In vivo Dosimetry for Proton TherapyNarayan Sahoo

Department of Radiation PhysicsUT MD Anderson Cancer Center, Houston, TXUSA

AcknowledgementCo-authors

Archana Singh Gautam, M.Sc.Falk Poenisch, Ph.D.X. Ronald Zhu Ph.D. Heng Li, Ph.D.Xiaodong Zhang, Ph.D.Richard Wu, M.S. Sam Beddar, Ph.D. Michael T. Gillin, Ph.D.

Outline

• Need for in vivo dosimetry (IVD)IVD: Measurement of dose during the medical procedure

• Detectors for in‐contact IVD in proton therapy• Proton therapy dose verification in patients• Proton therapy IVD with external devices• In vivo range verification in proton therapy• IVD in current clinical practice of proton therapy• Future outlook and concluding remarks

Need for IVD

Radiation therapy is high techInvolves a diverse team and computational

platformSusceptible to error

2008 WHO Report:3125 Major incidents (1976-2007)4616 Near misses (1992-2007)

Recent NY Times story and follow-up events

Need for IVDAAPM Policies

• AAPM TG-40 recommends access to in vivo dosimetry system

• AAPM TG-62 states that “ In vivo dosimetry is supplementary, not mandatory, to a good clinical program.”

• IVD is recommended in special situations like out of field dose to: Eye lens, pace makers, fetal dose, testicular dose, hip prostheses (AAPM TG-63)

Need for IVD for proton therapy• Many moving critical components- RMW,

range shifter, moving proton spots • Analytical Dose calculation algorithms in TPS

have limitations• Dose to critical organs close to the distal

range of the beams remains uncertain • Skin doses can be large and needs monitoring• Possibility of reduction of margins with in vivo

range verification

Type of IVD proceduresDose or range of the proton beam irradiation can be monitored by:Placement of doismeters on or in the patients

Same dosimeters used for photon and electron beam EBRT

Use of external devicesPET, Prompt gamma monitors and MRINo EPID due to lack of exit dose from the proton treatment field

Results are seen either in real-time or off-line

Desired features of dosimeters for IVD

• Minimal correction factors from reference calibration condition

• Tissue or water-equivalent materials• High spatial resolution• High dynamic range• Real-time monitoring• Wireless

Detectors for IVD in proton therapyIVD with real time dose values are possible with:• Diodes• Metal Oxide Semiconductor Field Effect Transistor

(MOSFET) detectors• Plastic Scintillation Detectors (PSDs)IVD with dose from off-line analysis are possible with:• Thermo Luminescence Dosimeters (TLDs)• Optically Stimulated Luminescent Dosimeters (OSLDs)• Radiophotoluminescent Glass Dosimeters • Films • Alanine and others (not covered in this talk)

Some useful references on dosimeters

S. Vatnitsky and H. Palmans, Detectors Systems, Chapter 11 of AAPM 2015 Summer School Proceedings

Karger CP et al, Dosimetry for ion beam radiotherapy. Phys Med Biol 2010; 55:R193-234.

ESTRO Methods for in vivo dosimetry in external radiaotherapy. Edited by Van Dam J and Marinello G. ESTRO Booklet No. 1 (ESTRO, Brussels, Belgium, 2006).

Features of dosimeters for IVD for proton therapy

• None of them are absolute dosimeters• Need calibration factors to covert response to dose• Require correction factors for irradiation conditions

that differ from calibration- Energy Field size Dose rate Geometry Environment LET

DiodesAdvantages• Immediate read-out• High sensitivity• Linear dose response• Good mechanical

Stability• Fairly small size• Available in arrays• No external bias

required

Disadvantages• Energy dependence• Angular dependence• Temperature

dependence• Sensitivity changes with

accumulated dose• LET dependence• Requires electrical

connection

Diodes

• Hi-p-type diodes are found to be more suitable for proton beam dosimetry(Ref: Grusell E, Medin J. Phys Med Biol2000; 45(9):2573-82)

• Has build up depth-Requires correction for entrance dose

• Should be calibrated at the same depth where the diode needs to be placed for IVD to minimize LET dependence

