Evaluierung der Radioligandentherapie mit Indium-111-Minigastrin zur Behandlung metastasierter medullärer Schilddrüsenkarzinome am Standort Marburg

Schilddrüsenkarzinome machen circa 2,3% der weiblichen und 1% der männlichen Krebsmorbidität in Deutschland aus. Medulläre Schilddrüsenkarzinome wiederum stellen circa 2 – 5% aller thyroidalen Malignome dar. Sie werden meist erst spät und als Zufallsbefund, zum Beispiel bei Strumaresektion entdeckt....

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Bibliographic Details
Main Author: Zimmer, Nico
Contributors: Luster, Markus (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2022
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Thyroid carcinoma accounts for approximately 2,3% of female and 1% of male cancer morbidity in Germany. Medullary thyroid carcinoma in turn represents approximately 2 – 5% of all thyroid carcinomas. It often is diagnosed incidentally in patients undergoing thyroid surgery. At the time of diagnosis, medullary thyroid carcinoma is metastatic and therefore incurable in many cases. The currently approved systemic therapy in Europe is the use of tyrosine kinase inhibitors vandetanib and cabozantinib. The expression of cholecystokinin-B receptors enables targeted therapy of the neuroendocrine tumor. At the University Hospital Marburg, this receptor-binding radioligand therapy was performed from April 2001 to May 2003. Nineteen patients suffering from metastatic medullary thyroid carcinoma were treated with the indication of compassionate use. The applied ligand minigastrin displays a high binding affinity to the cholecystokinin-B receptor. Its linked radionuclide In-111 emits gamma rays, as well as cytotoxic Auger electrons. The aim of this work was to evaluate the side effect profile and the biochemical response rates, as well as to discuss the peptide receptor radionuclide therapy using In-111-DTPA-[(D)-Glu1]-minigastrin as a therapeutic alternative. An average of 4,9 cycles were performed per patient, applying a mean activity of 10,7 GBq per cycle. Nausea or even vomiting occurred frequently at the time of and shortly after injection of the radiopharmaceutical. They were not rated as acute side effects because of their short duration. In the first days of the patient's hospital stay after injection, acute side effects occurred in 10,6% of the therapy cycles. Of these, 36,4% were due to a general feeling of unease, 27,3% due to flush symptoms, 18,2% due to fatigue, 9,1% due to an increase in tumor pain and 9,1% due to the occurence of an increased cough. With regard to the long-term side effects of the therapy, biochemical evidence of nephrotoxicity, haematotoxicity, hepatotoxicity and disturbances in the electrolyte balance was collected. In summary, 15,8% of the patients showed a higher-grade reduction of the glomerular filtration rate. Persistent renal insufficiency was seen in 10,5% of the patients. Lower-grade alterations of the blood count were seen in 63,2% of the patients, in 10,5%, an anemia occurred. Incidence rates were 10,5% for thrombocytopenia and 26,3% for leukocytopenia. Higher-grade anemia, thrombocytopenia, or leukocytopenia did not occur. Concerning the response rates by carcinoembryonic antigen serum concentration, stable disease was observed in 42,1% and progressive disease was seen in 42,1% of the patients. Regarding the calcitonin serum concentration, 31,6% showed a stable disease and 42,1% of the patients were in the state of a progressive disease. Therapy response for calcitonin was seen in 10,5% of the patients, of which 5,3% had a complete remission of serum calcitonin. The response rate of the therapy investigated (10,5%) is significantly lower than response rates of the established Y-90-DOTA- and Lu-177-DOTA-ligands (approximately 25% and 40%, respectively) or the tyrosine kinase inhibitors vandetanib and cabozantinib (28% and 69%, respectively). Considering the side effect profile of these radioligands, however, changes in the blood count (90,8% and 92,1%, versus 63,2%, respectively) and persistent renal insufficiency (34% and 13%, versus 10,5%, respectively) were seen more frequently than in In-111-minigastrin therapy. Also, during therapy with the established tyrosine kinase inhibitors vandetanib and cabozantinib, diarrhea, rash, fatigue or nausea occurred in over 30% of cases. Consequently, the lower long-term hematological and nephrological side effect profile of In-111-minigastrin compared to the therapy by Y-90- and Lu-177-labeled somatostatin analogs appears advantageous. In addition, the lower rate of clinical side effects compared to the tyrosine kinase inhibitors seems considerable. Although the observed response rates are subject to those of the comparative therapies, the examined radiopharmaceutical is in principle suitable as an alternative therapy option due to its safety profile. Furthermore, tumor visualization and therapy can be combined by using the radioligand in the sense of the future-oriented concept of theragnostics.