New Techniques in Radiotherapy

Slide 1: New Techniques in Radiation therapy Moderator: Dr S C Sharma Department of Radiotherapy PGIMER Chandigarh

Slide 2: Trends Number of Publications in Google Scholar 2000 1750 1500 1250 1000 750 500 250 0 1990 1995 2000 2005 3 DCRT IMRT IGRT

Slide 3: Overview 3 DCRT IMRT Teletherapy Tomotherapy IGRT DART Gamma Knife Radiation Stereotactic radiotherapy LINAC based Therapy Cyberknife Image Assisted Brachytherpy Brachytherapy Electronic Brachytherapy

Slide 4: Solutions ? Electrons Protons Neutrons Use alternative radiation Develop technologies to circumvent limitations modalities π- Mesons Heavy Charged Nuclei Antiprotons

Slide 5: Development Timeline Takahashi discusses conformal RT 1950 1st MLCs invented (1959) Proimos develops gravity oriented 1960 blocking and conformal field shaping Tracking Cobalt unit invented 1970 at Royal Free Hospital 1st inverse planning algorithm Brahame conceptualized inverse planning 1980 developed by Webb (1989) & gives prototype algorithm for (1982-88) Boyer and Webb develop Carol demonstrates NOMOS MiMIC (1992) principle of static IMRT (1991) Tomotherapy developed in Wisconsin (1993) 1990 Stein develops optimal dMLC equations (1994) First discussion of Robotic IMRT (1999)

Slide 6: Modulation: Examples Wedge: Block: Uniform Modulation Binary Modulation Fine spatial Coarse spatial and coarse intensity Coarse intensity Fine Spatial and Fine Intensity modulation

Slide 7: Conformal Radiotherapy Conformal radiotherapy (CFRT) is a technique that aims to exploit the potential biological improvements consequent on better spatial localization of the high- dose irradiation volume - S. Webb in Intensity Modulated Radiotherapy IOP

Slide 8: Problems in conformation Nature of the photon beam  is the biggest impediment Has an entrance  dose. Has an exit dose.  Follows the inverse  square law.

Slide 9: Types of CFRT Two broad subtypes :  Techniques aiming to  employ geometric fieldshaping alone Techniques to modulate  the intensity of fluence across the geometrically- shaped field (IMRT)

Slide 10: Modulation : Intensity or Fluence ? Intensity Modulation is a misnomer – The actual term is  Fluence Fluence referes to the number of “particles” incident on an  unit area (m-2)

Slide 11: How to modulate intensity Cast metal compensator  Jaw defined static fields  Multiple-static MLC-shaped fields  Dynamic MLC techniques (DMLC)  including modulated arc therapy (IMAT) Binary MLCs - NOMOS MIMiC and in  tomotherapy Robot delivered IMRT  Scanning attenuating bar  Swept pencils of radiation (Race Track  Microtron - Scanditronix)

Slide 12: Comparision

Slide 13: MLC based IMRT √

Slide 14: Step & Shoot IMRT Since beam is interrupted between  movements leakage radiation is less. Easier to deliver and plan.  More time consuming  Intesntiy Distance

Slide 15: Dynamic IMRT Faster than Static IMRT  Smooth intensity modulation  acheived Beam remains on throughout –  leakage radiation increased More susceptible to tumor  motion related errors. Additional QA required for MLC  motion accuracy. Intesntiy Distance

Slide 16: Caveats: Conformal Therapy Significantly increased expenditure:  Machine with treatment capability  Imaging equipment: Planning and Verification  Software and Computer hardware  Extensive physics manpower and time required.  Conformal nature – highly susceptible to motion and setup related  errors – Achilles heel of CFRT Target delineation remains problematic.  Treatment and Planning time both significantly increased  Radiobiological disadvantage:  Decreased “dose-rate” to the tumor  Increased integral dose (Cyberknife > Tomotherapy > IMRT) 

Slide 17: 3D Conformal Radiation Planning

Slide 18: How to Plan CFRT Patient positioning Volumetric Data Image Transfer and Immobilization acqusition to the TPS Target Volume Delineation Treatment Delivery Treatment QA Forward Planning Inverse Planning Dose distribution 3D Model Analysis generation

Slide 19: Positioning and Immobilization Two of the most important aspects of conformal radiation  therapy. Basis for the precision in conformal RT  Needs to be:  Comfortable  Reproducible  Minimal beam attenuating  Affordable  Holds the Target in place while the beam is turned on

Slide 20: Types of Immobilization Invasive Frame based Noninvasive Immoblization devices Frameless Usually based on a combination of heat deformable ➢ “casts” of the part to be immobilized attached to a baseplate that can be reproducibly attached with the treatment couch. ➢The elegant term is “Indexing”

