Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project.

Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have "good" or "bad" disease at diagnosis, and the clinical stage is currently the most significant and clinically relevant prognostic factor. Therefore, for an individual patient, proper staging is of paramount importance for risk assessment and selection of optimal treatment. In 2009, the International Neuroblastoma Risk Group (INRG) Project proposed a new staging system designed for tumor staging before any treatment, including surgery. Compared with the focus of the International Neuroblastoma Staging System, which is currently the most used, the focus has now shifted from surgicopathologic findings to imaging findings. The new INRG Staging System includes two stages of localized disease, which are dependent on whether image-defined risk factors (IDRFs) are or are not present. IDRFs are features detected with imaging at the time of diagnosis. The present consensus report was written by the INRG Imaging Committee to optimize imaging and staging and reduce interobserver variability. The rationales for using imaging methods (ultrasonography, magnetic resonance imaging, computed tomography, and scintigraphy), as well as technical guidelines, are described. Definitions of the terms recommended for assessing IDRFs are provided with examples. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.

The diagnostic utility of the flare phenomenon on bone scintigraphy in staging prostate cancer.

PURPOSE: Bone scintigraphy (BS) lacks sensitivity for detecting very early skeletal metastases (SM) in prostate cancer (PC) and is often limited by poor specificity. Also scintigraphic flare of SM can occur following effective treatment and mislead an early response assessment. We hypothesised that a flare reaction might amplify the signal from subclinical SM, increasing the sensitivity of BS and that the phenomenon may be specific for metastases. METHODS: We conducted a prospective study to determine the frequency of the flare phenomenon in patients with metastatic PC starting hormone therapy and to explore its utility in patients with negative staging scans but considered at high risk of SM and in those with equivocal baseline BS abnormalities. Ninety-nine patients commencing first-line hormone therapy had repeat BS at 6 weeks to score a flare reaction. RESULTS: Of 22 patients with unequivocal SM on the baseline scan, a flare occurred in 9 (41%). Of 36 high-risk localised prostate cancer patients with normal BS pre-treatment, the scan became positive for metastases at 6 weeks in 4 (11%). Of 41 patients with pre-treatment scintigraphic abnormalities of uncertain aetiology, a flare occurred in 8 cases (20%). All eight were confirmed to have SM by follow-up and imaging. Of the 33 remaining patients without a flare, 2 developed SM at 14 months and the remainder did not develop SM in a median follow-up period of 36 months. CONCLUSION: The flare phenomenon following initial hormone therapy can be used to improve both sensitivity and specificity of BS in PC.

In vitro cytotoxicity of Auger electron-emitting [67Ga]Ga-trastuzumab.

INTRODUCTION: Molecular radiotherapy exploiting short-range Auger electron-emitting radionuclides has potential for targeted cancer treatment and, in particular, is an attractive option for managing micrometastatic disease. Here, an approach using chelator-trastuzumab conjugates to target radioactivity to breast cancer cells was evaluated as a proof-of-concept to assess the suitability of 67Ga as a therapeutic radionuclide. METHODS: THP-trastuzumab and DOTA-trastuzumab were synthesised and radiolabelled with Auger electron-emitters 67Ga and 111In, respectively. Radiopharmaceuticals were tested for HER2-specific binding and internalisation, and their effects on viability (dye exclusion) and clonogenicity of HER2-positive HCC1954 and HER2-negative MDA-MB-231 cell lines was measured. Labelled cell populations were studied by microautoradiography. RESULTS: Labelling efficiencies for [67Ga]Ga-THP-trastuzumab and [111In]In-DOTA-trastuzumab were 90% and 98%, respectively, giving specific activities 0.52 ± 0.16 and 0.61 ± 0.11 MBq/µg (78-92 GBq/µmol). At 4 nM total antibody concentration and 200 × 103 cells/mL, [67Ga]Ga-THP-trastuzumab showed higher percentage of cell association (10.7 ± 1.3%) than [111In]In-DOTA-trastuzumab (6.2 ± 1.6%; p = 0.01). The proportion of bound activity that was internalised did not differ significantly for the two tracers (62.1 ± 1.4% and 60.8 ± 15.5%, respectively). At 100 nM, percentage cell binding of both radiopharmaceuticals was greatly reduced compared to 4 nM and did not differ significantly between the two (1.2 ± 1.0% [67Ga]Ga-THP-trastuzumab and 0.8 ± 0.9% for [111In]In-DOTA-trastuzumab). Viability and clonogenicity of HER2-positive cells decreased when each radionuclide was incorporated into cells by conjugation with trastuzumab, but not when the same level of radioactivity was confined to the medium by omitting the antibody conjugation, suggesting that 67Ga needs to be cell-bound or internalised for a therapeutic effect. Microautoradiography showed that radioactivity bound to individual cells varied considerably within the population. CONCLUSIONS: [67Ga]Ga-THP-trastuzumab reduced cell viability and clonogenicity only when cell-bound, suggesting 67Ga holds promise as a therapeutic radionuclide as part of a targeted radiopharmaceutical. The causes and consequences of non-homogeneous uptake among the cell population should be explored.

