Midgut Neuroendocrine Tumors Research Articles

Treatment of Liver Metastases from Midgut Neuroendocrine Tumours: A Systematic Review and Meta-Analysis.

Strong evidence comparing different treatment options for liver metastases (LM) arising from gastroenteropancreatic neuroendocrine tumours (GEP-NET) is lacking. The aim of this study was to determine which intervention for LMs from GEP-NETs shows the longest overall survival (OS). A systematic search was performed in MEDLINE, Embase and the Cochrane Library in February 2018. Studies reporting on patients with LMs of any grade of sporadic GEP-NET comparing two intervention groups were included for analysis. Meta-analyses were performed where possible. Eleven studies, with a total of 1108, patients were included; 662 patients had LM from pancreatic NETs (pNET), 164 patients from small-bowel NETs (SB-NET) and 282 patients of unknown origin. Improved 5-year OS was observed for surgery vs. chemotherapy (OR 0.05 95% CI [0.01, 0.21] p < 0.0001), for surgery vs. embolization (OR 0.18 95% CI [0.05, 0.61] p = 0.006) and for LM resection vs. no LM resection (OR 0.15 95% CI [0.05, 0.42] p = 0.0003). This is the largest meta-analysis performed comparing different interventions for LMs from GEP-NETs. Despite the high risk of bias and heterogeneity of data, surgical resection for all tumour grades results in the longest overall survival. Chemotherapy and embolization should be considered as an alternative in case surgery is not feasible.

Health-Related Quality of Life for Long-Acting Octreotide versus Placebo in Patients with Metastatic Midgut Neuroendocrine Tumors in the Phase 3 PROMID Trial

Background: In the phase IIIb PROMID study, octreotide long-acting significantly extended time to tumor progression compared with placebo in treatment-naïve patients with well-differentiated metastatic midgut neuroendocrine tumors. We report post hoc analyses for health-related quality of life (HRQoL). Methods: HRQoL was measured with EORTC QLQ-C30, a 30-item self-report questionnaire (5 functional, 1 global, 9 symptom scales). Assessments were completed at baseline and every 12 weeks until tumor progression. Time to definitive deterioration (TDD; worsening of ≥10 points without further improvement) was analyzed with the Kaplan-Meier method. Linear mixed models were fit to assess change from baseline in QLQ-C30 scores by treatment arm over time. Results: Among 85 patients, 82 (96%) completed the QLQ-C30 at baseline. There were few events of definitive deterioration for many scales. Significantly longer TDD was reported for long-acting octreotide versus placebo for fatigue (median 18.5 months vs. 6.8; p = 0.0006), pain (not reached [NR] vs. 18.2; p = 0.0435) and insomnia (NR vs. 16.4; p = 0.0046). Change from baseline to week 24 fatigue scores were stable for long-acting octreotide (mean 0.78; 95% CI –6.3 to 7.8) but worsened for placebo (mean 9.1; 95% CI 1.9–16.4), and for diarrhea there were improvements for long-acting octreotide (mean –8.0; 95% CI –19.6 to 3.5) and worsening for placebo (mean 11.2; 95% CI –0.7 to 23.1). Conclusions: HRQoL was maintained with few deteriorations in long-acting octreotide patients, whereas there was earlier and/or more deterioration in placebo patients. In long-acting octreotide patients, HRQoL was maintained or improved for the clinically important neuroendocrine tumor symptoms such as fatigue, insomnia, diarrhea and pain, whereas placebo patients experienced a deterioration of HRQoL scores for these symptoms.

Resection of primary tumor in liver only metastatic midgut neuroendocrine tumors.

