Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-dPhe1-Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

[⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide ([⁹⁰Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [⁸⁶Y]DOTA-dPhe¹-Tyr³-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [⁸⁶Y]DOTA-dPhe¹-Tyr³-octreotide was administered at two different peptide concentrations, namely 2 and 100 μg peptide per m² body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [⁸⁶Y]DOTA-dPhe¹-Tyr³-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1–3.3 mGy per MBq [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide injected. For the 100 μg/m² SMT487 protocol with amino acid co-infusion this dose was about 20%–40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide, respectively. The average effective dose equivalent amounted to 0.23–0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide in patients with somatostatin receptor-expressing tumours. Received 26 September and in revised form 18 November 1998     

Three-step radioimmunotherapy with yttrium-90 biotin: dosimetry and pharmacokinetics in cancer patients

. A three-step avidin-biotin approach has been applied as a pretargeting system in radioimmunotherapy (RIT) as an alternative to conventional RIT with directly labelled monoclonal antibodies (MoAbs). Although dosimetric and toxicity studies following conventional RIT have been reported, these aspects have not previously been evaluated in a three-step RIT protocol. This report presents the results of pharmacokinetic and dosimetric studies performed in 24 patients with different tumours. Special consideration was given to the dose delivered to the red marrow and to the haematological toxicity. The possible additive dose to red marrow due to the release of unbound yttrium-90 was investigated. The protocol consisted in the injection of biotinylated MoAbs (first step) followed 1 day later by the combined administration of avidin and streptavidin (second step). After 24 h, biotin radiolabelled with 1.85–2.97 GBq/m² of ⁹⁰Y was injected (third step). Two different chelating agents, DTPA and DOTA, coupled to biotin, were used in these studies. Indium-111 biotin was used as a tracer of ⁹⁰Y to follow the biodistribution during therapy. Serial blood samples and complete urine collection were obtained over 3 days. Whole-body and single-photon emission tomography images were acquired at 1, 16, 24 and 40 h after injection. The sequence of images was used to extrapolate ⁹⁰Y-biotin time-activity curves. Numerical fitting and compartmental modelling were used to calculate the residence time values (τ) for critical organs and tumour, and results were compared; the absorbed doses were estimated using the MIRDOSE3.1 software. The residence times obtained by the numerical and compartmental models showed no relevant differences (<10%); the compartmental model seemed to be more appropriate, giving a more accurate representation of the exchange between organs. The mean value for the τ in blood was 2.0±1.1 h; the mean urinary excretion in the first 24 h was 82.5%±10.8%. Without considering any contribution of free ⁹⁰Y, kidneys, liver, bladder and red marrow mean absorbed doses were 1.62±1.14, 0.27±0.23, 3.61±0.70 and 0.11±0.05 mGy/MBq, respectively; the effective dose was 0.32±0.06 mSv/MBq, while the dose to the tumour ranged from 0.62 to 15.05 mGy/MBq. The amount of free ⁹⁰Y released after the injection proved to be negligible in the case of ⁹⁰Y-DOTA-biotin, but noteworthy in the case of ⁹⁰Y-DTPA-biotin (mean value: 5.6%±2.5% of injected dose), giving an additive dose to red marrow of 0.18±0.08 mGy per MBq of injected ⁹⁰Y-DTPA-biotin. Small fractions of free ⁹⁰Y originating from incomplete radiolabelling can contribute significantly to the red marrow dose (3.26 mGy per MBq of free ⁹⁰Y) and may explain some of the high levels of haematological toxicity observed. These results indicate that pretargeted three-step RIT allows the administraton of high ⁹⁰Y activities capable of delivering a high dose to the tumour and sparing red marrow and other normal organs. Although ⁹⁰Y-biotin clears rapidly from circulation, the use of DOTA-biotin conjugate for a stable chelation of ⁹⁰Y is strongly recommended, considering that small amounts of free ⁹⁰Y contribute significantly in increasing the red marrow dose. Received 6 June and in revised form 19 September 1998     

