Intraoperative detection of radiolabeled compounds using a hand held gamma probe

Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

Intraoperative detection of radiolabeled compounds using a hand held gamma probe Marcel Ricard* Institut Gustave-Roussy and U-494 INSERM, 94805 Villejuif, France

Abstract Scintillation cameras in Nuclear Medicine allow external detection of cancerous lesions after administration of a speci"c radiopharmaceutical to the patient. In some particular cases the a$nity of the tracer is su$cient to consider the use of an intraoperative probe which enables the surgeon to identify radioactive tissues. A radiopharmaceutical consists of a radioisotope bound to a carrier molecule. The radioactive emissions must represent certain criteria in terms of half-life and energy to be detected during an operation. In the "eld of intraoperative detection radionuclides like  Tc, In, I and I fall into this category. Their energy, which ranges from some 10 to 364 keV, cannot be properly detected by a single type of detector. Two technologies have been developed to yield detectors which are handy and su$ciently sensitive: semiconductor CdTe or CdZnTe to detect low energies and scintillator CsI(Tl) for higher energies. Today the intraoperative detection has been evaluated in the case of several pathologies such as osteoid osteoma, colorectal cancer, neuroblastoma, reoperation of di!erentiated thyroid carcinoma and localization of sentinel node in breast cancer and cutaneous melanoma. Obviously, the results obtained are not comparable from one indication to the other. Nevertheless, the surgeons have noted a considerable advantage in using the intraoperative probe in the case of neuroblastoma and thyroid surgery, especially when the reoperation is di$cult or the localizations are ectopic or unusual. As regards the sentinel node, this concept represents a major new opportunity in the "eld of intraoperative detection and the results actually reported in the literature demonstrate that, when it is detected, elective node excision renders the staging of the disease more accurate. In conclusion, intraoperative detection supplies the surgeon with additional knowledge to be used in correlation with the patient's medical history.  2001 Elsevier Science B.V. All rights reserved.

1. Introduction Radiopharmaceutical compounds have been used for many years in nuclear medicine both for diagnostic and therapeutic purposes. Today the * Correspondence address: Service de Physique, Institut Gustave-Roussy, 39, rue Camilles Desmoulins, F-94805 Villejuif Cedex, France Tel.: #33 (0) 142 11 46 92; fax: #33 (0) 142 11 52 99. E-mail address: [email protected] (M. Ricard).

place of this imaging modality is well established in many "elds like cardiology, neurology or oncology. The main task of Nuclear Medicine is to provide functional information regarding a particular organ (like heart or brain) or the behaviour of speci"c molecules directed against tissues containing pathological cells. Intraoperative detection exploits these properties and has been proposed early on by nuclear medicine physicians. During World War II, Marinelli et al. [1] used a Geiger}MuK ller GM tube to measure the concentration of

0168-9002/01/$ - see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 8 - 9 0 0 2 ( 0 0 ) 0 0 8 4 7 - 0

