Maddalena Sansovini

Treatment with the radiolabelled somatostatin analog Lu-DOTATATE for advanced pancreatic neuroendocrine tumors

Background: We evaluated the activity and safety profile of 177Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced G1-G2 pancreatic neuroendocrine tumors. Patients and Methods: Fifty-two consecutive patients were treated at two different therapeutic dosages of 18.5 or 27.8 GBq in five cycles, according to the patients kidney function and bone marrow reserve, which are known to be the critical organs in PRRT. Results: Twenty-six patients received a mean full dosage (FD) of 25.5 GBq (range 20.7-27.8) and 26 a mean reduced dosage (RD) of 17.8 GBq (range 11.1-19.9). Both therapeutic dosages resulted in antitumor activity (disease control rate in the entire case series 81%), with 12% complete response, 27% partial response and 46% stable disease in the FD group, whereas we observed 4% complete response, 15% partial response and 58% stable disease in the RD group. Median progression-free survival was not reached in the FD group and was 20 months in the RD group. No major acute or delayed hematological toxicity occurred. Conclusion:177Lu-DOTATATE peptide receptor radionuclide therapy showed antitumor activity in advanced pancreatic neuroendocrine tumors even at a reduced total activity of 18.5 GBq. However, progression-free survival was significantly longer (p = 0.05) after a total activity of 27.8 GBq, which can thus be considered the recommended dosage in eligible patients.

Lymphocytic Toxicity in Patients After Peptide-Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC

PURPOSE Peptide-receptor radionuclide therapy (PRRT) with somatostatin analogs is an efficient new tool in patients with neuroendocrine tumors, with low risk of toxicity. Since lymphocytes express somatostatin receptors, the aim of this study was to evaluate lymphocytic toxicity after PRRT. METHODS From May 2005 to May 2007, 16 patients affected by neuroendocrine tumors received PRRT with (90)Y-DOTATOC (9), (177)Lu-DOTATATE (5), or both (2). Absolute count, percentage of leukocytes and lymphocytes, and lymphoid subsets (B, T, and NK) were tested at baseline and until 90 days after treatment. RESULTS A significant lymphoid toxicity (G2-3), mainly affecting B-cells, was observed. It was particularly evident after (90)Y-DOTATOC. Toxicity resulted in being transient and resolved completely at the end of the follow-up (90 days). CONCLUSION Lymphocyte toxicity in PRRT is mainly due to the selective targeting on B-cells. The relative sparing of T-lymphocytes could explain the absence of clinical side-effects in these patients, such as increased risk of infections. These findings open interesting perspectives in the treatment of B-cell lymphoproliferative disorders.

The role of dosimetry in the high activity 90Y-ibritumomab tiuxetan regimens: two cases of abnormal biodistribution.

Radioimmunotherapy (RIT) with a commercially available brand of yttrium-90 ((90)Y)-ibritumomab-tiuxetan at the prescribed activity of 14.8 MBq/kg (0.4 mCi/kg) represents a complementary approach in the treatment of resistant/refractory B-cell non-Hodgkins lymphoma. A trial based on higher activities is ongoing in our institute. In this paper, we report atypical pharmacokinetics and liver uptake in 2 patients. Before RIT, all patients underwent dosimetry with (111)In-ibritumomab-tiuxetan. Imaging data were analyzed to obtain predicted absorbed doses to nontarget organs. Therapy was administered only if a 20-Gy-limit dose to normal organs (except red marrow) was guaranteed. Both patients we describe showed abnormal liver uptake, increasing for 6 days post injection. In patient 1, there was atypical biodistribution in whole-blood images at 16 hours, with a prevalent high liver uptake (45% at 20 hours). Injected activity (IA%) was above 40% at 26 hours in the liver and lower than 60% in the total body. In patient 2, early images showed regular biodistribution. Subsequent images showed progressive increase of liver uptake (above 25% of percent injected activity at 25 hours). Liver-absorbed doses of 51 and 53 Gy, respectively, would have resulted with the administration of the prescribed 56 MBq/kg. Following these dosimetric results, both patients did not receive the planned therapy. These findings support the recommendation to include dosimetry in high-dose RIT.

