Binary therapies

in the treatment of cancer

translational research

from the physics

laboratory to the clinic

Stuart Green

University Hospital Birmingham and British Institute of Radiology

STFC Innovations

Birmingham, January 2010

Overview of techniques and projects

• External beam treatments

– X-ray therapy

– Proton and ion beam therapy

• Binary therapies

– Boron Neutron Capture Therapy

– High Z enhanced radiotherapy

• Systemic treatment

– Targeted radionuclide therapy

– chemotherapy

localised

disease

locally spread

disease

Systemic disease

Boron Neutron Capture Therapy

Cell

B 10

neutrons

B 11

Li7

0.84 MeV

alpha

1.47 MeV

photon

0.478 MeV

Ion combined range ~ 8-9µµµµm . Cell diameter ~ 10 µµµµm.

=> radiation damage mostly within cell

Plot is from Kiger et al, Journal of Neuro-Oncology 62:171-186 (2003)

Typical 10B concentrations, 15 µg/g in Blood and Brain, 52.5 µg/g in Tumour

BPA administered is approx 20g for an average person.

BPA pharmacokinetics

Photon Capture Therapy (PCT) - Physics

• Physics of the photo-electric effect is well known

• Energy not used to overcome binding is liberated as

electron kinetic energy (so range is tuneable?)

• Cross section increases roughly as Z4, and decreases

as 1/E3

• Introduction of a high Z material preferentially into a

tumour can significantly increase the local dose for

the same irradiating x-ray fluence

Photon Capture Therapy (PCT)

0.01 0.1

0.01

0.1

1

10

100

m ass absorption coeffic ient

(µ/ρ

) en

E (M eV)

I

G d

P t

A u

H20

Energies released per reaction are in the keV range (for BNCT, they

are in the MeV range) and both are cross-section driven

For similar dose enhancements, PCT requires local contrast agent

concentrations which are approx 1000 x those required for BNCT

Key requirements for binary therapies

• Efficient contrast agents with large interaction

difference from normal body materials

• Contrast agent with very low toxicity (to allow

administration at very high levels)

• Contrast agent must preferentially

accumulate in tumour cells

• Tumour must be accessible to the beam

(epithermal neutrons or low energy photons)

• But do they work?

Dose enhancement through high-Z targeted RT

EMT-6 mammary carcinomas in mice1.9nm Au particles administered IV up to 2.7 g Au/kg in phosphate buffered saline250 kVp RT, 30 Gy single fraction

Hainfeld et al., PMB, 49: N309, 2004

PCT and BNCT Comparisons for F98 Tumour model

F98 glioma model is the best we have of an infiltrating tumour

BNCT and PCT are the only techniques which have achieved cures in the

tumour model

But it is still a very controlled system without the complexity of a real human

tumour

Glioblastoma - clinical course

post-surgery

Head trauma

9M before

9M

Mild headache

Post-chemo-

radiotherapy

Courtesy of Tetsuya Yamamoto, Tsukuba, Japan

Walker et al. J Neurosurg 49 (1978) 333-343

A - surgery alone

B - surgery + chemotherapy

C - surgery + radiotherapy

D - surgery + chemo + R/T

Su

rviv

al

(%)

Glioblastoma Multiforme

Prognosis improvement in the last 30 years

Stupp et al., N Eng J Med 352 (2005) 987-996

Disease progression or recurrence through lack of local control

BNCT plus XRT

3-step cone-down

XRT plus boost

Conventional XRT

Dose escalation studies for GBM

EdemaMain Tm

11Courtesy of Tetsuya Yamamoto, Tsukuba, Japan

Medical Physics Building

Cyclotron vault

Dynamitron

Protons

NeutronsLi target, Beam moderator / shield

Maze

Neutron generation and moderation

scanned proton beam

shield

graphite reflector

FLUENTAL moderator / shifter

Li target

lead filter

heavy water cooling circuit

Neutron source is > 1 x 1012 s-1

Cut-away of Birmingham beam shaping

assembly

Li target during fabrication

Thermal neutron intensity map

20 40 60 80 100 120 140 160 180 200

20

40

60

80

100

120

140

160

0.5

1

1.5

2

2.5

3

3.5

4

x 10-4

Thermal neutrons per source neutron

Clinical Experience (Approx data to 2008)

Facility Approx. patients

(compound)

Tumours treated

Japan (various) >300 (BSH / BPA) Mainly GBM

Brookhaven, NY 54 (BPA) GBM

MIT, Boston 28 (BPA) GBM, melanoma (extremity and

brain)

Espoo, Finland >150 (BPA) GBM, Head and Neck

Studsvik, Sweden 52 (BPA) GBM

Pavia, Italy 2 (BPA) Metastases in liver

(ex -vivo)

Petten, Netherlands 34 (BSH) GBM, melanoma mets in brain

Rez, Czech Republic 5 (BSH) GBM

Barriloche, Argentina 7 (BPA) Melanoma of skin

BPA accumulation via the Phenylalanine transport mechanism

• Uptake of amino-acids into cells is surprisingly poorly understood

• Thought to be selectively transported across the blood brain barrier, endothelial cells and astrocytic cells by a common LAT-1 transporter system.