Preparation and biodistribution of yttrium-90 Lipiodol in rats following hepatic arterial injection

In this study, we labelled Lipiodol with yttrium-90 and analysed the biodistribution in rats after intrahepatic arterial injection. An RP-18 column (E. Merck) was used to separate⁹⁰Y from strontium-90.⁹⁰Y was retained on the column, which had been pretreated with yttrium-selective extraction reagent, di(2-ethylhexyl) phosphate, while⁹⁰Sr was washed out. A hexadentate nitrogen-donor chelating ligandN,N,N,N-tetrakis(2-ben-zymidazolylmethyl)-1,2-ethanediamine (EDTB) was synthesized by condensation of 1,2-benzenediamine and ethylene diamine tetra-acetic acid (EDTA). Lipiodol was covalently conjugated with EDTB. The final product was obtained by eluting the retained⁹⁰Y from the RP-18 column with EDTB-Lipiodol. Sixteen male rats (Sprague-Dawley) were sacrificed at 1 h, 24 h, 48 h and 72 h (four rats at each time) after injection of approximately 0.1 mCi⁹⁰Y Lipiodol via the hepatic artery. Samples of liver, spleen, muscle, lung, kidney, bone, whole blood and testis were obtained and counted to calculate the tissue concentrations. In addition, labelling efficiency and in vitro stability were determined by ITLC methods. We found that at 1 h after intrahepatic injection, most of the radiotracer was retained in the liver, but it was eliminated gradually over a few days. The radioactivity level in the lung was fair at 1 h and remained at roughly the same level throughout the study. Radioactivity in the kidney and spleen reached a relatively high level at 24 h, but declined rapidly. Bone uptake was low initially but showed an increase between 24 h and 72 h. Low concentrations of radioactivity were noted in the muscle, testis and whole blood. In the study of in vitro stability, radiochemical purity and labelling efficiency were higher than 90%, indicative of good stability. These initial results indicate that Lipiodol may be a possible carrier agent for⁹⁰Y The retention of⁹⁰Y-Lipiodol in the normal liver is high initially; however, elimination occurs over a period of a few days. Future studies should assess the biodistribution of⁹⁰Y Lipiodol in an animal model with liver cancer.     

Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-DPhe1- Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

[90Y]DOTA-DPhe1-Tyr3-octreotide ([90Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [86Y]DOTA-DPhe1-Tyr3-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [86Y]DOTA-DPhe1-Tyr3-octreotide was administered at two different peptide concentrations, namely 2 and 100 microg peptide per m2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [86Y]DOTA-DPhe1-Tyr3-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [90Y]DOTA-DPhe1-Tyr3-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide injected. For the 100 microg/m2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide, respectively. The average effective dose equivalent amounted to 0. 23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [90Y]DOTA-DPhe1-Tyr3-octreotide in patients with somatostatin receptor-expressing tumours.     

A systematic review of yttrium-90 radioembolization for unresectable liver metastases of melanoma

PurposeTo assess the effectiveness of yttrium-90 (⁹⁰Y) radioembolization in the treatment of unresectable liver metastases of melanoma.MethodsPubMed and EMBASE were systemically searched for all English language studies related to ⁹⁰Y radioembolization for unresectable liver metastases of melanoma, including clinical trials, observational studies, and abstracts from conferences, published between January 1991 and March 2016.ResultsA total of 12 reports (7 observational studies and 5 abstracts from conferences) involving 255 patients were included in the analysis. The primary sites of melanoma were cutaneous (n = 22; 8.6%), ocular (n = 197; 77.3%), rectal (n = 3; 1.2%), and unknown (n = 33; 12.9%). The median disease control rate at 3 months was 73.6% (range, 58.3%–88.9%). Among the 207 patients for whom tumor response at 3 months was reported, complete response was seen in 1.0% (2/207), partial response was seen in 19.3% (40/207), stable disease was seen in 46.9% (97/207), and progressive disease was seen in 32.9% (68/207). The median survival was 10 months (range, 7–13.4 months), and the median 1-year survival rate was 34.6% (range, 23%–80%). Complications of ⁹⁰Y radioembolization were reported in 13 cases. The most common side effects were fatigue (median, 36.1%), abdominal pain (median, 17.8%), and nausea (median, 15.0%).Conclusions⁹⁰Y radioembolization is a promising alternative therapy for the treatment of unresectable liver metastases of melanoma, with encouraging effects on disease control and survival. Some complications can occur, and side effects are frequent but mild.     

