PROTON BEAM THERAPY

PROTON BEAM THERAPYBY Dr Deepak kumar DasModerator- Dr Renu MadanAssistant ProfessorPGIMER

Radiation therapyEstablished treatment modality since over 100 years [1st treatment in 1896, one year after discovery of X-ray]60-70 % of all cancer patients require radiotherapy as a modality during their cancer course.Curative modality in 25-30% of cancers

Types Of RadiationPhotons X rayGamma ray

Particulate radiationElectrons Protons NeutronsHeavy ions

THERAPEUTIC RATIO

RATIONALE

Relative dose distribution

Constant principle in radiation oncology is that higher or more intense the radiation dose, the greater the probability of tumour control The primary barrier to maximising local tumour control through dose escalation or intensification is the risk of damaging normal tissues either by delivering too high dose or exposing too much of the normal tissue to radiation. In most clinical settings, there is an opportunity for improvement of therapeutic ratio by increasing disease control or by reducing toxicity. The most direct means of improving the therapeutic ratio is by reducing dose to non-targeted tissues, which both reduces toxicity and facilitates dose escalation for increased tumour control

Herein lies the rationale for proton therapy

Limitations of Conventional Photon based treatments-Significant exit dose -Dependent biological effect on oxygen (indirect effect; 70-80%)-Dose escalation not possible beyond a limit-Second malignancies

Problem with X-Rays and the promise and challenge of protons

Proton dose distributionDepends on the concept of Linear energy transfer (LET)LET is defined as dE/dx, where dE is the mean energy deposited over a distance dx in media.The rate of energy loss due to ionisation and excitation caused by a charged particle travelling in a medium is proportional to the square of the particle charge and inversely proportional to the square of its velocity.As the particle velocity approaches zero near the end of its range, the rate of energy loss becomes maximum.The sharp increase or peak in dose deposition at the end of particle range is called the Bragg peak.

Proton dose distribution

Low entrance dose (plateau)Maximum dose at depth (Bragg peak) Rapid distal dose fall-off

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The Bragg peak of a monoenergetic proton beam is too narrow to cover the extent of most target volumes.In order to provide wider depth coverage, the Bragg peak can be spread out by superim- position of several beams of different energies.Called as spread-out Bragg peak (SOBP).

SOBPActive modulationPassive modulationProblems with Bragg peak

SOBPActive modulationPassive modulation

SOBPActive modulationPassive modulationA beam of particles of fixed energy is attenuated by range shifters of variable thicknessCollimators & compensators are usedTreatment planning is simpleDisadv.- significant dose is delivered along the entrance path

A tightly focused pencil beam is deflected by 2 magnetic dipoles to allow scanning of the beam over t/t fieldEnergy of the incoming beam is varied during t/tDose distribution can be tailored to any irregular tm Treatment planning is complex

A safety margin is added for the movementIncreased nuclear fragments (including neutrons) are produced by nuclear interactions with beam modifiersExtremely sensitive to movements of the targetIntegral dose is minimized.

RBE

RBE OF PROTONS IS 1.1

In clinical practice, RBE of 1.1 is generally used (Same as photons but with better physical properties)However, RBE changes as there is change in LET (LET increases when energy decreases towards the end of the range)There is rapid rise in RBE during last several mm3 of the proton range producingan RBE value of 1.3. Actual RBE corrected dose may exceed physical dose by 25% at the end of the spectrumRelative biologic efficiency is a ratio of doses from two beams to produce the same effect

Conception of proton therapy-1946 Harvard physicist Robert Wilson :Protons can be used clinically Maximum radiation dose can be placed into the tumor Proton therapy provides sparing of healthy tissues Early proton: for research only1990: First hospital based proton therapy facility was opened at the Loma Linda University Medical Center (LLUMC) in California.

Proton therapy1954: First treatment of pituitary tumors1958 : First use of protons as a neurosurgical tool 1990: First hospital based proton therapy facility was opened at the Loma Linda University Medical Center (LLUMC) in California.

