A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone.

The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).

Iodine-131-metaiodobenzylguanidine dosimetry in cancer therapy: risk versus benefit.

UNLABELLED: In the treatment of neural crest tumors, such as pheochromocytoma, with[131I]MIBG, bone marrow toxicity limits the amount of administered activity and, thus, a therapeutically useful tumor dose. METHODS: We calculated tumor doses in a series of diagnostic studies with [123I]MIBG using accurate quantification of SPECT and planar scintigraphy. By extrapolating diagnostic results to therapeutic activities of [131I]MIBG, we could compare the results with whole-body doses from a series of therapies. RESULTS: The tumor dose was DT = 2.2 mGy MBq(-1) (median value of 27 measurements, range 0.04 < or = DT < or = 20 mGy MBq(-1) and the whole-body dose in a series of 16 patients undergoing 50 therapies was DWB = 0.12 +/- 0.04 mGy MBq(-1) (mean +/- s.d.). The therapeutic ratio varied between 130 to below 10 in some patients. CONCLUSION: The results were compared with published data. We found clearly skewed distribution of tumor doses, with a majority of tumors receiving only a few mGy per MBq administered activity. In some patients, however, doses did reach 20 mGy MBq(-1).

Strontium-89 therapy: measurement of absorbed dose to skeletal metastases.

We report measurements of absorbed dose to vertebral metastases in ten patients referred for 89Sr therapy for disseminated prostatic carcinoma. Patients received a tracer dose of 85Sr at the time of 89Sr treatment and metastatic strontium retention was monitored scintigraphically for 6 mo. Metastatic 85Sr activity corrected for tissue attenuation was measured using the conjugate view principle, with special care taken to eliminate errors due to the selection of the metastatic region of interest. Metastatic volume was determined from high resolution CT images, and density inferred from Hounsfield number using the QCT bone mineral calibration of Genant and Cann. The mean absorbed dose was 850 rad/mCi (23 cGy/MBq) with a range from 220-2260 rad/mCi (6 to 61 cGy/MBq). The wide range found was consistent with the variation expected to arise due to differences in strontium renal plasma clearance (range 0.1-11.81/day) and extent of skeletal metastatic disease (varying from two small metastases to a superscan on [99mTc]MDP images) among the patients studied.

Strontium-89 therapy: strontium kinetics and dosimetry in two patients treated for metastasising osteosarcoma.

We report a study of strontium kinetics in two patients who received 89Sr therapy for disseminated osteogenic sarcoma, together with estimates of absorbed dose to the principal metastases and to bone marrow. In neither patient did tumour uptake of strontium have a significant effect on whole-body retention. In one patient, whole-body strontium kinetics agreed closely with the ICRP standard model, while in the second, retention was extremely prolonged, probably due to hypertrophic osteoarthropathy. Strontium-85 scintigraphy, surface counting and high-resolution whole-body profiles agreed in showing that in both patients tumour turnover of strontium was very rapid, with a biological half-life of only a few days. Absorbed dose to tumour was found to be comparable in magnitude to the mean bone-marrow dose. We have no reason to believe that 89Sr therapy was of clinical benefit to either patient.

Strontium-89 chloride for pain palliation in prostatic skeletal malignancy.

In a multi-centre study strontium-89 was shown to be effective in relieving bone pain from prostatic carcinoma in patients who had failed conventional therapies. Of 83 patients assessed at 3 months, following the administration of a dose of at least 1.5 MBq/kg, 75% derived benefit and 22% became pain free. Symptomatic improvement usually occurred within 6 weeks and continued for between 4 and 15 months (mean 6 months). Based on the dose estimation part of this study the recommended dose of strontium-89 is 150 MBq. Toxicity was low, provided platelet levels were above 100 x 10(9) l-1 at the time of treatment. Repeat treatments with strontium-89 may be given at intervals of not less than 3 months. Strontium-89 is administered intravenously on an out-patient basis with no special radiological protection precautions.

Strontium-89 radionuclide therapy: a dosimetric study using impulse response function analysis.