90Y microsphere treatment of unresectable liver metastases: changes in 18F-FDG uptake and tumour size on PET/CT

Purpose The intra-arterial administration of ⁹⁰Y microspheres is a new palliative treatment option for unresectable liver metastases. The aim of this study was to quantitatively assess changes in FDG uptake and tumour size following ⁹⁰Y microsphere treatment (SIR-Spheres) using ¹⁸F-fluorodeoxyglucose (FDG) PET/CT imaging.Methods Five patients with unresectable liver metastases who had failed multiple prior chemotherapy regimens received seven ⁹⁰Y microsphere treatments to a single liver lobe. All patients underwent a baseline PET/CT scan prior to treatment, as well as up to four follow-up PET/CT scans. The tumour area of 30 liver metastases was measured on CT and the FDG uptake was semiquantitatively assessed by calculation of standardised uptake values (SUVs). A total of 18 FDG-PET/CT scans were performed.Results The SUVs in the 30 treated liver metastases decreased from 6.5±2.3 at baseline to 4.2±1.8 after the first follow-up PET/CT scan (p=0.001). In contrast, the SUVs of untreated metastases increased slightly from 7.2±2.3 to 8.0±0.8. There was no difference in FDG uptake in treated versus untreated normal liver tissue. Using a previously defined threshold of 20% decrease in SUV from baseline to determine response, 20 out of 30 liver metastases were considered to have responded at the first follow-up PET/CT scan approximately 1 month after treatment. In these metastases, the SUV decreased by 47±12%, compared with a slight increase by 5.9±19% in ten non-responding metastases (p=0.0001). The changes in tumour size did not correlate with changes in FDG uptake. On the first follow-up PET/CT scan, the tumour area on CT increased by 3.1±57% in treated metastases compared with 23.3±32% in untreated metastases. A wide range of post-treatment changes of target lesions was observed on CT, including an increase in the size of hypodense lesions, necrotic features and complete resolution of CT abnormalities.Conclusion The metabolic information obtained from FDG-PET/CT seems to provide a more accurate and earlier assessment of therapy response following ⁹⁰Y microsphere treatment than does the anatomical CT information.     

Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours

A uniform distribution of yttrium-90 (⁹⁰Y) microspheres throughout the entire liver has always been assumed for dose calculation in treating hepatic tumours. A simple mathematical model was formulated which allows estimation of the activities of a therapeutic dose of⁹⁰Y microspheres partitioned between the lungs, the tumour and the normal liver, and hence the radiation doses to them. The doses to the tumour and normal liver were verified by intra-operative direct beta-probing. The percentage of activity shunted to the lung and the tumour-to-normal tissue ratio (T/N) were obtained from gamma scintigraphy using technetium-99m-labelled macroaggregated albumin (MAA) which simulates the⁹⁰Y microspheres used in subsequent treatment. The intrahepatic activity was partitioned between the tumour and the normal liver based on the T/N and their masses determined from computerized tomography slices. The corresponding radiation doses were computed using the MIRD formula. The estimated radiation doses were correlated with the doses directly measured using a calibrated beta-probe at laparotomy by linear regression. The radiation doses to the tumour and the normal liver, estimated using the partition model, were close to that measured directly with coefficients of correlation for linear regression: 0.862 for the tumours and 0.804 for the normal liver compartment (P<0.001). The partition model permits a distinction between the radiation doses received by the tumour and the normal liver to be made and the doses thus estimated are close to the actual doses received. The optimal doses to the tumour and normal liver and hence the required quantity of⁹⁰Y microspheres to be administered can be easily predetermined.     

Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT<Superscript>®</Superscript>)

Purpose

A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT^®) application. Preclinical and clinical results are described.

Methods

⁹⁰Y and ¹⁷⁷Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated.

Results

High radiochemical purity (>99%) was routinely achieved with ⁹⁰Y or ¹⁷⁷Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both ⁹⁰Y- and ¹⁷⁷Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of ～85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was ～12 mGy/MBq.

Conclusion

These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials.

     

Human radiation dosimetry of [11C]MeAIB, a new tracer for imaging of system A amino acid transport

Purpose [N-methyl-¹¹C]α-methylaminoisobutyric acid ([¹¹C]MeAIB) is a promising positron emission tomography (PET) tracer for imaging hormonally regulated system A amino acid transport. Uptake of [¹¹C]MeAIB is totally specific for amino acid transport since [¹¹C]MeAIB is metabolically stable both extra- and intracellularly. The aim of this study was to measure cumulated radioactivity in different organs and estimate the absorbed radiation doses to humans with the Medical Internal Radiation Dosimetry (MIRD) method.Methods Radiation absorbed doses were calculated from PET images for 25 volunteers. Dynamic acquisition data were obtained for the thoracic, abdominal, femoral and head and neck regions. The median dose of intravenously injected [¹¹C]MeAIB was 422±35 MBq, with a range of 295–493 MBq. After PET imaging the radioactivity in voided urine was measured. Experimental human data were used for residence time estimates. Radiation doses were calculated with commonly used software.Results The effective dose for a 70-kg adult was 0.004 mSv/MBq, corresponding to a 1.72 mSv effective dose from the PET study with injection of 430 MBq [¹¹C]MeAIB. The highest absorbed doses were in the pancreas (0.018 mGy/MBq), kidneys (0.017 mGy/MBq), intestine (0.014 mGy/MBq), liver (0.008 mGy/MBq) and stomach (0.005 mGy/MBq). Only 0.57% of injected activity was excreted to urine within 1 h after injection.Conclusion Biodistribution of [¹¹C]MeAIB in the abdominal region reflected the high activity of the transportation of amino acids via system A and these organs also had the highest radiation doses. An effective dose of 0.004 mSv/MBq is fully justified when [¹¹C]MeAIB PET is performed to study system A activity in vivo.     

Prospective Study of Systemic Yttrium-90 Elution during Radioembolization of Hepatic Metastases

PurposeTo evaluate total blood radioactivity (BR) after SIR-Spheres yttrium-90 (⁹⁰Y) radioembolization and differences in BR based on delivery method.Materials and MethodsTwenty participants with hepatic metastases undergoing first radioembolization were prospectively enrolled from December 2017 to June 2018. Blood samples were drawn at baseline and 0, 10, 20, 60, and 120 minutes after ⁹⁰Y administration. BR was measured with a γ-counter and scaled by estimated blood volume. Percentage of instilled radioactivity in the bloodstream was calculated as area under the fitted curve, and differences between delivery methods were examined with nonparametric statistical tests.ResultsIn 10 participants, resin microspheres were instilled with 50% Isovue 300 diluted in saline solution in the D line, and 10 others were treated with dextrose 5% in water (D5W) in the D line. Median administered activities were 944 MBq (range, 746–1,993 MBq) and 1,213 MBq (range, 519–2,066 MBq), respectively. Fraction of ⁹⁰Y in blood was significantly higher with dilute contrast agent than with D5W (median, 0.5% of injected activity vs 0.2%; P = .001). Among all participants, the maximum activity delivered was 2,066 MBq, and a maximum of 1% of administered radioactivity was measured as free ⁹⁰Y in blood. Assuming these highest-case values and complete decay of all free ⁹⁰Y in bone, a dose to red marrow of 132.3 mGy was calculated by Organ Level INternal Dose Assessment/EXponential Modeling.ConclusionsBlood sampling after radioembolization allowed for estimation of the time–activity curve and BR. Delivery with 50% contrast agent in saline solution resulted in a significant increase in BR vs D5W, even though the total BR for both groups was nominal.     