M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

P (half-life 14.3 days, E "1.71 MeV) in some @  super"cial tissue of a living patient. Immediately after this period, Low-Beer et al. [2] proposed the same method as a possible diagnostic procedure in breast tumours in situ and in 1948, Moore [3] used a radioactive diiodo#uorescein for the diagnostic and localisation of brain tumours. Strictly speaking it seems di$cult to consider these applications as true intraoperative procedures, but these "rst interdisciplinary collaborations between surgeons and physical scientists laid down the basis for intraoperative detection. Considering the usefulness of radioactivity in clinical situations it could seem curious why the development of intraoperative detection has not been more important than the one of instrumentation in the "eld of nuclear medicine. There are several explanations. First, the surgeon must clearly claim the clinical interest for a given pathology. Second, the radiopharmaceutical must be of su$cient speci"city to allow a good signalto-noise ratio. Third, the radioactive emission must be well suited in terms of half-life and energy to be detected during an operation. Fourth, the probe must be able to detect the radiation with a good e$ciency given that the measurements are made at room temperature. Finally, the whole device must be designed to take into account the particular constraints of surgical procedures regarding probe size and shape, the versatility of associated electronics and the need to work with sterile instruments. During the 1950s the joint development of radionuclides and detectors enabled the surgeons to apply intraoperative detection in "elds which had not been explored before. The "rst intraoperative use of current radiation technology was published by Harris et al. [4] in 1956. In this paper the authors described the detection of I in the case of recurrent thyroid tumour using a CsI(Tl) detector with a light guide. However, the "rst localisation achieved by a surgeon holding a radiation detector is probably that of an osteoid osteoma [5}7]. As this benign osseous tumour is able to concentrate some bone-seeking tracer like HydroxyMethyneDiPhosphonate (HMDP) labelled with  Tc a conventional NaI(Tl) scintillator may be used to detect the gamma rays at 140 keV. In the "eld of oncology the concept of monoclonal

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antibodies which are macromolecules targeting cancer-speci"c antigens, encouraged some workers to evaluate the intraoperative detection of colorectal cancers. Two radionuclides were mainly investigated: I [8,9] and In [10,11] using detectors based on scintillator or CdTe. Unfortunately, the poor speci"city of monoclonal antibodies raised little enthusiasm in the medical community regarding the development of these new molecules. At the same time other speci"c molecules have been evaluated for neuroblastoma [12], pheochromocytoma [13,14], neuroendocrine [15] or carcinoid [16] tumours and for persistent or recurrent thyroid carcinoma [17]. Even if the real clinical interest has not yet been well established regarding all the previously listed applications, it is certain that the improvements of the probe and the associated electronics have led to more adaptable devices. Today the real enthusiasm with regard to the sentinel node localisation in breast cancer [18}20] and cutaneous melanoma [21] has been partly made possible because well-suited probes are now available. This major new opportunity which is the subject of many publications in the principal medical journals, is based on the concept that the sentinel node is the "rst draining lymph node of a tumour, thus indicating probable lymphatic metastases and completing the staging of the disease. In intraoperative detection the probes must be able to cover a wide "eld in terms of sensitivity, domain of energy, handling and so on with respect to the particular context of their use. This paper reports on the main physical considerations taken into account by contributors to build probes well adapted to the surgical request.

2. Radionuclides and probes Most of the tumours identi"ed clinically and detected in Nuclear Medicine after administration of a speci"c radiopharmaceutical may be investigated by intraoperative detection when they require a surgical treatment. This means that a great number of radiopharmaceuticals present a potential interest. For intraoperative use the best compromise must be found regarding both, the type and energy of the particles emitted, as well as the

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M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

Table 1 Physical properties of the main radionuclides used in the "eld of intraoperative detection

Half-life Type of emission Energy (keV) Intensity of emission (%)

I

I

I

In

 Tc

13.2 h Gamma rays 158.97 83.3

59.9 days X and gamma rays From 27.2 to 35.49 Max 73.2 at 27.4 keV 6.7 for gamma rays

8.0 days Gamma rays 364 81.6

2.8 days Gamma rays 171.28 and 245.35 90.2 and 94.0

6.0 h Gamma rays 140 89.0

Restricted to the emission helpful for intraoperative detection.

