V. Ralph McCready

The mechanism of accumulation of tumour-localising radiopharmaceuticals.

It has been the aim of almost every nuclear medicine physician to develop and use the so-called magic bullet. This would be the radiopharmaceutical of choice in tumour imaging owing to its ability to concentrate only in malignant tumours with a high degree of uptake. This ideal tumour-localising radiopharmaceutical would be valuable not only for diagnosis of tumours, but also for therapy since the labelled radionuclide could be changed to deliver beta or gamma radiation to ablate the malignant tumour. Over the course of the years many attempts have been made to discover the magic bullet: virtually every available radionuclide has been incorporated into different radiopharmaceuticals and injected into animals or humans to discover its tumour-localising abilities. Nearly all of them have had some degree of success since almost any radiopharmaceutical is turned over more slowly in the extracellular space of a tumour than in normal tissues. However, most tumour-localisation agents have shown poor uptake; this has resulted in very limited use in the clinic, reflecting their lack of clinical value in differential diagnosis or in determining the effectiveness of the various therapies. In only a few cases has there been a specific attempt at producing a designer molecule which might have a higher chance of success than the usual “try it and see” approach. It is therefore of value to review what is known about the mechanisms behind the uptake of the currently available radiopharmaceuticals used for tumour imaging. In the following, we shall first deal with the general characteristics of tumour cells, which provide a basis for elucidating the uptake mechanisms of tumour-localising radiopharmaceuticals. Thereafter, the radiopharmaceuticals currently used for tumour localisation are reviewed, concentrating on their mechanisms of uptake into tumour cells. An attempt is made to classify the various tumour-localising radiopharmaceuticals into groups with common methods of uptake. Finally, suggestions are made on how to improve our approach to the development of tumour-localising radiopharmaceuticals.

DETECTION OF BREAST CARCINOMA METASTASES IN BONE: RELATIVE MERITS OF X-RAYS AND SKELETAL SCINTIGRAPHY

Of 1116 patients receiving primary treatment for breast carcinoma at the Royal Marsden Hospital since 1976, 651 had an abnormal bone scintigram either at primary diagnosis (378) or on subsequent follow-up (273) and 167 developed radiographically detectable bone metastases (21 at the time of primary diagnosis). Comparison of bone scintigrams and X-rays showed that scintigraphy was an inaccurate localiser of existing radiographic detectable metastases. If X-rays alone are used to detect bone metastases a limited examination with five plates will detect metastases with 92% accuracy. After primary surgery, routine X-ray screening for bone metastases is not necessary since it is possible to identify patients at risk on the basis of clinical examination, chest X-ray, and serum alkaline phosphatase and gamma-glutamyl transpeptidase levels.

Imaging metastatic testicular germ cell tumours with 18FDG positron emission tomography: prospects for detection and management

The aim of this study was to investigate the role of positron emission tomography (PET) with [18F]fluoro-2-deoxyglucose (18FDG) in metastatic testicular germ cell tumours. Twenty-one patients with stage II–IV testicular germ cell tumours were imaged by PET with a multiwire proportional chamber PET system and18FDG. Avid18FDG uptake was seen in metastatic disease from primary seminoma and malignant teratoma. Normal tissue uptake was seen in differentiated teratoma or necrotic, fibrotic tissue.18FDG standard uptake values and tumour to normal tissue ratios were 6.0±1.4 and 1.7±0.4 (mean ± 1SD), respectively, for malignant tissue. Reduction of18FDG tumour to normal tissue ratios from pre-treatment to on-treatment scans was predictive of response (n=3). No significant reduction in18FDG uptake was seen in patients not responding to therapy (n=2). These results suggest a role for18FDG PET in the detection and management of metastatic testicular germ cell tumours.

Thyroid volume measurement in thyrotoxic patients: comparison between ultrasonography and iodine-124 positron emission tomography

Abstract. The aim of this paper was to compare ultrasound (US) assessment of thyroid volume with that obtained by positron emission tomography (PET), in patients scheduled for adaptive radioiodine therapy, in which 50 Gy was prescribed to the functional PET volume. Firstly a pilot study was performed to ascertain the optimum method for US assessment of thyroid volume. Then 17 comparative measurements of thyroid volume by US and PET were made on 15 patients (two male and thirteen female, ages 28–73 years) with suspected Graves’ disease. This comparison showed that in normal sized and enlarged thyroid glands (n=13), the ratio of functional PET to anatomical US volume was approximately 2:3. However, using the same ellipsoid model, PET and US assessment of anatomical volume agreed within the measurement errors. Owing to the presence of nodules and non-uniform distribution of radioiodine, the functional PET volume and anatomical US volume are often not equivalent. If high-resolution emission tomography (e.g. PET) is unavailable, the comparative data presented in this paper could be used to derive the functional volume from the US volume for calculating functional thyroid dose in hyperthyroid patients undergoing radioiodine therapy.