Radiation dosimetry of <Superscript>68</Superscript>Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing

Purpose

The clinical introduction of ⁶⁸Ga-PSMA-11 (“HBED-CC”) ligand targeting the prostate-specific membrane antigen (PSMA) has been regarded as a significant step forward in the diagnosis of prostate cancer (PCa). In this study, we provide human dosimetry and data on optimal timing of PET imaging after injection.

Methods

Four patients with recurrent PCa were referred for ⁶⁸Ga-PSMA-11 PET/CT. Whole-body PET/CT_low-dose scans were conducted at 5 min, and 1, 2, 3, 4 and 5 h after injection of 152–198 MBq ⁶⁸Ga-PSMA-11. Organs of moderate to high uptake were used as source organs; their total activity was determined at all measured time points. Time–activity curves were created for each source organ as well as for the remainder. The radiation exposure of a ⁶⁸Ga-PSMA-11 PET was identified using the OLINDA-EXM software. In addition, tracer uptake was measured in 16 sites of metastases.

Results

The highest tracer uptake was observed in the kidneys, liver, upper large intestine, and the urinary bladder. Mean organ doses were: kidneys 0.262?±?0.098 mGy/MBq, liver 0.031?±?0.004 mGy/MBq, upper large intestine 0.054?±?0.041 mGy/MBq, urinary bladder 0.13?±?0.059 mGy/MBq. The calculated mean effective dose was 0.023?±?0.004 mSv/MBq (=0.085?±?0.015 rem/mCi). Most tumor lesions (n?=?16) were visible at 3 h p.i., while at all other time points many were not qualitatively present (10/16 visible at 1 h p.i.).

Conclusions

The mean effective dose of a ⁶⁸Ga-PSMA-11 PET is 0.023 mSv/MBq. A 3-h delay after injection was optimal timing for ⁶⁸Ga-PSMA-11 PET/CT in this patient cohort.

     

Estimation of internal absorbed dose of l-[methyl-11C]methionine using whole-body positron emission tomography

l-[Methyl-¹¹C]-methionine (¹¹C-methionine) is proposed as a useful radiotracer for tumour diagnosis. Human biodistribution data of cumulated activities and absorbed doses estimated by the MIRD (medical internal radiation dosimetry) method for ¹¹C-methionine are not available in the literature. In this study we measured the organ activity for ¹¹C-methionine by using whole-body positron emission tomography (PET) and estimated the absorbed doses to 25 organs by the MIRD method. Whole-body dynamic PET scans were performed on five normal volunteers to measure the time course of the organ activity concentration (activity/volume) after intravenous administration of ¹¹C-methionine. Cumulated activities of the ten source organs were calculated from the time-activity curves, obtained from the dynamic PET data. Absorbed dose estimates were performed by the MIRD method for the Caucasian reference man and for the Japanese reference man. The organs which received the highest absorbed doses for the Caucasian reference man were found to be the bladder wall (2.7×10^–2 mGy/MBq), the pancreas (1.9×10^–2 mGy/ MBq), the liver (1.8× 10^–2 mGy/MBq) and the kidney (1.1×10^–2 mGy/MBq). The effective doses for the Caucasian reference man and the Japanese reference man were calculated as 5.2×10^–3 and 5.0×10^–3 mSv/MBq, respectively. Received 16 December 1997 and in revised form 30 January 1998     

Yttrium-90 Activity Quantification in PET/CT–Guided Biopsy Specimens from Colorectal Hepatic Metastases Immediately after Transarterial Radioembolization Using Micro–CT and Autoradiography

