Long-term toxicity of [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate in rats

Purpose and methods Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Results Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2×278 MBq groups. Three doses of 185 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469±18, 134±70 and 65±15 μmol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Conclusion Injection of high doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.     

Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate

Purpose In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Methods Male Lewis rats were injected with 278 or 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of ^99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Results Treatment with 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of ^99mTc-DMSA SPECT scintigrams at 130 days after [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate therapy correlated well with 1/creatinine (r ² = 0.772, p < 0.001). Conclusion Amifostine and lysine effectively decreased functional renal damage caused by high-dose [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.     

Comparison of [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is preferable for PRRT?

Purpose Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotide (¹⁷⁷Lu-DOTATOC) and [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-DOTATATE), to see which peptide should be preferred for PRRT with ¹⁷⁷Lu.Methods In the same patients, 3,700 MBq ¹⁷⁷Lu-DOTATOC and 3,700 MBq ¹⁷⁷Lu-DOTATATE was administered in separate therapy sessions. Amino acids were co-administered. Whole-body scanning was performed on days 1, 4 and 7 post therapy. Blood and urine samples were collected. We calculated residence times for tumours, spleen and kidneys.Results All patients had longer residence times in spleen, kidneys and tumours after use of ¹⁷⁷Lu-DOTATATE (p=0.016 in each case). Comparing ¹⁷⁷Lu-DOTATATE with ¹⁷⁷Lu-DOTATOC, the mean residence time ratio was 2.1 for tumour, 1.5 for spleen and 1.4 for kidneys. Dose-limiting factors for PRRT are bone marrow and/or kidney dose. Although the residence time for kidneys was longer when using ¹⁷⁷Lu-DOTATATE, the mean administered dose to tumours would still be advantageous by a factor of 1.5, assuming a fixed maximum kidney dose is reached. Plasma radioactivity after ¹⁷⁷Lu-DOTATATE was comparable to that after ¹⁷⁷Lu-DOTATOC. Urinary excretion of radioactivity was comparable during the first 6 h; thereafter there was a significant advantage for ¹⁷⁷Lu-DOTATOC.Conclusion ¹⁷⁷Lu-DOTATATE had a longer tumour residence time than ¹⁷⁷Lu-DOTATOC. Despite a longer residence time in kidneys after ¹⁷⁷Lu-DOTATATE, tumour dose will always be higher. Therefore, we conclude that the better peptide for PRRT is octreotate.     

Effects of therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate on endocrine function

Purpose  

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes.     

Individualized dosimetry in patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotate

Purpose

In recent years, targeted radionuclide therapy with [¹⁷⁷Lu-DOTA⁰, Tyr³]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging.

Methods

Attenuation-corrected SPECT data were analysed both by using organ-based volumes of interest (VOIs) to obtain the total radioactivity in the organ, and by using small VOIs to measure the tissue radioactivity concentration. During the first treatment session in 24 patients, imaging was performed 1, 24, 96 and 168 h after [¹⁷⁷Lu-DOTA⁰, Tyr³]octreotate infusion. Absorbed doses in non tumour-affected kidney, liver and spleen were calculated and compared for all three methods (planar imaging, SPECT organ VOIs, SPECT small VOIs).

Results

Planar and SPECT dosimetry were comparable in areas free of tumours, but due to overlap the planar dosimetry highly overestimated the absorbed dose in organs with tumours. Furthermore, SPECT dosimetry based on small VOIs proved to be more reliable than whole-organ dosimetry.

Conclusion

We conclude that SPECT dosimetry based on small VOIs is feasible and more accurate than conventional planar dosimetry, and thus may contribute towards optimising targeted radionuclide therapy.     

The use of the effective dose equivalent,H E,for 99mTc labelled radiopharmaceuticals

Using the concept of effective dose equivalent, H _E, it is shown that a knowledge of the detailed biodistribution data in most organs and tissues taking up ^99mTc labelled radiopharmaceuticals is unnecessary for the calculation of radiation risk. Reasonably precise dosimetry (±25%) can be obtained from urine excretion data alone providing there is no significant uptake within the gonads or the thyroid. Special attention should only be paid to absorbed dose measurements in red bone marrow, skin, lungs, gonads and thyroid, with the greatest attention directed toward the retention and dosimetric aspects of radioactivity in the latter two organs. An example H _E calculation for ^99mTc labelled d,1-HMPAO is presented to illustrate the importance of these specific five organs to radiation risk.     

Influence of whole-body vibration on biodistribution of the radiopharmaceutical [99mTc]methylene diphosphonate in Wistar rats

Abstract

Purpose: The radionuclide bone scan is the basis of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive method for indicating disease in bone. Mechanical stimulation in the manner of whole-body vibration (WBV) appears beneficial to the maintenance and/or enhancement of skeletal mass in individuals. The aim of this work was to evaluate the effect of WBV on the biodistribution of the radiopharmaceutical [^99mTc]methylene diphosphonate (^99mTc-MDP ) in Wistar rats.