Proton Therapy : An Emerging Modality42 centers in operation worldwide.26centers are under construction (To be started by 2014-2016)96537 patients have been treated till date

**www.ptcog.web.psi.ch

BASIC PHYSICSThe Existence of proton was first demonstrated by Ernest Rutherford in 1919Proton is the nucleus of hydrogen atomIt has a positive charge of 1.6 x 1019 cIts mass is 1.6x10-27 kg(1840 times of electron)It is the most stable particle in universe with half life of >1032 years

Proton Interactions It interacts with electrons and atomic nuclei in the medium through coulomb force a. Inelastic collisions b. Elastic scattering

Protons scatter through smaller angles so they have sharper lateral distribution than photons

To a first-order approximation, protons continuously lose kinetic energy via frequent inelastic Coulombic interactions withatomic electrons. Most protons travel in a nearly straight line because their rest mass is 1832times greater than that of an electron. In contrast, a proton passing close to the atomic nucleusexperiences a repulsive elastic Coulombic interaction which, owing to the large mass of thenucleus, deflects the proton from its original straight-line trajectory. Non-elastic nuclear reactions between protons and the atomic nucleus are less frequent but, in terms of the fate of anindividual proton, have a much more profound effect. In a nuclear reaction, the projectile protonenters the nucleus; the nucleus may emit a proton, deuteron, triton, or heavier ion or one ormore neutrons. Finally, proton Bremsstrahlung is theoretically possible, but at therapeutic protonbeam energies this effect is negligible20

Mass Stopping Power It is more with low atomic number materials and low with high atomic number materials High Z materials= Scattering Low Z materials= Absorption of energy and slowing down Protons

Unit of dose deliveredDose delivered with particles are prescribed in Gray equivalents(GyE) Cobalt Gray equivalents(CGE) often used with protons

These units are equal to measured physical dose in Gray times the specific RBE of the beam used

For protons absorbed dose is multiplied by 1.1 to express the biologic effective proton dose

Components of proton beam therapyProton acceleratorBeam transport systemGantryTreatment delivery system

GENERATION OF PROTONProtons are produced from hydrogen gas 1. Either obtained from electrolysis of deionized water or 2. commercially available high-purity hydrogen gas.

Application of a high-voltage electric current to the hydrogen gas strips the electrons off the hydrogen atoms, leaving positively charged protons.

Proton AcceleratorsLinear AcceleratorCyclotronSynchrotronHigh gradient Eletrostatic AcceleratorLaser Plasma particle Accelerator

Cyclotron

Two short metallic cylinders, called DeesPlaced between poles of direct magnetic fieldAn alternating potential is applied between Dees.Frequency is adjusted of alternating potential to accelerate the particle as it passes from one Dee to another.With each pass, the energy of the particle and the radius of the orbit increases.

Fixed energy machineMany cyclotron have an energy limit of only upto 70 Mev which suits them only for treating superficial tumors (orbital tumors)In order to treat all common tumors in human body, cyclotronshave to be able to deliver a beam with energy upto about 230 Mev (range 32 cm)Cyclotrons can produce a large proton beam current of up to 300nA and thus deliver proton therapy at a high doserateEnergy Degraders Modify Range and intensity of beam Energy selection system (ESS) consist of energy slits, bending magnets, and focusing magnets, is then used to eliminate protons with excessive energy or deviations in angular direction.

Disadvantage of cyclotronInability to change the energy of extracted particles directlyEnergy degradation by material in the beam path leads to an increase in energy spread and beam emittance and reduces the efficiency of the systemMore shielding is required because of secondary radiation

SYNCROTRON

Produce proton beams of selectable energy, thereby eliminating the need for the energy degrader and energy selection devices Beam currents are typically much lower than with cyclotrons, thus limiting the maximum dose rates that can be used for patient treatment, especially for larger field sizesThe maximum dose rate available from a commercially available synchrotron based proton delivery system for 2525 cm2 field has been specified at 0.8Gy per minute.