• LAT-1 is up-regulated in tumour cells and might be expected to enhance the concentration of L amino acids particularly in tumour cells.

Results for counted stained cell populations

in GBMs

A

0

10

20

30

40

50

60

70

80

90

100

LAT + PCNA+ LAT + PCNA+

LAT+ X-Bar = 72.6 ± 16.9

PCNA+ X-Bar = 22.8 ± 16.9

LAT+ PCNA

+ X-Bar = 4.8 ± 2.2

n = 29

60-90 % of tumour cells express LAT-1

A much lower proportion are proliferating

Slide courtesy of A Detta, Detta and

Cruickshank, Cancer Res 2009

BNCT Clinical Results from Tsukuba15 patients only

Overall Survival Time

Time to progression

BNCT alone

BNCT + XRT

Walker et al. J Neurosurg 49 (1978) 333-343

A - surgery alone

B - surgery + chemotherapy

C - surgery + radiotherapy

D - surgery + chemo + R/T

Su

rviv

al

(%)

Glioblastoma Multiforme

Prognosis improvement in the last 30 years

Stupp et al., N Eng J Med 352 (2005) 987-996

Disease progression or recurrence through lack of local control

The Tsukuba approach

Courtesy of Tetsuya Yamamoto, Tsukuba, Japan

Final thoughts

• Different treatment strategies are required depending on the type, stage and degree of spread of the cancer to be treated

• Binary therapies are aimed specifically at tumours which exhibit a high degree of infiltration into the surrounding healthy tissues

• Binary therapies are still at a very early stage of development (patient numbers for BNCT still < 1000)

• They require input from a wide range of scientific disciplines

• They are ripe for investment and provide a great opportunity for the UK to take a lead

• Can we afford to miss this opportunity ? (as we did with particle therapy)

• What can UK Research Councils do to help ?

Collaborations and Acknowledgements

UHB Trust: Profs Alun Beddoe and Bleddyn Jones (now Oxford), Drs Cecile

Wojnecki and Richard Hugtenburg (now Swansea Uni), Dr Spyros

Manolopoulos (ex STFC)

University of Birmingham: Profs David Parker and Garth Cruickshank, Drs

Monty Charles and Andy Mill

University of Oxford: Dr Mark Hill

PhD students: Zamir Ghani, Ben Phoenix, Shane O’Hehir, Adam Baker and

Mohammed Sidek

Funding bodies, EPSRC, CR-UK, UHB Charities

Work of Biston et al, Cures of rats bearing radioresistant F98 Glioma

tumours

• F98 glioma model is the best we have of an infiltrating tumour

• Pt-based chemotherapy drug (CDDP) administered via intra-tumoral injection (3 mg in 5 ml saline)

• Synchrotron irradiation at various energies above / below Pt K-edge

• Best median survival times at 78.8 keV (above Pt K-edge) = 206 days

• Best previous results for this tumour model are with BNCT where median survival time = 72 days (Barth et al, IJROBP 2000, 47, 209-1218)

CANCER RESEARCH 64, 2317–2323, April 1, 2004

This success has lead to further work to plan human clinical trials, although big questions remain on the nature of the observed effect

high Z

SR

1. Administration of a high Z element

therapy either via physical dose enhancementalone or from combination with chemotherapy (administration of a platinum chemotherapy drug)

beam fitted to the tumour size tumour = center of rotation monochromatic beam

2. Irradiation in tomography mode

Synchrotron Stereotactic Radiotherapy (SSR)

S

R

From the work of Boudou et al based around ESRF, Grenoble

34keV 50keV

85keV

iodine 10mg/ml

TomoTomoTomoTomo----irradiationirradiationirradiationirradiation• beam thickness: 2 cm• beam width: 2 cm

Isodose lines: red = 90%, green = 50%, blue=25%

6 MV, no iodine

Doses to Tumour and normal cells

Radiobiology of BNCT

For the reaction products (7Li and α particles) in BNCT, there is a

further confounding factor which relates to the uniformity, at the

sub-cellular level, of the alpha and 7Li dose which follows a neutron

irradiation

This distribution will vary depending on the carrier compound

Low CBE High CBE

Cell nucleus

Cell wall

10B atoms