PurposeTo evaluate the yttrium-90 (⁹⁰Y) activity distribution in biopsy tissue samples of the treated liver to quantify the dose with higher spatial resolution than positron emission tomography (PET) for accurate investigation of correlations with microscopic biological effects and to evaluate the radiation safety of this procedure.Materials and MethodsEighty-six core biopsy specimens were obtained from 18 colorectal liver metastases (CLMs) immediately after ⁹⁰Y transarterial radioembolization (TARE) with either resin or glass microspheres using real-time ⁹⁰Y PET/CT guidance in 17 patients. A high-resolution micro–computed tomography (micro-CT) scanner was used to image the microspheres in part of the specimens and allow quantification of ⁹⁰Y activity directly or by calibrating autoradiography (ARG) images. The mean doses to the specimens were derived from the measured specimens’ activity concentrations and from the PET/CT scan at the location of the biopsy needle tip for all cases. Staff exposures were monitored.ResultsThe mean measured ⁹⁰Y activity concentration in the CLM specimens at time of infusion was 2.4 ± 4.0 MBq/mL. The biopsies revealed higher activity heterogeneity than PET. Radiation exposure to the interventional radiologists during post-TARE biopsy procedures was minimal.ConclusionsCounting the microspheres and measuring the activity in biopsy specimens obtained after TARE are safe and feasible and can be used to determine the administered activity and its distribution in the treated and biopsied liver tissue with high spatial resolution. Complementing ⁹⁰Y PET/CT imaging with this approach promises to yield more accurate direct correlation of histopathological changes and absorbed dose in the examined specimens.     

Dosimetry of 60/61/62/64Cu-ATSM: a hypoxia imaging agent for PET

Purpose Cu-diacetyl-bis(N⁴-methylthiosemicarbazone (Cu-ATSM) is an effective marker for the delineation of hypoxic tissue. Dosimetry calculations by the established Medical Internal Radionuclide Dose (MIRD) approach were performed with both animal and patient data.Methods Human absorbed dose estimates extrapolated from rat data were based on the biodistribution of ⁶¹Cu-ATSM in adult rats. Eighteen tissues were harvested and time–activity curves generated. The measured residence times and the MIRD S-values for ⁶⁰Cu-ATSM were used to estimate human absorbed doses. The biodistribution of the tracer was directly measured in five patients injected with approximately 480 MBq of ⁶⁰Cu-ATSM and imaged by positron emission tomography (PET) with a whole-body protocol. The combined data from all patients were used to derive organ residence times, and organ doses were calculated by MIRD methodology for ⁶⁰Cu-ATSM, ⁶¹Cu-ATSM, ⁶²Cu-ATSM, and ⁶⁴Cu-ATSM.Results Human absorbed dose estimates extrapolated from rat biodistribution data indicated that the kidneys appeared to be the dose-limiting organ (0.083 mGy/MBq) with a whole-body dose of 0.009 mGy/MBq. Based on the human PET imaging data, the liver appeared as the dose-limiting organ, with an average radiation dose of 0.064 mGy/MBq. The whole-body dose was 0.009 mGy/MBq and the effective dose was 0.011 mSv/MBq.Conclusion These relatively small absorbed doses to normal organs allow for the safe injection of 500–800 MBq of ⁶⁰Cu-ATSM, which is sufficient for PET imaging in clinical trials.     

Indium-111 bleomycin complex for radiochemotherapy of head and neck cancer — dosimetric and biokinetic aspects

Bleomycin (BLM) is used for the treatment of head and neck cancer. In order to improve the effectiveness of this chemotherapeutic drug, BLM was combined with indium-111. A complex of these agents (¹¹¹In-BLMC), formed at low pH, was injected intravenously into ten head and neck cancer patients in escalating activities of 75, 175 and 375 MBq. The internally delivered dose to the tumours varied from 0.20 to 2.73 mGy at 75 MBq, from 0.33 to 2.51 mGy at 175 MBq, and from 0.87 to 31.3 mGy at the 375 MBq activity level. Uptake of radioactivity was 0.45±0.24×10^–3% ID/g in primary tumours and 0.52±0.20×l0^–3% ID/g in metastases (at 48 h). Tumour volumes varied from 0.51 to 49.0 cm³. The radioactivity half-lives in the tumours were 30±7 h. The activity distribution and penetration into tumour tissue were not affected by increasing the injected activity. There was a positive correlation between BLMC uptake and Ki-67/Mib activity as well as number of mitoses in tumour tissue. These data indicate that¹¹¹In-BLMC has potential as a radiochemotherapeutic agent in head and neck cancer and that adjuvant Auger-electron therapy is possible using^114m-In-labelled BLMC.     