half-life of the radionuclide. Ideally, the particle range must be su$cient to be detected at a distance from the point of emission but remain weak enough to avoid any signal from non-speci"c distant uptake; from this point of view I is well suited. The half-life must be chosen so that the biological behaviour of the radiopharmaceutical respects the rules of protection against radiation. From this point of view  Tc is unquestionably the best candidate. In addition, the labelling constraints for a given molecule must be taken into account in order to avoid any drop in biological e$ciency. Practically, the intraoperative probes can detect X- and gamma rays from a few keV I to more than 300 keV I as shown in Table 1. In summary, the properties of the material used to build the intraoperative probe must be well suited to the particular context of its application (shape, sensitivity, etc). In particular, the detector must be able to work at room temperature and protected against electromagnetic disturbances. It must detect X- and gamma rays with a good e$ciency and be shock resistant. Based on the scienti"c knowledge, the industrial development and above all the harnessing of gamma camera technology, the "rst detectors were NaI(Tl) or CsI(Tl) scintillators equipped with an optically coupled photomultiplier (PM) tube. In this type of detector, the scintillator absorbs the radiation and emits visible light in proportion to the energy absorbed. The visible light is then measured by means of the PM tube. Due to the size of the PM tube available when this solution was proposed (2.54 cm in diameter) a light pipe or "bre optic [22, 23] was employed to couple optically the PM tube with the smaller scintillator, in order to

Fig. 1. Typical spectrum of a CdTe detector.

reduce the active size of the probe and so increase its spatial resolution. Since smaller PM tubes or other devices like photodiodes are now available the collection of the light emitted by the scintillator has been improved. This leads to an improvement in energy resolution and rejection of scatter gamma rays (Compton events). From this point of view, semiconductors based on CdTe or CdZnTe (CZT) are good candidates. They o!er a high absorption coe$cient under a small volume due to their composition (Cd: 48, Te: 52, Zn: 30) as well as a good energy resolution at room temperature (Fig. 1) compared to a scintillator. In addition, these detectors can operate under low bias voltage. Unfortunately, these attractive characteristics are obtained when the thickness of the detector does not exceed 2 mm,

M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

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Table 2 Main characteristics of the detectors frequently mentioned in the literature Main characteristics

NaI(Tl) e"10 mm

CsI(Tl) e"10 mm

CdTe e"2 mm

CdZnTe e"2 mm

HgI  e"2 mm

CdWO  e"10 mm

Z g cm\ Energy per electron}hole (eV) at 300 K E$ciency at 122 keV

11}53 3.67 *

55}53 4.51 *

48}52 6.06 4.43

48}30}52 5.78 4.63

89}53 6.40 4.15

48}74}8 7.90 *

1

1

0.6

0.5

0.7

1

Response normalised at 1 for 10 mm NaI(Tl) detector.

which results in a lack of e$ciency when the energy of the gamma rays increases. When the thickness of the detector is larger (up to 3 mm) and it is employed in the pulse counting mode } as is usual for intraoperative application } a low-energy tailing e!ect a!ects the spectra which diminishes the scatter rejection. Of course, signi"cant progress has been made in the "eld of industrial engineering, for instance the high-pressure Bridgman CZT have more favourable characteristics, particularly in terms of resistivity. Table 2 shows some of the characteristics of the main detectors today available for X- and gamma ray detection. In clinical practice these physical considerations do not have a great impact on the performance of the probe compared to all the other unfavourable factors likely to interfere with the measurements. One of the main factors disturbing the measurement during an operation is the presence of unwanted photons due to non-speci"c uptake (radiopharmaceutical metabolism or radiation at distance of the point of injection). This plays a signi"cant role, especially when the radionuclide is a high-energy gamma ray emitter like I or In (Table 1). The high penetration power of gamma rays means that background events could come from any part of the patient. Thus, the ability to select only the photons from the point of interest is the main characteristic of the probe to avoid false positive information, as pointed out by Alan Britten in his excellent paper [24]. Thus, whatever the detector (scintillator or semiconductor), it is often necessary to protect it by using a collimator of heavy material like tungsten or tungsten alloy. The use of a collimator restricts the "eld of view of the

probe, except in the direction of the point of interest. Most of the collimators described in the literature appear like a hollow cylinder, so that the gamma-sensitive part of the probe is fully protected except at its tip. This is a very important point, since less than a few percent of the isotope are in the tumour or a node, leading to a signi"cant background radiation from the rest of the body. For instance, in the case of sentinel node localisation in breast cancer, the amount of radioactivity in the node is less than 1% of the total injected activity in the periphery of the tumour. As it is not unusual that the sentinel node is localised close to the tumour, the surgeon needs a well collimated probe. For example, Fig. 2 shows a diagram of a probe using a collimator of 5 mm tungsten alloy, but with a shielding leakage of about 3% in a particular direction.

