Proton and Heavier-Ion Therapy:Past, Present, and Future

Richard A. Amos, FIPEM

Associate Professor of Proton TherapyResearch Lead for Translational Proton Therapy Physics

Department of Medical Physics and Biomedical EngineeringUniversity College London

r.amos@ucl.ac.uk

• Co-PI on Varian research grant;

• Member of TAE Life Sciences’ Scientific Advisory Board.

Disclosures:

Rationale for particle beam radiotherapy

Brief history of Proton Beam Therapy

1946: Therapeutic use of proton beams first proposed by Robert Wilson1

1Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487-491

1954: First patient treated at the UC Lawrence Berkeley Laboratory (LBL)– Treated the pituitary gland with beams passing entirely through the brain.

– Studied other ions

1957: Proton radiosurgical techniques for brain tumors developed at the Gustaf-Werner Institute, Uppsala, Sweden

– First to use range modulation

1961: Radiosurgery of small intercranial targets at the Harvard Cyclotron Laboratory (HCL)

70s – 80s: Physics facilities worldwide – notably, the Paul Scherrer Institute (PSI) in Switzerland

1990: The world’s first hospital-based high-energy proton beam therapy facility opened at Loma Linda University Medical Center, California

2001: Clinical program moved from HCL to Massachusetts General Hospital, Boston– First to use commercially available proton therapy system

2000s - : Rapid growth in number of proton facilities internationally

Personal US experience in proton beam therapy

2002 – 2005: 2005 – 2013:

•First hospital-based high-energy proton therapy facility in the world.•First patient treated in 1990•18,362 patients treated by end of 2014*

•World-leading cancer treatment and research center.•Proton Therapy Center opened in 2006•First in the USA to treat with PBS in 2008•5,838 patients treated by end of 2014*

*Int J Particle Ther. 2015;2(1):50-54

•250 MeV synchrotron developed in collaboration with Fermi National Accelerator Laboratory•3 gantries (passive scattering)•1 fixed clinical beamline (passive scattering)•1 fixed ocular beamline (passive scattering)•1 fixed experimental beamline (passive scattering)

•250 MeV synchrotron (Hitachi PROBEAT system)•3 gantries (2 passive scattering + 1 pencil beam scanning)•1 fixed clinical beamline (passive scattering)•1 fixed ocular beamline (passive scattering)•1 fixed experimental beamline (passive scattering)

beamlineenergy selection system (ESS)

rotating gantrytreatment room

250 MeV cyclotron

Zakrzewska P, Pitt M, Amos RA, D’Souza D & Ahmed T.

Application of building information modelling (BIM) in the design, construction, and operations

management of a complex proton beam therapy facility in central London.

Proceedings of PTCOG 54. Int J Particle Ther. 2015;2(1):331-332

Cyclotron Synchrotron

Single-room proton therapy system:

Gantry-mounted 250 MeV synchrocyclotron

Capital cost:• Increased access to proton

therapy for patients• More clinical data

• Increased availability of research facilities

• Detector development• Radiobiological data• ….

Compact/modularity:• Construction and installation• Ease of maintenance

Reduced shielding:• Space and cost

Performance characteristics:• Motion mitigation techniques• Fast adaptive delivery• …..

Patient treatment in seated position?

CT scanner

Beam delivery system: Passive scattering

Beam delivery system: Pencil beam scanning

The PTV problem for proton beams

•Concept of GTV and CTV are the same for protons as they are for photons.

•Individual photon beams can only be geometrically conformed to the target in the plane perpendicular to the beam axis.

•Individual proton beams can be conformed to the target in three dimensions:

•Perpendicular to beam axis – aperture

•Parallel to beam axis – range and SOBP

•PTV concept does not directly apply to proton therapy planning.

•Single PTV is possible with multiple 2D projections

•Beam specific PTV’s necessary for protons

•Concept of treated and irradiated volumes remain consistent for both modalities, however their shape will differ.

Beam-specific distal margins (DM) and proximal margins (PM) giving rise to the concept of a “beam-specific PTV (bsPTV)” for each field.

