European Journal of

Nuclear Medicine Editorial

Peroperative nuclear medicine Alan Perkins

Department of Medical Physics, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, England

Tumours identified clinically or by external imaging fre- quently require surgical treatment. The effectiveness of such treatment is invariably dependent upon the com- plete excision of all tumour tissue. Microscopic and oc- cult disease not readily seen by the surgeon may remain in situ, ultimately leading to the patient's demise. De- spite the use of state-of-the-art imaging there are many instances where the surgeon may benefit from additional information as to the location and extent of diseased tissue. Radiopharmaceutical compounds have been used with great success for the detection of tumour tissue. The use of radiolabelled antibodies has led to recent increased interest in the peroperative technique [1 8]. However, the use of sterilizable probes for intraoperative detection of tumours is far from new. The first known studies were published by Selverstone et al. in 1949 [9], who used 30 150 MBq ~2p buffered sodium phosphate for the localization of brain tumours. Detection of the fl-emission was achieved using cylindrical GM tubes of 3 and 5 mm diameter made in the form of ventricular needles, which were sterilized in formalin prior to sur- gery. Other studies performed in the 1950s used surgical probe detectors for ocular melanoma and GI tumours [10, 11]. The first peroperative use of current radiation detector technology, the CsI(T1) detector with a light guide, was published in 1956 by Harris et al. [12] using aalI for the detection of recurrent thyroid tumours. More recently, solid-state detectors have been used for intraoperative studies [13-15].

The main intraoperative application to be accepted as standard surgical practice has been in the localization of osteoid osteoma [16]. This benign bony tumour oc- curs predominantly in adolescents. Patients experience intense pain at night, causing not only extreme discom- fort to the patient but much anxiety on the part of par- ents of young children. Symptoms may be relieved with analgesics, but surgery is the only solution and, if suc- cessful, provides a permanent cure. Since osteoid osteo- mas concentrate the conventional 99mTc bone imaging radiopharmaceuticals, they may be successfully localized using a suitable probe at operation. The paper by Kircher et al. in this tissue [17] demonstrates the reliabil- ity of the procedure after follow-up in 12 cases. The proven benefit to both the patient and surgeon is not only in the accurate delineation of the tumour, but also in knowing when the nidus has been successfully re-

moved, thus sparing normal bone tissue, which is especially important in the weight-bearing long bones.

Peroperative nuclear medicine procedures offer po- tential in the localization of a range of tumour types utilizing conventional radiopharmaceuticals (see Ta- ble 1). In addition, surgical probes have been used for detecting accessory spleen, sites of gastrointestinal bleed- ing, focal areas of myocardial damage, sites of plutoni- um deposition and a lost brachytherapy seed. A compre- hensive review article by Woolfenden and Barber [18] outlines the development of probe systems and their ap- plication in surgery. The optimization of the peropera- tive technique still leaves much room for investigation, with the choice of radionuclide and the design of intra- operative probes being the two critical factors affecting the performance of the technique.

For accurate localization it is desirable that low-ener- gy radionuclides are employed [1-3, 19]. The use of high- energy radionuclides reduces the specificity of the proce- dure since problems arise from scattered radiation from sites of high normal uptake of tracer, such as the liver [3]. The use of radionuclides having high gamma ener- gies also places a requirement on increased shielding around the detector element, making the probe heavy and bulky, thereby reducing its acceptability to the sur- geon. This therefore eliminates the routine use of lalI and 11 ~In, which have commonly been used for radiola- belling antibodies. Reports of radioimmunoguided sur- gery utilizing ~ ~ tin have concluded that the routine use of lower-energy radionuclides would be preferablein ad- dition to more specific antibodies with higher tumour to normal tissue uptake [3, 7], The use of 12~I for ra- dioimmunoguided surgery (RIGS) appeared to be at- tractive from a physical point of view [1, 2, 19], but would appear to be contraindicated for routine use be- cause of the high patient radiation-absorbed dose [3]. Regulatory authorities in at least one European state have refused permission for the use ~25I for routine use in RIGS. Radionuclides such as 99mTc and 12aI with their relatively low gamma energies would seem eminent- ly suitable for intraoperative use.