Slide 21: Cranial Immobilization BrainLab System TLC System Leksell Frame Gill Thomas Cosman System

Slide 22: Extracranial Immobilization Body Fix system Elekta Body Frame

Slide 23: Accuracy of systems System Techniqe Setup Accuracy Noninvasive Non invasive, 0.7– 0.8 mm (± 0.5–0.6 mm) Stereotactic frame mouthpiece Non invasive, x = 1.0 mm ± 0.7; y= 0.8 mm ± 0.8; z = 1.7 Latinen Frame nasion, earplugs mm ± 1.0 Non invasive, X = 0.35 mm ± 0.06; Y = 0.52 mm ± 0.09; GTC Frame mouthpiece Z= 0.34 mm ± 0.09 Stereotactic Body Non invasive, X = 5 – 7 mm ,Y = 1 cm Z = 1.0 cm (mean) Frame vacccum based Non invasive, Heidelberg frame X = 5 mm,Y = 5 mm, Z = 10 mm (mean) vaccum based Non invasive, X = 0.4 ± 3.9 mm , Y = 0.1 ± 1.6 mm Z = 0.3 Body Fix Frame Vacccum based ± 3.6 mm. Rotation accuracy of 1.8 ± 1.6 with plastic foil degrees. With the precision of the body fix frame the target volume will be underdosed (< 90% of prescribed dose) 14% of the time!!!

Slide 24: CT simulator 70 – 85 cm bore  Scanning Field of View (SFOV) 48 cm –  60 cm – Allows wider separation to be imaged. Multi slice capacity:  Speed up acquistion times  Reduce motion and breathing artifacts  Allow thinner slices to be taken – better  DRR and CT resolution Allows gating capabilities  Flat couch top – simulate treatment  table

Slide 25: MRI Superior soft tissue resolution  Ability to assess neural and marrow infiltration  Ability to obtain images in any plane - coronal/saggital/axial  Imaging of metabolic activity through MR Spectroscopy  Imaging of tumor vasculature and blood supply using a new  technique – dynamic contrast enhanced MRI No radiation exposure to patient or personnel 

Slide 26: PET: Principle Unlike other imaging can  biologically characterize a leison Relies on detection of photons  liberated by annhilation reaction of positron with electron Photons are liberated at 180° angle  and simultaneously – detection of this pair and subsequent mapping of the event of origin allows spatial localization The detectors are arranged in an  circular array around the patient PET- CT scanners integrate both  imaging modalities

Slide 27: PET-CT scanner PET scanner Flat couch top insert CT Scanner 60 cm Allows hardware based registration as the patient is scanned in the  treatment position CT images can be used to provide attenuation correction factors for the  PET scan image reducing scanning time by upto 40%

Slide 28: Markers for PET Scans Metabolic marker  2- Fluoro 2- Deoxy Glucose 18  Proliferation markers  Radiolabelled thymidine: F 18  Fluorothymidine Radiolabelled amino acids: C Methyl 11  methionine, 11C Tyrosine Hypoxia markers  Cu-diacetyl-bis(N-4- 60  methylthiosemicarbazone) (60Cu- ATSM) Apoptosis markers  Technicium Annexin V 99  m PET Fiducials

Slide 29: Image Registration Technique by which the coordinates of identical points in  two imaging data sets are determined and a set of transformations determined to map the coordinates of one image to another Uses of Image registration:  Study Organ Motion (4 D CT)  Assess Tumor extent (PET / MRI fusion)  Assess Changes in organ and tumor volumes over time  (Adaptive RT) Types of Transformations:  Rigid – Translations and Rotations  Deformable – For motion studies 

Slide 30: Concept

Slide 31: Process: Image Registration The algorithm first measures the degree of mismatch between  identical points in two images (metric). The algorithm then determines a set of transformations that  minimize this metric. Optimization of this transformations with multiple iterations take  place After the transformation the images are “fused” - a display which  contains relevant information from both images.

Slide 32: Image Registration

Slide 33: Target Volume delineation The most important and most error prone step in  radiotherapy. Also called Image Segmentation  The target volume is of following types:  GTV (Gross Target Volume)  CTV (Clinical Target Volume)  ITV (Internal Target Volume)  PTV (Planning Target Volume)  Other volumes:  Targeted Volume  Irradiated Volume  Biological Volume 

Slide 34: Target Volumes GTV: Macroscopic extent of the tumor as defined by  radiological and clinical investigations. CTV: The GTV together with the surrounding microscopic  extension of the tumor constitutes the CTV. The CTV also includes the tumor bed of a R0 resection (no residual). ITV (ICRU 62): The ITV encompasses the GTV/CTV with an  additional margin to account for physiological movement of the tumor or organs. It is defined with respect to a internal reference – most commonly rigid bony skeleton. PTV: A margin given to above to account for uncertainities  in patient setup and beam adjustment.