Lateral margins (LM) for both fields, similar in concept to the standard photon PTV.

“Beam-specific PTV” concept

Advantages of scanned beam delivery

1. Can “paint” any physically possible dose distribution.

2. Uses protons very efficiently as compared to passive scattering in which more than 50% of protons have to be “thrown away”.

3. Generally requires no patient-specific hardware.

4. The neutron background is substantially reduced as a result of points (2) and (3).

5. Allows the implementation of IMRT with protons – termed intensity-modulated proton therapy (IMPT)

Disadvantages of scanned beam delivery

1. The need to overcome “interplay effects” (Bortfeld, 2002)* induced by organ motion.

*Bortfeld T et al. (2002) Effects of intra-fraction motion on IMRT dose delivery: Statistical analysis and simulation. Phys Med Biol 47:2203-2220

Pencil beam scanning

Single Field Optimization (SFO)

Multi-Field Optimization (MFO)

Single Field Uniform Dose (SFUD)

Single Field Integrated Boost (SFIB)

Intensity Modulated Proton Therapy (IMPT)

VMAT IMPT

VMAT technique: 2 full arcs;5mm PTV expansion from CTV.

IMPT technique: Multi-field optimization (MFO) with 2 pencil beam scanning fields;positional uncertainty of 5mm & range uncertainty of 3% to robustly cover CTV.

Proceedings 55th International Conference of the Particle Therapy Co-Operative Group. Int J Particle Ther. Summer 2016, 3(1), 231

Advantages of scanned beam delivery

1. Can “paint” any physically possible dose distribution.

2. Uses protons very efficiently as compared to passive scattering in which more than 50% of protons have to be “thrown away”.

3. Generally requires no patient-specific hardware.

4. The neutron background is substantially reduced as a result of points (2) and (3).

5. Allows the implementation of IMRT with protons – termed intensity-modulated proton therapy (IMPT)

Disadvantages of scanned beam delivery

1. The need to overcome “interplay effects” (Bortfeld, 2002)* induced by organ motion.

*Bortfeld T et al. (2002) Effects of intra-fraction motion on IMRT dose delivery: Statistical analysis and simulation. Phys Med Biol 47:2203-2220

Positional uncertainty and anatomical variation over course of treatment

Plan robust optimization

Robustness analysis

x: +/- 5mm

y: +/- 5mm

z: +/- 5mm

Range: +/- 3%

Nominal planned dose Worse-case scenario dose diff.

Range probe / proton radiography

•Possible prior, during and after field delivery

•pCT only possible pre- or post-delivery

Prompt gamma

•Prompt γ emission within nanoseconds

•Only applicable for on-line range verification

PET

•Possible on-line, or short time after irradiation

•Biological wash-out can be an issue

MRI

•Retrospective range verification as a function

of tissue change.

Proton CT (pCT) Dual Energy CT (DECT)

• More information – greater accuracy• Reduction in CT artifacts

MRI

Dose PET

In-vivo verification

Relative biological effectiveness (RBE)

RBE is defined as the ratio of a dose of 250 kVp x-rays (DX) to

the dose of the ‘test’ radiation type (DT) required to produce the

same biological effect.

Effect may refer to cell killing, mutation, carcinogenesis, or

other end points.

For doses and end points of interest in radiation oncology,

the RBE of charged particles is > 1.0

As LET increases, radiation produces more cell

killing per Gray.

Data showing dependence of RBE on LET for

human kidney cells exposed in vitro for surviving

fraction (SF) levels of 0.8, 0.1 and 0.01.

Berendsen GW. Curr Topics Radiat Res. 1968;4:293-356

RBE of clinical SOBP beams

Distal most portion of the SOBP predominantly contains

Bragg peak high-LET particles, whereas the most proximal

portion of the beam increasingly contains higher-energy,

lower-LET particles.

RBE varies throughout the SOBP due to the changing

LET.

LET and RBE in V79 cells as a function

of depth in a 70 MeV proton beam with

a 2.5 cm SOBP.

Wouters B. et al. Radiat Res. 1996;146:159-170

RBE of clinical SOBP beams

Biological dose

Physical dose

RBE measurements in H4 mammalian

cells in vitro.

