Silvia Nicolini

PET/CT imaging in different types of lung cancer: An overview

Lung cancer (LC) still represents one of the most common tumours in both women and men. PET/CT is a whole-body non-invasive imaging procedure that has been increasingly used for the assessment of LC patients. In particular, PET/CT added value to CT is mainly related to a more accurate staging of nodal and metastatic sites and to the evaluation of the response to therapy. Although the most common PET tracer for LC evaluation is 18F-FDG, new tracers have been proposed for the evaluation of lung neuroendocrine tumours (68Ga-DOTA-peptides, 18F-DOPA) and for the assessment of central nervous system metastasis (11C-methionine). This review focuses on the main clinical applications and accuracy of PET/CT for the detection of non-small cells lung cancer (NSCLC), broncho-alveolar carcinoma (BAC), small cells lung cancer (SCLC), lung neuroendocrine tumours (NET) and solitary pulmonary nodules (SPN).

Non FDG PET

2- [(18)F]-fluoro-2-deoxy-D-glucose (FDG) is the radiopharmaceutical most frequently used for clinical positron emission tomography (PET). However, FDG cannot be used for many oncological, cardiological, or neurological conditions, either because the abnormal tissue does not concentrate it, or because the tissues under investigation demonstrate high physiological glucose uptake. Consequently, alternative PET tracers have been produced and introduced into clinical practice. The most important compounds in routine practice are (11)C-choline and (18)F-choline, mainly for the evaluation of prostate cancer; (1)C-methionine for brain tumours; (118)F-DOPA ((18)F-deoxiphenilalanine) for neuroendocrine tumours and movement disorders; (68)Ga-DOTANOC (tetraazacyclododecanetetraacetic acid-[1-Nal3]-octreotide) and other somatostatin analogues for neuroendocrine tumours; 11C-acetate for prostate cancer and hepatic masses and 18F-FLT (3-deoxy-3-fluorothymidine) for a number of malignant tumours. Another impetus for the development of new tracers is to enable the investigation of biological processes in tumours other than glucose metabolism. This is especially important in the field of response assessment, where there are new agents that are targeted more specifically at angiogenesis, hypoxia, apoptosis and other processes.

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.

Outcome Analysis of First-line Somatostatin Analog Treatment in Metastatic Pulmonary Neuroendocrine Tumors and Prognostic Significance of 18FDG-PET/CT

Introduction Pulmonary carcinoids (PCs) are classed according to the World Health Organization 2004 classification as typical or atypical carcinoids. Owing to their rarity, no dedicated clinical trials with somatostatin analogs (SSAs) have been carried out on primary PCs. Patients and Methods From January 2007 to December 2015, 30 patients with metastatic PCs underwent first‐line SSA treatment (20 with octreotide long‐acting repeatable 30 mg and 10 with lanreotide 120 mg every 28 days). Eight (23.3%) patients had typical carcinoids and 23 (76.7%) had atypical carcinoids. Results The median age was 65.5 years (range, 47‐82 years). All patients (23 males and 7 females) were Gallium‐68‐DOTA‐TOC‐positron emission tomography/computed tomography (PET/CT)‐positive (29 patients) or octreoscan‐positive (1 patient). Of the 20 patients who performed fluorine‐18‐fluorodeoxyglucose positron emission tomography/computed tomography (18FDG‐PET/CT), 14 (70.0%) were positive and 6 negative (30.0%). The median treatment duration was 10 months (range, 2‐59 months). One patient achieved a partial response (3.3%), and 26 (86.6%) showed stable disease. One patient interrupted SSA treatment owing to symptomatic cholelithiasis. Five‐year survival was 53.0% (95% confidence interval [CI], 15.0%‐80.0%). The median progression‐free survival (mPFS) was 11.1 months (95% CI, 7.0‐15.0 months). Negative 18FDG‐PET/CT patients had an mPFS of 15.2 months (95% CI, 7.6 months to not reached) compared with 7.0 months (95% CI, 4.0‐10.1 months) for 18FDG‐PET/CT‐positive patients. No differences in mPFS were found in relation to TTF1‐value, histologic subtype, and presence of extrahepatic metastases. Conclusion SSAs showed antitumor activity in terms of disease control rate and PFS and proved safe, even in patients with poor Eastern Cooperative Oncology Group status. 18FDG‐PET/CT would appear to be a prognostic factor. Micro‐Abstract The purpose of the present study was to investigate the efficacy of somatostatin analogs as first‐line treatment of metastatic non‐functioning neuroendocrine pulmonary carcinoids. Our results showed that both lanreotide and octreotide improved tumor control with very few side‐effects in progressive metastatic lung neuroendocrine carcinoids patients. Moreover, fluorine‐18 fluorodeoxyglucose‐positron emission tomography/computed tomography positivity was an independent prognostic factor of progression‐free survival identifying more aggressive tumors that may only marginally benefit from somatostatin analog treatment alone.

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.