Optimal dose of <Superscript>18</Superscript>F-FDG required for whole-body PET using an LSO PET camera

Reducing the acquisition time of whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) (corrected for attenuation) is of major importance in clinical practice. With the introduction of lutetium oxyorthosilicate (LSO), the acquisition time can be dramatically reduced, provided that patients are injected with larger amounts of tracer and/or the system is operated in 3D mode. The aim of this study was to determine the optimal dose of ¹⁸F-FDG required in order to achieve good-to-excellent image quality when a "3-min emission, 2-min transmission/bed position" protocol is used for an LSO PET camera. A total of 218 consecutive whole-body ¹⁸F-FDG PET studies were evaluated retrospectively. After excluding patients with liver metastases, hyperglycaemia and paravenous injections, the final study population consisted of 186 subjects (112 men, 74 women, age 59±15 years). Patients were injected with an activity of ¹⁸F-FDG ranging from 2.23 to 15.21 MBq/kg. Whole-body images corrected for attenuation (3 min emission, 2 min transmission/bed position) were acquired with an LSO PET camera (Ecat Accel,Siemens) 60 min after tracer administration. Patients were positioned with their arms along the body. Image reconstruction was done iteratively and a post-reconstruction filter was applied. Image quality was scored visually by two independent observers using a five-point scoring scale (poor, reasonable, good, very good, excellent). In addition, the coefficient of variability (COV) was measured in a region of interest over the liver in order to quantify noise. Of the images obtained in 118 patients injected with 8 MBq/kg ¹⁸F-FDG, 92% and 90% were classified as good, very good or excellent by observer 1 and observer 2, respectively. The COV averaged 10.63%±3.19% for doses 8 MBq/kg and 16.46%±5.14% for doses <8 MBq/kg. Administration of an ¹⁸F-FDG dose of 8 MBq/kg results in images of good to excellent quality in the vast majority of patients when using an LSO PET camera and applying a 3-min emission, 2-min transmission/bed position acquisition protocol. At lower doses, a rapid decline in image quality and increasing noise are observed. Alternative protocols should be adopted in order to compensate for the loss in image quality when doses <8 MBq/kg are used.     

Whole-body kinetics and dosimetry ofl-3-[123I]iodo-α-methyltyrosine

The synthetic amino acidl-3-[¹²³I]iodo--methyltyrosine (IMT) is currently under clinical evaluation as a single-photon emission tomography (SPET) tracer of amino acid uptake in brain tumours. So far, dosimetric data in respect of IMT are not available. Therefore we investigated the whole-body distribution of IMT in six patients with cerebral gliomas and the radiation doses were estimated. Whole-body scans were acquired at 1.5, 3 and 5 h after i.v. injection of 370–550 MBq IMT. The bladder was voided prior to each scan and the radioactivity excreted in the urine was measured. Based on the MIRD-11 method and the updated MIRDOSE3, the mean absorbed doses for various organs and the effective dose were calculated from geometric means of the anterior and posterior whole-body scans using seven source organs and the residence time. IMT was predominantly excreted by the kidneys (52.8%±11.5% at 1.5 h p.i., 63.0%±15.7% at 3 h p.i. and 74.6%±9.8% at 5 h p.i.). No organ system other than the urinary tract showed significant retention of the tracer. Early whole-body scans revealed slightly increased tracer uptake in the liver and in the bowel. Highest absorbed doses were found for the urinary bladder wall (0.047 mGy/MBq), the kidneys (0.010 mGy/MBq), the lower large intestinal wall (0.011 mGy/MBq) and the upper large intestinal wall (0.008 mGy/MBq). The effective dose according to ICRP 60 was estimated to be 0.0073 mSv/MBq for adults. This leads to an effective dose of 3.65 mSv in a typical brain SPET study using 500 MBq IMT. The MIRDOSE3 scheme yielded similar results. Thus, in spite of the relatively high tracer dose required for optimal brain scanning, radiation exposure in SPET studies with IMT is in the normal range of routine nuclear medicine investigations.     

Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin

While the incidence of brain tumours seems to be increasing, median survival in patients with glioblastoma remains less than 1 year, despite improved diagnostic imaging and neurosurgical techniques, and innovations in treatment. We have developed an avidin-biotin pre-targeting approach for delivering therapeutic radionuclides to gliomas, using anti-tenascin monoclonal antibodies, which seems potentially effective for treating these tumours. We treated 48 eligible patients with histologically confirmed grade III or IV glioma and documented residual disease or recurrence after conventional treatment. Three-step radionuclide therapy was performed by intravenous administration of 35 mg/m² of biotinylated anti-tenascin monoclonal antibody (1st step), followed 36 h later by 30 mg of avidin and 50 mg of streptavidin (2nd step), and 18–24 h later by 1–2 mg of yttrium-90-labelled biotin (3rd step). ⁹⁰Y doses of 2.22–2.96 GBq/m² were administered; maximum tolerated dose (MTD) was determined at 2.96 GBq/m². Tumour mass reduction (>25%–100%), documented by computed tomography or magnetic resonance imaging, occurred in 12/48 patients (25%), with 8/48 having a duration of response of at least 12 months. At present, 12 patients are still in remission, comprising four with a complete response, two with a parital response, two with a minor response and four with stable disease. Median survival from ⁹⁰Y treatment is 11 months for grade IV glioblastoma and 19 months for grade III anaplastic gliomas. Avidin-biotin based three-step radionuclide therapy is well tolerated at the dose of 2.2 GBq/m², allowing the injection of ⁹⁰Y-biotin without bone marrow transplantation. This new approach interferes with the progression of high-grade glioma and may produce tumour regression in patients no longer responsive to other therapies. Received 9 September and in revised form 15 November 1998     

Yttrium-90 DOTATOC: first clinical results

In a pilot study, DOTA-d-Phe¹-Tyr³-octreotide (DOTATOC), which can be labelled with the β-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of ⁹⁰Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of ⁹⁰Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120±1347 MBq/m²) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of ≥3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity ≤ grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of ≤7400 MBq/m². Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m² and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. ⁹⁰Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment – at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during ⁹⁰Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing. Received 12 February and in revised form 16 May 1999     

放射性核素肾动态显像中的辐射剂量计算

目的 研究在放射性核素肾动态显像中肾脏和膀胱所受到的内照射剂量。方法 建立一个双隔室链肾脏-膀胱排泄模型并推导出相关的数学表达式,模拟放射性核素肾动态显像剂被人体摄入后的转移、排泄过程,计算核素在肾脏、膀胱和人体其余组织内的总衰变数,再采用蒙特卡罗模拟的方法,计算核素衰变释放的射线在肾脏以及膀胱内产生的能量沉积,最后根据辐射的品质因数计算它们的有效剂量。结果 以 ¹³¹I-OIH和 ⁹⁹Tc^m-DTPA显像剂为例,肾脏受到的内照射剂量分别为0.058mGy/MBq(¹³¹I-OIH)和0.0054 mGy/MBq(⁹⁹Tc^m-DTPA);膀胱受到的内照射剂量分别为0.40mGy/MBq(¹³¹I-OIH)和0.033mGy/MBq(⁹⁹Tc^m-DTPA)。结论 常规剂量水平下的放射性核素肾动态显像对肾脏和膀胱造成的辐射剂量很小。