Targeted radionuclide therapy: current status and potentials for future improvements

target cell while the absorption of the radioactivity in non-target tissue should be as low as achievable. Usually, this goal is reached by coupling the radionuclide to a vector which recognises a structure, e.g. receptor, on the target cell. By far the most established combination is the somatostatin receptor (sst) and radiolabeled somatostatin analogues. The majority of neuroendocrine tumours feature a strong over-expression of the somatostatin receptors (sst), mainly subtype 2 (sst2). Somatostatin receptors are attractive targets for radiolabelled peptides since the density of sst on tumours is vastly higher than on non tumour tissue. In addition to the favourable receptor distribution, sst2 internalises into the cell after a ligand bound to the receptor. Consequently, radioactivity delivered by the vector is captured in the target cell after binding

Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour patients treated with targeted radiopeptide therapy

Purpose: Administration of positively charged amino acids has been introduced to reduce the nephrotoxicity of targeted radiopeptide therapy (TRT). However, the amino acid solution may have side effects, including hyperkalaemia. The aim of this study was to evaluate the frequency and the magnitude of hyperkalaemia in neuroendocrine tumour (NET) patients undergoing TRT. Methods: Enrolled in the study were 31 patients with NET eligible for TRT with [90Y-DOTA(0),Tyr(3)]octreotide (90Y-DOTATOC). Their mean age was 54 ± 14years. Of these 31 patients, 21 (67%) were referred for the first treatment cycle, while 10 (33%) were referred for a subsequent therapy cycle. Patients were treated with therapeutic doses of 90Y-DOTATOC ranging from 7,030 to 35,520MBq. To inhibit tubular reabsorption of 90Y-DOTATOC, 1l of physiological saline solution containing 25g of arginine hydrochloride and 25g of lysine hydrochloride was given over 4h starting 1h before 90Y-DOTATOC injection. All patients underwent a standard biochemical blood analysis at baseline, and 4h and 24h after the beginning of the amino acid infusion. Results: ANOVA repeated measures showed a significant overall effect on K+ levels over time (F = 118.2, df = 2, P 0.05) to baseline K+ levels. Intravenous administration of 40mg furosemide 1h after the beginning of the amino acid infusion did not have a significant effect on K+ levels (P>0.05). No clinical characteristic was predictive for the increase in K+ levels (chi-squared test, P > 0.05). Conclusion: Hyperkalaemia is a frequent, potentially life-threatening side effect of basic amino acid infusion during TRT. K+ levels 4h after the beginning of the infusion should be monitored in patients at risk of complications, such as those with heart disease and those with risk factors for nephrotoxicit

Preoperative staging of non-small-cell lung cancer: comparison of whole-body diffusion-weighted magnetic resonance imaging and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography

Objective: To investigate the diagnostic value of whole-body magnetic resonance imaging (MRI) including diffusion-weighted imaging with background signal suppression (DWIBS) for preoperative assessment of non-small-cell lung cancer (NSCLC) in comparison to 18F-fluorodeoxyglucose 18FDG) positron emission tomography/computed tomography (PET/CT). Methods: Thirty-three patients with suspected NSCLC were enrolled. Patients were examined before surgery with PET/CT and whole-body MRI including T1-weighted turbo spin echo (TSE), T2-weighted short tau inversion recovery (STIR) and DWIBS sequences (b = 0/800). Histological or cytological specimens were taken as standard of reference. Results: Whole-body MRI with DWIBS as well as PET/CT provided diagnostic image quality in all cases. Sensitivity for primary tumour detection: MRI 93%, PET/CT 98%. T-staging accuracy: MRI 63%, PET/CT 56%. N-staging accuracy: MRI 66%, PET/CT 71%. UICC staging accuracy: MRI 66%, PET/CT 74%. Sensitivity for metastatic involvement of individual lymph node groups: MRI 44%, PET/CT 47%. Specificity for individual non-metastatic lymph node groups: MRI 93%, PET/CT 96%. Assessment accuracy for individual lymph node groups: MRI 85%, PET/CT 88%. Observer agreement rate for UICC staging: MRI 74%, PET/CT 90%. Conclusion: Whole-body MRI with DWIBS provides comparable results to PET/CT in staging of NSCLC, but shows no superiority. Most relevant challenges for both techniques are T-staging accuracy and sensitivity for metastatic lymph node involvement. Key Points : • Numerous radiological methods are available for the crucial staging of lung cancer • Whole-body DWIBS MRI provides comparable results to PET/CT in NSCLC staging. • No evident superiority of whole-body DWIBS over PET/CT in NSCLC staging. • Challenges for both techniques are T-staging and detection of small metastase

In vitro characterization of 177Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

Purpose: 131I- and 90Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin's lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20min) with either 177Lu or 90Y. Materials and methods: Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. Results: The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 105 times excess of diethylenetriaminepentaacetic acid (DTPA, 37°C, 7days). Two patients with relapsed NHL were treated with 740MBq/m2 body surface 177Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314mGy. The administration of 177Lu-DOTA-rituximab was tolerated well. Conclusion: Our results show that DOTA-rituximab (4:1) can be labelled with 177Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NH

Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA-substance P—results from a phase I study

Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA-substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA-substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA-substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA-substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA-substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevan

Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

Purpose: Radiolabelled somatostatin-based antagonists show a higher uptake in tumour-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labelling with radiometals such as 111In and 68Ga. Methods: RM2 was synthesized on a solid support and evaluated in vitro in PC-3 cells. IC50 and Kd values were determined. The antagonist potency was evaluated by immunofluorescence-based internalization and Ca2+ mobilization assays. Biodistribution studies were performed in PC-3 and LNCaP tumour-bearing mice with 111In-RM2 and 68Ga-RM2, respectively. PET/CT studies were performed on PC-3 and LNCaP tumour-bearing nude mice with 68Ga-RM2. Results: RM2 and 111In-RM2 are high-affinity and selective ligands for the GRP receptor (7.7±3.3nmol/l for RM2; 9.3±3.3nmol/l for natIn-RM2). The potent antagonistic properties were confirmed by an immunofluorescence-based internalization and Ca2+ mobilization assays. 68Ga- and 111In-RM2 showed high and specific uptake in both the tumour and the pancreas. Uptake in the tumour remained high (15.2±4.8%IA/g at 1h; 11.7±2.4%IA/g at 4h), whereas a relatively fast washout from the pancreas and the other abdominal organs was observed. Uptake in the pancreas decreased rapidly from 22.6±4.7%IA/g at 1h to 1.5±0.5%IA/g at 4h. Conclusion: RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that 111In-RM2 and 68Ga-RM2 are ideal candidates for clinical SPECT and PET studie

4D-SPECT/CT in orthopaedics: a new method of combined quantitative volumetric 3D analysis of SPECT/CT tracer uptake and component position measurements in patients after total knee arthroplasty

Objective: The purpose was to evaluate the intra- and inter-observer reliability of combined quantitative 3D-volumetric single-photon emission computed tomography (SPECT)/CT analysis including size, intensity and localisation of tracer uptake regions and total knee arthroplasty (TKA) position. Materials and methods: Tc-99m-HDP-SPECT/CT of 100 knees after TKA were prospectively analysed. The anatomical areas represented by a previously validated localisation scheme were 3D-volumetrically analysed. The maximum intensity was recorded for each anatomical area. Ratios between the respective value and the mid-shaft of the femur as the reference were calculated. Femoral and tibial TKA position (varus-valgus, flexion-extension, internal rotation- external rotation) were determined on 3D-CT. Two consultant radiologists/nuclear medicine physicians interpreted the SPECT/CTs twice with a 2-week interval. The inter- and intra-observer reliability was determined (ICCs). Kappa values were calculated for the area with the highest tracer uptake between the observers. Results: The measurements of tracer uptake intensity showed excellent inter- and intra-observer reliabilities for all regions (tibia, femur and patella). Only the tibial shaft area showed ICCs 0.84). Conclusion: This combined 3D-volumetric standardised method of analysing the location, size and the intensity of SPECT/CT tracer uptake regions ("hotspots”) and the determination of the TKA position was highly reliable and represents a novel promising approach to biomechanic

Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called "remainder of the body" to the bone marrow

Targeted radiotherapy with radiolabeled somatostatin analogs

Targeted radiopeptide therapy with (90)Yttrium- or (177)Lutetium-labeled somatostatin analogs has been proven to improve significantly quality of life and survival in patients suffering from metastatic or unresectable neuroendocrine tumors (NETs). Roughly 25% of patients achieve partial remission; progression-free survival is estimated to be 30 to 40 months. A wide range of protocols using different somatostatin analogs, isotopes, injected activity per cycle of administration, and number of cycles are reported. More patient-based therapy protocols are under development, taking into consideration the complexity of NET cell biology, dosimetric issues, and the availability of different radiolabeled analogs. This article reviews the effectiveness and safety of the different protocols and discusses several clinical algorithms used in an attempt to optimize targeted radiopeptide therapy

Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma

AIM: Paragangliomas and pheochromocytomas are rare tumors arising from chromaffin cells. Approximately 10% are malignant. Treatment options are limited in metastatic, surgically incurable situations. These tumors often express somatostatin receptors in high density. Therefore, treatment with the radiolabeled somatostatin analogue [DOTA-Tyr(3)]-octreotide (DOTATOC) is an option. We evaluated the effectiveness and toxicity of radiolabeled DOTATOC in patients with metastatic paraganglioma and pheochromocytoma. METHODS: Twenty-eight patients (16 female and 12 male) with surgically incurable paragangliomas and pheochromocytomas were included. Twenty-five patients were scheduled for treatment with a total of 200 mCi/m(2) body surface [(90)Y]DOTATOC and 3 for one cycle with 100 mCi/m(2) [(90)Y]DOTATOC followed by 2 cycles of 200 mCi [(177)Lu]DOTATOC. Restaging was performed 8-12 weeks after the last treatment cycle, followed by regular controls every 3 to 6 months. RESULTS: The treatment was well tolerated. At restaging we found 2 partial remissions, 5 minor responses; 13 stable disease, 2 mixed responses and 6 patients remained progressive. We found 1 thrombocytopenia grade I and 1 anemia grade I. No non-hematological toxicity, especially no kidney toxicity occurred. The follow-up ranged from 6 to 50 months (mean: 19+/-14.6 months). Time to progression ranged from 3 to <42 months. Ten responses, 9 stable diseases and one partial remission, are still ongoing. CONCLUSIONS: In these 28 patients, it was shown that radiolabeled DOTATOC can be effective in patients with somatostatin receptor positive paraganglioma. However, the therapy seems to be less effective than in gastroentero-pancreatic neuroendocrine tumors. Nevertheless, DOTATOC appears to be a treatment option for surgically incurable paragangliomas, because toxicity is very low and especially the fact that long lasting remissions could be achieved justifies the treatment. The final time to progression is not yet reached after a mean follow-up time of 19 months