (82).

    Benign Brain Tumours (Cranipharyngioma,

    Meningioma, Pituitary, Acoustic Neuroma) Dosimetric data:

    A dosimetric comparison between three differenttechniques, IMRT, 3D-PRT and IMPT was donewith dose prescription of 50.4 CGE at 1.8Gy/#with PTV coverage of 95% or better. Adequate

    PTV coverage was achieved by all modalities andproton therapy compared with IMRT deliveredlower integral dose to hippocampus,subventricular zone, dentate gyrus, vascular areasand rest of the brain (83).

    A dosimetric study of 14 patients compared IMRT,Double scatter proton (DSP) and IMPT techniquesand found that conformity Index and optic nervedose of IMPT plans were significantly better thanthose of the IMRT and DSP plans showed lowercochlear, optic chiasm, brain, and scanned bodydoses (84).

    Clinical Outcome:

    Craniopharyngioma: In a retrospective study of 40 pts treated

    with fractionated SCRT (FSRT), with a

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    median follow up of 98 months resultsshowed 100% local control and 89% OS at10 years. Most pts were treated atprogression after surgery (85).

    In another retrospective study of 55 ptstreated with FSRT, with a median follow upof 128 months results showed LC and OSat 20 yrs are 88.1% and 67.8% respectively.No difference in LC and OS was foundbetween pts treated upfront or atprogression (86).

    24 paediatric pts in a retrospective reviewtreated with IMRT to dose of 50.4 Gy,demonstrates 5 and 10 yr OS of 96% and83.8% and PFS of 65.8% & 60.7%respectively (87).

    Eighty eight children treated with CRT orIMRT at St. Jude Hospital, after a medianfollow up of 5 years demonstrate nodifference in PFS based on CTV margin of

    5mm or >5mm (88). 137 pts of residual or recurrent

    craniopharyngiomas treated with gammaknife radiosurgery (GKS) to a median doseof 12 Gy (range 9.5-16 Gy) at a medianisodose line of 55% (range 50%78%)

    demonstrated after a median follow up of45.7 months, tumor control rates of 72.7%,

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    73.9%, and 66.3% for the solid, cystic andmixed tumors, respectively. Overall survivalrates at 5 and 10 yr of 91.5% and 83.9%respectively (89).

    46 pts of residual or recurrentcraniopharyngiomas treated with GKS to amedian dose of 13Gy and after a meanfollow up of 62 months reported 5 yr OSand PFS rate of 97.1% and 91.6%respectively (90).

    Retrospective review of 52 children treatedwith IMRT or Proton therapy showed 3 yrOS of 96% and no difference in OS and localcontrol rates between treatment arms (91).

    10 pts were treated with combined photonand proton treatment with 2 fields byphoton and one or two field by proton perday. Total dose prescribed ranged from 53.4to 67.5 cobalt Gray equivalent (CGE) andmedian proton dose as part of the total dose

    was 26.9 CGE (47%). Actuarial 5 and 10year local control rates were 93% and 85%,respectively and actuarial 10-year survivalrate was 72%(92).

    Meningioma:

    In a retrospective review of 46 patients of

    meningioma treated with IMRT, localrecurrence occurred in 8 patients with 2 and

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    3 year actuarial LC of 92% and 74%,respectively. Results also showed low risk ofmarginal failure with reduced marginsafter IMRT treatment (93).

    46 patients treated with combination ofprotons and photons (59 CGE) atMassachusetts General Hospital (MGH),demonstrated overall survival of 95% and77% at 5 years and 10 years and localcontrol of 100% and 88% at 5 and 10 yearsrespectively (94).

    Pituitary:

    51 patients treated with protons to dose of60.6 CGE reported overall survival of 100%

    and local control of 98% at 4 years. 2/51patients developed Grade III toxicity andunilateral hearing loss with completepituitary deficiency (95).

    In a study of 47 pts treated with protons(54 CGE) and had at least 6 months of follow

    up showed 85% biochemical control rateand 40% hormonal normalization ratewithout significant morbidity (96).

    In a randomized trial of proton Vs carbon ion of260 pts of meningiomas, pituitary adenoma, LGGand HGG after median follow up of 12 months,no recurrences were found for meningiomas andlow grade gliomas. No severe late toxicities were

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    observed. Local recurrences were seen in highgrade tumours (97).

