Current Radiopharmaceuticals - Volume 8, Issue 1, 2015

Molecular imaging is the only way of defining biological target volume (BTV) for externalbeam radiation therapy (EBRT) and may be used for advanced targeting in dose planning and dose painting. There are, however, no reports about the EBRT response when dose planning is based on BTV target definition in advanced prostate cancer. Clinical and biochemical results of two clinically equal group of patients with advanced prostate cancer patients were compared. Both groups were treated with volumetric modulated arc therapy (VMAT) based on target definition by PET/CT (1st group) or conventional imaging (2nd group). Biochemical relapse occurred in 16.6% (in 1 out of 6) of the patients in the first group and 50% (3 out of 6) patients in the second group during the follow up period. Clinical manifestation of disease occurred in 33% (2 out of 6) patients of the first group and in 5 out of 6 (83,3%) patients in the second one. 4 patients in the first group had no biochemical relapse and no clinical manifestation during the follow up period. The difference in the duration of progression free period was statistically significant between the groups (p<0.010) being in the first group 16.5±5.4 (10-24) months and 4.6±2.9 (2-10) months in the second one. Because patients with PET/CT based VMAT had lower incidence of biochemical relapse, less clinical manifestations and longer, statistically significant duration of progression free period as compared to patients treated with VMAT based on conventional imaging, our preliminary results suggest introducing BTV definition based on PET imaging for VMAT in the EBRT of prostate cancer.

The aim of modern intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) is to define the target areas including the smallest non-invaded margins, thus reducing the radiation dose to radiosensitive organs. To reach this goal, these methods require a more precise target delineation by imaging to better define the viable part of the tumor. Image-guided selection and demarcation of Gross Tumor Volume (GTV), Clinical Target Volume (CTV) and Organs at Risk (OAR) are the main steps to reach a satisfactory radiation treatment plan. Hybrid machines, such as PET-CT, SPECT-CT and, more recently, PET-MRI, may significantly increase diagnostic accuracy improving either sensitivity and specificity achievable alone by the single constituents of the hybrid tools. While the implementation contribution of PET-CT in radiotherapy, with respect to CT stand alone, has been extensively and successfully investigated, few papers have been at present written on the possible role of SPECT-CT for the same purpose. With an identical contribution to CT, SPECT may give similar information with respect to PET, when suitable radiopharmaceuticals are available. In particular, SPECT may provide additional information to CT, better defining the viable tumor mass; as a consequence, a more effective delineation of the GTV, saving the maximum normal tissue as possible, may be allowed. In this paper, we review some of the most important applications of SPECT-CT in oncology, as a premise to its possible utilization in tumor target definition in radiotherapy. In particular, we discuss sentinel lymph node (SLN) detection, tumor imaging with cationic lipophilic radiotracers, as 99mTc-methoxyisobutylisonitrile (MIBI) and 99mTc-tetrofosmin (TF) in breast cancer, thymoma, and lung cancer, 99mTcmethylene diphosphonate (MDP) for bone scan, 131Iodine and 123Iodine in differentiated thyroid cancer (DTC), as useful methods to optimize GTV and CTV definition. A reflection on the possible role in radiotherapy of other radiotracers labeled with gamma emitters, such as In-111 pentreotide has also been included.

In this paper, we give an overview of articles on non-choline tracers for PET/CT for patients with prostate cancer and planning of radiotherapy guided by PET/CT. Nineteen articles described 11C-Acetate PET/CT. Of 629 patients 483 (77%, 95% CI 74% - 80%) had positive 11C-Acetate PET/CT scans. Five articles described 18F-FACBC PET/CT. Of 174 patients, 127 (73%, 95% CI 68% - 78%) had positive scans. Both tracers detected local lesions, lesions in regional lymph nodes, and distant organs. Ten articles described 18F-NaF PET/CT and found that 1289 of 3918 patients (33%) had positive reactive lesions in bones. PET/CT scan can guide external beam radiotherapy (EBRT) planning for patients with loco-regional prostate cancer. In six studies with 178 patients with localized prostate cancer, PET/CT pointed out dominant intraprostatic lesions (DIL). Oncologists gave EBRT to the whole prostate and a simultaneously integrated boost to the DIL. Four studies with 254 patients described planning of EBRT for patients with PETpositive lymph nodes. After the EBRT, 15 of 29 node-positive patients remained in remission for median 28 months (range 14 to 50 months). Most articles describe 11C- and 18F-Choline PET/CT. However, 11C-Acetate and 18F-FACBC may also be useful tracers for PET/CT. Planning of radiotherapy guided by MRI or PET/CT is an investigational method for localized prostate cancer. Current clinical controlled trials evaluate whether the method improves overall survival.