Materials and methods: In the biodistribution analysis, animals were anesthetized with sodium thiopental, the radiopharmaceutical ^99mTc-MDP was administered via ocular plexus and after 10 min the animals were submitted to vibration of 20 Hz (1 min) in an oscillatory platform. Following, the animals were sacrificed, the organs were isolated, the radioactivity determined in a well counter, and the percentages of radioactivity per gram (%ATI/g) in the organs were calculated. An unpaired t-test following Welch test (p < 0.05) was done for statistical analysis of the results.

Results: The biodistribution was significantly (p < 0.05) decreased in kidney, bone, lung, stomach, prostate and bowel.

Conclusion: The analysis of the results indicates that the vibration could produce metabolic alterations with influence in the uptake of the radiopharmaceutical ^99mTc-MDP in bone, stomach, bowel, prostate, kidney and bladder.     

[177Lu-DOTA0,Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients

The somatostatin analogue [DOTA⁰,Tyr³]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA⁰,Tyr³]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate) with [¹¹¹In-DTPA⁰]octreotide (¹¹¹In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after ¹⁷⁷Lu-octreotate expressed as a percentage of the injected dose was comparable with that after ¹¹¹In-octreotide. Urinary excretion of radioactivity was significantly lower than after ¹¹¹In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of ¹⁷⁷Lu-octreotate, was comparable to that after ¹¹¹In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, ¹⁷⁷Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of ¹⁷⁷Lu as compared with ⁹⁰Y may be especially important for small tumours.     

Subacute haematotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate: prognostic factors,incidence and course

Purpose

In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from ¹³¹I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit.

Methods

The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined.

Results

Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0?×?10⁹/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67?±?7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients.

Conclusion

The incidence of subacute haematological toxicity after PRRT with ¹⁷⁷Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from ¹³¹I, seems not to be valid for PRRT with ¹⁷⁷Lu-DOTATATE.

     

Personalized <Superscript>177</Superscript>Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study

Purpose

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course.

Methods

Thirty-six patients underwent 122 fixed-IA ¹⁷⁷Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6?±?2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2?±?5.5, 1.3?±?0.8, and 114?±?66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle.

Results

In the P-PRRT regime, cumulative IA could have been increased to 43.7?±?16.5 GBq over four induction cycles (10.9?±?5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5?±?2.5, 1.63?±?0.61, and 163.4?±?85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68–2.64-fold; P?=?0.0013).

Conclusion

By standardizing the renal absorbed dose delivered during the induction course, P-PRRT has the potential to significantly increase tumour absorbed dose, thus to augment the therapeutic benefit while limiting toxicity.

     

Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin’s lymphoma

Dosimetry studies in patients with non-Hodgkin’s lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from ⁹⁰Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of ⁹⁰Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received ¹¹¹In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of ⁹⁰Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of ¹¹¹In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n =56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2–7.8 Gy), 2.6 Gy to lungs (range 0.72–4.4 Gy), and 0.38 Gy to kidneys (range 0.07–0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8–67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T _1/2, blood AUC, plasma T _1/2, and plasma AUC. It is concluded that ⁹⁰Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T _1/2, reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population. Received 24 January and in revised form 20 March 2000     

Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y-DOTATOC and <Superscript>177</Superscript>Lu-DOTATATE: the role of associated risk factors

Purpose  Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumours with ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE is promising. The kidney is the critical organ and despite renal protection, function loss may become evident years later. The aim of this study was to analyse renal parameters in patients who had undergone dosimetry before PRRT. Methods  Among those in protocols at our institution, 28 patients were considered: 23 received ⁹⁰Y-DOTATOC (3.8–29.2 GBq, median 12.2) and five received ¹⁷⁷Lu-DOTATATE (20.7–29.2 GBq, median 23.2). Patients were followed up after therapy for creatinine and creatinine clearance loss (CCL) for 3–97 months (median 30). Renal doses and bio-effective doses (BED) were calculated (MIRD, LQ model). Results  After ⁹⁰Y-DOTATOC toxicity on creatinine according to NCI criteria occurred in nine cases (seven grade 1, one grade 2, one grade 3), CCL at 1 year was >5% in 12 cases and >10% in eight. A 28-Gy BED threshold was observed in patients with risk factors (mainly hypertension and diabetes), while it was 40 Gy in patients without risk factors. Probably due to the low number of patients, despite the absence of severe toxicity after hyper-fractionated PRRT, clear correlations between fractionation and toxicity could not be found. After ¹⁷⁷Lu-DOTATATE, no toxicity occurred in 1–2 year follow-up; CCL at 1 year >5% occurred in three patients and >10% in two. Conclusions  Our results indicate the importance of clinical screening for risk factors: In this case, a BED <28 Gy is recommended. Fractionation of therapy is important in order to decrease toxicity, and further studies are needed to evaluate its clinical impact. An erratum to this article can be found at     

