Stefano Severi

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.

Peptide Receptor Radionuclide Therapy for Advanced Neuroendocrine Tumors

Peptide receptor radionuclide therapy (PRRT) consists of the systemic administration of a synthetic peptide, labeled with a suitable β-emitting radionuclide, able to irradiate tumors and their metastases via internalization through a specific receptor (usually somatostatin S2), over-expressed on the cell membrane. After almost 2 decades of experience, PRRT, with either (90)Y-octreotide or (177)Lu-octreotate, has established itself to be an efficient and effective therapeutic modality. As a treatment, it is relatively safe up to the known thresholds of absorbed and bio-effective isotope dosages and the renal and hematological toxicity profiles are acceptable if adequate protective measures are undertaken.

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.

Single bone metastasis from adenocarcinoma of the lacrimal gland: A case report

Malignant tumors of the lacrimal gland are rare, and single bone metastases from lacrimal gland carcinoma are an exceptional event. We present the case of a 71-year-old man with a history of lumbar pain and left exophthalmos. Surgical resection of the lacrimal lesion and a bone biopsy gave a final histopathological diagnosis of primary ductal adenocarcinoma of the lacrimal gland with bone metastasis. The pathological tissue from both procedures was positive for androgen receptor expression. The patient underwent embolization and radiotherapy in association with total androgen blockade. After 20 months, the patient is still asymptomatic and has maintained the partial response at L1 with no progression to other sites. Our patient would appear to have a better prognosis and the disease a more indolent clinical course than the other cases of ductal adenocarcinoma of the lacrimal gland reported in the literature.

A case of metachronous double primary neuroendocrine cancer in pancreas/ileum and uterine cervix

Abstract We describe an unusual case of a 50-year-old female patient developing two primary cancers with neuroendocrine features. Initially the patient underwent surgery for an entero-pancreatic neuroendocrine carcinoma. During the subsequent follow-up she experienced some episodes of vaginal bleeding with negative PET scanning with the tracer fluorine-18 (F-18) fluorodeoxyglucose (FDG). A Papanicolaou (pap) smear and an endometrial biopsy revealed a primary neuroendocrine cancer of the uterine cervix. The present case underlines the importance of clinical follow-up after a diagnosis of intestinal neuroendocrine tumor, investigating any new symptom. Female patients, after the diagnosis of entero-pancreatic neuroendocrine carcinoma, must be recommended to continue screening pap test examinations for the likelihood of classical squamous and glandular cervical cancers and also for neuroendocrine cervical cancer.

Quantitative accuracy of 177Lu SPECT imaging for molecular radiotherapy

The purpose of this study is to investigate the optimal reference geometry for gamma camera calibration. Yet another question of interest was to assess the influence of the number of 3D Ordered Subsets Expectation Maximization (3D-OSEM) updates on activity quantification for SPECT imaging with 177Lu. The accuracy of 177Lu activity quantification was assessed both in small and in large objects. Two different reference geometries, namely a cylindrical homogeneous phantom and a Jaszczak 16 ml sphere surrounded by cold water, were used to determine the gamma camera calibration factor of a commercial SPECT/CT system. Moreover, the noise level and the concentration recovery coefficient were evaluated as a function of the number of 3D-OSEM updates by using the SPECT/CT images of the reference geometry phantoms and those of a cold Jaszczak phantom with three hot spheres (16ml, 8ml and 4ml), respectively. The optimal choice of the number of 3D-OSEM updates was based on a compromise between the noise level achievable in the reconstructed SPECT images and the concentration recovery coefficients. The quantitative accuracy achievable was finally validated on a test phantom, where a spherical insert composed of two concentric spheres was used to simulate a lesion in a warm background. Our data confirm and extend previous observations. Using the calibration factor obtained with the cylindrical homogeneous phantom and the Jaszczak 16 ml sphere, the recovered activity in the test phantom was underestimated by -16.4% and -24.8%, respectively. Our work has led us to conclude that gamma camera calibration performed with large homogeneous phantom outperforms calibration executed with the Jaszczak 16ml sphere. Furthermore, the results obtained support the assumption that approximately 50 OSEM updates represent a good trade-off to reach convergence in small volumes, meanwhile minimizing the noise level.

Metastatic neuroendocrine neoplasia treatments in patients over 70 years of age: A retrospective outcome analysis.

e16181Background: Neuroendocrine Neoplasia (NEN) incidence increases with age above all at 70 years-old. This population is usually underestimated in clinical trials and because of co-morbidities a...

