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.