DOTATOC: A powerful new tool for receptor-mediated radionuclide therapy

This study presents the first successful use of a peptidic vector, DOTATOC, labelled with the -emitting radioisotope yttrium-90, for the treatment of a patient with somatostatin receptor-positive abdominal metastases of a neuroendocrine carcinoma of unknown localization. Tumour response and symptomatic relief were achieved. In addition, the new substance DOTA-TOC was labelled with the diagnostic chemical analogue indium-111 and studied in three patients with histopathologically verified neuroendocrine abdominal tumours for its diagnostic sensitivity and compared with the commercially available OctreoScan. In all patients the kidney-to-tumour uptake ratio (in counts per pixel) was on average 1.9-fold lower with¹¹¹In-DOTATOC than with OctreoScan. DOTATOC could be a potential new diagnostic and therapeutic agent in the management of neuroendocrine tumours.     

[111In]DOTATOC as a dosimetric substitute for kidney dosimetry during [90Y]DOTATOC therapy: results and evaluation of a combined gamma camera/probe approach

Purpose During [⁹⁰Y]DOTATOC therapy, for determination of kidney doses a conventional approach using co-injected [¹¹¹In]DOTATOC was evaluated for validity, reliability and reproducibility as well as for the influence of methodological variations and bremsstrahlung. Biologically effective doses were estimated by calculating the relative effectiveness (RE) of kidney doses.Methods Fractionated [⁹⁰Y]DOTATOC therapy (n=20 patients, 3.1±0.7 GBq/therapy cycle, 45 therapy cycles) included co-injection of 157±37 MBq [¹¹¹In]DOTATOC and a nephroprotective infusion regimen. From serial gamma camera/probe measurements, individual region of interest (ROI) sets were established and kidney doses were determined according to MIRDOSE3 (corrected for individual kidney mass) by use of three methodological variants: (1) correction for interfering organs (liver/spleen) and background activity, (2) correction for interfering organs alone and (3) no corrections. A phantom study was performed with ¹¹¹ In alone and with ¹¹¹In +⁹⁰Y to estimate the influence of ⁹⁰Y bremsstrahlung.Results Mean kidney dose (method 1, n=20 patients, 20 therapy cycles) was 1.51±0.60 Gy/GBq [⁹⁰Y]DOTATOC (1.41±0.48 Gy/GBq for n=20 patients, 45 therapy cycles). With partial correction (method 2) or no correction (method 3) for interfering activity, kidney doses increased significantly, to 2.71±1.26 Gy/GBq and 3.15±1.22 Gy/GBq, respectively. The span of REs ranged from 1.02 to 1.24. Inter-observer variability was as high as ±32% (±2SD). ⁹⁰Y bremsstrahlung accounted for a 4–11% underestimation of obtained target activity.Conclusion The obtained kidney doses are highly influenced by methodological variations. Full correction for interfering activity clearly underestimates kidney doses. By comparison, ⁹⁰Y bremsstrahlung and variability in the relative effectiveness of kidney doses cause minor bias. Inter-observer variability must be considered when interpreting kidney doses.     

[I]-TYR3-octreotide: clinical dosimetry and use for internal radiotherapy of metastatic paraganglioma and carcinoid tumors

Dosimetry and therapeutic application of [¹³¹I]-Tyr3-octreotide were evaluated in three patients with metastatic paraganglioma and carcinoid tumor. The in vitro stability of [¹³¹I]-Tyr3-octreotide was verified. Tumor uptake and residence time were between 0.02 and 0.1% and 0.5 to 9.8 h, respectively. The calculated tumor radiation doses were between 0.105 and 0.696 mGy·MBq⁻¹. No intolerance or adverse effects were observed after the therapeutic doses (3.3–6.6 GBq). A partial tumor response was obtained in one patient and no response occurred in two patients.     

Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0,d-Phe1,Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy

In vitro octreotide receptor binding of [¹¹¹In-DOTA⁰,d-Phe¹,Tyr³]octreotide (¹¹¹In-DOTATOC) and the in vivo metabolism of⁹⁰Y or¹¹¹In-labelled DOTATOC were investigated in rats in comparison with [¹¹¹In-DTPA⁰]octreotide [¹¹¹In-DTPAOC).¹¹¹In-DOTATOC was found to have an affinity similar to octreotide itself for the octreotide receptor in rat cerebral cortex microsomes. Twenty-four hours after injection of⁹⁰Y or¹¹¹In-labelled DOTATOC, uptake of radioactivity in the octreotide receptor-expressing tissues pancreas, pituitary, adrenals and tumour was a factor of 2–6 that after injection of¹¹¹In-DTPAOC. Uptake of labelled DOTATOC in pituitary, pancreas, adrenals and tumour was almost completely blocked by pretreatment with 0.5 mg unlabelled octreotide, indicating specific binding to the octreotide receptors. These findings strongly indicate that⁹⁰Y-DOTATOC is a promising radiopharmaceutical for radiotherapy and that¹¹¹In-DOTATOC is of potential value for diagnosis of patients with octreotide receptor-positive lesions, such as most neuroendocrine tumours.     

Magnetic resonance imaging of bone marrow changes in Gaucher disease during enzyme replacement therapy: first German long-term results

Objective: . Since 1991, enzyme replacement therapy (ERT) has been available for patients with Gaucher disease in Germany. The aim of this study was to analyse the MR pattern of bone marrow involvement and response to ERT in Gaucher disease type I. Patients and design: . Thirty patients with Gaucher disease type I had MRI examinations prior to initiation of ERT with alglucerase/imiglucerase and during follow-up. Median MR follow-up and duration of ERT were 36 months. Coronal T1- and T2-weighted spin-echo images of the lower extremities were obtained to evaluate changes in the appearance of yellow marrow. MR images were categorized as having either a homogeneous (type A) or non-homogeneous patchy (type B) appearance of bone involvement and response to ERT was assessed by two radiologists. Results: . Overall, 19 of 30 patients (63%) showed an increased signal intensity on T1- and T2-weighted images after 36 months of ERT, consistent with partial reconversion of fatty marrow during treatment. Focal bone lesions surrounded by a low signal intensity (SI) rim did not respond to ERT, suggesting bone infarcts. Of the 11 patients with bone infarcts (low SI rim lesion), 82% had the non-homogeneous type B pattern (P=0.0021). In 86% of patients with splenectomy, bone infarcts were seen (P<0.05). Conclusions: . MRI using T1- and T2-weighted spin-echo sequences is a valuable, non-invasive method for monitoring bone marrow response in patients receiving ERT. A non- homogeneous patchy signal intensity of bone marrow involvement correlates with the presence of bone infarcts (P=0.0021). Received: 27 July 2000 Revision requested: 26 October 2000 Revision received: 9 March 2001 Accepted: 12 March 2001     

Quantitative Dosimetry for Yttrium-90 Radionuclide Therapy: Tumor Dose Predicts Fluorodeoxyglucose Positron Emission Tomography Response in Hepatic Metastatic Melanoma

PurposeTo assess a new method for generating patient-specific volumetric dose calculations and analyze the relationship between tumor dose and positron emission tomography (PET) response after radioembolization of hepatic melanoma metastases.Methods and MaterialsYttrium-90 (⁹⁰Y) bremsstrahlung single photon emission computed tomography (SPECT)/computed tomography (CT) acquired after ⁹⁰Y radioembolization was convolved with published ⁹⁰Y Monte Carlo estimated dose deposition kernels to create a three-dimensional dose distribution. Dose-volume histograms were calculated for tumor volumes manually defined from magnetic resonance imaging or PET/CT imaging. Tumor response was assessed by absolute reduction in maximum standardized uptake value (SUV_max) and total lesion glycolysis (TLG).ResultsSeven patients with 30 tumors treated with ⁹⁰Y for hepatic metastatic melanoma with available ⁹⁰Y SPECT/CT and PET/CT before and after treatment were identified for analysis. The median (range) for minimum, mean, and maximum dose per tumor volume was 16.9 Gy (5.7–43.5 Gy), 28.6 Gy (13.8–65.6 Gy) and 36.6 Gy (20–124 Gy), respectively. Response was assessed by fluorodeoxyglucose PET/CT at a median time after treatment of 2.8 months (range, 1.2–7.9 months). Mean tumor dose (P = .03) and the percentage of tumor volume receiving ≥ 50 Gy (P < .01) significantly predicted for decrease in tumor SUV_max, whereas maximum tumor dose predicted for decrease in tumor TLG (P < .01).ConclusionsVolumetric dose calculations showed a statistically significant association with metabolic tumor response. The significant dose-response relationship points to the clinical utility of patient-specific absorbed dose calculations for radionuclide therapy.     