MOSFET detectorsAdvantages• Immediate read-out• High sensitivity• Linear dose

response• Good mechanical

Stability• Small size• Available in arrays• Waterproof

Disadvantages• Not water equivalent• Limited life-time• Temperature dependence

for single bias system• Sensitivity changes with

accumulated dose• LET dependence• Requires electrical

connection in some systems

MOSFET detectors• Mobile MOSFET system by BEST Medical

(Thomson-Nielsen, Ottawa, Canada)• One Dose and DVS (Dose Verification System)

by Sicel Technologies Inc. (Morrisville, NC, US)Useful references: • Cygler JE, Scalchi P. MOSFET Dosimetry in

Radiotherapy. In “Clinical Dosimetry Measurements in Radiotherapy (2009 AAPM Summer School)”.

• Gopiraj et al., Rep Pract Oncol Radiother2008;13:114–125.

Characterization of MOSFET detectorsOne dose system from Sicel Technologies was studied by Cheng et al, (Med. Phys. 37: 4266 (2010)).It is a single use detector with a wireless reader and comes with factory Co-60 calibration in batches of 32.Cheng et al. found:Pronounced energy dependence at depthLarge LET dependenceSmall energy dependence at the surface (within

3%)Small angular dependence (about 2% in 60

degrees angle)

Dosimetric features of MOSFET1% intra-batch and 3% inter-batch variation in

responseIVD accuracy within 6.5%

Kohno et al. studied TN-502RD (0.5 μm) and TN-252RD (0.25 μm) MOSFET detectors from Best Medical (Phys Med Biol 23:6077 (2006), J Appl Clin Med Phys13:159 (2012).They determined correction factors to detector response using Monte-Carlo simulation andshowed that it is possible to measure dose accurately (within 6%) with MOSFET in inhomogeneous media.

Plastic Scintillation Detectors (PSDs)

• Consists of a plastic scintillating material of organic scintillating molecules in a polymerized solvent that emits light when exposed to ionizing radiation(Archambault et al., IJROBP, 78: 280 (2010))

• Amount of light is proportional to dose• Light is collected by optical fiber and converted to

electric charge to be read by an electrometer• Have been characterized for proton dosimetry by

Wang et al. (Phys. Med. Biol. 57: 7767 (2012)) and Wootten et al. (Phys. Med. Biol. 60: 1185 (2015))

PSDsAdvantages• Immediate read-out• High sensitivity• Linear dose response• Small size (1 mm)• Waterproof• Water equivalent• No angular

dependence• Resistant to radiation

damage

Disadvantages• Stem effect-radiation

induced light from optical fiber

• Temperature dependence• Energy and LET

dependence for protons• Needs quenching

correction• Requires electrical

connection

PSDs for IVD in proton therapyStudied by Wootten et al. (Phys. Med. Biol. 60: 1185 (2015)) for entrance dose measurementFound that:• Contribution of radiation induced light is negligible• With quenching corrections, PSD measured dose

agrees with ionization chamber.• An additional LET-dependent correction factor is

needed for IVD by PSD at some depth in the patientCurrently PSD is used to monitor the skin dose of prostate cancer patients under an IRB approved protocol at MDACC.

TLDsAdvantages• Small size (1 mm)• Wide linear dose

response range • No angular

dependence• Dose rate

independence• Cable free irradiation• Well studied

Disadvantages• Instability in sensitivity• Energy and LET

dependence for protons• Susceptible to

contamination and damage

Ref: DeWerd LA, Bartol LJ, Davis SD. ThermoluminescentDosimetry. In 2009 AAPM Summer School Proceedings, Medical Physics Publishing.

TLDs for IVD in proton therapyBetter precision requires calibration under similar conditions of treatment field irradiation:

• Energy• Dose• LET

TLDs are Used by IROC Houston QA Center for beam calibration check and phantom dose verification. A phantom study by Zullo el al. (Med. Dosim. 35: 63 (2010)) showed that proton therapy dose verificationwithin 5% accuracy is possible with TLD 100 powder.