446 Background: Surgical management of metastatic midgut neuroendocrine tumors (NET) remains controversial. Resection of primary tumor only without liver resection is advocated only in select patients, frequently for palliation. Additionally, no standard algorithm exists, and the risk profile for these patients is not well documented in the literature. We evaluated these midgut NETs with liver metastasis in the National Cancer Data Base (NCDB) to determine if resection of the primary tumor only affected survival outcomes. Methods: The NCDB was queried to identify patients with liver only metastatic midgut NET tumors between 2010 and 2015. Patients who underwent surgery of their liver metastasis were excluded. The cohort was separated into two groups, those who underwent resection of the primary tumor and those who did not. Patient demographics, year of diagnosis, clinicopathologic tumor characteristics and Charlson/Deyo comorbidity index were compared among the two groups. The primary outcome was overall survival (OS). Kaplan-Meier estimates were used to predict OS. Results: One-thousand nine hundred fifty-two patients with median age of 63 were identified. Median tumor size was 2.4 cm. Of these, 1,295 (66.0%) patients underwent resection of the primary tumor and 667 (34.0%) did not. Patients undergoing resection were younger (median age 63 vs. 65, p &lt; 0.001) and had smaller tumors (median 2.3 cm vs. 3.0 cm, p &lt; 0.001). There was no difference between the groups with respect to sex, year of diagnosis or Charlson/Deyo Comorbidity Score. Median follow up time was 42.8 months (IQR 29.7). A total of 483 deaths occurred in the entire cohort with a 5-year OS of 60.8%. The 5-year OS for patients undergoing resection of the primary tumor was 65.9% and 49.3% for those not undergoing resection (p &lt; 0.001). Conclusions: Patients with liver only metastatic midgut neuroendocrine tumors had an overall survival advantage when the primary tumor was resected. Patients with liver only metastatic midgut NET may benefit from surgical resection and should be evaluated for surgery at the time of diagnosis.

Circulating tumour cells and their association with bone metastases in patients with neuroendocrine tumours

BackgroundBone metastases are associated with a worse outcome in patients with neuroendocrine tumours (NETs). Tumour overexpression of C-X-C chemokine receptor 4 (CXCR4) appears predictive of skeletal involvement. We investigated the role of circulating tumour cells (CTCs) and CXCR4 expression on CTCs as potential predictors of skeleton invasion.MethodsBlood from patients with metastatic bronchial, midgut or pancreatic NET (pNET) was analysed by CellSearch. CXCR4 immunohistochemistry was performed on matched formalin-fixed paraffin-embedded (FFPE) samples.ResultsTwo hundred and fifty-four patients were recruited with 121 midgut and 119 pNETs, of which 51 and 36% had detectable CTCs, respectively. Bone metastases were reported in 30% of midgut and 23% of pNET patients and were significantly associated with CTC presence (p = 0.003 and p < 0.0001). In a subgroup of 40 patients, 85% patients with CTCs had CTCs positive for CXCR4 expression. The proportion of CXCR4-positive CTCs in patients with bone metastases was 56% compared to 35% in those without (p = 0.18) it. Staining for CXCR4 on matched FFPE tissue showed a trend towards a correlation with CXCR4 expression on CTCs (p = 0.08).ConclusionsCTC presence is associated with bone metastases in NETs. CXCR4 may be involved in CTC osteotropism and present a therapeutic target to reduce skeletal morbidity.

The Search for an Alternative to [68Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of 18F-labeled Somatostatin Analog Development.

The trend to inform personalized molecular radiotherapy with molecular imaging diagnostics, a concept referred to as theranostics, has transformed the field of nuclear medicine in recent years. The development of theranostic pairs comprising somatostatin receptor (SSTR)-targeting nuclear imaging probes and therapeutic agents for the treatment of patients with neuroendocrine tumors (NETs) has been a driving force behind this development. With the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial reporting encouraging results in the treatment of well-differentiated, metastatic midgut NETs, peptide radioligand therapy (RLT) with the 177Lu-labeled somatostatin analog (SSA) [177Lu]Lu-DOTA-TATE is now anticipated to become the standard of care. On the diagnostics side, the field is currently dominated by 68Ga-labeled SSAs for the molecular imaging of NETs with positron emission tomography-computed tomography (PET/CT). PET/CT imaging with SSAs such as [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-TOC, and [68Ga]Ga-DOTA-NOC allows for NET staging with high accuracy and is used to qualify patients for RLT. Driven by the demand for PET/CT imaging of NETs, a commercial kit for the production of [68Ga]Ga-DOTA-TATE (NETSPOT) was approved by the U.S. Food and Drug Administration (FDA). The synthesis of 68Ga-labeled SSAs from a 68Ge/68Ga-generator is straightforward and allows for a decentralized production, but there are economic and logistic difficulties associated with these approaches that warrant the search for a viable, generator-independent alternative. The clinical introduction of an 18F-labeled SSTR-imaging probe can help mitigate the shortcomings of the generator-based synthesis approach, but despite extensive research efforts, none of the proposed 18F-labeled SSAs has been translated past prospective first-in-humans studies so far. Here, we review the current state of probe-development from a translational viewpoint and make a case for a clinically viable, 18F-labeled alternative to the current standard [68Ga]Ga-DOTA-TATE.

The eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience

BackgroundMetastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT.Case presentationsPatient 1 is a 72 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy.Patient 2 is a 68 year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control.Patient 3 is a 63 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly.Patient 4 is a 72 year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since.Patient 5 is a 61 year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease.ConclusionsNETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients.

Transcription factors in tumor diagnosis

Transcription factors are aheterogeneous group of DNA-binding proteins that regulate the transcription of distinct genes. Due to their cell-type specificity and cell lineage restriction, numerous transcription factors have been established in recent years as excellent, sensitive, and specific immunohistochemical tumor markers. As compared to other cytoplasmic and membranous differentiation markers, the nuclear immunolocalization of transcription factors is often more stably preserved. Therefore, cell lineage-specific transcription factors can be detected even in poorly differentiated metastatic tumors. However, for their reliable diagnostic use, detailed knowledge is required on their expression profiles, which are often more complex than initially assumed.CDX2 is asensitive marker for colorectal adenocarcinomas but is also expressed in upper abdominal adenocarcinomas, mucinous carcinomas of lung and ovary, and midgut neuroendocrine tumors. Ahigher degree of specificity for colorectal origin is provided by SATB2. TTF-1 is avaluable marker particularly for pulmonary adenocarcinomas, but may also be focally expressed "aberrantly" in abdominal and gynecological adenocarcinomas. GATA3 is found in breast and urothelial carcinomas but also in squamous cell carcinomas. PAX8 is ahighly sensitive marker of all subtypes of gynecological adenocarcinomas, renal cell carcinomas, and thyroid carcinomas. Further transcription factors characterized by molecular biology have meanwhile become diagnostically relevant, the number of which is increasing.Principally, for the diagnostic use of transcription factors as immunohistochemical tumor markers, clinical and radiological data as well as conventional histopathology should always be carefully considered and if necessary they should be applied in the context of amarker panel.

1311PD - Health-related quality of life (HRQoL) for octreotide long-acting (oct l-a) vs. placebo (PBO) in patients (pts) with metastatic midgut neuroendocrine tumors (mmNETs) in the phase IIIb PROMID trial

1311PD - Health-related quality of life (HRQoL) for octreotide long-acting (oct l-a) vs. placebo (PBO) in patients (pts) with metastatic midgut neuroendocrine tumors (mmNETs) in the phase IIIb PROMID trial

Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours

PurposeTherapy with [177Lu-DOTA,Tyr3]octreotate is effective in patients with grade I/II metastasized and/or inoperable bronchial neuroendocrine tumour (NET) or gastroenteropancreatic NET (GEP-NET). In this study, we investigated the efficacy and safety of salvage treatment with [177Lu-DOTA,Tyr3]octreotate.MethodsPatients with progressive bronchial NET or GEP-NET were selected for re-(re)treatment if they had benefited from initial peptide receptor radionuclide therapy (I-PRRT) with a minimal progression-free survival (PFS) of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [177Lu-DOTA,Tyr3]octreotate over two cycles per retreatment with PRRT (R-PRRT) or re-retreatment with PRRT (RR-PRRT).ResultsThe safety and efficacy analyses included 181 patients and 168 patients, respectively, with bronchial NET or GEP-NET. Overall median follow-up was 88.6 months (95% CI 79.0–98.2). Median cumulative doses were 44.7 GBq (range 26.3–46.4 GBq) during R-PRRT (168 patients) and 59.7 GBq (range 55.2–≤60.5 GBq) during RR-PRRT (13 patients). Objective response and stable disease, as best response, were observed in 26 patients (15.5%) and 100 patients (59.5%) following R-PRRT, and in 5 patients (38.5%) and 7 patients (53.8%) following RR-PRRT, respectively. Median PFS was 14.6 months (95% CI 12.4–16.9) following R-PRRT and 14.2 months (95% CI 9.8–18.5) following RR-PRRT. Combined overall survival (OS) after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0–95.6). Grade III/IV bone marrow toxicity occurred in 6.6% and 7.7% of patients after R-PRRT and RR-PRRT, respectively. Salvage therapy resulted in a significantly longer OS in patients with bronchial NET, GEP-NET and midgut NET than in a nonrandomized control group. The total incidence of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) was 2.2%. No PRRT-related grade III/IV nephrotoxicity was observed.ConclusionA cumulative dose of up to 60.5 GBq salvage PRRT with [177Lu-DOTA,Tyr3]octreotate is safe and effective in patients with progressive disease (relapse-PD) following I-PRRT with [177Lu-DOTA,Tyr3]octreotate. Safety appears similar to that of I-PRRT as no higher incidence of AML or MDS was observed. No grade III/IV renal toxicity occurred after retreatment.

Clinical outcomes of patients with G1/G2 neuroendocrine tumors arising from foregut or hindgut treated with somatostatin analogs: a retrospective study.

Neuroendocrine tumors (NET) are rare tumors for which somatostatin analogs (SSA) are used not only for symptom control due to a functioning tumor, but also for the disease control of unresectable NET. The efficacy of SSA for midgut NET has been verified by previous studies, but insufficient evidence exists for SSA treatment of NET in the foregut and hindgut (F/H-NET). The aim of this retrospective study was to evaluate the efficacy of SSA for unresectable F/H-NET. Patients with unresectable F/H-NET treated with SSA between February 2011 and August 2017 at our hospital were retrospectively reviewed. Parameters of efficacy were progression-free survival (PFS), overall survival, objective response rate (ORR), and adverse events. Twelve cases with unresectable F/H-NET were extracted from our database. With a median follow-up time of 25.9months, the median PFS was 13.6months. Two- and 3-year survival rates were 87.5 and 62.5%, respectively. The ORR was 8.3%, and the disease control rate was 75%. Serious adverse events were not observed. Subgroup analysis, including G1/G2, and hepatic tumor load, which is the volume of NET liver metastases, did not reveal a difference in PFS. The efficacy and safety of SSA for F/H-NET seemed similar to that found in the PROMID study, highlighting its relevance for the treatment of this disease.

Hidden Figures: Occult Intra-Cardiac Metastases in Asymptomatic Neuroendocrine Tumor Patients.

Carcinoid heart disease is a devastating paraneoplastic consequence of unchecked hormone production from neuroendocrine tumors (NET) and often results in right-sided heart failure. While it occurs frequently in NET patients with carcinoid syndrome, cardiac metastases occur much less often and are usually only incidentally found. Gallium-68 dotatate (ga-68) is an imaging tracer which binds to somatostatin receptor 2 with greater avidity than Indium-111, the tracer used commonly in octreotide scans. Ga-68 PET/CT is the most sensitive study for detecting occult NET metastases and has emerged as the current imaging gold standard. We describe two cases from Vanderbilt University Medical Center and Stanford University Medical Center where asymptomatic patients with well-differentiated midgut NET were diagnosed with intra-cardiac metastases using ga-68 PET/CT. Management of these patients was altered based on the findings as they underwent extensive cardiac evaluation and initiation of therapy with octreotide. Fortunately, they have not suffered life-threatening cardiac complications seen in some NET patients, from other published series, such as bradycardia, heart block, syncope and arrhythmias. These possibilities suggest early cardiology evaluation and consideration of other therapies beyond octreotide, such as surgery or PRRT, may be essential for all NET patients found to have intra-cardiac metastases.

Peptide Receptor Radionuclide Therapy in Grade 3 Neuroendocrine Neoplasms: Safety and Survival Analysis in 69 Patients.

