Federica Fioroni

Validation of 68Ge/68Ga generator processing by chemical purification for routine clinical application of 68Ga-DOTATOC

INTRODUCTION Imaging of somatostatin receptor expressing tumours has been greatly enhanced by the use of (68)Ga-DOTATOC and PET/CT. METHODS In this work, a purification method for the (68)Ge/(68)Ga generator eluate and a method to produce (68)Ga-DOTATOC suitable for clinical use were evaluated. The generator eluate was purified and concentrated on a cation-exchange cartridge in HCl/acetone media. The efficacy of this procedure in eliminating metal impurities from the (68)Ga solution was investigated by ICP-MS. The radiotracer quality was evaluated by radio-TLC, GC and gamma-ray spectrometry. RESULTS (68)Ga-DOTATOC preparations (n=33) were carried out with a mean synthesis yield of 59.3+/-2.8% (not corrected for decay) and a batch activity ranging from 555 to 296 MBq. The radiochemical and radionuclidic purity were >98% and 99.9999%, respectively. With this purification process, >95% of the Fe(III), Zn(II) and Mn(II) were eliminated from the solution. CONCLUSIONS (68)Ga-DOTATOC produced with this method can be efficiently used in nuclear medicine departments for PET evaluations.

Differentiated Thyroid Cancer: A New Perspective with Radiolabeled Somatostatin Analogues for Imaging and Treatment of Patients

BACKGROUND The expression of somatostatin receptors (SSTR) in thyroid cells may offer the possibility to identify metastatic lesions and to select patients for peptide receptor radionuclide therapy (PRRT). We investigated (68)Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) to select patients with progressive differentiated thyroid cancer (DTC) for PRRT as well as treatment response and toxicity in treated patients. METHODS We enrolled 41 patients with progressive radioiodine-negative DTC (24 women and 17 men; mean age=54.3 years, median=59 years, range=19-78 years). In all patients, [(18)F]FDG-PET/CT was performed to determine recurrent disease with enhanced glucose metabolism, and (68)Ga-DOTATOC PET/CT was used to identify SSTR expression. Dosimetric evaluation was performed with (111)In-DOTATOC scintigraphy. Eleven patients were treated with PRRT receiving a fractionated injection of 1.5-3.7 GBq (90)Y-DOTATOC/administration. Serial (68)Ga-DOTATOC PET/CT scans were performed in all treated patients to evaluate treatment response. Parameters provided by (68)Ga-DOTATOC PET/CT were analyzed as potential therapeutic predictors to differentiate responding from nonresponding. In all treated patients, adverse events and toxicity were recorded. RESULTS (68)Ga-DOTATOC PET/CT were positive in 24/41 of radioiodine-negative DTC patients. Based on the high expression of SSTR detected by (68)Ga-DOTATOC PET/CT, 13 patients were suitable for PRRT. Two out of 13 patients were not treated due to the lack of fulfillment of other study inclusion criteria. PRRT induced disease control in 7/11 patients (two partial response and five stabilization) with a duration of response of 3.5-11.5 months. Objective response was associated with symptoms relief. Functional volume (FV) over time obtained by PET/CT was the only parameter demonstrating a significant difference between lesions responding and nonresponding to PRRT (p=0.001). Main PRRT adverse events were nausea, asthenia, and transient hematologic toxicity. One patient experienced permanent renal toxicity. CONCLUSIONS In our series, SSTR imaging provided positive results in more than half of the cases with radioiodine-negative DTC, and about one third of patients were eligible for PRRT. (68)Ga-DOTATOC PET/CT seems a reliable tool both for patient selection and evaluation of treatment response. In our experience, FV determination over time seems to represent a reliable parameter to determine tumor response to PRRT, although further investigations are needed to better define its role.