Slide 35: Target Volumes

Slide 36: Definitions: ICRU 50/62 GTV CTV Treated Volume: Volume of the  tumor and surrounding normal ITV tissue that is included in the isodose surface representing the irradiation dose proposed for the treatment TV (V95) Irradiated Volume: Volume  included in an isodose surface with PTV a possible biological impact on the IV normal tissue encompassed in this volume. Choice of isodose depends on the biological end point in mind.

Slide 37: Example PTV CTV GTV

Slide 38: Organ at Risk (ICRU 62) Normal critical structures whose  radiation sensitivity may significantly influence treatment planning and/or prescribed dose. A planning organ at risk volume  (PORV) is added to the contoured organs at risk to account for the same uncertainities in patient setup and treatment as well as organ motion that are used in the delineation of the PTV. Each organ is made up of a  functional subunit (FSU)

Slide 39: Biological Target Volume A target volume that  incorporated data from molecular imaging techniques Target volume drawn  incorporates information regarding: Cellular burden  Cellular metabolism  Tumor hypoxia  Tumor proliferation  Intrinsic Radioresistance or  sensitivity

Slide 40: Biological Target Volumes Lung Cancer:  30 -60% of all GTVs and PTVs are changed with PET.  Increase in the volume can be seen in 20 -40%.  Decrease in the volume in 20 – 30%.  Several studies show significant improvement in nodal  delineation. Head and Neck Cancer:  PET fused images lead to a change in GTV volume in 79%.  Can improve parotid sparing in 70% patients. 

Slide 41: 3 D TPS Treatment planning systems are complex computer systems  that help design radiation treatments and facilitate the calculation of patient doses. Several vendors with varying characteristics  Provide tools for:  Image registration  Image segmentation: Manual and automated  Virtual Simualtion  Dose calculation  Plan Evaluation  Data Storage and transmission to console  Treatment verification 

Slide 42: Planning workflow Total Dose Total Time of delivery of dose Define a dose objective Total number of fractions Organ at risk dose levels Choose Number of Beams Choose beam angles and couch angles Choose Planning Technique Forward Planning Inverse Planning

Slide 43: “Forward” Planning A technique where the planner will try a variety of  combinations of beam angles, couch angles, beam weights and beam modifying devices (e.g. wedges) to find a optimum dose distribution. Iterations are done manually till the optimum solution is  reached. Choice for some situations:  Small number of fields: 4 or less.  Convex dose distribution required.  Conventional dose distribution desired.  Conformity of high dose region is a less important concern. 

Slide 44: Planning Beams Digital Composite Beams Eye View Radiograph Display Room's Eye View

Slide 45: “Inverse” Planning Inverse Planning 1. Dose distribution specified Forward Planning 3. Beam Fluence modulated to recreate 2. Intensity map created intensity map

Slide 46: Optimization Refers to the technique of finding the best physical and  technically possible treatment plan to fulfill the specified physical and clinical criteria. A mathematical technique that aims to maximize (or  minimize) a score under certain constraints. It is one of the most commonly used techniques for inverse  planning. Variables that may be optimized:  Intensity maps  Number of beams  Number of intensity levels  Beam angles  Beam energy 

Slide 47: Optimization

Slide 48: Optimization Criteria Refers to the constraints that need to be fulfilled during the  planning process Types:  Physical Optimization Criteria: Based on physical dose coverage  Biological Optimization Criteria: Based on TCP and NTCP  calculation A total objective function (score) is then derived from these  criteria. Priorities are defined to tell the algorithm the relative  importance of the different planning objectives (penalties) The algorithm attempts to maximize the score based on the  criteria and penalties.