Re-assessing gallium-67 as a therapeutic radionuclide.

INTRODUCTION: Despite its desirable half-life and low energy Auger electrons that travel further than for other radionuclides, 67Ga has been neglected as a therapeutic radionuclide. Here, 67Ga is compared with Auger electron emitter 111In as a potential therapeutic radionuclide. METHODS: Plasmid pBR322 studies allowed direct comparison between 67Ga and 111In (1MBq) in causing DNA damage, including the effect of chelators (EDTA and DTPA) and the effects of a free radical scavenger (DMSO). The cytotoxicity of internalized (by means of delivery in the form of oxine complexes) and non-internalized 67Ga and 111In was measured in DU145 prostate cancer cells after a one-hour incubation using cell viability (trypan blue) and clonogenic studies. MDA-MB-231 and HCC1954 cells were also used. RESULTS: Plasmid DNA damage was caused by 67Ga and was comparable to that caused by 111In; it was reduced in the presence of EDTA, DTPA and DMSO. The A50 values (internalized activity of oxine complexes per cell required to kill 50% of cells) as determined by trypan blue staining was 1.0Bq/cell for both 67Ga and 111In; the A50 values determined by clonogenic assay were 0.7Bq/cell and 0.3Bq/cell for 111In and 67Ga respectively. At the concentrations required to achieve these uptake levels, non-internalized 67Ga and 111In caused no cellular toxicity. Qualitatively similar results were found for MDA-MB-231 and HCC1954 cells. CONCLUSION: 67Ga causes as much damage as 111In to plasmid DNA in solution and shows similar toxicity as 111In at equivalent internalized activity per cell. 67Ga therefore deserves further evaluation for radionuclide therapy. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: The data presented here is at the basic level of science. If future in vivo and clinical studies are successful, 67Ga could become a useful radionuclide with little healthy tissue toxicity in the arsenal of weapons for treating cancer.

A Phase 1, Open-Label Study of the Biodistribution, Pharmacokinetics, and Dosimetry of 223Ra-Dichloride in Patients with Hormone-Refractory Prostate Cancer and Skeletal Metastases.

UNLABELLED: The aim of this single-site, open-label clinical trial was to determine the biodistribution, pharmacokinetics, absorbed doses, and safety from 2 sequential weight-based administrations of (223)Ra-dichloride in patients with bone metastases due to castration-refractory prostate cancer. METHODS: Six patients received 2 intravenous injections of (223)Ra-dichloride, 6 wk apart, at 100 kBq/kg of whole-body weight. The pharmacokinetics and biodistribution as a function of time were determined, and dosimetry was performed for a range of organs including bone surfaces, red marrow, kidneys, gut, and whole body using scintigraphic imaging; external counting; and blood, fecal, and urine collection. Safety was assessed from adverse events. RESULTS: The injected activity cleared rapidly from blood, with 1.1% remaining at 24 h. The main route of excretion was via the gut, although no significant toxicity was reported. Most of the administered activity was taken up rapidly into bone (61% at 4 h). The range of absorbed doses delivered to the bone surfaces from α emissions was 2,331-13,118 mGy/MBq. The ranges of absorbed doses delivered to the red marrow were 177-994 and 1-5 mGy/MBq from activity on the bone surfaces and from activity in the blood, respectively. No activity-limiting toxicity was observed at these levels of administration. The absorbed doses from the second treatment were correlated significantly with the first for a combination of the whole body, bone surfaces, kidneys, and liver. CONCLUSION: A wide range of interpatient absorbed doses was delivered to normal organs. Intrapatient absorbed doses were significantly correlated between the 2 administrations for any given patient. The lack of gastrointestinal toxicity is likely due to the low absorbed doses delivered to the gut wall from the gut contents. The lack of adverse myelotoxicity implies that the absorbed dose delivered from the circulating activity may be a more relevant guide to the potential for marrow toxicity than that due to activity on the bone surfaces.