Proton pulse exiting a pre-accelerator, with energy typically upto 7 MeV is injected into ring shaped accelerator.Each complete circuit of the proton pulse through the accelerator increases the proton energy. When the desired energy is reached, the proton pulse is extracted from the applicator.

Beam line/ transport systemThe proton beam has to be transported to the treatment room(s) via the beam transport system. Consists of bending and focusing magnets and beam profile monitors to check and modify beam quality as it is transported through the beam transport system.Gantries are usually large because of 2 reasons-protons with therapeutic energies can only be bent with large radii and -Beam monitoring and beam shaping devices have to be positioned inside the treatment head affecting the size of the nozzleNozzle has a snout for mounting and positioning of field specific aperture and compensator

One of the gantries at the Northeast Proton Therapy Center

SCATTERING BEAM TECHNIQUE

Beam delivery systemThe proton beam exiting the transport system is a pencil-shaped beam with minimal energy and direction spread. Narrow Bragg peak, not suitable for practical size of tumorsPencil beam is modified either by

1.Scattering Beam Technique

2.Scanning Beam Technique

Scattering beam techniqueSmall fields: single scattering foil (made out of Lead) Larger field sizes: double-scattering system (bi-material: High and low z material) to ensure a uniform, flat lateral dose profileModulator wheel: variable thickness absorbers in circular rotating tracks that result in a temporal variation of the beam energy

It aims to produce a dose distribution with a flat lateral profile. The depth-dose curve with a plateau of adequate width is produced by summing a number of Bragg peaks.Range modulation wheels consisting of variable thicknesses of acrylic glass or graphite steps are traditionally used for this purpose.The width and thickness of the modulation wheels are calibrated to achieve SOBP.The width of SOBP is controlled by turning the beam off when a prescribed width is reached.

RANGE MODULATOR WHEEL

Scanning beamtechniqueDouble scattering technique

Scanning beam techniqueAn alternative to the use of a broad beam is to generate a narrow mono-energetic "pencil" beam and to scan it magnetically across the targetTypically the beam is scanned in a zigzag pattern in the x-y plane perpendicular to the beam directionAs the pencil beam exits the transport system, it is magnetically steered in the lateral directions to deliver dose to a large treatment field

SCANNING BEAM TECHNIQUE

SCANNING BEAM TECHNIQUE

Scanning beam techniqueThe proton beam intensity may be modulated as the beam is moved across the field, resulting in the modulated scanning beam technique or IMPT.Current implementation of IMPT uses so called spot scanning technique, in which the beam spot is moved to a location within the target and the prescribed dose is delivered to the spot, before it is moved to the next spot to deliver its prescribed dose.

Advantage of scanning

In contrast to broad beam technique, arbitrary shapes of uniform high dose regions can be achieved with a single beam No first and second scatterers, less nuclear interactions and therefore the neutron contamination is smallerGreat flexibility, which can be fully utilized in intensity-modulated proton therapy (IMPT) Disadvantage: Technically difficult and more sensitive to organ motion than passive scattering

Treatment planningTreatment planning for proton therapy requires a volumetric patient CT scan dataset.The CT HU numbers are converted to proton stopping power values for calculating the proton range required for the treatment field.Uncertainties in the conversion of CT numbers to proton stopping power in proton dose calculation translate into range calculation uncertainties and errors.Marking the intended SOBP with a distal margin beyond the target and a proximal margin before the target in the range calculation of each treatment field.Other consideration in determining the margins include target motion, daily set up errors, beam delivery uncertainties and uncertainties in the anatomy and physiologic changes in the patient.

In contrast to x-ray planning, the PTV for proton therapy is specific for each treatment field. Lateral margins are identical to traditional definitions, but the distal and proximal margins along the beam axis are calculated to account for proton specific uncertainties.

