V. R. McCready

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates.

The potential of intratumoural unsealed radioactive source therapy.

Unsealed source radiotherapy has not been as successful as one would expect considering the targeting nature of the technique. This could arise from a variety of reasons, including variation in the uptake of the radiopharmaceutical throughout a lesion and consequently large variation in the dose delivered. The fractional uptake into the tumour is usually low and the residence time in the lesion may be short, resulting in a low dose. In principle the dose could be increased in a variety of ways. For example, the transit time might be lengthened in differentiated carcinoma of the thyroid by administering thyroid hormone soon after the administration of the radioiodine to remove the TSH drive to expel the radiolabelled hormone from the tumour tissue. Improved uptake in tumours being treated with mIBG might be achieved by blocking mIBG uptake in normal tissues with non-radioactive mIBG. Different analogues of somatostatin might improve uptake in neuroendocrine tumours with different types of receptors. Cocktails of beta-emitting radionuclides could theoretically improve the cell kill in tumours of different sizes where there is a uniform distribution of the radiopharmaceuticals [1] or by using the bystander effect in tumours where the uptake of the radiopharmaceuticals varies owing to the variable degree of tumour differentiation, as is found in thyroid tumours or neuroblastomas. There is evidence that doses in excess of 100 Gy are needed for successful ablation of tumour tissue when using beta emitters [2]. In many cases, doses less than this are achieved, although on the radioisotope scan the lesion appears to have high uptake. In contrast, lesions which seem to have relatively low uptake may regress following therapy. Thus there is still much to be learnt about how to give the optimum treatment using unsealed source therapy. A relatively new method of using unsealed source therapy which may overcome some of these problems is the intratumoural administration of the radiopharmaceutical. This method has the advantage of delivering the maximum amount of the radioactivity to the point where it is needed. Although cancer is often viewed as a systemic disease which should be treated by systemic therapy, in fact of the order of 30% of patients with cancer [3] die of locoregional disease without metastases, indicating the continuing need for local therapy. Improvements in locoregional tumour control should therefore lead to prolongation of patient survival, and this has been seen in practice [4]. Since in the United States alone more than 140,000 patients die from locoregional disease, there is a large potential population who could benefit from innovations in treatment to improve local tumour control [3]. The technique of intratumoural radioisotope therapy was first described by Order et al. in the United States [5]. They treated 18 patients with carcinoma of the pancreas but also used external beam radiotherapy and chemotherapy. Westlin et al. [6] carried out a similar study in 17 patients using only 32P colloidal chromic phosphate and up to four injections into small tumours (median size 13 ml). They found an overall response rate of 53%. Recently, Firusian and Dempke [7] used 32P colloidal chromic phosphate in 17 patients with a variety of histologies excepting carcinoma of the pancreas and found a good response rate of 71%, with complete remission being seen in 41%. These authors also gave multiple injections using from 74 MBq up to 555 MBq depending upon the size of the tumours, which were up to 300 ml in volume. We have studied a group of patients with inoperable carcinoma of the pancreas in a dose escalation study using a single injection of 32P colloidal chromic phosphate [8, 9]. Autoradiographic studies showed that the colloid remained localised to the point of injection at 18 weeks. There were no significant side-effects, confirming the safety of the technique. The intratumoural therapy was well tolerated by the patients requiring merely ulV. Ralph McCready (✉) Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, SM2 5PT, UK Editorial

Anatomically derived attenuation coefficients for use in quantitative single photon emission tomography studies of the thorax

Elimination of errors due to poor attenuation correction is an essential part of any quantitative single photon emission tomography (SPET) technique. Attenuation coefficients (μTc) for use in attenuation correction of SPET data were determined using technetium 99m and cobalt 57 flood sources and using topographical information obtained from computed tomography (CT) scans and magnetic resonance (MR) images. In patients with carcinoma of the bronchus, the mean attenuation coefficient for 99mTc was 0.096 cm−1 when determined across a transverse section of the thorax at the level of the tumour by means of a 57CO flood source (13 patients) and 0.093 and 0.074 cm−1 as determined from CT scans for points in the centre of the tumour and contralateral normal lung, respectively (21 patients). In 18 patients with breast tumours, the mean attenuation coefficient for 99mTc was 0.110 and 0.076 cm−1 when determined from MRI cross-sections for points in the centre of the tumour and normal contralateral lung, respectively. This indicates significant overcorrection for attenuation when the conventional value of 0.12 cm−1 is used. A value in the range 0.08–0.09 cm−1 would be more appropriate for SPET studies of the thorax. An alternative approach to quantitative region of interest (ROI) analysis is to perform attenuation correction appropriate to the centre of each ROI (using topographical information derived from CT or MRI) on non-attenuation-corrected reconstructions.