OSLDsOSLDs have many features similar to TLDs. Light is used for stimulation instead of heat.Compared to TLDs, OSLDs have:

• Greater sensitivity• Faster post-irradiation readout (~10 minutes)• Repeated readouts are possible• Energy independence

Fading with time and depletion with repeated readings are found to be minimal.Disadvantage: Sensitive to light, need light tight packaging

OSLDsRead out protocols are established and response is well characterized. Cygler JE, Yukihara EG, In 2009 AAPM Summer School Proceedings, Medical Physics Publishing;Reft CS, Med. Phys. 36: 1690 (2009); Kerns JR, Kry SF and Sahoo N (Med. Phys. 39: 1854 (2012)) showed that for proton beam dosimetry:Supralinerity exits: 1% at 200 cGy, 5% at 1000 cGy.With correction factors for fading, depletion, dose linearity, detector sensitivity, OSLD can measure dose with accuracy within 1%.

OSLDsGranville DA, Sahoo N, Sawakuchi GO (Radiation Measurements 71: 69 (2014)) observed that OSLDs have:LET dependent response- specific to the emission band. Blue band: Independent of LETUV band and mixed-band: LET dependentRatio of UV/Blue emission signal intensities can be used to determine LET distribution of proton beam.IROC, Houston QA Center is using OSLDs for remote audit with phantom irradiation.

Radiophotoluminescent Glass Dosimeters

• GD-301 (AGC Techno Glass Corp, Shizuoka, Japan) are silver-activated phosphate glass dosimeters

• Effective readout size is 1 mm diameter and 0.6 cm thick

• Stable radiophotoluminescence (RPL) centers are created in these dosimeters upon exposure to ionizing radiation

• When RPL centers are excited by pulsed UV laser, orange luminescent photons proportional to the given dose are emitted

• Luminescent photons are read with photo detections systems- Automatic readers are available

Glass Dosimeters for proton beam dosimetry

Study by Rah et al. (IJROBP 84: e251-256 (2012)) showed that GD-301 response: is linear with dose, is reproducible within 1.5%, changes within 1.5% with dose rate, changes within 3% with energy, fades less than 2%.

Angular dependence of the response of GD-301 remains to be studied.Lateral profiles and PDD can be measured with GD-301 with acceptable accuracy.

Glass Dosimeters for IVD in Proton Therapy

Study by Rah et al. (IJROBP 84: e251-256 (2012)) showed that GD-301 in a cylindrical poly-methylmethacrylate phantom showed the following.• Dose measured by GD-301 at the surface and at a

depth in a modulated proton beam agreed with Eclipse calculated values within 5%.

• Overall uncertainty in proton beam dosimetry with glass dosimetry is estimated to be 4.3%.

• Glass dosimeters have better dosimetriccharacteristics compared to TLDs and MOSFET detectors.

• GD-301 is well suited for IVD in proton therapy.

Films• Film dosimetry is well established.Ref: 1. AAPM TG 55 report, Niroomand Rad A. et al, Med. Phys. 25: 2093 (1998), 2. AAPM TG-69 report, Pai et al., Med. Phys. 34: 2228 (2007), 3. Zhao L and Das IJ, Phys. Med. Biol. 55: N291-N301 (2010)• Can be used to measure 2-D dose distribution in

patients• EBT film is a boon for IVD

FilmsResponse has strong dependence on LET and beam quality.Accuracy is better for measurements of relative dose distribution in conditions of constant LET.(Karger CP et al., Phys Med Biol 2010; 55:R193-234).Need careful calibration and characterization for proton beam dosimetry.(Arjomandy et al., Med. Phys. 37: 1942 (2010))IROC Houston QA Center uses EBT film for dose verification in phantoms.May be good for IVD application.

Dose verification in patients with dosimeters on or in the patient

• Dosimeters can only be placed on the skin or accessible body cavities for IVD

• Challenge is not dosimetry, but placement at suitable location to extract meaningful information

• Skin or entrance doses do not give information about the target dose

• In proton beam, skin dose may be useful to estimate the dose at the target

• Mostly useful for quality assurance • External devices may be more useful

In vivo proton beam dosimetry with external devices

Carnicer A et al., Study of the secondary neutral radiation in proton therapy: Toward an indirect in vivo dosimetry. Med Phys 2012; 39: 7303-7315.H/D for photons or H*10/D is related to dose/MU.Can be measured by a larger ionization Chamber at a fixed location in the room. Dose/MU depends on:

• Range,• SOBP width, • field shaping device.

One can monitor the constancy of dose delivery.

