Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings.
ABSTRACT In preclinical studies in rats we evaluated biodistribution and therapeutic effects of different somatostatin analogs, [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide and [(177)Lu-DOTA,Tyr(3)]octreotate, currently also being applied in clinical radionuclide therapy studies. [Tyr(3)]octreotide and [Tyr(3)]octreotate, chelated with DTPA or DOTA, both showed high affinity binding to somatostatin receptor subtype 2 (sst(2)) in vitro. The radiolabelled compounds all showed high tumor uptake in sst(2)-positive tumors in vivo in rats, the highest uptake being reached with [(177)Lu-DOTA,Tyr(3)]octreotate. In preclinical therapy studies in vivo in rats, excellent, dose dependent, tumor size responses were found, responses appeared to be dependent on tumor size at therapy start. These preclinical data showed the great promise of radionuclide therapy with radiolabelled somatostatin analogues. They emphasised the concept that especially the combination of somatostatin analogs radiolabeled with different radionuclides, like (90)Y and (177)Lu, is most promising to reach a wider tumor size region of high curability. Furthermore, different phase I clinical studies, using [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide or [(177)Lu-DOTA, Tyr(3)]octreotate are described. Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-DTPA(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Radionuclide therapy with [(90)Y-DOTA,Tyr(3)]octreotide started in 3 different phase I trials. Overall, antimitotic effects have been observed: about 20% partial response and 60% stable disease (N = 92) along with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative [(90)Y-DOTA,Tyr(3)]octreotide dose was about 26 GBq, without reaching the maximum tolerable dose. New is the use of [(177)Lu-DOTA,Tyr(3)]octreotate, which shows the highest tumor uptake of all tested octreotide analogs so far, with excellent tumor-to-kidney ratios. Radionuclide therapy with this analog in a phase 1 trial started recently in our center in 63 patients (238 administrations), Interim analysis of 18 patients with neuroendocrine tumors was performed very recently. According to the WHO, toxicity criteria no dose limiting toxicity was observed. Minor CT-assessed tumor shrinkage (25% - 50% reduction) was noticed in 6% of 18 patients and partial remission (50% - 100% reduction, SWOG criteria) in 39%. Eleven percent of patients had tumor progression and in 44% no changes were seen. These data show that radionuclide therapy with radiolabelled somatostatin analogs, like [DOTA, Tyr(3)]octreotide and [DOTA, Tyr(3)octreotate is a most promising new treatment modality for patients who have sst(2)-positive tumors.
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Article: Somatostatin Analogue Therapy[Show abstract] [Hide abstract]
ABSTRACT: This chapter reviews the basis of somatostatin (SST) analogue therapy and the current analogues available and under investigation. Present analogues decrease the secretion of bioactive products from tumors but have a limited anti-proliferative effect. The advantage of analogues with a longer duration of action has increased the duration of therapeutic control from days up to 3 –5 weeks. Ultimately the majority of patients experience loss of symptom control as drug tolerance develops or the tumor produces more secretory products. This loss of sensitivity may be associated with the emergence of cell clones lacking SST receptors (SSTRs) or down-regulation of SST receptors. Acromegalics appear to be less susceptible to this phenomenon in that tachyphylaxis is rare even after > 10 years of daily SST analogue injections. The therapeutic effects of radiolabeled SST analogues are of interest since internalization of the isotope produces local cell death. A variety of isotopes (111Indium, γ emitter; 90Yttrium, β emitter; 177Lutetium, β and γ emitter) are under investigation. β-emitting radionuclides exhibit a greater therapeutic potential since they emit sufficient energy to cause local tumor cell death without damaging surrounding tissue. In addition, systemic adverse effects are minimal although renal and bone marrow toxicity may occur. 177Lu induces significant tumor regression and may be of particular benefit in the treatment of small tumors by minimizing radiation exposure of distant cells. A potential therapeutic strategy for individuals with micro-metastases or tumors of different sizes is treatment with a combination of different radionuclides with varying degrees of penetrance. Similarly, targeting co-expressed receptors (GRP, CCK, VIP) that have proliferative regulatory effects, in addition to SSTRs, may have therapeutic relevance. Since individual tumors exhibit heterogeneous expression of receptors, a combination of receptor-selective radiopeptides may further amplify therapeutic efficacy. The concept of “cocktail” isotope therapy designed to target different receptors with a variety of isotopes synchronously is a potentially attractive therapeutic prospect.