Peptide Receptor Radionuclide Therapy in a Case of Multiple Spinal Canal and Cranial Paragangliomas

Case Report In 2000, a 32-year-old man was admitted to the hospital with lower back pain. Gadolinium-enhanced lumbar (L1-S1) magnetic resonance imaging (MRI) revealed a clearly delimited, ovoid, expansive, intradural mass with a strong contrast enhancement behind the L4 vertebral body, occupying the vertebral foramina, mildly scalloping the vertebral body. MRI findings were interpreted as caudal ependymoma. After radical surgery, the symptoms vanished. The tumor mass measured 3 2.5 2 cm and had a yellowish brown cut surface with hemorrhagic and cystic foci. The specimens were fixed in 10% buffered formalin and embedded in paraffin. Sections (3 m thick) were stainedwithhematoxylinandeosin(Fig1A; 10),Grimelius Masson trichrome (Bio-Optica, Milano, Italy), and periodic acid-Schiff (PAS; Merck, Darmstadt, Germany). Immunohistochemical analyses were carried out by using synaptophysin (Fig 1B; 10; positive stain), CD56 (Fig 1C; 20; positive stain), avidin-biotin complex method for low-molecular-weight cytokeratin (Fig 1D; 10; punctiform expression of anticytokeratin marker [CAM 5.2]), somatostatin, serotonin, neuronspecific enolase, Leu-7, inhibin, and S-100 protein. A positive SDHB immunohistochemistry (Fig 1E; 10) was also reported. At light microscopy, the tumors presented as solid proliferation of round cells with eosinophilic cytoplasm and regular, monomorphic, oval central nuclei in an alveolar arrangement (Zellballen pattern) surrounded by thin capillaries and a flattened layer of sustentacular cells. Pleomorphism, mitotic figures, and bizarre nuclear forms were occasionally seen. Positive expression of chromogranin A and synaptophysin and the presence of chief (type 1) cells were consistent with the neuroendocrine nature of the tumor. Few sustentacular cells were positive for S-100 protein, and immunoreactivity for glial

Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life

Peptide receptor radionuclide therapy (PRRT), developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate). These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide) and peptide receptor affinity (due to the analog) but share the common characteristic of binding specific membrane somatostatin receptors that are (generally) overexpressed in neuroendocrine neoplasms (NENs) and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs]) and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%–70% of all NENs). They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases). Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon). Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors. Our results on the retreatment of patients previously administered 90Y-DOTA-Tyr3-octreotide with a low dosage of 177Lu-Dotatate are also included. A comment on potential future developments of PRRT in GEP-NETs is provided.

Radiolabeling optimization and reduced staff radiation exposure for high-dose 90Y-ibritumomab tiuxetan (HD-Zevalin)

INTRODUCTION (90)Y-Zevalin labeling may cause severe finger radiation exposure, especially in high-dose protocols (HD-Zevalin), where up to 7.4 GBq could be injected. In this work, we optimized the labeling of HD-Zevalin with special regard to simplicity, speed, safety and radiation protection. METHODS Factors influencing labeling outcome (activity, specific activity, time, final volume, stability) were studied separately. The critical steps of a standard radiolabeling procedure were optimized to reduce finger exposure, developing an alternative labeling procedure and including a different (90)Y supplier. Finger doses were monitored by thermoluminescent dosimeters at each fingertip under anti-X gloves, considering both absolute values and values after normalization to 1.48 GBq. RESULTS Labeling of (90)Y-Zevalin was safe and reproducible up to 7.4 GBq with a simple and single-step procedure offering good stability for several hours. Radiolabeling specific activity was found critical, being kept at 740 MBq mg(-1). Radiochemical purity values >or=98% were routinely achieved. The alternative procedure allowed a sensible reduction of finger dose, due to both the different (90)Y vial and the handling. Finger exposure was reduced from 6.6+/-4.3 to 3.1+/-0.8 mSv/1.48 GBq in the case of the original (90)Y vial and from 1.5+/-0.9 to 0.3+/-0.1 mSv/1.48 GBq using a shielded (90)Y vial. CONCLUSIONS HD-Zevalin can be prepared in a safe and reproducible way, giving high radiochemical purity values, good stability and low finger exposure. This study may improve the safety of nuclear medicine professionals involved in the preparation of Zevalin.