Measurements made across a 5 cm

SOBP and several mm distal to the

SOBP.

These higher RBE values extend the

biologically effective range of the beam

by 1 to 2 mm.

Robertson J. et al. Cancer. 1975;35:1664-1677

RBE determined in vitro and in vivo

All known published RBE values at all dose levels for

mammalian cell lines studied in vitro in proton beams

in the clinical energy range.

All RBE vs. dose values for acute- and late-reacting

experimental animal systems.

Paganetti1 reviewed and tabulated the data above an

determined that the average RBE was 1.1.

1. Paganetti H. et al. Int J Radiat Oncol Biol Phys. 2002;53:407-421

Generic RBE value for clinical proton beams

•No proton RBE data based on human tissue response.

•RBE factor of 1.1 applied to clinical proton beams.

DRBE = 1.1 x D

Uncertainty in RBE

Biological effect: LET based planning

Summary of Uncertainties

1

Summary of Uncertainties

2

Summary of Uncertainties

3

Summary of Uncertainties

4

Prostate

Proton therapy IMRT

PTCOG 56, 2017

Amos R, et al. Variation in dose distribution with tumor shrinkage for proton therapy of lung

cancer. Proceedings of PTCOG 46, Zibo, Shandong, China, 2007

Howell R, Amos R, Kanke J, et al.

Predicted risk of cardiac effects with modern cardiac-sparing radiation therapy techniques

Proceedings of PTCOG 53. Int J Particle Ther. 2014;1(2):617-618

Heavier-ion therapy

Electrons Protons Carbon ions

Heavy-ion facilities

HIMAC at NIRS in Japan first

to treat with C-ions in 1996

FLASH-RT: Ultra-high dose rate radiotherapy

Dose rate >40 Gy s-1

Data from:

Favaudon V, et al. Ultrahigh dose-rate FLASH irradiation increases the differential response

between normal and tumor tissue in mice. Sci Transl Med 2014; 6: 245ra93.

Dose rate ~ 5 Gy/min

Dose rate ~ 300 Gy/s

36 weeks post-irradiation of mini-pig skin:

• Conv-irradiation – severe fibronecrotic lesions

• FLASH-irradiation – normal appearance of skin

FLASH-RT for SCC

75 yr old patient with multi-resistant CD30+ T-Cell cutaneous lymphoma

FLASH-RT - 15 Gy in 90 ms

Day 0 5 Months

Proton Minibeam Radiation Therapy (pMBRT)

• Spatially fractionated proton beams – spares proximal normal tissue.

• Minibeam FWHM approx. 1 – 2mm.

• Minibeams created with either PBS or PSPT system with slit collimation.

Prezado Y. et al. Int J Radiat Oncol Biol Phys 2019 Jun 1;104(2):266-271

In conclusion, this proof of concept study shows that pMBRT may provide satisfactory treatment plans for brain

tumor patients with only one or two proton minibeam arrays delivered by an existing set-up using a multi-slit

collimator at a clinical center. The dose distribution in the target complies with the standard criteria, while the

spatial fractionation in normal tissues might significantly increase the therapeutic index.

Boron Neutron Capture Therapy (BNCT)

• First proposed by Gordon Locher in 1936.

• Patient infused with a non-toxic 10B targeting drug which selectively accumulates in

tumor cells.• Drug traditionally used is boronphenylalanine (BPA) – others now being developed

• Tumor irradiated with low energy (< 0.1eV) neutrons.

• Nuclear reaction emits 7Li-ions and α-particles.

• These high-LET ions deliver therapeutic dose to 10B-loaded cancer cells whilst

limiting damage to surrounding normal cells without 10B.

Accelerator-based BNCT clinical systems

• Early BNCT systems relied on reactor-

based neutron sources – not suitable for

hospital-based clinical facilities.

• Novel accelerator-based neutron sources

enabling a renaissance in BNCT to occur.

• Clinical systems based on low-energy

(approx. 2.5 MeV) proton accelerators.

• Research:• Dose verification;

• Image-guided targeting;

• ……

Thank you!