Dose verification by positron emission tomography (PET)

Positron emitter distribution: • Has correlation with dose distribution,• Cannot be easily compared with planned dose

distribution.Measured activity distribution from PET is compared with calculated activities destruction.Promising with many challenges to overcome• Low count rate and signal to noise ratio• All the dose is not deposited by nuclear interaction• No activity below 8 MeV threshold for NI• Reduction in activities due to local perfusion

IVD for proton therapy with PETMonitoring the dose delivery using an iterative activity distribution reconstruction procedureRef: Enghardt W,. Radiother Oncol 2004; 73 (Supplement 2): S96–S98.

IVD for proton therapy with PET

• Can be online or off-line• Off-line is cost effective• The advantage of online PET are:Higher count rateShorter acquisition timeLower biological washoutRigid physical correlation between

patient position, delivered particles and activity

In vivo range verification in proton therapy

Proton range verification in patients is: • A desirable goal,• Remains as an unrealized goal due to many

challenges to measure range in vivo.Ref: Knopf A C, Lomax T: In vivo proton range verification: a review. Phys Med Biol 2013;58: R131–R160.Some promising methodsUse of implanted dosimeters,Use of external devices to monitor range dependent

processes inside the patient during the treatment

Range verification with implanted dosimeters

Proposed by H. M. Lu and developed by his groupLu H-M, Mann G and Cascio E.. Med Phys 2010; 37:5858 -5866.Range can be measured by monitoring time-dependent dose rate at different depths of proton dose distribution.An array of 12 diodes, a special amplifier and software was used for feasibility study with promising results.Samuel D. et al, Med. Phys.(abstract) 41: 326 (2014).Alternative simplified method of split SOBP is also proposed by H. M. Lu.Lu HM. Phys Med Biol 2008;53: N415-N422.

Range verification with implanted dosimeters

• A flat SOBP field can be spit into two sloping depth dose fields by adjusting beam current modulation.

• Ratio of dose of the two split fields at any depth is sensitive to depth.

020406080100120

0 100 200 300

PDD

Depth (mm)

SOBP Part 1 Part 2

This ratio can be measured by implanted dosimeters to provide WET at the dosimeter location.

Range verification with implanted dosimeters

• Slit SOBP technique can be applied to scanned proton pencil beam.

• The technique was tested in water tank using MOSFET detectors.

Limitation:• WET information can be obtained only at the

location of the dosimeter.• Dosimeter can be placed only at accessible

sites.External devices are thought to be more suitable for in vivo range verification.

Range verification with external devices

Range probe with multilayer ionization chamber (MLIC)Proton beam of known range with sufficient energy

to pass through the patientMeasure the range shift with MLIC placed at the exit

of the beamMumot M et al., Phys Med Biol 55:4771 (2010).Only WET in the entire path of the beam can be determined.May be useful to check the accuracy of CT number to relative stopping power (RSP) conversion curve

Range verification with external devices

Proton radiographyGives a planar projection of water equivalent path length (WEPL) of the proton beam passing through known location in a 2-D gridProton tomographyMeasured integral WEPL in 3-D is used to reconstruct the 3D map of proton RSP.Both can be used to verify the changes in the RSP or WET in the beam path during the course of treatmentRef: Chapter 7, 2015 AAPM Summer School proceedings

In vivo range verification by PET with implanted markers

Cho et al. (Cho J, Phys Med Biol 58:7497 (2013)) showed:• Biocompatible implantable markers with 18O, 63Cu

and 68Zn have 100 times more activation than tissue elements,

• Can be used for range verification in vivo.Limitations

• Needs surgical implant• Positional uncertainties• Limited information

In vivo range verification by prompt gamma imaging

Prompt gamma (PG) emission due to nuclear interaction has correlation with depth dose distribution of proton beam (Polf et al.,Phys. Med. Biol. 54:731(2009).With suitable gamma and Compton cameras, PG can

be used to verify proton beam range in vivo.Still in research and developmental phaseReviewed in:Chapter 7, AAPM 2015 Summer School Proceedings;

In vivo range verification by prompt gamma imaging

Prompt gamma (PG) emission due to nuclear interaction has correlation with depth dose distribution of proton beam (Polf et al.,Phys. Med. Biol. 54:731(2009).With suitable gamma and Compton cameras, PG can

be used to verify proton beam range in vivo.Promising, still in research and developmental phaseReviewed in:Chapter 7, AAPM 2015 Summer School Proceedings; Prototype has been tested successfully.Smeets et al., Phys. Med. Biol. 57:3371 (2012)Perali et al., Phys. Med. Biol. 59:5849 (2014)

Range verification by MRIRadiation induced changes can be seen in MRI under certain conditions, e.g.