68Ga- DOTA0-Tyr3octreotide (DOTATOC) positron emission tomography (PET)/CT in five cases of ectopic adrenocorticotropin-secreting tumours

Cushing’s syndrome results from autonomous and/or excessive glucocorticoid secretion. In most cases, it is adrenocorticotropin (ACTH)-dependent, originating either from a pituitary ACTHsecreting tumour (Cushing’s disease) or, less frequently, from nonpituitary tumours secreting ACTH (ectopic ACTH-secreting [EAS] tumours). About one-half of patients with EAS tumours have lung cancer, such as small-cell lung carcinoma and bronchial carcinoid tumours. However, the source of ACTH remains unidentified in about 8–19% of cases. Despite recent advances in endocrine investigations, no single test is accurate enough to distinguish between ectopic and pituitary sources of ACTH. Similarly, no single imaging modality is capable of identifying and localizing tumours responsible for ectopic ACTH secretion. The diagnostic utility of somatostatin receptor scintigraphy (SRS) with [In-DTPA]-octreotide (In-pentetreotide – Octreoscan) for the localization of EAS tumours has been evaluated in several studies with conflicting results. The development of novel positron emission tomography (PET) tracers which specifically bind to somatostatin receptors (SSTR2-5) permits the visualization of neuroendocrine tumours with higher sensitivity than other imaging procedures, such as CT or SRS. Several different DOTA-peptides such as [DOTA-Tyr]octreotide (DOTA-TOC), [DOTA1NaI]octreotide (DOTA-NOC) and [DOTA-Tyr]octreotate (DOTA-TATE) are used in the clinical setting, the main difference between these compounds being a slightly different affinity for SSTR subtypes. Ga-DOTA-peptides PET/CT is increasingly being used for diagnosis, therapy monitoring and follow-up of neuroendocrine tumours. To the best of our knowledge, however, only two ‘case reports’ have been published on the use of Ga-DOTA-peptides PET/CT in patients with EAS tumours. In particular, Gani and co-workers failed to localize a lung ACTH-secreting carcinoid tumour with Ga-DOTATOC PET/CT. Subsequent thoracotomy and removal of the nodule allowed the diagnosis eighteen months after the onset of symptoms. Conversely, Willhauck and co-workers detected an ACTH-positive neuroendocrine tumour of the right sphenoidal sinus using Ga-DOTATATE PET/CT. Previous extensive imaging procedures, including CT scan of chest and abdomen, SRS and magnetic resonance imaging of the chest and pituitary gland, had not succeeded in finding the source of ACTH secretion. We report our experience with Ga-DOTATOC PET/CT in five patients with clinical and biochemical evidence of EAS tumours of unknown origin. Among patients submitted to Ga-DOTATOC PET/CT at the European Institute of Oncology between 2008 and 2012, we retrospectively identified five (four females and one male, aged 37–67 years) who underwent the examination to identify the source of ectopic ACTH secretion. Patients 1 and 2 had repeated investigations over a period of four and 7 years, respectively, which failed to locate an ACTH ectopic source. Patient 3 had a newly diagnosed EAS tumour that was not detected by SRS and conventional imaging. Patients 4 and 5 had suspected lesions in the right lung and right pulmonary hilar region, respectively. Diagnosis of ACTH-dependent Cushing’s syndrome was based on standard biochemical criteria, and the suspicion of EAS originated from the absence of a central/ peripheral ACTH gradient during bilateral inferior petrosal sinus sampling in the two patients with pituitary adenomas (cases 3 and 5). PET/CT scans were carried out with a hybrid PET/CT scanner (Discovery; GE Medical System, Waukesha, WI, USA) 50 min after the intravenous administration of 3MBq/kg of Ga-DOTATOC. Neither the isotope nor the radiopharmaceutical gave adverse events. Visual analysis was performed on digital transaxial PET, CT and fused images; any focal uptake higher than the surrounding normal tissue (target to nontarget ratio – T/nT) was considered as a positive result. Lesions expressing somatostatin receptors were found in all patients. Patients 2 and 3 had a lung nodule smaller than one centimetre characterized by a modest uptake of the tracer (larger diameter 5 8 and 7 4 mm; T/NT equal to 6 1 and 2 9, respectively, – Fig. 1 a–b). A high uptake of tracer (T/NT equal to 9 7) confirmed the right pulmonary hilar lesion in patient 5 Correspondence: Giovanni Paganelli, Division of Nuclear Medicine, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. Tel.: 390257489043; Fax: 390294379223; E-mail: divisione.medicinanucleare@ieo.it