Quantification of the whole-body distribution of PET radiopharmaceuticals,applied to 3-N-([18F]fluoroethyl)spiperone

Using a multi slice whole body PET scanner PC4096-15WB, diagnostic measurements of the cerebral distribution of the D₂ receptor ligand 3-N-([¹⁸F]fluoroethyl)spiperone were extended to quantify the biodistribution of this PET radiopharmaceutical. As a rotating line source was used for measured attenuation correction, transmission scans could be combined with emission scans even after injection of the tracer. Only 1 of the total administered dose (TAD) was found in the whole brain at 180 min, but the striatum and pituitary were still excellently delineated. Urinary bladder, gall bladder, and liver were the organs with the highest TAD ranging from 6% to 25%. The gall bladder is the critical organ with an absorbed dose of about 200 mGy/kBq followed by the urinary bladder and liver with 83 and 66 mGy/kBq, respectively. In the rest of the body radioactivity was evenly distributed. The total body dose was found to be 11.9 mGy/kBq.     

Peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y-DOTATOC in recurrent meningioma

Purpose  Meningiomas are generally benign and in most cases surgery is curative. However, for high-grade histotypes or partially resected tumours, recurrence is fairly common. External beam radiation therapy (EBRT) is usually given in such cases but is not always effective. We assessed peptide receptor radionuclide therapy (PRRT) using ⁹⁰Y-DOTATOC in a group of patients with meningioma recurring after standard treatments in all of whom somatostatin receptors were strongly expressed on meningioma cell surfaces. Methods  Twenty-nine patients with scintigraphically proven somatostatin subtype 2 receptor-positive meningiomas were enrolled: 14 had benign (grade I), 9 had atypical (grade II) and 6 had malignant (grade III) disease. Patients received intravenous ⁹⁰Y-DOTATOC for 2–6 cycles for a cumulative dose in the range of 5–15 GBq. Clinical and neuroradiological evaluations were performed at baseline, during and after PRRT. Results  The treatment was well tolerated in all patients. MRI 3 months after treatment completion showed disease stabilization in 19 of 29 patients (66%) and progressive disease in the remaining 10 (34%). Better results were obtained in patients with grade I meningioma than in those with grade II–III, with median time to progression (from beginning PRRT) of 61 months in the low-grade group and 13 months in the high-grade group. Conclusion  PRRT with ⁹⁰Y-DOTATOC can interfere with the growth of meningiomas. The adjuvant role of this treatment, soon after surgery, especially in atypical and malignant histotypes, deserves further investigation.     

[99mTc]Demotate 2 in the detection of sst2-positive tumours: a preclinical comparison with [111In]DOTA-tate

Purpose The aim of this study was to evaluate [^99mTc]Demotate 2 ([^99mTc-N₄ ^0-1,Asp⁰,Tyr³]octreotate) as a candidate for in vivo imaging of sst₂-positive tumours and to compare it with [¹¹¹In]DOTA-tate ([¹¹¹In-DOTA⁰,Tyr³]octreotate). Methods Labelling of Demotate 2 with ^99mTc was performed at room temperature using SnCl₂ as reductant in the presence of citrate at alkaline pH. Radiochemical analysis involved ITLC and HPLC methods. Peptide conjugate affinities for sst₂ were determined by receptor autoradiography on rat brain cortex sections using [DOTA⁰,¹²⁵I-Tyr³]octreotate as the radioligand. The affinity profile of Demotate 2 for human sst₁–sst₅ was studied by receptor autoradiography in cell preparations using the universal somatostatin radioligand [¹²⁵I][Leu⁸,(D)Trp²²,Tyr²⁵]somatostatin-28. The internalisation rates of [^99mTc]Demotate 2 and [¹¹¹In]DOTA-tate were compared in sst₂-positive and -negative control cell lines. Biodistribution of radiopeptides was studied in male Lewis rats bearing CA20948 tumours. Results Peptide conjugates showed selectivity and a high affinity binding for sst₂ (Demotate 2 IC₅₀=3.2 nM and DOTA-tate IC₅₀=5.4 nM). [^99mTc]Demotate 2, like [¹¹¹In]DOTA-tate, internalised rapidly in all sst₂-positive cells tested, but not in sst₂-negative control cells. After injection in CA20948 tumour-bearing rats both radiopeptides showed high and specific uptake in the sst₂-positive organs and in the implanted tumour and rapid excretion from non-target tissues via the kidneys. Conclusion [^99mTc]Demotate 2, similarly to the known sst₂-targeting agent [¹¹¹In]DOTA-tate, showed promising biological qualities for application in the scintigraphy of sst₂-positive tumours.     