62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases

Abstract. The aim of this study was to establish a quantitative positron emission tomography (PET) method for investigating angiotensin II (AII)-induced changes in blood flow distribution in the liver. This was in order to evaluate the role of vascular manipulation applied to locoregional chemotherapy treatment in patients with colorectal liver metastases. The tracer selected was copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (62Cu-PTSM), which exhibits high first-pass extraction and tissue retention following intra-arterial administration. The short half-life of the tracer and its availability from a 62Zn/62Cu generator enabled short-interval repeat PET scans on patients in a single imaging session. Distribution of tracer within the liver was imaged in a single view using a PET camera with rotating large-area detectors. By optimisation of the acquisition protocol, it was possible to acquire sufficient data to produce good-quality images and to quantify tracer uptake with an accuracy of ≤10%. Reproducibility of the imaging method was assessed in a single patient in whom three consecutive 62Cu-PTSM PET scans were obtained, and in whom no vascular manipulation was performed. Sets of scans (before, during and immediately after a 45-min AII infusion) were obtained in nine patients to assess blood flow changes associated with prolonged vascular manipulation. Significant individual responses, varying in both the magnitude and the duration of flow change, were observed in the majority of cases (7/11 lesions; 7/9 patients). These findings illustrate the potential of 62Cu-PTSM and PET for pharmacological studies. The wide range of individual patient responses to AII infusion suggests that PET blood flow assessment would be of value for selecting patients in whom this procedure may be effective.

Scintigraphic studies of space-occupying liver disease

Abstract Liver scanning is now a routine part of the workup of patients with a wide variety of diseases. Examinations may be carried out on either the Anger camera or the rectilinear scanner. The gamma camera offers speed and the ability to take multiple pictures in a short time if short-lived radionuclides are used. Space-occupying lesions indicate an absence of radioactivity in almost all cases. The minimum lesion that can be detected is on the order of 2-3 cm. In spite of this, a high degree of accuracy is reported in most series. It is usually impossible to differentiate different pathologic conditions on the basis of scan appearance alone, but by careful attention to such details as the position of lesions, whether they are multiple or single, and the degree of splenic concentration of colloid, useful conclusions about the pathologic diagnosis can be made. Liver scanning is complimentary to other methods of liver investigation. It is a particularly easy, atraumatic, and quick means of discovering or excluding disease with a high degree of accuracy.

99mTc-HMPAO as a tumour blood flow agent

The cerebral blood flow agent, 99mTc-HMPAO (‘CeretecTM’) has been investigated to see if it can be used to estimate tumour blood flow. Its distribution in Balb/c mice bearing either a subcutaneously implanted sarcoma or a plasmacytoma has been shown to be similar to that of 86RbCl. The changes in peripheral blood flow caused by the beta-blocker, propranolol, and by Nembutal anaesthesia, are manifested equally by 99mTc-HMPAO and 86Rb. We conclude, therefore, that HMPAO may be useful in estimating tumour perfusion.

Initial experience with Tc-99m-HM-PAO in the study of brain tumors

A preliminary study of the distribution of the 99mTc complex of hexamethylpropylene amine oxime (HM-PAO) in 12 patients with brain neoplasms before, during, and after radiotherapy has been performed. Untreated brain tumors were found to exhibit a range of 99mTc-HM-PAO uptake, varying from areas of markedly increased isotope activity to photopenic areas, when compared to normal brain tissue. A ratio of 99mTc-HM-PAO tumor uptake to contralateral normal tissue uptake was calculated prior to and during radiotherapy. This ratio tended to return towards unity in lesions responding to therapy. A predictable alteration in whole brain 99mTc-HM-PAO uptake during radiotherapy was not demonstrated. Unlike the radiolabeled amines, 99mTc-HM-PAO localizes in primary tumors, probably indicating that its uptake mechanism is independent of non specific amine receptors. 99mTc-HM-PAO may be useful in the study of brain tumor physiology and response to therapy.