Slide 49: Multicriteria Optimization Intestine Sliders for adjusting EUD Bladder DVH display Rectum PTV GTV

Slide 50: Plan Evaluation Differential DVH Cumulative DVH Colour Wash Display

Slide 51: Image Guided Radiotherapy and 4D planning

Slide 52: Why 4D Planning? Organ motion types: Types of movement:   Interfraction motion Translations:   Intrafraction motion Craniocaudal   Lateral Even intracranial structures   Vertical can move – 1.5 mm shift  when patient goes from Rotations:  sitting to supine!! Roll  Pitch  Yaw  Shape:  Flattening  Balloning  Pulsation 

Slide 53: Interfraction Motion Prostate: Rectum:   Motion max in SI and AP Diameter: 3 – 46 mm   SI 1.7 - 4.5 mm Volumes: 20 – 40%   AP 1.5 – 4.1 mm In many studies decrease   in volume found Lateral 0.7 – 1.9 mm  Bladder:  SV motion > Prostate  Max transverse diameter Uterus:   mean 15 mm variation SI: 7 mm  SI displacement 15 mm  AP : 4 mm  Volume variation 20% -  Cervix: 50%  SI: 4 mm 

Slide 54: Intrafraction Motion Liver: Lung:   Normal Breathing: 10 – 25 Quiet breathing   mm AP 2.4 ± 1.3 mm  Deep breathing: 37 – 55 mm Lateral 2.4 ± 1.4 mm   Kidney: SI 3.9 ± 2.6 mm   2° to Cardiac motion: 9 ± 6  Normal breathing: 11 -18  mm lateral motion mm Tumors located close to the  Deep Breathing: 14 -40 mm  chest wall and in upper lobe Pancreas: show reduced interfraction  motion. Average 10 -30 mm  Maximum motion is in  tumors close to mediastinum

Slide 55: IGRT: Solutions Imaging techniques USG based Video based Planar X-ray CT MRI BAT AlignRT ● ● ●Sonoarray ●Photogrammetry Fan Beam Cone Beam ●I-Beam ●Real Time Video guided ●Resitu IMRT Tomotherapy ● ●Video substraction ●In room CT MV CT KV CT Mobile C arm Siemens ● ● KV X-ray OBI ●Varian OBI ●Elekta ●Siemens Inline Gantry Mounted Room Mounted MV X-ray Varian OBI EPI Cyberknife ● ● ● ●Elekta Synergy ●RTRT (Mitsubishi) ●IRIS ●BrainLAB (Exectrac)

Slide 56: IGRT: Solution Comparision DOF = degrees of freedom – directions in which motion can be corrected – 3 translations and 3 rotations

Slide 57: EPI Uses of EPI:  Correction of individual interfraction errors  Estimation of poulation based setup errors  Verification of dose distribution (QA)  Problems with EPI:  Poor image quality (MV xray)  Increased radiation dose to patient  Planar Xray – 3 dimensional body movement is not seen  Tumor is not tracked – surrogates like bony anatomy or  implanted fiducials are tracked.

Slide 58: Types of EPID Liquid Matrix Ion Chamber*  Camera based devices  Amorphous silicon flat panel detectors  Amorphous selenium flat panel detectors  Electrode High voltage applied connected to high voltage “Output” Output read out ionized liquid Liquid 2,2,4 - electrode by the lower trimethylpentane electrodes

Slide 59: On board imaging Intensifier Gantry mounted OBI KV Xray Room Mounted OBI

Slide 60: 4 D CT acqusition Axial scans are acquired with the use of a RPM camera attached to couch. The “cine” mode of the scanner is used to acquire multiple axial scans at predetermined phases of respiratory cycle for each couch position

Slide 61: RPM System Patient imaged with the RPM system to ascertain baseline motion profile A periodicity filter algorithm checks the breathing periodicity Breathing comes to a rythm Breathing cycle is recorded

Slide 62: 4D CT Data set Normal

Slide 63: Problems with 4 D CT The image quality depends on the reproducibility of the  respiratory motion. The volume of images produced is increased by a factor of  10. Specialized software needed to sort and visualize the 4D  data. Dose delivered during the scans can increase 3-4 times.  Image fusion with other modalities remains an unsolved  problem

Slide 64: 4D Target delineation Target delineation can be done on all images acquired.  Methods of contouring:  Manual  Automatic (Deformable Image Registration)  Why automatic contouring?  Logistic Constraints: Time requirement for a single  contouring can be increased by a factor of ~ 10. Fundamental Constraints:  To calculate the cumulative dose delivered to the tumor during  the treatment. However the dose for each moving voxel needs to be integrated  together for this to occur. So an estimate of the individual voxel motion is needed. 