    Late Toxicity:

    In a prospective study of 22 pts, it was observedthat neuropsychological impairment andBarthels index were low even before starting RTand SCRT did not worsen it. It was concludedfrom the study that the above parameters mayhave been impaired due to surgical and tumour

    related factors even before the start of RT (98). In a single center randomized trial of 200 pts

    conducted at TMH, investigating betweenconventional RT and CRT using stereotacticguidance, low intelligence score was presentbefore treatment only. Intelligence score arebetter preserved in conformal arm at 2 yrs and 5yrs post treatment. Verbal quotient and memoryquotient are also better preserved at 5 yrs inconformal arm as compared to conventional arm(6).

    The observations of the study were as follows.

    Mean full IQ scale at baseline remained

    unchanged at 2 year follow up however onethird of patients did show a >10% declinein FSIQ (99).

    Patients aged 10% dropin FSIQ than older patients (53% Vs.

    10%)(100).

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    Dosimetric comparison in patients showinga >10% decline Vs 43.2 Gyto >13% of volume left temporal lobe werethe ones to show a significant drop in FSIQ(100).

    Hormonal dysfunction was present at initialdiagnosis in 42% pts of craniopharyngiomas andafter surgical intervention in 74% prior to IMRT

    indicating possible role of tumor and surgicalintervention(87).

    In a study by Lee et al ,Gamma knife surgery wasdone for craniopharyngiomas,new-onset orworsened pituitary deficiencies was seen in 11patients and smaller tumor volume was

    significantly associated with good outcome withSRS(89).

    High Grade Gliomas (grade III, IV)

    For primary high grade gliomas like anaplastic astrocytomasand glioblastomas, the standard radiation technique is 3D-CRT. The use of high precision techniques like IMRT is

    generally avoided in view of the highly infiltrative natureof these tumours as there is a higher chance of missingthe infiltrative component of the tumour.

    Dosimetric data:

    In a study of 58 patients of high grade gliomastreated with IMRT technique, dosimetric IMRT

    plans were compared with 3D-CRT plans. Therewas no observed difference between IMRT and3D-CRT in terms of target volume coverage and

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    this was irrespective of tumor location. However,in terms of normal tissue sparing, IMRT wasbetter than 3D CRT especially in reducing the

    maximum dose to the eyes, optic nerve and spinalcord (101).

    Clinical Outcome:

    There are no randomized studies conducted tilldate to compare the efficacy of IMRT over 3DCRT in high grade gliomas especially for GBM.

    However, the landmark randomized study ofstupp et al in which 573 patients of GBM wereenrolled compared the efficacy of conformal RTVs. Conformal RT+TMZ showed a clearimprovement in median OS in patients who havebeen treated with concurrent RT+TMZ. Themedian survival further improved in patients who

    were MGMT gene promoter methylators (3). Ina retrospective study of 31 pts of GBM treatedwith IMRT and concurrent TMZ was evaluatedand found median survival of 17.4 months forpts receiving 60 Gy which concurs with the dataof 14.6 months of Stupp et al (8). Based on theabove studies, it is evident that the clinical

    outcome is governed by the addition of TMZ toRT rather than the RT technique in glioblastomas.

    Hypofractionated RT in GBM

    In a prospective study of 25 pts treated withhypofractionated IMRT with helical Tomotherapyalong with TMZ in the radical setting, two dose

    levels 54.4Gy/20# and 60Gy/22# were delivered.Median OS and PFS were 15.6 and 6.7 monthsrespectively(102).

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    In a phase II trial of 24 pts treated withhypofractionated course of radiation (60Gy/10#)using IMRT along with concomitant and adjuvant

    temozolomide and after a median follow up of14.8 months, median overall survival was 16.6months (103).

    Dose escalation in high grade gliomas

    RTOG 9803 was a phase Ifeasability study whichlooked at radiation dose escalation along with

    BCNU in GBM patients (n=209) using 3D CRTand two PTVs. PTV1 (GTV+1.8 cm) received 46Gy/23# and PTV2 (GTV+0.3 cm) received 4 doselevels of 66, 72, 78 and 84 Gy. Patients weredivided into two groups based on the PTVvolumes. Group 1 consists of PTV 75 cc andGroup 2 PTV 75 cc. The final conclusion of the

    study did not show any improvement in clinicaloutcome in terms of OS with dose escalation.Moreover, acute toxicities did not increase withescalated doses, but late RT induced necrosisincreased with dose escalation although notstatistically significant (104).

    Dose escalation with IMRT to dose of 66-81Gyalong with temozolomide was tried in 38 pts ofGBM. No late toxicity of radiation necrosis wasobserved in pts receiving 75 Gy. Median OS andPFS were 20 and 9 months respectively(105).