Evaluation of 64Cu-labeled DOTA-d-Phe1-Tyr3-octreotide (64Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors

Objective  In-111 (¹¹¹In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 (⁶⁴Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a ⁶⁴Cu-labeled octreotide analog, ⁶⁴Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-d-Phe¹-Tyr³-octreotide (⁶⁴Cu-DOTA-TOC). Methods   ⁶⁴Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45°C. The stability of ⁶⁴Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by HPLC analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of ⁶⁴Cu-DOTA-TOC and ¹¹¹In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of ⁶⁴Cu-DOTA-TOC or ⁶⁴Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide (⁶⁴Cu-TETA-OC). The tumor was imaged using ⁶⁴Cu-DOTA-TOC, ⁶⁴Cu-TETA-OC, and FDG with an animal PET scanner. Results   ⁶⁴Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. ⁶⁴Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of ⁶⁴Cu was higher than that of ¹¹¹In in all organs except kidney. In tumor-bearing mice, ⁶⁴Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81 ± 1.17 at 6 h after administration. ⁶⁴Cu-DOTA-TOC showed significantly higher accumulation in the tumor than ⁶⁴Cu-TETA-OC. ⁶⁴Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of ¹⁸F-FDG PET and very similar to that of ⁶⁴Cu-TETA-OC. Conclusions   ⁶⁴Cu-DOTA-TOC clearly imaged a somatostatin receptor-positive tumor and seemed to be a potential PET tracer in the clinical phase.     

Value of 111In-DOTA-lanreotide and 111In-DOTA-DPhe1-Tyr3-octreotide in differentiated thyroid cancer: results of in vitro binding studies and in vivo comparison with 18F-FDG PET

Purpose Radioiodine-negative thyroid cancer presents diagnostic and therapeutic difficulties, warranting the implementation of new imaging and treatment strategies. The purpose of this study was twofold. First, we investigated in vitro the binding characteristics of ¹¹¹In-DOTA-lanreotide (¹¹¹In-DOTA-LAN) and ¹¹¹In-DOTA-DPhe¹-Tyr³-octreotide (¹¹¹In-DOTA-TOC) to cells derived from differentiated thyroid cancer (DTC). Second, we evaluated the value of somatostatin receptor (SSTR) scintigraphy with these radioligands, as compared with ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET), for the detection of tumour lesions in DTC patients.Methods Binding of ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC to cells isolated from surgically removed thyroid tissue was evaluated in vitro by performing saturation and displacement studies. Eighteen DTC patients with elevated thyroglobulin (12 radioiodine-negative, six radioiodine-positive) were investigated with ¹¹¹In-DOTA-LAN, ¹¹¹In-DOTA-TOC and ¹⁸F-FDG PET scans.Results Large numbers of SSTR binding sites for ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC were found on the cells investigated. Both SSTR radioligands exhibited a high binding affinity for these SSTR binding sites. ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC scintigraphy detected 37 and 33 lesions, respectively, in 17 (94%) patients each, whereas ¹⁸F-FDG PET revealed 30 lesions in 15 (83%) patients. Uptake of both SSTR radioligands was found in several radioiodine-negative sites. No striking differences in lesion imaging by ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC were found. In both radioiodine-negative and radioiodine-positive patients, more lesions were SSTR-positive/¹⁸F-FDG-negative than were ¹⁸F-FDG-positive/SSTR-negative.Conclusion Adding a SSTR scan with these radioligands to the diagnostic work-up increases the diagnostic capacity in DTC, and should be considered particularly in radioiodine-negative patients with elevated thyroglobulin levels.These studies were supported in part by the Austrian National Bank (Anniversary Foundation, Projects No. 7487 and 8185) and by a Foundation of the Mayor of the City of Vienna.