Slide 65: 4D Manual Contouring The tumor is manually contoured in end expiration and end  inspiration The two volumes are fused to generate at MIV – Maximum  Intensity Volume The projection of this to a DRR is called MIP (Maximum  Intensity Projection) End Inspiration MIV End Expiration

Slide 66: Automated Contouring Technique by which a single moving voxel is matched on CT  slices that are taken in different phases of respiration The treatment is planned on a reference CT – usually the  end expiration (for Lung) Matching the voxels allows the dose to be visualized at each  phase of respiration Several algorithms under evaluation:  Finite element method  Optical flow technique  Large deformation diffeomorphic image registration  Splines thin plate and b 

Slide 67: Automated Contouring Movement vectors

Slide 68: Automated Contouring Individaul Pixels + = Day 1 Image Day 2 Image Due to the changes in shape of the object the same pixel occupies a different coordinate in the 2nd image Deformable Image registration circumvents this problems

Slide 69: 4D Treatment Planning A treatment plan is usually  generated for a single phase of CT. The automatic planning  software then changes the field apertures to match for the PTV at each respiratory phase. MLCs used should be aligned  parallel to the long axis of the largest motion.

Slide 70: Limitations of 4D Planning Computing resource intensive – Parallel calculations require  computer clusters at present No commercial TPS allows 4 D dose calculation  Respiratory motion is unpredictable – calculated dose good  for a certain pattern only Incorporating respiratory motion in dynamic IMRT means  MLC motion parameters become important constraints Tumor tracking is needed for delivery if true potential is to  be realized The time delay for dMLC response to a detected motion  means that even with tracking gating is important

Slide 71: 4D Treatment delivery Options for 4D delivery Ignore motion Freeze the motion Follow the motion (Tracking) Patient breaths normally Breathing is controlled Respiratory Gating Breath holding (DIBH) Jet Ventilation Active Breathing control

Slide 72: Minimizing Organ Motion Abdominal Compression(Hof Breath Hold technique:   et al. 2003 – Lung tumors): Patients instructed to hold  breath in one phase Cranio-caudal movement of  tumor 5.1±2.4 mm. Usually 10 -13 breath holding  sessions tolerated (each 12 -16 Lateral movement 2.6±1.4  sec) Anterior-posterior  Reduced lung density in movement 3.1±1.5 mm  irradiated area – reduced volume of lung exposed to high dose Tumor motion restricted to 2-3  mm (Onishi et al 2003 – Lung tumors)

Slide 73: Minimizing Organ Motion Active Breathing Control  Consists of a spirometer to “actively” suspend the patients  breathing at a predetermined postion in the respiratory cycle A valve holds the respiratory cycle at a particular phase of  respiration Breath hold duration : 15 -30 sec  Usually immobilized at moderate DIBH (Deep Inspiration Breath  Hold) – 75% of the max inspiratory capacity Max experience: Breast  Intrafractional lung motion reduced  Mean reproducibility 1.6 mm 

Slide 74: Tracking Target motion Also known as Real-time Postion Management respiratory  tracking system (RPM) Various systems:  Video camera based tracking (external)  Radiological tracking:  Implanted fiducials  Direct tracking of tumor mass  Non radiographic tracking:  Implanted radiofrequncy coils (tracked magnetically)  Implanted wireless transponders (tracked using wireless signals)  3-D USG based tracking (earlier BAT system) 

Slide 75: Results a = includes setup error

Slide 76: Adaptive Radiotherapy Planning

Slide 77: Adaptive Radiotherapy (ART) Adaptive radiotherapy is a technique by which a conformal  radiation dose plan is modified to conform to a mobile and deformable target. Two components:  Adapt to tumor motion (IGRT)  Adapt to tumor / organ deformation and volume change.  4 ways to adapt radiation beam to tracked tumor motion:  Move couch electronically to adapt to the moving tumor  Move a charged particle beam electromagnetically  Move a robotic lightweight linear accelerator  Move aperture shaped by a dynamic MLC 

Slide 78: ART: Concept 1. 2. 3. Offline ART ● Conventional Rx Online ART ● ➢ Individual patient based ● ➢ Individual patient based ➢ Sample Population based margins margins margins ➢ Frequent imaging of ➢ Daily imaging of patients ➢ Accomadates variations of patients ➢ Daily error corrected setup for the populations ➢ Estimated systemic error prior to the treatment ➢ No or infrequent imaging corrected based on ➢ Smallest margin required ➢ Largest margin repeated measurements ➢ Plans adapted to the ➢ A small margin kept for changing anatomy daily! random error ➢ Plans adapted to average changes

Slide 79: ART: Why ? Due to a change in the contours (e.g. Weight Loss) the actual dose received by the organ can vary significantly from the planned dose despite accurate setup and lack of motion.

Slide 80: ART: Problem Real time adaptive RT is not possible “today”

Slide 81: ART: Steps..