3. Main surgical probes and manufacturers From the moment on intraoperative detection has been included in clinical practice, all of the detection devices manufactured use either a scintillator or a solid state detector. Today some manufacturers are able to o!er some compact devices for intraoperative localisation. Usually, these devices are made up of one or more probes connected to an electronic control unit indicating both a visual and sonorous information proportional to the counting rate. Concerning the market and in alphabetical order, the main products today available are provided by Auto Suture (Navigator), CareWise (C-Trak), Eurorad (EUROPROBE sold as GAMMED 4 by Capintec in the United States) and

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M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

Fig. 2. Angular response of a commercial CsI(Tl) probe;P(a) axis of the probe;P(b) shielding leakage (C 3%).

whole industrial process from detector to electronics. In the "eld of CdTe Eurorad has supplied some companies like Neoprobe or RMD during many years before CZT. The device from Eurorad can accommodate two probes. The "rst is a CdTe detector for low- and middle-energy range, the second a CsI(Tl) linked to a silicon photodiode for middle- and high-energy range. Quality assurance tests can be carried out with a commercially calibrated source which can be placed in a specially designed `probe-sourcea holder, to perform the accurate measurements. Usually Co is preferred to  Tc and Ba to I, because their longer halflife facilitates the constancy tests. In addition, the spectrum measured by the probe may also be displayed by the electronic device. 3.4. System from Neoprobe

Neoprobe (Neoprobe 1500 & neo2000). The Table 3 summarises their main characteristics. 3.1. System from Auto Suture The intraoperative system proposed by this company is based upon the previous works of Radiation Measurement Device (RMD). As the probe uses a CdTe detector, it is well adapted for the detection of gamma and X-rays from a few keV I to 140 keV  Tc As a matter of fact, due to the loss of sensitivity with energy increase, it seems di$cult to extend the application to above 200 keV. 3.2. System from CareWise For many years this manufacturer has been proposing a detection device which is able to accommodate three probes using a NaI(Tl) scintillator and a photomultiplier tube. Although this technology allows to detect the whole range of energy covered by Nuclear Medicine, only CareWise is still using it. This is probably due to the high sensitivity of the PM tube regarding shocks and electromagnetic perturbations. 3.3. System from Eurorad Among all the intraoperative device providers, Eurorad is probably the only one able to handle the

Initially, this company developed the Neoprobe 1500 to perform the intraoperative localisation of monoclonal antibody labelled with I in the case of metastatic colorectal cancer. The neo2000 is an evolution of this "rst system with signi"cant improvements in spectrometric capabilities. At the beginning Neoprobe worked with CdTe detectors today replaced by CZT for all the probes. Regarding the performance of the intra-operative gamma probe, Alan Britten [24] proposes a method based upon standard sensitivity and spatial resolution measurements at depth in water. Unfortunately, the method described in this paper is mainly directed toward lymph node localisation and does not take into account isotopes other than  Tc. Its conclusions clearly showed di!erences regarding the performances of the probes which can be transposed to practical use. Nevertheless, the concepts described by Britten may be considered as a standard to compare the probes even when another isotope has to be detected.