In a series of patients receiving 89Sr palliation for metastasised prostatic carcinoma, strontium renal plasma clearance was found to vary from 0.14 to 11.81 day-1, and the extent of skeletal metastatic disease seen on 99Tcm-MDP images varied from a few small metastases to a superscan. Using a numerical technique based on impulse response function (IRF) analysis, we have investigated the effect of such variation between patients on 89Sr dosimetry. The whole-body IRF, HWB(t), is defined by the deconvolution of the whole-body strontium retention function, RWB(t), with the plasma retention function, P(t). For patients with minimal metastatic bone disease we assumed HWB(t) = HO(t), where HO is the IRF derived from the International Commission on Radiological Protection model for normal strontium metabolism. The strontium plasma clearance, k, was allowed to vary, and the resulting variation of RWB(t), P(t) and absorbed dose to bone marrow calculated. By convoluting P(t,k) with the IRF measured for a discrete metastasis, the effect of varying k on tumour dose was investigated. Tumour and bone marrow dose were shown to change by a factor of three as k varied over the range observed in patients. For patients with extensive metastatic bone disease we assumed HWB(t) = (1-beta)HO(t) + beta HS(t), where HS was the IRF measured for a superscan patient and beta was a parameter reflecting the extent of skeletal metastatic disease. The effect of varying beta on tumour and bone marrow dose was investigated, and dose shown to decrease by a factor of five as beta increased from zero to unity. Impulse response function analysis was found to be a powerful and useful aid in clarifying the relationship between strontium kinetics and 89Sr dosimetry.

The limitations of the dual radionuclide subtraction technique for the external detection of tumours by radioiodine-labelled antibodies.

A dual radionuclide subtraction technique for external detection of tumours has been evaluated to determine the viability of the method for use with radioisotope labelled antibodies. A number of external scintigraphic investigations have been carried out with 131I-labelled antibodies to carcinoembryonic antigen (CEA). The investigations were performed on patients with metastatic disease known to produce CEA. The dual radionuclide subtraction technique was used to account for the blood and tissue background. The 131I-labelled antibodies were found to localise in the metastatic lesions, but the subtraction technique using 99Tcm-labelled HSA and pertechnetate gave ambiguous results, which included the production of artefacts. The ambiguities noted in the clinical results were substantiated by experimental data, which highlight the unreliability of this technique.

The relationship of 67Ga uptake to citrate dose, compared with 67Ga-chloride and 67Ga-transferrin in rodent tissues and tumours.

The uptake of 67Ga-citrate in the tissues of the mouse and rat and in two mouse tumours, S180 and PC6, has been measured and shown to be independent of the citrate concentration of the injection dose. The tumour uptake and tissue distribution of 67Ga-chloride and 67Ga-transferrin were identical with those of the citrate complex. Whole-body retention data for 67Ga-citrate in the mouse for 14 days after injection are also presented.

Strontium kinetics in metastasized prostatic carcinoma: a comparison with the predictions of impulse response function analysis.

Amongst patients referred for 89Sr palliation of disseminated prostatic carcinoma, we have found wide variations in extent of skeletal metastatic disease and in strontium renal plasma clearance. A numerical technique using impulse response function analysis is reviewed which enables the effect of such variations on the total body, plasma and metastatic strontium retention functions to be calculated. The prediction of the model are compared with kinetic data from patients presenting for radiostrontium therapy, and correlations that have important implications for 89Sr dosimetric studies are confirmed. The simplest kinetic data required to allow for these effects in studies of dose-response and haematological toxicity following radio-strontium treatment are discussed and attention is drawn to a small group of patients who may form a significant exception to the general model.

The urinary excretion of gallium-67 citrate in patients with neoplastic disease.

The urinary excretion of gallium-67 has been studied in twenty-nine patients with considerable variation, ranging from 2.71 to 35.21 per cent of the injected dose in the first twenty-four hours. The data was analyzed to determine whether differences in excretion could be related to sex, age, plasma level, site or extent of disease but no significant relation could be found. While chemotherapy or radiotherapy has been shown to affect both the plasma clearance and protein binding they have no influence upon the urinary excretion of the isotope in this study. This study shows that all patients with high urinary excretion had bone metastasis from various types of primary tumour. Not all patients with bone metastasis have high urinary excretion of gallium-67. It would appear, however, from our limited series that patients with bone metastasis and normal urinary excretion of gallium-67 show a good response to treatment.

Measurements of the strontium plasma clearance rate in patients receiving 89Sr radionuclide therapy.