    A randomized phase II study (CLEOPATRA),evaluating role of carbon ion boost 18 CGE in 6

    fractions at a single dose of 3 CGE) applied afterconcurrent RT+ Temozolomide versus a proton

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    boost (10 CGE in 5 single fractions of 2) afterConcurrent RT+ Temozolomide in patients withprimary glioblastoma has been initiated. This is

    the first such study which is looking at the roleof particle therapy in improving OS.Thesecondary endpoint of the study are PFS, toxicityand safety. Results are eagerly awaited.

    Late Toxicity

    In a prospective multi institutional trial of 252

    pediatric HGGs(COGL991 study) 54 childrenwith long term follow up of 15 years wereretrospectively evaluated for neuropsychological,behavioral and QOL. Intellectual functioning,executive functioning and verbal memory werewithin low average range. QOL was within orabove normal limits for both physical and

    psychosocial domains in approximately 75% ofpts (106).

    In EORTC trial, baseline HRQOL was comparablebetween RT alone Vs RT+TMZ arm. At 1stfollowup, Social functioning score was better in RTalone Vs TMZ arm (mean score 79 Vs 69.4). Atsubsequent follow up, HRQOL was samebetween treatment arms (107).

    In a phase II trial of 34 patients of HGG treatedusing conformal therapy, baseline and serialevaluation of neurocognition were performed.40% of patients had IQ score of less than 85before CRT. Intelligence quotient decreased from

    baseline to 6 months and then increased slightlyat 12 months. However adaptive functioning

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    decreased significantly from baseline till 12months (108).

    SRS and Brachytherapy in HGG

    A randomized trial for malignant astrocytomabetween EBRT followed by brachytherapy boostwith temporary stereotactic Iodine125 implantdelivering dose upto 60Gy Vs EBRT 50Gy/25#has shown no improvement in survival (109).

    A prospective randomized study for GBM pts

    (RTOG 9305) investigating the role of SRSfollowed by EBRT+Carmustine Vs. EBRT+Carmu-stine failed to show any survival benefit. However,one must keep in mind that the study wasconducted even before TMZ was introduced intothe clinics (110).

    GiloSite involves the use of an expandableballoon filled with radioactive I125 and is placedduring tumour debulking. Its an active area ofinvestigation by Brain Tumour Therapy CentralNervous System Consortium that involves deliveryof 40-60Gy to the target volume in recurrentdisease.

    IORT for HGGIORT delivers high doses of electrons (Giordano FA)or low energy X-rays to the tumor bed wheremaximum recurrences are known.

    INTRAGO is a phase I/II dose escalation study ofIORT delivered with low energy X rays by spherical

    applicators. Primary end point is evaluation ofmaximum tolerated dose and secondaryendpoint is PFS and OS.

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    Stem Cell Niches in GBM

    Neural progenitor cells (stem cells) are thought to bepresent in the subventricular zones (SVZ) that areproposed to promote tumorigenesis. These cells canmigrate out through their niches leading toprogressive disease. It has been proposed thatirradiation of niches in the SVZ may influence survivaloutcomes.

    Gupta et al have analyzed dose-volume

    parameters to the SVZ that correlate with survivaloutcomes in GBM. Older age (>50 years), poorRPA class, and higher than median of meancontralateral SVZ dose were associated withsignificantly worse PFS and OAS. Multivariateanalysis identified RPA class, KPS and meanipsilateral SVZ dose as independent predictors

    of survival. The authors have observed thatincreasing mean dose to the ipsilateral SVZ wasassociated with significantly improved OAS(111).

    How robust is the evidence for modern radiotherapytechniques in Brain tumours.

    In general the evidence for using IMRT in brain

    tumours is at level II or III. For benign tumourss, LGG and ependymoma a

    single center large randomized trial from TMC,Mumbai comparing efficacy of stereotacticconformal radiotherapy (SCRT) versusconventional RT in children and young adultsTMC ( SCRT trial: NCT00517959) is expected to

    report its final results shortly.

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    For high grade gliomas: The role of using 3DCRTis established. However the role of IMRT isdebatable with the evidence level at III/IV.

    CONCLUSION:Evidence supports a clear advantage of conformaltechniques like IMRT/IGRT in benign brain tumours, lowgrade gliomas and in CSI in term of outcome and betterlate profile (mainly late) translating into better QoL. Focalconformal radiotherapy with 3D-CRT for high gradegliomas is a standard practice all over the world, althoughthere is weak evidence for the usage of IMRT in high gradegliomas and should be used with great caution due tothe infiltrative nature of these tumours. In the presentscenario, IMRT should always be complemented withimage guidance (IG-IMRT). Finally, practising high-precision

    radiotherapy in brain tumours, needs a clear perspectiveand rationale on the part of the treating clinician especiallyin a country like India where the teledensity is quite low.

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