Reply to: Predicting the outcome of peptide receptor radionuclide therapy in neuroendocrine tumors: the importance of dual-tracer imaging

Dear Sir, We would like to thank Zanotti-Fregonara et al. for their interesting letter about our recent study, BLong-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with 177Lu-DOTATATE^, published in the March 2017 issue [1]. In addition to the positive comments on the importance of dual-tracer imaging, Zanotti-Fregonara et al. raise the question as to whether the uptake level in somatostatin receptor imaging (SRI) plays a role in predicting response to peptide receptor radionuclide therapy (PRRT). Whilst we agree that high SUV values of 68Ga-dota peptide PET are important and may be predictive of a good objective response, as reported elsewhere [2], this was not the case in our series of 60 P-NET patients. We welcome this opportunity of presenting our data on the relevance of SRI uptake in this group. All 60 patients had an uptake score of 3 or 4 at the pretherapy SRI with Octreoscan or 68Ga–Dotatoc PETaccording to the Rotterdam scale, as described in the NETTER study [3]. Fifty-five underwent FDG PET before PRRT. Of these, 32 (58%) showed increased FDG uptake at tumor sites, while 23 (42%) showed no uptake. Whole-body images acquired 16 hours after 177LuDOTATATE injection revealed that 22 (69%) of FDG PETpositive patients had an uptake score of 4, while the remaining 10 (31%) had a score of 3. Among the 23 FDG PET-negative patients, 12 (52%) showed a score of 4 and 11 (48%) a score of 3. Pre-therapy and post-therapy SRI values were concordant. The statistical analysis of our data revealed that the uptake level of SRI was not significant in terms of progression-free survival (PFS) and so the SRI uptake value was not included in the univariate-multivariate analysis and thus not in the final paper (Tables 1 and 2) [1]. PFS was estimated using the Kaplan–Meier method and survival curves were compared using the logrank test. The multivariable Cox regression model was used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI).

Terapia radiorecettoriale dei tumori neuroendocrini pancreatici

SommarioLa terapia radiorecettoriale con 177Lu-DOTATATE (Lu-PRRT) è una valida opzione di terapia mirata nei tumori neuroendocrini pancreatici G1–G2 (pNET). È una terapia efficace in oltre l’80% dei casi. Complessivamente è ben tollerata, con tossicità midollare e renale lieve e reversibile, in particolare con frazionamento della dose totale di radiofarmaco. Nella gestione dei pazienti pNET, la PET con FDG è un importante fattore prognostico legato al metabolismo glucidico tumorale.

Development of sentinel node localization and ROLL in breast cancer in Europe

The concept of a precise region in which to find the lymph nodes that drain the lymph directly from the primary tumor site can be traced back to a century ago to the observations of Jamieson and Dobson who described how cancer cells spread from cancer of the stomach in a single lymph node, which they called the “primary gland”. However, Cabanas was the first in 1977 to realize the importance of this concept in clinical studies following lymphography performed in patients with penile cancer. Thanks to Morton’s studies on melanoma in 1992, we began to understand the potential impact of the sentinel lymph node (SN) on the surgical treatment of this type of cancer. The use of a vital dye (blue dye) administered subdermally in the region surrounding the melanoma lesion led to the identification of the sentinel node, and the vital dye technique was subsequently applied to other types of solid tumors, e.g. breast, vulva. However, difficulties in using this technique in anatomical regions with deep lymphatic vessels, e.g. axilla, led to the development of lymphoscintigraphy, started by Alex and Krag in 1993 on melanoma and breast cancer and optimized by our group at European Institute of Oncology (IEO) in Milan in 1996. Today, lymphoscintigraphy is still considered as the most reliable method for the detection of the SN. In 1996, a new method for the localization of non-palpable breast lesion called radioguided occult lesion localization (ROLL) was also developed at IEO. Retrospective and prospective studies have since shown that the ROLL procedure permits the easy and accurate surgical removal of non-palpable breast lesions, overcoming the limitations of previous techniques such as the wire-guided localization. The purpose of this paper is to describe the evolution of SN biopsy and radioguided surgery in the management of breast cancer. We also include a review of the literature on the clinical scenarios in which SN biopsy in breast cancer is currently used, with particular reference to controversies and future prospects.