Development of intra-operative β− probe

for cancer surgery

Ph.D. candidate: Francesco CollamatiSupervisor: prof. Riccardo Faccini

La Sapienza, Universita di RomaDottorato di Ricerca in Fisica, XXVII ciclo

One of the most fundamental target of each cancer surgery is the com-pleteness of the tumor resection. Even if it is obvious that a total removalof the neoplastic mass is to be considered the optimum for each procedures,there are different reasons for which this is a difficult task to be carriedout. Moreover, in some particular cases, the completeness of the resectionis crucial in determining the outcome of the patient after the surgery.

This is the case for example of neuroncology. In a patient with cerebralcancer (Fig. 1), a partial or incomplete removal significantly increases therisk of secondary tumors, which originate from residual damaged cells inthe brain. However, a complete resection of cancers is possible only in a lowpercentage of these cases, due to the difficulty to distinguish intraoperativelythe tumor’s margins.

Figure 1: NMR image of cerebral Glioblastoma (in white).

Despite the diffusion of extremely precise preoperative imaging tech-niques like NMR, and the recent development of several highly technological

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tools like neuro navigators (Fig. 2), that allows the surgeon to know wherehis instruments are in reference to the NMR image of the operating filed,such a millimetric precision is spoiled by different causes during the surgery.Firstly, the brain shift that follows the craniotomy makes pre operative im-ages no more reliable. Moreover, once the bulk tumoral mass is removed, afurther shift occurs inside the brain.

Figure 2: Left: Screenshot of a neuronavigator: the surgeon’s instruments arelocalized within the preoperative NMR. Right: Intraoperative Magnetic Resonanceapparatus.

For these reasons, a number of different techniques has been developed,ranging from Intraoperative Magnetic Resonance (Fig. 2) to ultrasoundand fluorescence-guided surgery. Even so, in most cases the percentage ofincomplete resection remained high.

Another field in which a complete resection is highly desirable is Pediatricsurgery. When dealing with children, it is fundamental for the surgery tobe both complete and conservative, avoiding to remove unnecessary healthytissue, being one of the most difficult task for the surgeon for example thediscrimination between healthy and damaged lymph nodes.

During my PhD thesis I will investigate a possible technique to fulfillthese requirements. This method is based on the labeling of neoplastic cellswith a radioactive isotope, identifying it’s decay by means of a small detector(named “probe”) to be used by the surgeon itself within the operation.

This approach is not new. The idea of employing a hand-held radiationdetector to assist the physician in locating and removing tumors was partof the fallout from the Manhattan project.

In the last years, “gamma probes” (Fig. 3) have gained a certain diffu-sion, mainly because they are easy to design and projecting, being photondetector so widespred, and also to the presence of a well known and testedknow-how about tracers that can be used with such a probe (99Tc,18F).

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Figure 3: A commercially available probe for intraoperative detection of photonsand its utilization in breast surgery

Moreover, there are other probes specially designed to detect positrons fromisotope decay [4], but these ones have not gained wide diffusion, due tointrinsic drawbacks of positron decay. Working with positron decaying iso-topes, in fact, brings to a highly gamma contaminated environment, due topositron annihilation in tissue.

The last possibility to explore is the detection of electrons. Between allthe mentioned approaches, this is the less diffused today. It must be saidthat it was in this direction that the first steps toward an intraoperativescanning were moved decades ago. In fact, the first attempts were carriedon using 32P as decaying isotope, and detecting the emitted electron usinga simple Geiger-Muller tube (Fig. 4).

Anyway, technology and physics know how where not developed enoughat the time for such a tricky application, carrying to a too much high doseto be administered to the patient to have a sufficient signal [1], [2], [3]. Mythesis aims at demonstrating that the limitations of this approach have nowbeen overcome.

On the other hand, detecting electrons is extremely advantageous forseveral reasons, with respect to photons and positrons. Firstly, directlydetecting emitted electrons, a much higher spatial resolution is achievable.MeV electrons indeed can travel in the tissue for about 2 mm, maintaininghigh proximity with the production point. Such a high resolution can be ofoutstanding significance in detecting small amounts of neopastic cells, andin a precise identification of tumor boundaries.

Secondly, β− particles constitute a much more specific signal for theprobe compared to photons, being the background for electrons from thebody and the environment very weak.

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Figure 4: Photograph of the earliest GM tubes used as intraoperative probes.

On the other side, the main drawback for this technique is the lack ofwell known, tested and protocoled radio tracers, being β− emitters differentfrom β+ ones. There is thus the necessity to find new compounds to use asisotope carriers, with particular affinity with desired kinds of tumors.

The other open question is the detection of electrons, which requires atotally different approach from the one to detect photons.