The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists ⁹⁰Y-DOTATOC ([⁹⁰Y-DOTA⁰,Tyr³]-octreotide) or ¹⁷⁷Lu-DOTATATE ([¹⁷⁷Lu-DOTA⁰,Tyr³,Thr⁸]-octreotide or [¹⁷⁷Lu-DOTA⁰,Tyr³]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving ¹⁷⁷Lu-DOTATATE or ⁹⁰Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts’ opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency.     

Samarium — 153 EDTMP therapy of disseminated skeletal metastasis

¹⁵³Sm-EDTMP (ethylenediaminetetramethylene phosphonate), prepared from a kit, was administered to 28 patients in a clinical trial of therapy for painful skeletal metastases unresponsive to all conventional treatment. The 103 keV gamma emission of ¹⁵³Sm was utilized for prospective individual estimation of beta radiation absorbed dose to red marrow to minimize myelotoxicity and provide optimum internal radiotherapy to skeletal metastases in each patient. Pain relief occurred within 14 days of administration of ¹⁵³Sm-EDTMP in 15 of 19 patients (79%) who could be evaluated at 6 weeks, when clinical response was maximal. Duration of response ranged from 4 to 35 weeks. Recurrence of pain responded to retreatment with ¹⁵³Sm-EDTMP in five of eight cases. No dose-response relationship was apparent for pain relief but reversible myelotoxicity was frequently observed at radiation absorbed doses to bone marrow 270 cGy. Dosimetry calculation was based on pharmacokinetic studies of a tracer administration of ¹⁵³Sm-EDTMP in each patient. Assumptions inherent in this prospective method of predicting dose to bone marrow were validated experimentally. Biodistribution studies in rats demonstrated rapid skeletal uptake and long term retention of ¹⁵³Sm-EDTMP in bone over 5 days. Urinary clearance accounted for 40% of injected dose, and less than 1.0% of administered activity was retained in non osseous tissue. Microdensitometry of autoradiographs of sheep vertebra and femur confirmed surface uptake of ¹⁵³Sm-EDTMP in cortical bone and demonstrated relatively high trabecular bone activity which is the major component of radiation absorbed dose to bone marrow. Haematological studies in rabbits showed ¹⁵³Sm-EDTMP-induced myclotoxicity to be transient and no histopathological abnormalities were demonstrable with doses ten times greater than those administered to patients.     

Nephrotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate

Purpose

After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with ⁹⁰Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]-Octreotate (¹⁷⁷Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with ⁹⁰Y-radiolabelled somatostatin analogues.

Methods

The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.

Results

Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5?–?3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (±?SD) was 108?±?5 ml/min and the estimated average annual decrease in CLR (±?SD) was 3.4?±?0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1?±?4.9 Gy.

Conclusion

Nephrotoxicity in patients treated with ¹⁷⁷Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with ⁹⁰Y-labelled somatostatin analogues, does not seem valid for PRRT with ¹⁷⁷Lu-octreotate.

     

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.     

Evaluation of 99mTc-dextran as a lymphoscintigraphic agent in rabbits

Dextran (clinical grade, average mol. wt. 82,200) was labelled with ^99mTc and the labelling efficiency was checked by paper and thin-layer chromatography and electrophoresis. The amount of free ^99mTcO ₄ ^- was always less than 1%. The radiopharmaceutical was injected ID into the web space in hind legs of ten rabbits (200–600 Ci/0.05 ml). Scintigrams were taken at 10-min intervals up to 3 h in three rabbits. The injection site and the hind legs were massaged after injection in the other seven rabbits and scintigrams were taken at 10-min intervals up to 2 h. Blood samples were obtained at 5, 15, 30, 90 and 120 min in both groups. In addition a 180-min sample, was also taken in the first group. At the end of the study the rabbits were killed and the popliteal lymph nodes and the organs were removed to be weighed, and counted. Our results indicated a high concentration of radioactivity in the popliteal lymph nodes and massage at the injection site increased the average uptake of the popliteal lymph node from 1.12%±0.77% to 4.28%±1.57% at 3 and 2 h, respectively (P<0.001). In scintigrams the lymph channels and the nodes were very well visualised. The blood radioactivity levels were too low to present a background problem. With massage 30% of the injected dose was removed from the injection site in 2 h. We have shown that ^99mTc-dextran is a good radiopharmaceutical for the visualisation of the lymph system and deserves further experimental and clinical studies.