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INTRODUCTION: Medullary thyroid cancer (MTC) is characterized by overexpression of cholecystokinin-2/gastrin receptors (CCK2R). There are limitations of calcitonin as a tumor marker in MTC diagnosis and prognosis. Procalcitonin is gaining a role as a complementary tumor marker. This study aimed to assess the feasibility of procalcitonin measurements on top of the calcitonin measurements after CCK2R agonist stimulation in patients with MTC. MATERIAL AND METHODS: The assessment was part of the GRAN-T-MTC translational study conducted through a Phase I multicenter clinical trial in patients with locally advanced and/or disseminated MTC. Patients were administered intravenously the CCK2R agonist CP04 labelled with indium-111 ([¹¹¹In]In-CP04); the first four patients at a lower mass amount of 10 μg, and afterwards the whole group at a higher mass amount of 50 μg. Blood samples for calcitonin and procalcitonin measurements were obtained shortly before and 2, 5, 10, and 20 minutes after start of [¹¹¹In]In-CP04 administration. RESULTS: Sixteen patients were included in the study. After injection of the higher mass amount of [¹¹¹In]In-CP04, the median maximum ratio for stimulated calcitonin was 2.97 (interquartile range [IQR] 2.35) pg/mL and procalcitonin 2.01 (IQR 2.07) pg/mL. The maximum stimulated/baseline calcitonin ratio was 5.2 ± 4.0 and 4.1 ± 3.8 in the low and high mass amount groups, respectively, and the maximum stimulated/baseline procalcitonin ratio was 4.6 ± 5.1 and 2.9 ± 3.1 in the low and high mass amount groups, respectively. There was a significant linear correlation between calcitonin and procalcitonin concentrations (p < 0.001) at each test time point and between the maximum procalcitonin and maximum calcitonin increment ratio (r = 0.94, p < 0.0001). Mild, short-lasting side effects (transient tachycardia, flushing) were observed in one patient during the injection of low and in two patients during the injection of high mass amount of [¹¹¹In]In-CP04. The side effects were not related to the baseline calcitonin or procalcitonin concentrations. CONCLUSION: Procalcitonin concentrations after CP04 stimulation were highly correlated with calcitonin concentrations. Unlabeled CP04, if available commercially, may be considered an alternative stimulating agent in MTC patients, even in lower mass amounts. Further studies, including healthy controls, are required to prove this concept and calculate the diagnostic thresholds.

IntroductionMedullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach.Materials and methodsA translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 μg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment.ResultsSixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 μg and 50 μg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging.ConclusionIn the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.