Slide 82: ART: Steps

Slide 83: Helical Tomotherapy

Slide 84: Helical Tomotherapy Gantry dia 85 cm  Integrated S Band LINAC  6 MV photon beam  No flattening filter – output  increased to 8 Gy/min at center of bore Independant Y - Jaws are  provided (95% Tungsten) Fan beam from the jaws can  have thickness of 1 -5 cm along the Y axis

Slide 85: Helical Tomotherapy Binary MLCs are provided – 2  LINAC positions – open or closed Pneumatically driven 64 leaves  Cone Beam Open close time of 20 ms  Y jaw Width 6.25 mm at isocenter Binary MLC  10 cm thick  Interleaf transmission – 0.5% in  Y jaw field and 0.25% out field Maximum FOV = 40 cm  Fan Beam However Targets of 60 cm dia  meter can be treated.

Slide 86: Helical Tomotherapy Flat Couch provided allows  automatic translations during treatment Target Length long as 160 cm  can be treated “Cobra action” of the couch limits  the length treatable Manual lateral couch translations  possible Automatic longitudinal and  vertical motions possible

Slide 87: Helical Tomotherapy Integrated MV CT obtained by an  integrated CT detector array. MV beam produced with 3.5 MV photons  Allows accurate setup and image guidance  Allows higher image resolution than cone  beam MV CT (3 cm dia with 3% contrast difference) Tissue heterogenity calculations can be  done reliably on the CT images as scatter is less (HU more reliable per pixel) Not affected by High Z materials (implant)  Dose 0.3 – 3 Gy depending on slice  thickness Dose verification possible 

Slide 88: Newer Techniques in Radiation therapy Treatment Results (Clinical)

Slide 89: Prostate Cancer Late rectal toxicity (Gr 2 or more) is seen in 20 – 30%; ED occurs in 50 -60%!!!

Slide 90: Prostate Cancer Zelefsky et al (2006, J. Urol) –  561 patients (1996 - 2000) All localized prostate cancer  Risk group according to the  NCCN guidelines Treated with IMRT ± NAAD  Dose: 81 Gy in 1.8 Gy  PTV dose homogenity ± 10%  Rectal wall constraints:  53% vol = 46 Gy  36% vol = 75.6 Gy 

Slide 91: Prostate Cancer 8 yr biochemical relapse free  survival rates: 85% - Favourable  76% - Intermediate  72% - Unfavourable  CSS (8 yrs):  100% - Favourable  96% - Intermediate  84% - Unfavourable  NAAT: No significant  difference in outcomes

Slide 92: Prostate Cancer Rectal Toxicity:  Grade 2: 7 patients (1.5%); Grade 3: 3 patients (less than  1%) The 8-year actuarial likelihood of late grade 2 or greater rectal  toxicity 1.6%. Urinary Toxicity:  Grade 2 chronic urethritis in 50 patients (9%); Urethral  stricture requiring dilation (grade 3) developed in 18 patients (3%). The 8-year actuarial likelihood of late grade 2 or greater  urinary toxicities was 15%. 47% patient developed ED (43% IMRT alone; 57% ADT)  No 2nd cancers! 

Slide 93: Prostate Cancer Arcangeli et al (2007) WP-IMRT  with Prostate boost 91% N = 55; All had NAADT, Risk of  71% nodal mets > 15% 63% Dose:  55 – 59 Gy (Pelvis)  66 – 80 Gy (Prostate)  33 – 40 fractions  No Gr III toxicity  Late Gr II toxicity:  Rectum: 2 yr actuarial probablity  8%

Slide 94: Head and Neck Cancers Author Year N CCT Dose Result Huang 2003 41 (I) Yes 70/60/50 (2.18 68% Stage IV; 31% Gr III mucositis; (P,NR) Gy per #) 7% Gr IV mucositis; Gr II xerostomia 58.5%; 2 yr Locoregional control 89% ; 2 yr OS 89% Wendt 2006 39 (I) Yes 60-70 Gy / 48 Gr III mucositis 11%; 12% Gr III (P,NR) -54 Gy (I) xerostomia at 6 months; 2yr Crude LC 70%; 50 % recurrences outside high dose region Yao (P,NR) 2007 90 (I) Yes 70/60/54 Gy All N2/N3 disease; 71% Oropharynx; (SIB) 3 yr LC 96%; OS 67.5%; PET useful in patient selection for ND (10) All oropharynx; 92% ≥ St III; 33% Arruda 2006 50 (I) Yes 70 / 59.4 -54 Gy Gr II xerostomia (1 yr); Gr III (P,NR) (76% - SIB) mucositis 38%; 2 yr LRC 88%; OS 98% Table showing Results of IMRT in H&N Ca

Slide 95: Head and Neck Cancers Author Year N CCT Dose Result Chao 2003 126 Yes 72 -68/ 64 -60 Gy 59% Post op IMRT; 67% St IV; 2 yr (P,NR) (I) (30%) (SIB) LRC 85% ; 89% (Post ND) Thorstad 2005 356 Yes 70/56 Gy – Def.; 63% Post op; 90% ≥ St III; 5 Yr LRC (P,NR) (I) (40%) 64/54 Gy – 76%; 14% of the failures were Postop marginal. All marginal failures in post op patients. Wolden 2005 79 (I) Yes 70 Gy (59 – All Npx; 80% ≥ Stage III; 3 yr (P,NR) Hyperfractionated actuarial LC 91%; OS 83%; Gr III ; 15 - SIB) hearing loss 15%; 32% Gr II xerostomia at 1 yr; distant mets dominant form of therapy Daly 2007 69 (I) Yes 66 Gy -Def (2.2 33% Post op; 2 yr LC and OS 92% and (P,NR) Gy per #); 60.2 – 74%(Def); 87% and 87% (Post op); Post op (2.15 per Mean xerstomia significantly improved #) than CRT Schwartz 2007 49 (I) Yes 60 / 50 Gy (25#) All Stage III/IV; Gr III mucositis 55%, (P,NR) - SIB Gr III dermatitis 8%; 2 yr LC 83% ; OS 80% Table showing results of IMRT in H& N Ca

Slide 96: Head and Neck Cancers Author Year N CCT Dose Result Huang 2003 41 (I) Yes 70/60/50 68% Stage IV; 31% Gr III mucositis; 7% (P,NR) (2.18 Gy per Gr IV mucositis; Gr II xerostomia 58.5%; #) 2 yr Locoregional control 89% ; 2 yr OS 89% Jabbari 2004 30 (I), No 60-78 Gy (I); At 12 months, median XQ and HNQOL (P,NR) 10 (C) 63 -76.8 (C) scores were lower (better) in the IMRT compared with the standard RT patients by 19 and 20 points, respectively Pow (P,R) 2006 24 No 68-70 / 66- All Stage II Npx; At 1 yr 83% had (I),21 68(I); 68 / 66 recovered 25% of the pre RT parotid flow (C) (C) in IMRT (9.5% in Conv RT arm). Subscale scores for role-physical, bodily pain, and physical function were significantly higher in the IMRT group Braam 2006 30 (I), No I – 69/66/54 83% in I arm treated definitively (23% in (P,NR) 26 (C) (30#), C – 50 C arm);mean parotid flow ratio was 18% -70/46-50(25 (C) and 64% (I); parotid gland – 35#) complication rate was 81% (C) and 56% (I) (p = 0.04). Table showing Salivary sparing and QOL improvement with IMRT

Slide 97: Breast Cancer Largest randomized trial  Donovan et al (2007) 305 patients – 156(standard)  and 150 (IMRT) 1997 – 2000  Aim:Impact of improved  radiation dosimetry with IMRT in terms of external assessments of change in breast appearance and patient self-assessments of breast discomfort, breast hardness and quality of life. Dose: 50 Gy / 25# with 10 Gy  boost

Slide 98: Breast Cancer The control arm had 1.7 times (95% CI 1.2–2.5) more likely to have had some ➢ change than the IMRT arm, p = 0.008. Areas with dose > 105% have 1.9 times higher risk of any change in cosmesis ➢

Slide 99: Breat Cancer Leonard et al 2007 – APBI  55 patients , Non randomized  All patients stage I  Dose: 34 Gy (n=7) / 38.5 (n = 48) BID over 5 days  Median F/U – 1 yr  Good to excellent cosmesis:  Patient assessed: 98% (54)  Physician assessed: 98% (54)  Considered a reasonable option for patients who have large  target volumes and/or target volumes that are in anatomic locations that are very difficult to cover.

Slide 100: Lung Cancer Author Year N CCT Dose Result Yom et al 2005 37 (I) Yes 63 Gy (median) 7% incidence of Gr III (R, NR) pneumonitis Yorke et al 2005 78 No Dose escalation 22% incidence of Gr III (P, NR) (3D) (50.7 – 90 Gy); pneumonitis above doses of 70 Gy. Videtec (R, 2006 28 (I) No 50 Gy in 5 fraction 64% T1; 2.6% Gr II pneumonitis, NR) (SBRT) no Gr III reactions; LC and OS at 1 yr 96.4% and 93% respectively Scarbrough 2006 17 (I) Yes 71.2 Gy (69–73.5 Mean age 70; 73% IIIB, FU 1 yr, (R, NR) Gy) No Gr III tox, 2 yr OS 66% Jensen (P, 2007 17 (I) Yes 66 Gy Patients no suited for CCRT. 1 Gr NR (citux) III esophagitis; 79% response (6 mo) 60% stage IIIB, FU = 8 mo Yom et al 2007 68 (I), Yes 63 Gy (median); (R, NR) 222 Dose > 60 Gy (median); Gr III pneumonitis 8% (3D) 84% (I), 63% (32% for 3D CRT); V20 35% (I) vs (3D) 38%(3D) (p = 0.001) Table showing results of IMRT in Lung Cancer

Slide 101: Brain Tumors Author Year N Dose Result Sultanem 2004 25 60 Gy (GTV); 40 All GBM,Post op volume < 110 cc; Gy (CTV); 20 # Majority RPA class 4/5; The 1-year overall survival rate is 40%, Median survial 9 mo. No late toxicity. Luchi 2006 25 48 – 68 Gy 2 AA patients; Median KPS 70; 2 yr PFS (GTV); 40 Gy 53.6%; 2 yr survival 55.6%; Pattern of (CTV1); 32 Gy death – CSF dissemination most (CTV2); 8 # common cause of death! Narayana 2006 58 60 Gy (PTV); 70% GBM; 1 yr OS 30% (2 yr 0%) for 30# GBM; No Gr III late toxicity; Pattern of failure – local Table showing results of IMRT in brain tumors

Slide 102: Cervical Cancer Author Year N CCT Dose Result Mundt 2003 36 Y 45 Gy (1.8 80% stage I-II; PTV S3 to L4/5 (P,NR) (53%) Gy/#) interspace; Chronic GI toxicity 15% (n= 3; 1 Gr II, 2 Gr I); 50% incidence in Conventional Mundt 2002 40 Y 45 Gy (1.8 60% Acute Gr II toxicity (90% Gr II in (P,NR) Gy/#) Conv.); Less GU toxicity (10% vs 20%); Patients not requiring antidiarrheal halved! Chen 2007 33 Y 50.4 Gy / All Stage I -II; All Post Hysterectomy; 1 (P,NR) 28# yr LRC 93%; Acute GI toxicity 36% (Gr I- II); Acute Gu toxicity 30% (Gr I-II) Beriwal 2007 36 Y 45 Gy 2 Yr LC 80%; 2 yr OS 65%; 11 had (P,NR) (EFRT) + recurrences – 9 distant; Gr III toxicity – 10-15 Gy 10% boost Kochanski 2005 62 Y 45 Gy (1.8 29% Post op; 20 Stage IIB-IIIB; 3 yr DFS (64%) Gy /#) 72.7%; 3 yr pelvic control 87.5%; 5% Gr II or higher late toxicity

Slide 103: Anal Canal Author Year N CCT Dose Result Salama et 2006 40 (I) Yes 45 Gy WP + 9 Gy 12.5% Gr III GI toxicity, 0 Gr III al (R, NR) boost skin toxicity, 2 year colostomy- free, disease free, and overall survival 81%, 73%, and 86% Milano et al 2005 17 (I) Yes 45 Gy WP + 9 Gy 53% Gr II GI toxicity, No Gr III (P, NR) boost acute or late complications. 82% CR rate, the 2-year CFS, PFS, and overall survial are: 82%, 65%, and 91% Devisetty 2006 34 (I) Yes 45 Gy WP + 9 Gy 17% Acute GI toxicity; volume of (P,NR) boost bowel receiving 22 Gy (V22) was correlated with toxicity (31.8% acute GI toxicity for V22 > 563 cc vs. 0% for V22 ≤ 563 cc) Hwang 2006 12 (I) Yes 30.6 Gy WP + 42% Gr III dermal toxicity, 8% Gr (P,NR) 14.4 Gy Low III GI toxicity, 83% CR rate Pelvic + 9 Gy boost

Slide 104: New Techniques in Stereotactic Radiation therapy

Slide 105: Stereotaxy Derived from the greek words Stereo = 3 dimensional space  and Taxis = to arrange. A method which defines a point in the patient’s body by  using an external three-dimensional coordinate system which is rigidly attached to the patient. Stereotactic radiotherapy uses this technique to position a  target reference point, defined in the tumor, in the isocenter of the radiation machine (LINAC, gamma knife, etc.). Units used:  Gamma Knife  LINAC with special collimators or mico MLC  Cyberknife  Neutron beams 

Slide 106: Stereotactic Radiation Two braod groups: Rigid application of a stereotactic  frame to the patient Radiosurgery: Single  treatment fraction 3 D Volumetric imaging with the Radiotherapy: Multiple  frame attached fractions Frameless stereotactic  Target delineation and Treatment radiation is possible in one planning system – cyberknife Sites used:  Postioning of patinet with the frame after verification Cranial