BEAM SPECIFIC PTVAccounted for three types of uncertainties Geometrical miss of the CTV due to lateral set up error Range uncertainties accounted by giving proximal and distal margin Range error caused due to tissue heterogeneity

STEPS FOR BEAM SPECIFIC PTV

Pencil-beam algorithms are used for proton therapy dose calculations which model proton interaction and scattering in various heterogeneous media of the beam path, including the nozzle, range compensators, and the patient.

Monte Carlo calculations has been used to study the accuracy of such dose calculation algorithms which indicates errors near surfaces of media differing significantly in density and composition, such as air cavity and bones

Advantages: Proton TherapyReduction in integral dose to normal tissues :Reduced toxicitiesDose escalation to tumors increased local controlTreat tumors close to critical organs eye, spinal cord

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Clinical situations: Proton therapyPediatric malignancies:Craniospinal Axis Irradiation: MedulloblastomaCraniopharyngiomaProstate cancersSkull base tumorsParanasal sinus tumors, Lymphomas, Lung CancersGI Malignancy: HCC, Pancreatic cancers

When Should We Use Protons?Better organ sparing (Skull base tumors)Better local control needed (Ca Prostate)Late morbidity (Pediatric malignancies)Complex geometry (Ocular melanoma)Large target volume (Childhood Medulloblastoma)

Zietman, Goiten, Tepper JCO 2010

UVEAL MELANOMA

Paediatric tumours

The Exit dose from photon therapy exposes the thyroid, heart, lung, gut, and gonads to functional and neoplastic risks that can be avoided with proton therapy.Medulloblastoma : A case scenario for ideal PBT

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Medulloblastoma: Late Toxicity

SKULL BASED CHORDOMAS

CARCINOMA PROSTATE

NSCLC

SECOND MALIGNANCY

Due to higher integral dose produced by neutron scatter

SECOND MALIGNANCYHarvard Cyclotron LaboratoryMatched 503 HCL proton patients with 1591 SEER patientsMedian follow up: 7.7 years (protons) and 6.1 years (photon) Second malignancy rates6.4% of proton patients (32 patients) 12.8% of photon patients (203 patients) Photons are associated with a higher second malignancy risk: Hazard Ratio 2.73, 95% CI 1.87 to 3.98, p< 0.0001Chung et al. ASTRO 2008

COST EFFECTIVENESS

PROBLEMS WITH PROTON THERAPYPatient related Patient set up Organ motion Patient movementPhysics related CT number conversion DosimetryMachine relatedCumbersomeCost

CONCLUSIONSCurrently, proton therapy is a rare medical resource best used in situations where outcomes with commonly available radiation strategies present opportunities for improvement in the therapeutic ratio via improvements in dose distributions

At this stage in the development of proton therapy, there are no clear class solutions to treatment planning. In addition, the full potential for dose distribution improvements with protons has not been realized because of uncertainties in both treatment-planning algorithms and delivery modes.

Strategies for motion management and quality assurance are not fully developed. Finally, the clinical impact of some patterns of dose distribution improvements achievable with proton therapy may require time, careful trial design, and special assessments to define.

THANK YOU

Difference Between scattering and scanning beam techniqueSCATTERINGSCANNINGUse of patient specific beam modifying devicesDual scattering generates neutrons which increases integral radiation dose to the patientDual scattering can not do IMPT. However multiple fields can do but because of switching of compensators and aperatures in each field , the treatment time increases No use of beam modifying devices, making it a greener optionWithout scattering material, produces fewer neutronsScanning makes IMPT possible. With scanning, dose distribution can be varied voxel by voxel

SCATTERINGSCANNINGScattering is more forgiving for tumour and organ motion because of the smearing effect of the broadened beamSimpleScattering decreases the penetrating power of the proton beamEnhanced ability of proton scanning to paint dose more conformally, voxel by voxel, increases the chance of target misses due to organ motionComplexFor any given accelerator, scanning penetrates deeper than scattering. So scanning can treat deeper tumours

PhotonsProtons