Over the years, external beam radiotherapy (EBRT) has been used in the treatment management of many malignancies, including head and neck squamous cell carcinomas (HNSCC). Hypoxia is a common feature in HNSCC. Hypoxic segments in HNSCC have proven to be more resistant to radiotherapy. The ability to identify hypoxia using SPECT and PET tracers has been investigated since the late 1970s. Nitroimidazole-based compounds labelled with positron emitters have been developed to more specifically image hypoxia. This article reviews the current data from research publications on18F–FMISO, 18F-FAZA, 18F-EF5 and 64Cu-ATSM.

Positron Emission Tomography (PET) is increasingly being used in radiotherapy planning, with the development of hybrid imaging technology such as PET/CT allowing more accurate volumes being generated for treatment with external beam radiation. This article will discuss the use of FDG PET in radiotherapy planning of various types of malignancies, as well as some pitfalls and practicalities of integrating PET/CT into radiotherapy planning.

Due to somatostatin receptor expression in meningiomas, PET with somatostatin analogs appears to be useful in radiotherapy treatment planning. We report the case of a 63-year-old man diagnosed with meningioma of the left frontal lobe in 2011. He underwent total tumor excision (pathology was atypical meningioma WHO 2) and radiotherapy, but one year after the completion of treatment, he complained about diplopia and left upper eyelid ptosis. The MRI showed a new parasagittal lesion and the patient received stereotactic radiotherapy. Few weeks later, two new lesions were found – one in the sella turcica region and the other adjacent to the greater wing of the right sphenoid bone. The patient underwent transsphenoidal biopsy, but was not qualified for neurosurgery due to high risk of bleeding. In the radiotherapy treatment planning, we used a fusion of MRI and 68Ga-DOTA-(Tyr3)-octreotate PET/CT images. The patient received stereotactic radiotherapy, first to the parasellar lesion and then to the progressing tumor adjoining the sphenoid bone. In both cases, PET/CT scans helped to define the target, its volume being bigger on PET/CT than on MRI images. In patients with meningiomas, 68-Ga-DOTA-(Tyr3)-octreotate PET/CT can be considered as a useful imaging modality in radiotherapy treatment planning, which helps to visualize the tumor extension and to define the target.

Peptide receptor radionuclide therapy (PRRT) is an established treatment for progressive neuroendocrine tumours with nephrotoxicity as the limiting factor. It is therefore important to monitor kidney function changes after PRRT treatment. We aimed to investigate kidney function by different methods and during a 4-hour and a 24-hour amino acid (AA) infusion protocol. We measured the Glomerular Filtration Rate (GFR) in 28 patients before and 3, 6, 12, and 18 months after 90YDOTATOC therapy. We used standardized 51Cr-EDTA plasma clearance (Cr-GFR) and estimated GFR (eGFR) by the simplified 4 variable Modification of Diet in Renal Disease based on serum creatinine values. Further, we determined GFR in 15 patients treated with a 4-hour infusion of AA compared to 13 patients with a 24-hour infusion at 3, 6, 12 and 18 months after therapy. Pre-existing risk factors associated with kidney failure were seen in 82% of the patients. We observed a significant reduction in Cr-GFR up to 12 months after PRRT (mean loss 27 ml/min/1.73 m2 (32%)). The eGFR continuously overestimated the Cr-GFR with a bias of 8%. There was no significant difference between the two AA protocols, however, the 24-hour AA protocol tended to reduce mean Cr-GFR loss 12 months post therapy. Pre-existing risk factors for kidney failure were highly prevalent in this patient cohort, and kidney function after PRRT treatment is best monitored by 51Cr-EDTA plasma clearance. Further, the use of a 24-hour AA kidney protection protocol seems to reduce the loss of kidney function in these patients.