In my PhD Thesis, I will study the design and realization of a probe fordetecting β− particles for intraoperative scannig, focusing on this last issue.

One crucial point of this technique is the ability to maintain low the dosetransferred to both the patient and the surgeon. In fact, whereas the for-mer does not represent a real problem, being the injected dose considerablysmaller than the ones used in diagnostics, the physician exposition can bean issue, due to its repetitions.

In order to keep these doses adequately low, a very sensitive probe isnecessary. For this reason, I will analyze different scintillating materials,measuring their physical properties (light yield, attenuation length) withthe aim to choose the most suitable one.

The first material I have started to study is Para-Terphenyl. This isa aromatic hydrocarbon isomer, formed by three benzene rings in orthoposition. Though polychlorinated terphenyls were used as heat storage andtransfer agents, p-terphenyl is currently under investigation as a material tobe used in opto-electronic devices, such as organic LED devices (OLEDs) [5]and currently used in laser dyes and sunscreen lotions. In particle physicsit has been used as a wavelength shifter, exploiting its sensitivity to VUVradiation, to read out scintillation light from liquid Xenon. P-terphenyl hasalso been used as a doping component for liquid scintillators [6, 7].

The most peculiar characteristic of this material is that the ScintillationLight Production depends on the doping itself, and can be increased at the

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cost of shortening the Light Attenuation Length. Due to this, the crystalswe studied have short λ, due to reabsorption of scintillation light (Fig. 5).In fact, a short light attenuation length could be a counter-indication for

T (mm)3 4 5 6 7 8 9

RLY

e

0

1

2

3

4

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Figure 5: Light yield (in arbitrary units) of p-Terphenyl versus scintillated thick-ness

common uses of scintillators, where the scintillating material is also thetransport mean for the scintillation light. However, different approachescould benefit from this property. In particular, detection of low energycharged particles does not require thick scintillators and can therefore copewith small attenuation lengths.

The response of a low Z, high LY and short λ scintillator to low energyelectrons, photons and αs is an unexplored field that will be studied in myPhD thesis.

In addition to the choice of the material, a strong optimization of thewhole apparatus is needed. For example, a matrix configuration of morecrystals could allow to gain information about signal directionality (Fig. 6).It is possible to conceive a two-probe system: a large ”matrix” one for thefirst, fast scan, and a second smaller one for precise identification of margins.

Furthermore, I will examine the response of this probe to the expectedsignal for radio-tracer electrons, optimizing electronics and data acquisitionsetup. For this purpose, a Monte Carlo simulation has been set up. Us-ing FLUKA, I have simulated different prototypes of probe, studying theirresponse to different sources, taking into account optical effects due to scin-tillation. In such a way it is possible to compare different geometries and

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Figure 6: Possible geometrical configuration of the β− probe. On the left, a singleP-Terphenyl crystal laterally shielded with PVC to gain frontal directionality; onthe right, a matrix configuration, allowing segmentation and directionality

configuration, in addition to various materials for the detector.A Monte Carlo simulation will be also necessary in the further to estimate

the total dose to the surgeon, when all the others parameters will be fixed.On this project several collaborations are starting with different institu-

tions: Carlo Besta foundation in Milan, and Ospedale Pediatrico BambinGesu in Rome.

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References

[1] Moore G.E., Use of radioactive diiodofluorescein in the diagnosis andlocalization of brain tumors, Science. 107: 569-571 (1948), 621

[2] Selverstone, B., and Solomon, A. K. , Radioactive isotopes in the studyof intracranial tumors, Trans. Am. Neurol. Ass. 73: 115-119 (1948)

[3] Low-Beer, B. Surface measurements of radioactive phosphorus inbreast tumors as a possible diagnostic method., Science 104: 104:399(1946)

[4] Bonzom, S. et al., An Intraoperative Beta Probe Dedicated to GliomaSurgery: Design and Feasibility Study., Nuclear Science, IEEE Trans-actions on 54: 30-41 (2007)

[5] H. Sasabe, J. Kido, Multifunctional Materials in High-PerformanceOLEDs: Challenges for Solid-State Lighting, Chem. Mater. 23 (2011),621

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[8] G. Battistoni et al., The FLUKA code: Description and benchmarking,Proceed. of the Hadronic Shower Simulation Workshop2006, (2007),aIP ConferenceProceed. 896(2007)3149.

[9] A.Ferrari, P.R.Sala, A.Fasso’, J.Ranft, FLUKA: a multi particle trans-port code, Tech. Rep. CERN-2005-10, INFN/TC05/11, SLAC-R-773(2005).

[10] E. Browne and J.K. Tuli, Nuclear Data Sheets for A = 137, NuclearData Sheets, n 10 (2007), vol 108, pp 2173-2318

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