To date, limited data are available concerning peptide receptor radionuclide therapy (PRRT) of grade 3 (G3) neuroendocrine neoplasms (NENs) with a Ki-67 proliferation index of greater than 20%. The purpose of this study was to analyze the long-term outcome, efficacy, and safety of PRRT in patients with somatostatin receptor (SSTR)-expressing G3 NENs. Methods: A total of 69 patients (41 men; age, 28-81 y) received PRRT with 177Lu- or 90Y-labeled somatostatin analogs (DOTATATE or DOTATOC). Twenty-two patients had radiosensitizing chemotherapy. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT, including a subgroup analysis for patients with a Ki-67 index of less than or equal to 55% and a Ki-67 index of greater than 55%. Treatment response was evaluated according to RECIST 1.1 as well as molecular imaging criteria (European Organization for Research and Treatment of Cancer). Short- and long-term toxicity was documented (Common Terminology Criteria for Adverse Events, v 5.0) using a structured database (comprising >250 items per patient) and retrospectively analyzed. Results: Forty-six patients had pancreatic NENs, 11 had unknown primary cancer, 6 had midgut NENs, 3 had gastric NENs, and 3 had rectal NENs. The median follow-up was 94.3 mo. The median PFS was 9.6 mo, and the median OS was 19.9 mo. For G3 NENs with a Ki-67 index of less than or equal to 55% (n = 53), the median PFS was 11 mo and the median OS was 22 mo. Patients with a Ki-67 index of greater than 55% (n = 11) had a median PFS of 4 mo and a median OS of 7 mo. For patients with positive SSTR imaging but no 18F-FDG uptake, the median PFS was 24 mo and the median OS was 42 mo. A significant difference was found for both PFS and OS, with median PFS of 16 mo and 5 mo and median OS of 27 mo and 9 mo for an SUVmax of greater than 15.0 and an SUVmax of less than or equal to 15.0, respectively, on SSTR PET. In the group with 18F-FDG uptake scored as 3 or 4, the median PFS was 7.1 mo and the median OS was 17.2 mo. In the group with 18F-FDG uptake scored as 0-2, the median PFS was 24.3 mo and the median OS was 41.6 mo. PRRT was well tolerated by all patients; no grade 3 or grade 4 hematotoxicity occurred, and no clinically significant decline in renal function was observed. There was no hepatotoxicity. Conclusion: PRRT was tolerated well, without significant adverse effects, and was efficacious in G3 NENs; the clinical outcome was promising, especially in patients with a Ki-67 index of less than or equal to 55% and even in patients for whom chemotherapy had failed. Baseline 18F-FDG along with SSTR molecular imaging was useful for stratifying G3 NEN patients with high uptake on SSTR PET/CT and no or minor 18F-FDG avidity-a mismatch pattern that was associated with a better long-term prognosis.

Improved survival with higher doses of octreotide long-acting release in gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent a heterogeneous group of tumors that is associated with an indolent course. Octreotide has a positive effect on disease stabilization in well-differentiated midgut NETs, but a meaningful survival analysis was not possible due to insufficient events. Higher doses of octreotide long-acting release (LAR) are often used in clinical practice for control of carcinoid symptoms and our objective was to determine if dose of octreotide correlates with survival. We reviewed all patients with advanced GEP NETs who initiated treatment with octreotide LAR between 2000 and 2013 in a large, representative Canadian province. We compared overall survival in patients who received low (< 30mg) compared to high (≥ 30mg) doses of octreotide. A total of 170 patients were identified. Baseline characteristics in the low- and high-dose groups were similar: median age 62/63years, 50/58% were male, 46/48% originated from the small bowel, and 74/66% had liver metastases at diagnosis. The median time from diagnosis to treatment initiation was 5.5 and 6.0months. Octreotide LAR was initiated with the intent of symptom management (71%), disease stabilization (23%), or biomarker control (6%). Median overall survival (OS) was better in the high-dose group, 66months compared to 22months (multivariate HR 0.5, p < 0.01). Age ≥ 65 (HR 1.9, p < 0.01), ECOG ≥ 2 (HR 2.7, p < 0.01), and pancreatic NETs (HR 1.7, p = 0.03) were all predictors of worse survival. Our findings suggest that octreotide may confer survival benefits in GEP NETs. Further prospective studies are warranted to validate the impact of high-dose octreotide on outcomes.

Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors.

Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy.

99mTc-Hynic-TOC imaging in the diagnostic of neuroendocrine tumors.

The aim of this study was to assess the potential of 99mTc-Hynic-TOC imaging in the primary diagnosis and follow-up of midgut neuroendocrine tumors (NETs). In comparison to 111In-octreotide, 99mTc-Hynic-TOC has a higher imaging quality and leads to a lower radiation absorption in patients. 99mTc-Hynic-TOC was used for assessing primary diagnosis (n = 14) and during follow-up (n = 17) in patients with NETs. The scintigraphic findings were compared with computed tomography scans and follow-up. In 31 patients, 34 somatostatin receptor scans using 99mTc-Hynic-TOC were performed. The primary diagnoses were midgut NET. The scintigraphy was true positive in 17 patients, true negative in 9, false negative in 4, and false positive in 1. From these data, a sensitivity of 81%, specificity of 90%, positive predictive value of 94%, and negative predictive value of 69% were calculated. In summary, 99mTc-TOC represents a useful radiotracer in imaging SSTR-expressing tumor lesions with slightly higher sensitivity, higher imaging quality, and lower radiation exposure for patients compared to 111In-octreotide. A 1-day double-acquisition protocol should be used to reduce false-positive findings of the gut.

Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial

Purpose Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of 177Lu-Dotatate treatment on time to deterioration in health-related QoL. Methods The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with 177Lu-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration ≥ 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date. Results TTD was significantly longer in the 177Lu-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning. Conclusion This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, 177Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.

First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors.

4099Background: The final per-protocol statistical analysis (cut–off date 24 July 2015) of PFS, the primary endpoint of the NETTER-1 study, showed a significant difference (p < 0.0001) between the ...

Clinical outcomes in patients with baseline renal dysfunction in the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors.

4102Background: Might potential nephrotoxicity be a risk for therapy with 177Lu-Dotatate? Among patients randomised in the NETTER-1 study, nephrotoxicity and treatment efficacy were evaluated in th...

Mo1206 - Assessing the Prognostic Validity of the American Joint Committee on Cancer Staging Classification for Midgut Neuroendocrine Tumors

Mo1206 - Assessing the Prognostic Validity of the American Joint Committee on Cancer Staging Classification for Midgut Neuroendocrine Tumors

Recent advances in theranostics and challenges for the future.

Theranostic nuclear oncology is on the cusp of adoption into routine clinical management of neuroendocrine tumours (NETs) following publication of the Phase3 randomised controlled trial, NETTER-1. For the first time, level 1b evidence of efficacy and safety of 68-gallium/177-lutetium-DOTA-octreotatepeptide receptor radionuclide therapy, of mid-gut neuroendocrine tumours was established. Multicentre Phase 2 studies of 68-gallium/177-lutetium-prostatespecific membrane antigen theranostic approaches to management of end-stage metastatic castrate-resistant prostate cancer, are also very encouraging. However, the retrospective uncontrolled data currently available are inadmissible for formal regulatory agency evaluation. The challenge is to engage with oncologists and urologists, and to collaborate with the pharmaceutical industry, to design and perform the controlled clinical trials required for regulatory approval, and eventual reimbursement for theranostic nuclear oncology procedures. Strategies to facilitate timely establishment of an evidence base are considered in this review of theranostic advances over the past year. The prime objective is the provision of novel, effective, safe, personalised, tumour-targeted molecular theranostic management of metastatic castrate-resistant prostate cancer, and other cancers, such as non-Hodgkin lymphoma, which express the appropriate molecular receptor tumour targets. It would also be desirable to offer theranostic treatments at an earlier stage of malignant disease when the benefit is likely to be greater. The ultimate goal of theranostic nuclear oncology is to prolong survival and to improve quality of life for cancer patients worldwide. This may only be achieved through close collaboration between oncologists, nuclear physicians, radiologists, dosimetric physicists, Pharma, and, above all, with the patients themselves, in ways which are explored in this review.