The aim of this study was to investigate the capability of phenazine dioxides, recognized bioreductive antitumour agents, as carriers for 99mTc in order to generate potential theranostic radiopharmaceuticals towards hypoxic solid tumours. Two different phenazine dioxides were used as ligands for the 99mTc-tricarbonyl core in order to prepare the potential radiopharmaceuticals. The main physicochemical and biological properties were evaluated. Biodistribution of the two radiotracers was studied at different time points after intravenous injection in tumour bearing animals. Both compounds were obtained in high yield and radiochemichal purity. They were stable in labelling milieu, in human plasma and in the presence of histidine. Biodistribution studies in mice were characterized by slow blood clearance and persistent liver uptake, results that correlate with the values of lipophilicities and protein binding. Both the complexes showed good tumour uptake, which remained constant during the studied period. Tumour/muscle ratios proved very favourable, comparable to those of FMISO in the same animal model. On the other hand, tumour/blood ratios were low due to high blood uptake. The use of phenazine dioxides as ligands for the preparation of potential 99mTc-radiopharmaceuticals towards solid tumours is possible since tumour uptake and retention are promising although high blood and liver uptake are drawbacks worth consideration.

Rituximab when radiolabelled with 177Lu or 90Y has been investigated for the treatment of patients with Non-Hodgkin’s Lymphoma. In this study, we optimized the preparation of antibody conjugates with chelating agent in the freeze-dried kit. It shortens procedures needed for the successful radiolabeling with lutetium-177 and yttrium-90 and assures reproducible labelling yields. Various molar ratios of Rituximab:DOTA (from 1:5 to 1:100) were used at the conjugation step and different purification method to remove unbound DOTA were investigated (size-exclusion chromatography, dialysis, ultrafiltration). The final monoclonal antibody concentration was quantified by Bradford method, and the number of DOTA molecules was determined by radiolabeling assay using 64Cu. The specific activity of 177Lu-DOTA-Rituximab and 90Y-DOTA-Rituximab were optimized using various amounts of radiometal. Quality control (SE-HPLC, ITLC) and stability study were performed. An average of 4.2 ± 0.8 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab. The ultrafiltration system was the most efficient for purification and resulted in the highest recovery efficiency (77.2%). At optimized conditions the 177Lu-DOTARituximab and 90Y-DOTA-Rituximab were obtained with radiochemical purity >99% and specific activity ca. 600 MBq/mg. The radioimmunoconjugates were stable in human serum and 0.9% NaCl. After 72 h of incubation the radiochemical purity of 177Lu-DOTA-Rituximab decreased to 94% but it was still more than 88% for 90Y-DOTA-Rituximab. The radioimmunoconjugate showed stability after six months storage at 2 - 80C, as a lyophilized formulation. Our study shows that Rituximab-DOTA can be efficiently radiolabeled with 177Lu and 90Y via p-SCN-Bn-DOTA using a freezedried kit.

Cognitive training has reported to improve cognitive performance in Mild Cognitive Impairment (MCI) as well as in older healthy subjects. 18F-FDG-PET is widely used in the diagnoses of dementia for its ability to identify early metabolic changes. This study was aimed to assess the effect of cognitive stimulation on brain metabolic network and clinical cognitive performance. Thirty aMCI subjects were enrolled in the study and allocated in two groups matched for cognitive profile, sex and schooling and then randomly assigned to the training arm or to the placebo arm. All subjects underwent neuropsychological assessment and PET imaging before and after intervention. We found significant association between brain metabolism and cognitive stimulation in treated aMCI subjects. Brain metabolic changes included Brodmann areas reported to be involved in working memory and attentive processes as well as executive functions. Our study shows that metabolic changes occur earlier than possible clinical changes related to the intervention. 18F-FDG-PET could provide a useful biomarker of response to identify a population of aMCI suitable to respond to treatment, according to most recent data on default network mode and its adaptivity to external stimuli.