The measurement of radiation doses from P32 chromic phosphate therapy of the peritoneum using SPECT

Single photon emission computed tomography (SPECT) has been shown to be of value in estimating the radiation dose to the peritoneum from 32P therapy. Simple dosimetry calculations, assuming uniform irradiation of tissue, indicate that radiation doses of ∼40 Gy to the peritoneal surface are achieved. However, the images show that the radionuclide distribution is non-uniform, giving rise to radiation dose variations of at least a factor of 10.

Clinical significance of technetium-99m methylene diphosphonate myocardial uptake: association with carcinoma of the prostate.

Benign myocardial uptake of technetium-99m labelled phosphates, not related to cardiac or metabolic disorders, has been documented except in the case of99mTc-methylene diphosphonate (MDP). The aim of this study was to assess the frequency of myocardial uptake and its possible association with malignant tumours in general and prostatic carcinoma in particular. We reviewed bone scintigrams performed with either99mTc-hydroxydiphosphonate (HDP) or99mTc-MDP over a period of more than 2 years for all patients with prostatic carcinoma and a matching group of patients suffering from other malignant and non-malignant disorders. A total of 965 scintigrams of 812 patients (males=559, females=253; age range 50–91 years, average age 69.2 years) were reviewed. Increased myocardial uptake was detected in 19 scintigrams (MDP=13, HDP=6) of 18 patients (17 males, one female). Most of the male patients with increased myocardial uptake had prostatic carcinoma (13/17) and were over 80 years of age (12/17). All patients were free of any cardiac or noncardiac disorder that might account for such uptake. When scintigraphy was repeated in the same patient, the uptake of99mTc-HDP was more diffuse and of higher grade than that of99mTc-MDP “Benign” myocardial uptake of99mTc-MDP is more common than previously thought. Although uptake of radiophosphates is attributed to asymptomatic atherosclerotic changes associated with old age, a strong association with prostatic carcinoma exists which may indicate variations in the bone: soft tissue affinity of different MDP complexes.

An evaluation of99mTc-HMPAO uptake in cerebral gliomas —a comparison with X-ray CT

Nineteen patients with biopsy-proven cerebral gliomas were studied with99mTc-HMPAO single photon emission tomography (SPELT) imaging and X-ray computed tomography (CT). The uptake of99mTc-HMPAO was correlated with tumour size and morphology as shown by X-ray CT, and overall patient survival. It appears that uptake of99mTc-HMPAO is associated with larger, ill-defined tumours and was an adverse factor in patient survival. In those tumours with normal or increased uptake,99mTc-HMPAO imaging is useful in distinguishing the tumour margin from surrounding oedema.

Quantitative single-photon emission tomography for tumour blood flow measurement in bronchial carcinoma

A single-photon emission tomography (SPET) technique for the absolute measurement of tumour perfusion is described. Phantom studies have shown that source-background ratios are dependent upon source size and radial position within the phantom. A means of correcting source-background count ratios for these variables has been developed and used to correct tumour-lung ratios obtained in 28 patients with bronchial carcinomas who underwent technetium-99m hexamethyl-propylene amine oxime (99mTc-HMPAO) SPET. On SPET images, the normal lung appears as a relatively homogeneous background. The relationship between 99mTc background concentration (kBq/ml) and counts/pixel was determined from phantom studies and the tumour 99mTc concentration from the background 99mTc concentration and corrected tumour-lung ratio. The total activity of the lipophilic 99mTc-HMPAO species injected was measured. The activity reaching the systemic circulation (Asys) was obtained by subtracting the activity trapped in the pulmonary circulation (obtained from background 99mTc concentration and lung volume). Tumour blood flow may then be calculated from fraction of Asys contained in the tumour provided cardiac output and extraction fraction are known. Blood flow through the central region of tumours ranged from zero to 59.0 (mean 14.1) ml min−1 100 g−1 and through the whole tumour from 0.6 to 68.0 (mean 20.6) ml min−1 100 g−1.

The uptake of gallium 67 in colonic macrophages.

A case is presented in which a patient with a well-differentiated adenocarcinoma showed high gallium concentration in the segment with melanosis coli proximal to the obstruction. Although in this case the Gallium was associated with an increased number of faecal pigment containing macrophages it is unlikely that macrophages are the main factor in tumour uptake of Gallium compounds.