A number of surgical probe systems coupled to scaler- ratemeters are now commercially available (Table 2). Some are designed for general use while others have been produced for specific procedures, such as with ra- diolabelled antibodies (Oncoprobe and Neoprobe). The

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design of the probe itself is extremely important. The shape of the probe stem should allow access through small surgical incisions and into awkward cavities. The probe should be manufactured of high-grade metal such as stainless steel or silver anodized aluminium in order to facilitate cleaning and sterilization. The chosen meth- od of sterilization will affect the availability of the equip- ment. In most cases this is performed using ethylene oxide gas since the detectors cannot be heated using an autoclave. While the sterilization procedure is rela- tively quick, a delay of a number of days ensues in order to perform the culture tests necessary to demonstrate sterility. The use of sterile latex covers as used for intra-

Table 1. Some applications of surgical probe guided tumour detec- tion

Ligand Radionuclide Pathology

HDP 99mTc Bone lesions; osteoblastoma; Hamartoma; Brodie's abscess; demarcation of dead bone

Antibodies 99mTC, 1231, 125I Colorectal tumour metastases; ovarian tumour metastases; axillary spread from breast tumour; Head and neck cancers

MIBG ~23I, ~ 2 5 I Metastatic neuroblastoma; pheocromocytoma

Thallous chloride 2°~T1 Ectopic parathy- roid adenoma

Pentetreotide ~ ~ ~ In Somostatin receptor positive endocrine tumours, e.g. insulinoma

vDMSA 99mTc Medullary thyroid carcinoma

luminal ultrasound probes does, however, offer an alter- native means of ensuring sterility during surgery, and they are especially useful if more than one patient is to be operated on during a theatre session.

The detector elements that have been employed are generally NaI(T1), CsI(Na) or solid state such as CdTe, with a signal preamplification stage housed in the probe handle, thus obviating any problems from stray signal detection within the cable or extended light guide where problems have previously been experienced [14]. Crystal sizes are commonly of the order of 10 mm diameter, with collimation giving a detector aperture of 5 mm di- ameter or less. The directional properties of the detector are crucial and will only be adequate providing the crys- tal is effectively shielded at the back and sides. The sensi- tive volume of the probe should be well defined. There should be good lateral discrimination at a superficial depth, with a rapid decrease in response with increasing depth to limit the detection of activity contained in deeper structures [15, 20]. The probe characteristics can be determined from phantom studies. A number of workers have performed in vitro studies using hot spheres in a tank of varying background concentrations of activity, giving T:NT uptake ratios of the order achieved in vivo [3, 17, 20]. In theory, intraoperative tumour detection should be more sensitive than conven- tional external scintigraphy. Comparison of clinical and surgical studies using radiolabelled antibodies is difficult since studies have been undertaken using different anti- bodies with different radionuclides. Studies from Mar- tin's group at the Ohio State University have found that use of the intraoperative probe using lzSI-labelled B72.3 antibody altered the surgical procedure in 26% of pa- tients with colorectal carcinoma [1, 2]. The practical findings of detailed comparative studies are still awaited. One problem encountered during surgical use lies in de- ciding what degree of uptake in a lesion constitutes path- ological concentration of tracer. The lowest uptake ratio that appears to be acceptable at surgery is 1.5:1, with any greater uptake indicating positive accumulation [5, 7]. There does, however, seem to be a poor correlation

TabLe 2. A list of the main nuclear surgi- cal probes and manufacturers Probe system Detector Manufacturer

Mitsubishi Probe NaI(T1)

Modelo 2 NaI(T1), CdTe, BGO (high sensitivity), Plastic/%scintillator

Neoprobe 1000 CdTe

C-Trak Oncoprobe NaI(T1)

RMD Surgical Probe/CTC4 CdTe

Tec Probe 200 CsI(Na)

Mitsubishi Atomic Power Ltd., Japan DAMRI/ORIS Industrie, Gif-Sur-Yvette, France

Neoprobe Corp., Columbus, Ohio, USA Oncoprobe, Carewise, Largo, Fla., USA Radiation Monitoring Devices, Watertown, Mass., USA Stratec Elektronik GmbH, Birkenfeld, Germany

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between the ratio of uptake measured at surgery and the count rates per gram of excised tissue. Uptake ratios will inevitably vary with the particular radiopharmaceu- tical being employed. For example, using 99mTc-HDP, uptake ratios of the order of 3 : 1 are commonly encoun- tered in osteoid osteoma. Uptake ratios of the order of 15 : 1 have been indicated in preliminary studies using 111pentetreotid e and greater than 25:1 with 125I-MIBG [21]. As a good working guide, clear visualization on the preoperative images will assure successful intraoper- ative detection, with surgery being undertaken at the same time after administration as that for optimal imag- ing.

At the present time the peroperative probe technique is established in only a few pathological conditions. In the case of osteoid osteoma, peroperative localization can make a potentially difficult operation very easy. I am aware of a number of orthopaedic surgeons who will not operate without such assistance. Some logistical problems concerning radiation protection, transport and waste disposal do have to be faced when taking radio- pharmaceuticals to the operating theatre. However, it is unlikely that procedures will result in any significant hazard to theatre staff since they are unlikely to be ex- posed to higher levels of radiation than nuclear medicine technologists [22]. A number of new applications are currently being assessed. In particular, the development of new receptor-based radiopharmaceuticals such as Pentetreotide is expected to increase the demand for per- operative nuclear medicine studies. The application of these new agents is likely to extend our area of influence outside nuclear medicine departments.

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European Journal of Nuclear Medicine Vol. 20, No. 7, July 1993