Abstract 1789: A gene expression-based nomogram predicts overall and progression free survival in PRRT-treated gastroenteropancreatic neuroendocrine tumors

Background: Nomograms and grading/staging systems are fundamental in guiding oncology disease management. Histological grading has efficacy in the management of gastroenteropancreatic neuroendocrine tumors (GEP-NET) but tumor heterogeneity renders outcome unpredictable. Clinical parameters alone have limited prognostic ability. A previously described NET nomogram calculated risk for overall survival (OS). To augment accuracy, we developed a circulating NET multigene expression blood test. The NETest exhibits high level metrics as a molecular prognostic for progression free survival (PFS). We evaluated whether combining clinical information with the NETest would provide accurate prognostic information for PRRT treatment. Aim: Create a combined clinical and gene expression nomogram to predict OS and PFS in PRRT-treated GEP-NETs. Methods: 177Lu-based-PRRT-treated GEP-NETs (n=57; median age 65 yrs (31-83); 34M:23F; small bowel (47%), pancreas (35%), predominantly G2: 65%) followed for a median 15 months (range 1-33). The clinical nomogram comprised 10 variables (including: age, gender, grade, Ki67, stage symptoms, liver metastases, somatostatin analog use, surgery extent, Chromogranin A level) with a score range: 25-200. This data was interpolated with pre-therapy NET transcript analysis results (range 0-100) into a hybrid molecular nomogram (range: 25-300). Outcomes were OS and PFS (RECIST criteria). Receiver operating characteristics (ROC), Kaplan-Meier survival and non-parametric (Mann-Whitney) analyses were performed. Results: Median OS was not reached (8 deaths); mPFS was 19 months (20/57 disease progression). Neither grade nor stage alone predicted a difference in OS or PFS. Clinical nomogram scores for non-survivors was significantly higher (139±20 vs. 87±6, p 130 exhibited an AUC for OS prediction of 0.84±0.05, (p=0.002) with a Hazard ratio (HR) of 8.7 (2.1-35.4, p Conclusions: Hybrid molecular nomogram data derived from a circulating gene expression signature combined with a clinical NET nomogram accurately predicts OS in PRRT-treated GEP-NETs. The nomogram also predicted PFS particularly individuals with elevated transcript values who will not respond to PRRT. Citation Format: Mark Kidd, Lisa Bodei, Stefano Severi, Ignat Drozdov, Sylvia Nicolini, Giovanni Paganelli, Irvin M. Modlin. A gene expression-based nomogram predicts overall and progression free survival in PRRT-treated gastroenteropancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1789. doi:10.1158/1538-7445.AM2017-1789

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.

Abstract 3106: A blood-based neuroendocrine tumor multi-transcript test predicts and defines PRRT efficacy in neuroendocrine tumors

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment for neuroendocrine tumors (NETs). Somatostatin receptor expression defines suitability for therapy. Elevated somatostatin receptor uptake (Krenning scale grade 4) at baseline has ∼60% predictive accuracy for efficacy. Increased (>600ng/ml) baseline levels of chromogranin A (CgA) are also considered as predictive. A blood-based 51 multigene NET transcript analysis (NETest) including gene clusters defining cell signaling and metabolism directly correlates with tumor activity. A multialgorithm-derived NETest scale 0-100% (low activity <40%) defines clinical disease activity. Aim: Assess the effectiveness of the NETest as a predictive biomarker in PRRT-treated NETs. Methods: 177Lu-based-PRRT treated NETs (n = 54) were followed for 33 months. At baseline we evaluated: histological grade, somatostatin receptor imaging (SRI), CgA (ELISA, normal <108ng/ml) and NETest (qRT-PCR with multianalyte algorithmic analyses). A mathematical genomic response index comprising NETest genes regulating metabolism and growth factor signaling integrated with grade was developed as a predictive quotient. RECIST criteria were used to evaluate disease control (responder vs non-responder). Statistical analyses: multiple regression, Kaplan-Meier survival, Chi2 analyses. Results: PRRT demonstrated a 72% response with median PFS not achieved (median follow-up 16 months). The only baseline clinical characteristic associated with outcome was low grade (G1/G2 [Ki67 40% predicted treatment response and a longer PFS (HR 2.97, p = 0.05). NETest accurately (89%, χ2 = 27.4; p = 1.2×10−7) correlated with RECIST-determined treatment response. The baseline NETest decreased in 88% of responders; and increased in 90% of non-responders. Baseline gene expression for metabolism and growth factor signaling had 76% accuracy for predicting PRRT-response. The Predictive Quotient Index (NETest and grade) accurately predicted responders (97%) and non-responders (91%). This offered a significantly better prediction than elevated SRI uptake (94% vs. 38% accuracy: Chi2 = 31.8, p<0.0001). Conclusions: The blood-based NETest provided a predictive multi-molecular biomarker for PRRT. Alterations in levels correlate with RECIST responses and assess real time treatment efficacy. A predictive quotient index (NETest and grading) is highly accurate (94%) in predicting efficacy and significantly outperforms (p<0.0001) SRI assessment. NET multigene measurement in blood can be used to predict patients responsive to PRRT. Citation Format: Lisa Bodei, Mark Kidd, Stefano Severi, Ignat Drozdov, Silvia Nicolini, Dik Kwekkeboom, Eric Krenning, Richard Baum, Giovanni Paganelli, Irvin Modlin. A blood-based neuroendocrine tumor multi-transcript test predicts and defines PRRT efficacy in neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3106.