Targeted radionuclide therapy for neuroendocrine tumours.

Evidence supporting the potential contribution of targeted radiotherapy to the management of neuroendocrine tumours is now strong. Acting systemically, this is an effective option for patients with inoperable or multi-site disease. Toxicity is generally low, being limited to reversible myelosuppression and theoretical nephrotoxicity. Prerequisites for treatment success include demonstration of high tumour uptake relative to non-target tissues on quantitative diagnostic radionuclide imaging and stable haematological and biochemical function. In addition to (131)I metaiodobenzylguanidine therapy, which is now well established, there is growing interest in radiolabelled peptide therapy using a range of somatostatin receptor analogues such as (90)Y DOTATOC and (90)Y lanreotide. The results of clinical experience are summarised and the direction for future research is discussed.

A practical guide to targeted therapy for bone pain palliation.

Targeted radionuclide therapy is an effective and cost efficient treatment for multi-site metastatic bone pain. This paper discusses the physical characteristics of the licensed radiopharmaceuticals (153)Sm ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) ((153)Sm-EDTMP), (186)Re 1,1-hydroxyethylidenediphosphonate ((186)Re-HEDP) and (89)SrCl(2) and considers the factors influencing treatment choice in specific clinical settings. The advantages and practical limitations of this approach are discussed, with emphasis on defining criteria for patient selection and response monitoring. Opportunities for future research and development are outlined.

Isotopic evaluation and therapy in patients with malignant endocrine disease.

The contribution of nuclear medicine to the diagnosis and treatment of endocrine malignancy is increasing. Advances in molecular biology offer new opportunities for tumour targeting via surface receptor recognition and tumour-specific metabolic markers. Imaging the biodistribution of these markers allows quantitative, in vivo characterization of tumour function. There is growing interest in the therapeutic potential of nuclear medicine targeting, substituting therapeutic beta-emitting radionuclides for the gamma-emitters used in diagnostic imaging. Limited clinical experience supports the rationale of this approach in patients with inoperable or disseminated disease and controlled trials are in progress. This chapter outlines the place of nuclear medicine techniques in the routine management of endocrine malignancy and explores areas for further development.

Cancer therapy using bone-seeking isotopes.

Bone pain is a common symptom in disseminated malignancy and may be difficult to manage effectively. Radiation is of proven benefit for pain palliation and there is growing interest in the therapeutic potential of bone-seeking radiopharmaceuticals. Clinical data relating to the use of phosphorus-32, strontium-89, samarium-153 EDTMP, rhenium-186 HEDP and tin-117m DTPA are reviewed in the context of the pathophysiology of metastatic bone pain. Possible mechanisms of action of palliative radiotherapy and, in particular, the theoretical role of early response genes are discussed. The application of Monte Carlo simulation to targeted radiotherapy for bone metastases may provide the basis for a clearer understanding of the microdosimetry and radiobiology of bone pain palliation and for reliable prediction of clinical response and toxicity.

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).

A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer.

From 1988 to 1991, 284 patients with prostatic cancer and painful bone metastases were treated with either radiotherapy or strontium-89 (200 MBq). Patients were first stratified according to suitability for local or hemibody radiotherapy, then randomly allocated that form of treatment or strontium-89 (i.v. injection). After 4, 8 and 12 weeks pain sites were mapped, toxicity monitored, and all additional palliative treatments recorded. There was no significant difference in median survival (after > 80% had died); 33 weeks following strontium-89 and 28 weeks following radiotherapy (p = 0.1). All treatments provided effective pain relief; improvement was sustained to 3 months in 63.6% after hemibody radiotherapy compared with 66.1% after strontium-89, and in 61% after local radiotherapy compared with 65.9% in the comparable strontium-89 group. Fewer patients reported new pain sites after strontium-89 than after local or hemibody radiotherapy (p < 0.05). Radiotherapy to a new site was required by 12 patients in the local radiotherapy group compared with 2 after strontium-89 (p < 0.01), although there was no significant difference between hemibody radiotherapy (6 patients) and strontium-89 (9 patients) in this respect. Platelets and leukocytes fell by an average 30-40% after strontium-89 but sequelae were uncommon, and other symptoms rare.

Targeted radionuclide therapy for bone metastases.

Recent advances in targeted radiotherapy offer a new approach for the management of metastatic bone pain. This paper will review the scientific basis for radionuclide therapy and will examine the evidence for clinical efficacy. The therapeutic potential of targeted radiotherapy can only be appreciated by comparison with established treatments. Alternative treatment options will, therefore, be discussed, to bring the potential advantages and hazards of targeted radiotherapy into perspective and to define its place in routine management.

Palliation of bone metastases in prostate cancer. Hemibody irradiation or strontium-89?

The palliation of bone pain is a common clinical problem once metastatic prostate cancer has escaped from hormonal control. This retrospective study compares the results of treatment using hemibody irradiation (HBI) at the Royal Marsden Hospital (27 cases) with isotope therapy using the bone-seeking isotope strontium-89 (89Sr) at Southampton General Hospital (51 cases). Prior to analysis patients were matched for potential prognostic factors (performance status, bone scan extent of disease, age, histology and duration of hormone response) to minimize the effect of treatment selection bias. Pain control assessed at 3 months was similar for HBI and matched 89Sr cases, with 63% and 52% respectively showing some benefit. Median survival was similar for these groups at 20 and 21 weeks respectively. The unmatched 89Sr group, which had more favourable prognostic factors, had a better outcome with 96% showing improvement in pain and with a median survival of 59 weeks. Subsequent univariate analysis demonstrated that performance status and extent of disease on bone scan were of overriding importance in determining outcome. Transfusion requirements were higher for the HBI group than for the matched 89Sr group (50% and 25% respectively) but other bone marrow toxicity was similar. Despite routine anti-emetic therapy 37% of patients treated with HBI had some nausea or vomiting. Although expensive, 89Sr appears as effective a treatment option as HBI. Response is most likely with either approach when patients have a good performance status and a limited extent of disease.

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.

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.

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).

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.

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 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.

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.