Therapy of neuroendocrine tumors with radiolabeled somatostatin-analogues.
Peptide receptor scintigraphy with the radioactive somatostatin-analogue [111In-DTPA0]octreotide (DTPA = diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of 111In- or 90Y-labeled octreotide-analogues. PRECLINICAL: We investigated the radiotherapeutic effect of 90Y- and 111In-labeled [DOTA0,Tyr3]octreotide (DOTA = tetraazacyclododecanetetraacetic acid) or [111In-DTPA0]octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in A) the flank or B) in the liver.


METHODS
Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. PRECLINICAL RESULTS: A) Flank model: at least two 111MBq injections of [111In-DOTA0,Tyr3]octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of [90Y-DOTA0,Tyr3] octreotide yielded transient stable disease. B) Liver model: we found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq [111In-DTPA0]octreotide or 93 MBq [90Y-DOTA0,Tyr3]octreotide can inhibit the growth of somatostatin receptor-positive metastases.


RESULTS
There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur. Promising beneficial effects on clinical symptoms, hormone production and tumor proliferation were found. Of the 21 patients with progressive disease at baseline and who received a cumulative dose of more than 20 GBq [111In-DTPA0]octreotide, 8 patients showed stabilisation of disease and 6 other patients a reduction in size of tumors. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand.


CONCLUSIONS
Radionuclide therapy with octreotide-derivatives is feasible, both with 111In and 90Y as radionuclides.
De Jong
M
M
Department of Nuclear Medicine, University Hospital and Erasmus University, Rotterdam, The Netherlands.
Breeman
W A
WA
Bernard
H F
HF
Kooij
P P
PP
Slooter
G D
GD
Van Eijck
C H
CH
Kwekkeboom
D J
DJ
Valkema
R
R
Mäcke
H R
HR
Krenning
E P
EP
D000818:Animals; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D018358:Neuroendocrine Tumors / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000532:radiotherapy; D051381:Rats; D011917:Rats, Inbred Lew; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; C094279:indium-111-octreotide; D015282:Octreotide