• Fatty conversion of bone marrow (GensheimerMF et al., IJROBP 78: 268-275 (2010))

• Changes in liver (Yuan Y et al., Radiotherapy Oncol 106:378 (2013))

It is a late process-3 to 4 months after proton therapyThe depth-dose distribution is created using dose to signal intensity calibration in the lateral penumbra.Can be used to verify range- not in vivo at this timeLarge uncertainties due inherent large spatial resolution

Clinical experience with IVD in proton therapy

Hsi WC et al. (Med Phys.40:051715 (2013)) used TLDs on the surface of endorectal balloon to monitor rectal dose of prostate cancer patients• Used image guidance and radiopaque markers to

position the TLDs at 12 o’clock position• 81 in vivo TLD measurements in 6 patients• 83% of all measured dose were within -10% to 5% of

the planned dose (mean -2.1%, SD 3.5%)Established the feasibility of IVD in clinical practice with acceptable accuracy

Clinical experience with IVD in proton therapy

Rah et al. (IJROBP 84: e251-256 (2012)) used glass dosimeters to measure surface dose for six proton therapy patientsThe average difference between measured and Eclipse calculated dose was 5.9%+1.8%.The difference between dose measured by glass dosimeters and TLD was within 2%.There is paucity of published results of IVD for proton therapy patients with other dosimeters.Routine use of IVD in clinical practice is very limited.

Clinical experience with IVD in proton therapy using PET imaging

Nishio T et al. (Int J Radiat Oncol Biol Phys 76:277 (2010)) used in-beam PET to monitor the activity distribution for 48 patients.

• First day activity was used as reference• Could detect regions with anatomical changes in

head and neck cancer patients• Three patients were re-planned

LimitationsNo information on deviation from planned dose

Clinical experience with IVD in proton therapy using PET imaging

Knopf AC et al. (Int J Radiat Oncol Biol Phys 79:297-304 (2011)) used off-line PET/CT scanner for range verification of 23 patients at MGH, Boston.Monte Carlo based calculation was used to determine the 3-D activity distributionPredicted and measured distal fall-off of the activity distribution was used to verify the range of proton treatment fields.• Results were found to depend on tumor location• Useful for intracranial, cervical spine, arteriovenous

malformation, sites with metal implants

Clinical experience with IVD in proton therapy using PET imaging

Proton range verification with PET imaging within 2 mm is feasible for head and neck cancer patients.Factors contributing to uncertainties are:

• reproducibility of the off-line PET, • biological wash out effect, • accuracy of the calculated activity distribution

used as reference, • organ motion, • image registration accuracy, • beam arrangement.

Technique requires further improvement

Clinical experience with range verification in proton therapy using MRI

Gensheimer MF et al., (IJROBP 78: 268-275 (2010)) reported results of range verification by MRI for 10 spine patients.Found MRI measured range to be 1.9 mm more than planned range with uncertainties of 1.9 mmYuan Y et al., (Radiotherapy Oncol 106:378 (2013)) reported results of range verification by MRI for five liver patients.Found the mean difference between MRI measured and planned range to be -2.18±4.89 mm for anterior-posterior beam and -3.90±5.87 mm for the lateral beams.

Concluding remarks • IVD with dosimeters has limited use• Monitoring of induced secondary neutral particles for

daily treatment QA looks attractive• IVD with external devices like PET imaging and prompt

gamma (PG) imaging looks promising• Challenges remain to be overcome to make PET

imaging and PG imaging available for routine use• Proton radiography and tomography will be useful• Thermo-acoustic imaging look promising, but long way

to go to become feasible for clinical use• Many question remain to be answered for using MRI

for IVD in proton therapy

Last slide

IVD for proton therapy is a desirable goal, but remains elusive at this time.Ongoing research and developmental effort may fulfil this desire in the near future.

Thank you very much for listening.