Time Evolution of DOTATOC Uptake in Neuroendocrine Tumors in View of a Possible Application of Radioguided Surgery with β− Decay

A novel radioguided surgery (RGS) technique exploiting β− radiation has been proposed. To develop such a technique, a suitable radiotracer able to deliver a β− emitter to the tumor has to be identified. A first candidate is represented by 90Y-labeled DOTATOC, a compound commonly used today for peptide radioreceptor therapy. The application of this β− RGS to neuroendocrine tumors (NET) requires study of the uptake of DOTATOC and its time evolution both in tumors and in healthy organs and evaluation of the corresponding performance of the technique. Methods: Uptake by lesions and healthy organs (kidneys, spleen, liver and healthy muscle) was estimated on 177Lu-DOTATOC SPECT/CT scans of 15 patients affected by NET with different localizations, treated at IRCCS–Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. For each patient, SPECT/CT images, acquired at 0.5, 4, 20, 40, and 70 h after injection, were studied. For each lesion, the tumor-to-nontumor ratio (TNR) with respect to all healthy organs and its time evolution were studied. A subset of patients showing hepatic lesions was selected, and the TNR with respect to the nearby healthy tissue was calculated. By means of a Monte Carlo simulation of the probe for β− RGS, the activity that is to be administered for a successful detection was estimated lesion-by-lesion. Results: Uptake of DOTATOC on NETs maximized at about 24 h after injection. The cases of hepatic lesions showed a TNR with respect to the tumor margins compatible with the application of β− RGS. In particular, 0.1-mL residuals are expected to be detectable within 1 s with 5% false-negative and 1% false-positive by administering the patient as little as 1 MBq/kg. Conclusion: The balance between tumor uptake and metabolic washout in healthy tissue causes the TNR to increase with time, reaching its maximum after 24 h, and this characteristic can be exploited when a radiotracer with a long half-life, such as 90Y, is used. In particular, if 90Y-DOTATOC is used with liver NET metastases, the proposed RGS technique is believed to be feasible by injecting an activity that is one third of that commonly used for PET imaging.

Radiation protection in 90Y-labelled DOTA-D-Phe1-Tyr3-octreotide preparations.

ObjectiveBeta-emitting radionuclides are being increasingly used in targeted radionuclide therapy in nuclear medicine. In particular, the pure high-energy &bgr;-emitter 90Y (Emax=2.27 MeV) has a physical half-life compatible with the pharmacokinetics of peptides. The use of this isotope implies an increase in the radiation dose received by the nuclear medicine staff. The aim of this study is thus the evaluation of the personal &bgr;-dosimetry data related to therapeutic 90Y-labelled DOTA-D-Phe1-Tyr3-octreotide preparation and administration in a nuclear medicine department. MethodsPersonal dose measurements were carried out with a series of thin active layer ultrasensitive MCP-Ns (LiF: Mg, Cu, P) dosimeters fixed at the operators fingertips and by means of some direct reading dosimeters; other individual protection devices, such as shielded aprons and anti-X gloves, were also used. ResultsThe 95th percentile of the chemists skin equivalent dose distribution was 1.759 mSv/GBq by using 0.10-mm anti-X gloves and 0.265 mSv/GBq by using 0.20-mm anti-X gloves. The 95th percentile of the physicians skin equivalent dose distribution was 1.198 mSv/GBq by using 0.10-mm anti-X gloves. The use of an anti-X apron during administration permits saving absorbed doses by a factor over 97% for both Hp(10) and Hp(0.07). ConclusionBecause of the physical properties of &bgr;-emitters, an increased number of therapeutic sessions is to be expected. The dose values measured till now, resulting from a high radioprotection level modus operandi, have always respected the threshold limits reported by the European Directive EURATOM 96/29 05/13/1996 for exposed workers, even in addition to other clinical practices in the department.

The Italian multicentre dosimetric study for lesion dosimetry in (223)Ra therapy of bone metastases: Calibration protocol of gamma cameras and patient eligibility criteria.