The total strontium plasma clearance rate due to excretion through the kidneys and gut has an important influence on the absorbed does delivered to skeletal metastases and red bone marrow in patients receiving 89Sr radionuclide therapy for disseminated prostatic carcinoma. Although a measurement of the renal strontium plasma clearance rate may readily be obtained through a 24-h urine collection, little information is available on the correlation between renal and total clearances. We describe a method of determining total strontium plasma clearance rate from whole body counter measurements of total body strontium retention and measurements of plasma strontium concentration following administration of a 85Sr tracer dose at the time of 89Sr therapy. Amongst the 26 patients whom we studied, the total clearance rate varied from 1.2-15.0 l/day, renal clearance rate from 0.1-11.5 l/day, and the mean gut clearance rate was 2.0 l/day. A close correlation was found between total and renal clearance, with the renal component accounting for 96% of the variance in total strontium plasma clearance. A weak collection may exist between gut and renal clearance.

Radiolabelled metaiodobenzylguanidine targeted radiotherapy for malignant phaeochromocytoma.

Metaiodobenzylguanidine (MIBG) targeted radiotherapy is a promising treatment for malignant phaeochromocytoma. It is an effective palliative therapy and may influence prognosis by reducing tumour metabolic function and preventing excessive catecholamine secretion. Repeated treatments are necessary to achieve tumour arrest and disease regression, and it is essential that patients are followed closely for life. Toxicity is limited to myelosuppression but is cumulative. Bone marrow harvesting is recommended for all patients who are likely to undergo repeated treatments. Heightened clinical awareness and easier diagnosis of malignancy using MIBG scintigraphy are likely to result in an increasing number of referrals for treatment. It is essential, therefore, that experience is pooled from individual centres and that patients are treated according to agreed protocols, so that results can be directly compared.

The enzyme-inhibitor approach to cell-selective labelling--II. In vivo studies with pIBS in small animals and man.

p-Iodobenzenesulphonamide (pIBS), a potent red cell carbonic anhydrase inhibitor, was used as a carrier for radioiodine in the enzyme-inhibitor approach to cell-specific blood labelling. Radioactivity distribution was monitored in rats and man following i.v. administration of the radiolabelled carrier or of pre-labelled red cells. Rat blood activity fitted a two compartment model; the half-life for overall elimination was 69 +/- 27 h. At 24 h most activity remained associated with red cells, but there was a significant uptake in the large intestine (10 +/- 6%). In man there was no significant accretion by gut or any other organ over 93 h, and the blood clearance was mono-exponential (t1/2 = 9.8 +/- 1.5 days).

The stability and distribution of Tc-HIDA in vivo and in vitro.

Tc-HIDA is a promising new agent for imaging the biliary system. In this study radiochromatography on paper or Sephadex G25 gel has been used to measure the proportions of TcHIDA, 'hydrolysed Tc' and pertechnetate in solutions from a commercial kit (CIS TCK 15) and in body fluids from patients and rats receiving this radiopharmaceutical. The tissue distribution in male and female rats has shown the radiopharmaceutical to be rapidly removed from the blood by the liver and then excreted via the intestines. There appears to be a sex difference in the uptake in the kidneys and in the urinary excretion in both rats and patients.

Sr-89 therapy: strontium kinetics in disseminated carcinoma of the prostate.

Strontium kinetics were investigated in a group of 14 patients receiving 89Sr palliation for metastatic bone disease secondary to prostatic carcinoma. Using 85Sr as a tracer, total body strontium retention R(t) was monitored for a 3 month period following 89Sr administration, and at 90 days was found to vary from 11% to 88% and to correlate closely with the fraction of the skeleton showing scintigraphic evidence of osteoblastic metastatic involvement. Strontium renal plasma clearance varied from 1.6 l/day to 11.6 l/day, and in nine patients was significantly reduced compared with values found in healthy adult men, probably due to increased renal tubular reabsorption associated with the disturbance of calcium homoeostasis. Renal clearance rate was the principal factor determining R(t) for t less than 6 days, and was an important secondary factor at later times. Over the interval 30 days less than t less than 90 days, R(t) was closely fitted by the power law function R(t) = R30 (t/30)-b, with R30 and b showing the close correlation expected from the effect of R(t) on strontium recycling. The correction of the data for this effect to determine the true skeletal release rate is described. Measurement of localized strontium turnover in individual metastatic deposits from whole body profiles and scintigraphic images gave retention curves that typically rose to a plateau by 10 days after therapy, and then decreased very slowly. In contrast, retention curves for adjacent normal trabecular bone showed more rapid turnover, peaking at 1 day and subsequently decreasing following a t-0.2 power law function.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular filtration rate and the kinetics of 123I-metaiodobenzylguanidine.

We have recently reported evidence that the calcium antagonist nifedipine can improve the tumour retention of 131I-metaidobenzylguanidine (131I-MIBG) in patients with malignant phaeochromocytoma. During studies of the pharmacological modification of tumour MIBG kinetics, it is important to distinguish clearly between a direct effect on MIBG cellular retention by a pharmaceutical, and secondary effects due, for example, to a change in glomerular filtration rate (GFR). In order to provide the fundamental kinetic data required for the numerical modelling of the effect of nifedipine on tumour MIBG kinetics, we have investigated the influence of GFR on MIBG plasma and renal kinetics. The 123I-MIBG plasma curve and MIBG renal plasma clearance rate were studied in ten patients, ranging from subjects without biochemical or scintigraphic evidence of phaeochromocytoma to individuals with widely disseminated metastatic disease. GFR was measured using the 99mTc-DTPA plasma clearance method. In four cases, the studies were repeated with the patients taking oral nifedipine. Statistically significant correlations were found between GFR and the MIBG plasma concentration. MIBG renal plasma clearance rate and the early (0 to 5 min) renal excretion of MIBG. The data permit the evaluation of the plasma integral during the first few min following bolus injection, a quantity important in the numerical modelling of tumour kinetics. GFR was found to have a major influence on whole-body MIBG kinetics, but there was also evidence of the effect of the metastatic tumour burden.

89Sr radionuclide therapy: dosimetry and haematological toxicity in two patients with metastasising prostatic carcinoma.

We present dosimetry for spinal metastases and red bone marrow in two patients who received 89Sr therapy for disseminated prostatic carcinoma. Absorbed dose to metastases was estimated by combining 85Sr gamma camera studies with computed tomographic measurements of bone mass, and doses of 20 cGy/MBq and 24 cGy/MBq were found for vertebral metastases that uniformly involved the bodies of L3 and D12 respectively. Absorbed dose to red bone marrow was estimated from total body strontium retention studies using the ICRP model for bone dosimetry, and a ratio of metastatic to marrow dose of around 10 was found in each patient. Although they received comparable treatment activities of around 200 MBq, the patients showed markedly different haematological response, this difference being confirmed when each received a second 89Sr treatment 6 months after the first. As a result, clinically significant thrombocytopenia occurred in one patient which prevented further radiostrontium therapy being given.

Modification by nifedipine of 131I-meta-iodobenzylguanidine kinetics in malignant phaeochromocytoma.

Following a case report that oral nifedipine can suppress the secretion of noradrenaline by phaeochromocytoma, we examined the effect of nifedipine on the tumour kinetics of tracer 131I-meta-iodobenzylguanidine (131I-mIBG) in five patients referred for mIBG radionuclide therapy for disseminated malignant phaeochromocytoma. In one subject a striking modification of mIBG kinetics was found that resulted in a doubling of the absorbed dose to tumour while the patient was taking nifedipine. At the same time, urinary excretion of noradrenaline was suppressed by a factor of three. The effect of nifedipine in this patient was confirmed when tracer studies were repeated nine months later. The changes in tumour kinetics were shown to be due to prolonged retention of mIBG rather than increased tumour blood flow or alteration of the curve of mIBG plasma concentration as a function of time.

89Sr therapy: strontium plasma clearance in disseminated prostatic carcinoma.

Strontium plasma clearance is an important factor determining the absorbed dose to metastases and bone marrow in patients receiving 89Sr radionuclide therapy for metastatic bone disease. Amongst male patients with disseminated prostatic carcinoma, the renal component of strontium clearance is frequently greatly reduced compared with values reported for healthy middle aged men. We report a study of renal and gut strontium plasma clearance, renal function, calcium urinary excretion, parathyroid function and extent of skeletal osteoblastic metastatic disease in patients referred for radiostrontium therapy for metastasised prostatic malignancy. The wide variation in net strontium clearance was principally due to variation in the renal component. Low values of strontium renal clearance were found to correlate with the elevation of serum PTH and nephrogenous cyclic AMP, which in turn correlated with extent of skeletal metastatic disease. This suggests that the osteosclerotic metastases characteristic of prostatic carcinoma induce secondary hyperparathyroidism due to the high avidity of the skeleton for calcium. The resulting reduction in strontium excretion may be beneficial to the objectives of radiostrontium therapy.