4. Potential evolution of intraoperative probes Regardless of the evolution of imaging probes } which are not the purpose of this paper } the commercially available gamma probes for intraoperative uses are generally based on a single

NaI(Tl)

CdTe

CareWise C-Trak

Eurorad EUROPROBE

CZT

CZT

Neoprobe 1500

neo2000

CsI(Tl)

CdTe

Detector

Auto suture NAVIGATOR

Manufacturer and type

Non-collimated probe plus additional collimators

Internal & additional collimators

Non-collimated probe plus additional collimators

Internal collimator

Collimator

10}180

120}500

20}200

80}500

10}200

Energy range (keV)

Table 3 Manufacturers and properties of intraoperative probes

Threshold & window

Threshold

Threshold & window

Threshold & window

Threshold

Spectrometry

14

10

16

11

15 19 25

10 14

External diameter (mm)

Battery

Battery

Battery

Battery

Power supply

Variable frequency

Variable frequency or pulse signal

Pulse

Variable frequency or pulse signal

Audio output

Digital & bargraph

Digital & bargraph

Digital & analogical

Digital & LED

Display

No

Yes

No

No

Spectrum display

M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33 31

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M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

Fig. 3. Front view of the four detector gamma probe.

scintillation crystal (NaI(Tl), CsI(Tl)) or semiconductor detector (CdTe or CZT) having a size ranging from 5 to 20 mm in diameter. The localisation of the hot spot is achieved by searching for the maximal counting rate. This simple but coarse method is easy to carry out when the speci"city of the radiopharmaceutical provides a high signal and/or signal-to-noise ratio, as in sentinel node localisation. In some less favourable cases it is sometimes di$cult to "nd the hot spot. To improve the performances of these single detector gamma probes, Dusi et al. [25] proposed a new probe based on a non-imaging approach which is characterised by a sensitive device based on a square array of four coplanar CdTe semiconductor detectors (5;5 mm}2 mm thick) as shown in Fig. 3. With this probe the hot spot is localised using the bidimentional gradient calculated from the individual response of the four detectors. In this way the measurement is less sensitive to the uniform background which is subtracted by default. The preliminary results (Fig. 4) seem very promising, more particularly in the case of small lesions (volume of a few tens of cubic millimetres or less) hidden by a background activity.

5. Conclusion In terms of industrial o!er, the manufacturers of intraoperative probes use either scintillators or

Fig. 4. Plot of d(x) against the position of a point source moved along x, when d(y)"0.

semiconductors which are well adapted for the range of energy covered by nuclear medicine. Depending upon the type of application, some particular probes and electronic devices have been designed to supply the surgeon with the best information. In all cases and for a given radiopharmaceutical, the characteristics of the mono-pixel probes are a function of the usual parameters like size of the useful "eld of view, shape and thickness of the collimator or shape and thickness of the detector. Fig. 5 shows an example of the curves of isosensitivity of a commercial product (CdTe Probe from EURORAD) when the data were obtained with a point source of  Tc being displaced inside a Lucite phantom. These results show clearly that the complete description of the probe characteristics cannot be limited by the expression of sensitivity and the point spread function in air as it had been planned. In order to compare two probes the users have to know their whole behaviour in the presence of attenuation and scatter which are closely related to the general design of the probe. At the present time, the intraoperative probe technique is well established in some indications particularly for sentinel node localisation (breast cancer and cutaneous melanoma). Moreover, a number of new applications are currently being

M. Ricard / Nuclear Instruments and Methods in Physics Research A 458 (2001) 26}33

Fig. 5. Curves of iso-response for a CdTe probe when a point source of  Tc is moved inside a tissue equivalent phantom (useful "eld of view of the probe 5 mm-spectrometry 110}170 keV).

assessed. In particular, the development of somastotatin receptors like pentetreotide labelled with In may increase the demand for intraoperative nuclear medicine. In any case, intraoperative detection supplies the surgeon with additional knowledge to be used in correlation with the patient's medical history. Acknowledgements The author is grateful to Mrs. Ingrid Kuchental for helpful discussion during the revision of the manuscript.

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[4] C.C. Harris, R.R. Bigelow, J.E. Francis, G.G. Kelley, P.R. Bell, Nucleotronics 14 (1956) 102. [5] C.L. Colton, E.D. Orth, J.G. Hardy, J. Bone, Joint Surg. 65-A (1983) 1019. [6] H.T. Harcke, J.J. Conway, M.O. Tachdjian, L.S. Dias, H.B. Noble, G.D. MacEwen, S. Weiss, Skeletal Radiol. 13 (1985) 211. [7] M. Wioland, A. Sergent-Alaoui, Eur. J. Nucl. Med. 23 (1996) 1003. [8] E.W. Martin Jr., J.P. Minton, L.C. Carey, Ann. Surg. 202 (1985) 310. [9] A. Sardi, M. Workman, C. Mojzisik, G. Hinkle, C. Nieroda, E.W. Martin Jr., Arch. Surg. 124 (1989) 55. [10] C. Curtet, J.P. Vuillez, G. Daniel, G. Aillet, A. Chetanneau, J. Visset, M. Kremer, P. TheH drez, J.F. Chatal, Eur. J. Nucl. Med. 17 (1990) 299. [11] B.R. Davidson, W.A. Waddington, M.D. Short, P.B. Boulos, Br. J. Surg. 78 (1991) 664. [12] H. Martelli, M. Ricard, M. Larroquet, M. Wioland, F. Paraf, M. Fabre, P. Josset, P.G. Helardot, F. Gauthier, M.J. Terrier-Lacombe, J. Michon, O. Hartmann, M.D. Tabone, C. Patte, J. Lumbroso, M. GruK ner, Surgery 123 (1998) 51. [13] C.A.G. Proye, B.M. Carnaille, J.B.E. Flament, C.A. Hossein-Foucher, P.P. Lecou!e, X.M. Marchandise, S. Lennquist, Surgery 111 (1992) 634. [14] M. Ricard, F. Tenenbaum, M. Schlumberger, J.P. Travagli, J. Lumbroso, Y. Revillon, C. Parmentier, Eur. J. Nucl. Med. 20 (1993) 426. [15] W.J. Schirmer, T.M. O'Dorisio, T.P. Schirmer, C.M. Mojzisik, G.H. Hinkle, E.W. Martin, Surgery 114 (1993) 745. [16] B. Meunier, J. Le Cloirec, L. Dazord, J. Leveque, T. Lesimple, P. Tas, P. Bourguet, Eur. J. Nucl. Med. 22 (1995) 281. [17] J.P. Travagli, A.F. Cailleux, M. Ricard, E. Baudin, B. Caillou, C. Parmentier, M. Schlumberger, J. Clin. Endocrinol. Metab. 83 (1998) 2675. [18] A.E. Giuliano, D.M. Kirgan, J.M. Gunther, D.L. Morton, Ann. Surgery 220 (1994) 391. [19] J.J. Albertini, G.H. Lyman, C. Cox, T. Yeatman, L. Balducci, N. Ku, S. Shivers, C. Berman, K. Wells, D. Rapaport, A. Shons, J. Horton, H. Greenberg, S. Nicosia, R. Clark, A. Cantor, J. Am. Med. Assoc. 276 (1996) 1818. [20] A.E. Giuliano, J. Surgical Oncol. 62 (1996) 75. [21] J.C. Axel, D.L. Weaver, J.T. Fairbanks, B.S. Rankin, D. Krag, Surg. Oncology 2 (1993) 303. [22] A.C. Morris Jr., T.R. Barclay, R. Tanida, J.V. Nemcek, Phys. Med. Biol. 16 (1971) 397. [23] K.L. Swinth, J.H. Ewins, Med. Phys. 3 (1976) 109. [24] A. Britten, Eur. J. Nucl. Med. 26 (1999) 76. [25] W. Dusi, D. Bollini, C. Moroni, M. Ricard, Proceedings of the IEEE Nuclear Science Symposium and Medical Imaging Conference, Toronto, Canada, Vol. II, 1998, 754.

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