PURPOSE The aims of this work were to explore patient eligibility criteria for dosimetric studies in 223Ra therapy and evaluate the effects of differences in gamma camera calibration procedures into activity quantification. METHODS Calibrations with 223Ra were performed with four gamma cameras (3/8-inch crystal) acquiring planar static images with double-peak (82 and 154keV, 20% wide) and MEGP collimator. The sensitivity was measured in air by varying activity, source-detector distance, and source diameter. Transmission curves were measured for attenuation/scatter correction with the pseudo-extrapolation number method, varying the experimental setup. 223Ra images of twenty-five patients (69 lesions) were acquired to study the lesions visibility. Univariate ROC analysis was performed considering visible/non visible lesions on 223Ra images as true positive/true negative group, and using as score value the lesion/soft tissue contrast ratio (CR) derived from 99mTc-MDP WB scan. RESULTS Sensitivity was nearly constant varying activity and distance (maximum s.d.=2%). Partial volume effects were negligible for object area ⩾960mm2. Transmission curve measurements are affected by experimental setup and source size, leading to activity quantification errors up to 20%. The ROC analysis yielded an AUC of 0.972 and an optimal threshold of CR of 10, corresponding to an accuracy of 92%. CONCLUSION The minimum calibration protocol requires sensitivity and transmission curve measurements varying the object size, performing a careful procedure standardisation. Lesions with 99mTc-MDP CR higher than 10, not overlapping the GI tract, are generally visible on 223Ra images acquired at 24h after the administration, and possibly eligible for dosimetric studies.

4D-PET data sorting into different number of phases: a NEMA IQ phantom study

This study aims to evaluate the dependence of 4D‐PET data sorting on the number of phases in which the respiratory cycle can be divided. The issue is to find the best compromise to reduce the conflicting effects induced by increasing the number of phases: lesion motion on each set of images decreases, but on the other hand image noise increases. The IQ NEMA 2001 IEC body phantom was used to simulate the movement of neoplastic lesions in the thorax and abdomen, investigating the effect of: target size (10 37 mm), lesion‐to‐background activity concentration ratio (4:1 and 8:1), total acquisition time (3, 6, 12, 20 min), and number of phase partitions (1, 2, 4, 6, 8, 10, 13). The phantom was moved in a cranial‐caudal direction with an excursion of 25 mm and a period of 4.0 sec. Five parameters associated to lesion volume and activity concentration were considered to assess the capability of the 4D‐PET technique to “freeze” the phantom motion. The results for all the parameters showed the capability of the 4D‐PET acquisition technique to “freeze” the lesion motion. The division into six phases was found to be the best compromise between temporal resolution and image noise for the phase where the “lesions” move faster; whereas the partition into four phases could be used if a stable breathing phase is considered. PACS number: 87.57.uk; 87.57.cp

Personnel exposure in labelling and administration of 177Lu- DOTA-D-Phe1-Tyr3-octreotide

ObjectiveThe introduction of peptide receptor radionuclide therapy, mainly performed with 90Y and 177Lu-labelled somatostatin analogues, has widened the therapeutic horizon of nuclear medicine.The handling of 177Lu-labelled pharmaceuticals implies an increase of the personnel exposure and this aspect is evaluated in this paper, in comparison with personal exposure in 90Y manipulation. Materials and methodsPersonal dose measurements were performed during 26 177Lu-DOTATOC preparations by using a series of thin active layer LiF: Mg,Cu,P thermoluminescence dosimeters fixed at the operator’s fingertips to evaluate the skin equivalent dose and by means of direct reading dosimeters positioned at the chest to evaluate the personal effective dose. Individual protection devices, such as shielded aprons and anti-X gloves, were also used. ResultsThe 95th percentile of the skin equivalent dose distribution for 177Lu operations by using 0.20-mm anti-X gloves was 0.080 mSv/GBq for the chemist and 0.011 mSv/GBq for the physician, whereas the 75th percentile was 0.058 mSv/GBq for the chemist and 0.006 mSv/GBq for the physician. The use of the 0.25 mm Pb-equivalent anti-X apron halved the personal equivalent dose measured over the apron by a direct reading dosimeter. Skin doses were compared with 90Y-DOTATOC procedures: no relevant exposure reduction is observed for chemists, whereas doses are considerably lower during administration procedures performed by physicians. ConclusionIn this study, an evaluation of the skin equivalent doses during 177Lu-DOTATOC labelling and administration is presented. These data can be useful to assess the risk for workers in centres that are starting to implement PRRT using 177Lu. The use of appropriate protection devices and procedures allows the observance of International Commission for Radiological Protection dose limits for exposed workers.