Uptake of technetium-99m hexamethylpropylene amine oxime labelled white cells in lymph nodes involved in non-Hodgkin's lymphoma

Radiolabelled white cell scanning is widely used to detect the presence of infection. We present a case of non-Hodgkins lymphoma manifesting with signs and symptoms suggestive of infection, in which a technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) white cell scan demonstrated high uptake in lymph nodes involved by lymphoma. Differential cell analysis showed preferential lymphocyte labelling. The classification and management of the disease were changed accordingly. Our findings suggest that a future role for99mTc-HMPAO labelled white cells in the assessment of disease activity of lymphoma should be investigated.

A different approach to the use of unsealed radionuclides for cancer therapy

Unsealed radionuclides have been used successfully for the treatment of carcinoma of thr thyroid and thyrotoxicosis since the 1940s. More recently they have been used for neuroectodermal tumours and other cancers using labelled antibodies with much less success. While there are signs that the results achieved with these techniques are improving [1 ], problems remain. Even in the case of thyroid carcinoma, where treatment with radioiodine is generally successful, the response to the radiation therapy differs in different lesions in the same patient. Patients with bone metastases have a much worse prognosis than those with soft tissue metastases [2]. It is only recently that an explanation of this variable response has been found. Positron emission tomographic studies using iodine-124 have shown that tumours that receive an adequate dose from the administered activity respond, while those in the skeleton often have subtumoricidal doses and do not respond [3]. This may be expected, but until techniques for the measurement of the tissue dose from radionuclides have been developed further, it will not be possible to decide whether a lack of response is due to a low dose from the radionuclide in the lesion or to resistance of the cancer to the radiation. In the cases where radioiodine therapy for differentiated carcinoma of the thyroid has been successful it is the therapists dream. A simple intravenous injection or oral administration is all that is required. There are minimal side-effects since most of the administered radioactivity is taken up by the abnormal tissue. The quest for a universal radionuclide treatment for other cancers has not been so successful [4]. Improvements in radionuclide therapy with unsealed sources is unlikely unless more thought is given to radiobiology and tumour metabolism and physiology. The dose from a radiopharmaceutical depends upon the concentration of the radioactivity in the lesion, the residence time and the characteristics of the radionuclide used. These include the energy and type of radiation beta, alpha or gamma or a mixture of these. The concentration of a radiopharmaceutical in the lesion depends upon the carrier. This may be metabolised by the tumour, e.g. MIBG uptake in neuroendocrine tumours, or it may be taken up by an unknown mechanism such as DMSA in medullary carcinoma of the thyroid or it may concentrate in normal tissues adjacent to a tumour, e.g. radiolabelled Lipiodol in lymph nodes involved by tumour. The uptake in a tumour depends upon the delivery of the radiopharmaceutical, which may be via the supplying arteries or lymphatics or by direct injection into the lesion itself. The uptake in the tumour is also related to the blood level. This is high soon after injection and often decreases thereafter at differing rates, slow when the carrier is a protein and usually quickly in the case of small molecules. The uptake also depends upon the extraction efficiency of the tumour. This is high in cases where the extraction efficiency is high such as Ceretec and low in the case of many proteins. Tumour perfusion is more important in the case of the former and less important in the case of radiopharmaceuticals with low extraction efficiency. Much of the apparent tumour perfusion may not be effective in the delivery of the radiopharmaceutical since arterio venous shunting may divert blood away from the tumour cells. The use of intralymphatic delivery, although superficially attractive, is not necessarily logical since turnout can block the normal lymphatic pathways, diverting the compound away from the tumour and on to normal tissue. The residence time of the radiopharmaceutical may be maximum in the case of intracavitary delivery, long in the case of microspheres delivered arterially and relatively short in the case of metabolisable compounds such as MIBG due to release again from the tumour. The position of the radionuclide in the molecule and the type of emission from it determines the energy deposited in the tumour cell [5]. For example in the case of iodine-125 the radionuclide must be taken into the cell being treated to optimize the data from Auger electrons. Beta particles travel various distances before giving up their energy so the radionuclide must be at the mean length of the beta particle from the tumour cell if it is going to have a chance of being lethal. For example, consider the potential use of bone-seeking beta emitters such as strontium-89 for the treatment of bone metastases, e.g. in carcinoma of the prostate. Depending upon the size of the lesion, the deposition of the radionuclide in the osteoblastic reaction may only result in the outer rim of the tumour being irradiated.