PET systems: the value of added length

The past decade has brought unbelievable advances in CT technology. These have been reflected in a progressive widening of the radiation beam in the axial direction (from “fan beam” to “cone beam” geometry) and in a corresponding increase in the number of detector rings. From the four detectors and 2 cm axial field of view (AFOV), acquired in half a second, that characterised the systems of a decade ago, we now have, with the present technology, 256/312 multi-row detectors that allow the acquisition of an 8/16 cm axial field in less than a third of a second. In addition, dual-source CT is offering a wealth of new possibilities. These new systems, whose realisation demanded the solution of complex mechanics, electronics and information technology problems, have opened up a completely new field of medical investigation: the four-dimensional study of the heart and the vascular system. The past few years have also seen evolutions in the field of PET/CT. Indeed, this combined modality has benefitted not only from improved CT technology, but also from gradual advances in the PET sphere—advances prompted by the introduction of new crystal detectors (such as LSO, GSO, LYSO), new iterative reconstruction algorithms, faster electronics, the “gating” technique (synchronisation of data acquisition with respiratory motion) and, especially, “time of flight” PET technology (TOF) [1–4]. Yet despite these significant improvements, the length of the detector cylinder, or length of the system’s sensitive volume (“field of view”), has remained essentially the same (15–18 cm). With this acquisition geometry, only a very small fraction of the radiation emitted at any given instant is acquired (geometric efficiency ≤0.2). Therefore, to obtain, for example, a “whole-body” study of about 80 cm in length (from the temples to the bladder of the patient), a series of six to eight static scans (“views”) need to be acquired. The adjacent single views, obtained with the movement of the bed, must, of course, also provide an appropriate region of overlap. Obviously, the acquisition time increases in proportion to the number of views. A “standard study” with the injection of 10 mCi of F-FDG takes about 3 min per view and, therefore, approximately 25 min per entire study. To this about a minute should be added for the CT scan. However, when used for wholebody studies in diagnostic oncology—this use accounts for approximately 90% of all PET scans—this procedure presents major limitations. The limited length of the sensitive volume not only imposes the need for multiple views, and thus prolongs the overall duration of the examination, it also (and this is particularly important) limits the maximum “line of response” (LOR) angle (with G. Borasi (*) : F. Fioroni Medical Physics Department, Santa Maria Nuova Hospital, V. le Risorgimento 80, 42100 Reggio Emilia, Italy e-mail: giovanni_borasi@libero.it

Therapeutic schemes in 177Lu and 90Y-PRRT: radiobiological considerations.

BACKGROUND The purpose of this work is to implement a radiobiological model to compare different treatment schedules for Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu and 90Y. The principal radiobiological quantities were studied as a function of radionuclides, fractionation schemes, activity distribution in kidneys and tumor radiosensitivity. METHODS Clinical data were used to derive representative absorbed doses for several treatment schemes for 177Lu-PRRT and for 90Y-PRRT and considered as input data for the radiobiological model. Both uniform and non-uniform activity distributions were considered for kidneys and cortex; for tumors a possible uptake reduction after each cycle and inter-patient radiosensitivity variability were investigated. Normal-Tissue-Complication-Probability (NTCP) and Tumor-Control-Probability (TCP) were evaluated. RESULTS Hyper-cycling has a limited advantage in terms of BED reduction on kidneys for 177Lu, while for 90Y the effect is sizable and helps in reducing the NTCP. For all 177Lu-schemes the renal toxicity risk is negligible while for some 90Y-schemes the NTCP is not null. In case of tumor uptake reduction with cycles the treatment efficacy is reduced with a BED loss up to 46%. The TCP decreases when assuming normally-distributed tumor radiosensitivity values. CONCLUSIONS This paper discusses how the combination of dosimetry and radiobiological modeling may help in exploring the link between the treatment schedule and the potential clinical outcome. The results highlight the capability of model to reproduce the available clinical data and provide useful qualitative information. Further investigation on dose distribution and dose uptake reduction with accurate clinical data is needed to progress in this field.

The 68Ge phantom-based FDG-PET site qualification program for clinical trials adopted by FIL (Italian Foundation on Lymphoma)

PURPOSE The quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life. METHODS We set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of (18)F and (68)Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR). RESULTS The use of a (68)Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the (18)F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with (68)Ge and (18)F respectively. CONCLUSIONS The (68)Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement.