Gastrointestinal Neuroendocrine Tumors Research Articles

P30.01: Neuroendocrine tumours of the female genital tract: a small case series

Both primary and secondary gynecological neuroendocrine tumours (NET) or carcinoid tumours are uncommon, and there is very little literature regarding their features on ultrasound (US) examination of the pelvis. The aim of this study is to describe the clinical and US features of NET of the female genital tract. Patients with a confirmed histological diagnosis of NET, who had undergone a transvaginal US in our Gynecology Assessment Clinic 2007-2016, were identified using data from histopathology laboratory and our clinical data base. King's College Hospital is a regional centre for the treatment of gastrointestinal NET. The ultrasound scans were performed by an experienced US examiner and described according to IOTA or IETA criteria as appropriate. Eight patients were identified in total. There were 4 cases of metastatic tumours in women already known to have had NET of the gastro-intestinal tract. These women had minimal or no symptoms and they were referred for surveillance CT scans. The US imaging in these tumours showed solid, irregular, hypoechoic heterogeneous tumours. The ovarian lesions were bilateral. Subjective assessment of vascularity of the tumours varied between scores of 1 to 3. One woman had a primary endometroid tumour with neuroendocrine differentiation. She presented with cerebellar metastasis and only complained of postmenopausal bleeding as a relatively late symptom. Her tumour was solid, heterogeneous, irregular and poorly vascularised on US examination. The remaining three patients had foci of NET found within dermoid cysts, none of which were suspected on preoperative US and none of whom have had recurrent disease. NET of the female genital tract tend to be multiple and solid in morphology. These tumours are much rarer than breast, stomach, lymphatic or colorectal cancers as a cause of ovarian metastases, but should be added to the list of differential diagnoses when solid tumours are found in the pelvis.

Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31). HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. Novartis Pharmaceuticals.

Maintaining quality of life for patients with neuroendocrine tumours

Ideally, new treatments should either improve overall survival or the health-related quality of life (HRQOL) of patients, or both, and should have a favourable cost-to-benefit ratio. For instance, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) significantly improves progression-free survival, overall survival, and HRQOL compared with gemcitabine in patients with metastatic pancreatic adenocarcinoma, even though it causes substantially more side-effects. 1 Gourgou-Bourgade S Bascoul-Mollevi C Desseigne F et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013; 31: 23-29 Crossref PubMed Scopus (344) Google Scholar , 2 Conroy T Desseigne F Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364: 1817-1825 Crossref PubMed Scopus (5177) Google Scholar After publication of the RADIANT-3 and RADIANT-4 randomised, placebo-controlled, phase 3 studies, everolimus was approved for all non-functional, advanced, neuroendocrine tumours (NETs), including those of the pancreas, 3 Yao JC Shah MH Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 514-523 Crossref PubMed Scopus (2257) Google Scholar lung, and gastrointestinal tract, 4 Yao JC Fazio N Singh S et al. for the RAD001 in Advanced Neuroendocrine TumoursFourth Trial (RADIANT-4) Study GroupEverolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016; 387: 968-977 Summary Full Text Full Text PDF PubMed Scopus (784) Google Scholar and sunitinib has been approved for pancreatic NETs (pNETs). 5 Raymond E Dahan L Raoul JL et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 501-513 Crossref PubMed Scopus (1959) Google Scholar Everolimus did not improve overall survival compared with placebo but was approved on the basis of a significant improvement versus placebo in progression-free survival. 3 Yao JC Shah MH Ito T et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 514-523 Crossref PubMed Scopus (2257) Google Scholar , 4 Yao JC Fazio N Singh S et al. for the RAD001 in Advanced Neuroendocrine TumoursFourth Trial (RADIANT-4) Study GroupEverolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016; 387: 968-977 Summary Full Text Full Text PDF PubMed Scopus (784) Google Scholar Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trialHRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. Full-Text PDF

Prognoses in patients with primary gastrointestinal neuroendocrine neoplasms based on the proposed new classification scheme.

The aim of this study is to investigate the clinicopathological characteristics, as well as explore the prognostic accuracy of the proposed new classification in gastrointestinal NENs (GI-NENs) patients. Patients diagnosed with GI-NENs were retrospectively indentified from existing databases of the pathological institute at our institution from January 2009 to November 2015. We identified 414 patients with GI-NENs, 250 cases were diagnosed as neuroendocrine tumor G1 (NET G1), 25 as neuroendocrine tumor G2 (NET G2), 53 as neuroendocrine tumor G3 (NET G3), 55 as neuroendocrine carcinoma G3 (NEC G3), and 31 as mixed adenoneuroendocrine carcinoma (MANEC); the overall survival (OS) rate at three years were 94.9%, 91.7%, 74.3%, 62.7% and 38.1%, respectively. The difference in progression-free survival (PFS) duration among the patients with NET G1, NET G2, NET G3, NEC G3, and MANEC was statistically significant (P<0.001). However, the PFS of NEC G3 and MANEC was low and similar (P = 0.090). In multivariate analysis of patients with GI-NENs, surgical margin, comorbidity, proposed new classification and tumor location were useful predictors of OS (P<0.05). Our findings suggest that the proposed new classification can accurately reflect the clinical outcome, together with surgical margin, comorbidity, and tumor location may be meaningful prognostic factors for the OS of GI-NENs.

Standardized development of transanal endoscopic microsurgery

Transanal endoscopic microsurgery (TEM) is currently the only one-port system in endoscopic surgery, which a direct endoluminal approach can lead to the target organ through a natural opening of human body. TEM has been applied in colorectal surgery for over 3 decades. Compared with radical surgery, TEM has the advantages, such as quicker recovery, shorter hospital stay and fewer complications. One perfect TEM surgical system, which mainly consists of three parts, namely peculiar rectoscope for surgery, special surgical instruments and imaging system, is the foundation of standardized development of TEM. Accurate preoperative evaluation and staging is the key for good outcomes in TEM technology. In addition to digital examination of rectum, rigid sigmoidoscopy(or rectoscopy) should be routinely performed to confirm the location of the lesion and record it in a "time-in-clock" form. For lesions with undetermined nature, biopsy should be performed. For patients with rectal tumor, pelvic MRI examination can be used on the basis of routine endorectal ultrasonography (ERUS). Endoluminal suture is the challenge for standardized development of TEM, especially for those with large intestinal wall defects. Professional training is required to master suture technique. In 2016, the consensus of experts on TEM technology was formulated by TEM Study Group of Colorectal Cancer Specialty Committee of Chinese Anticancer Association. The recommended surgical indications for TEM include (1)rectal adenoma; (2)early rectal cancer with good histopathological features; (3)extended resection of locally malignant polyps by colonoscopy; (4)other rectal tumors suitable for local resection; (5)benign stricture or anastomotic stricture of the rectum; (6)repair of anastomotic leakage after low anterior resection of rectum; (7)diagnosis of rectal hemorrhage; (8)biopsy of rectum and surrounding lesions; (9)repair of rectovaginal fistula or mucosal flap transposition of the internal mouth of anal fistula; (10)treatment of rectal foreign body. With the maturity of TEM technology, the indication of TEM continues to expand. Nowadays, TEM is applicable to rectal neuroendocrine tumor or gastrointestinal stromal tumor resection, as well as rectovaginal fistula repair. It can even serve as a "bottom-up" operation platform for transanal total mesorectal excision (taTME). This article introduces the standardization of TEM, its current indications, novel implications, and future perspectives, expecting that TEM will be further popularized and healthily developed in China.

Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review

Liver transplantation to treat neuroendocrine tumors, especially in the setting of diffuse liver involvement not amenable to operative resection remains controversial. We sought to perform a systematic review of the current literature to summarize data on patients undergoing liver transplantation with neuroendocrine tumors liver metastases as the indication. A systematic review was conducted in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Eligible studies were identified using 3 distinct databases through March 2017: Medline (PubMed), ClinicalTrials.gov, and Cochrane library, Cochrane Central Register of Controlled Trials using a search algorithm: "(neuroendocrine or NET) and transplantation and liver." From the 1,216 records retrieved, 64 studies were eligible. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry and the United Network for Organ Transplantation/Organ Procurement and Transplantation Network databases, 3 were multicenter studies. The largest cohort of data on patients undergoing liver transplantation for neuroendocrine tumors liver metastasis indication were from single center studies comprising a total of 279 patients. Pancreas was the primary tumor site for most patients followed by the ileum. Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous neuroendocrine tumors liver metastasis ranged from 17.7% to 38.7%. Overall, recurrence after liver transplantation ranged from 31.3% to 56.8%. Reported 1-, 3-, and 5-year overall survival was 89%, 69%, and 63%, respectively. Several prognostic factors associated with worse long-term survival including transplantation >50% liver tumor involvement, high Ki67, as well as a pancreatic neuroendocrine tumors versus gastrointestinal neuroendocrine tumors tumor location. Liver transplantation may provide a survival benefit among patients with diffuse neuroendocrine tumors metastases to the liver. However, due to high recurrence rates, strict selection of patients is critical. Due to the scarcity of available grafts and the lack of level 1 evidence, the recommendations to endorse liver transplantation for extensive liver neuroendocrine tumors metastases warrants ongoing deliberations.

Rationale and protocol of MetNET-2 trial: Lanreotide Autogel plus metformin in advanced gastrointestinal or lung neuroendocrine tumors.

Metformin (MET) has recently emerged as a potentially active agent in cancer prevention and treatment. MET is thought to exert its antitumor effects either via modification of systemic metabolism or through cell-autonomous effects (e.g., activation of AMPK and inhibition of the mTOR pathway). Preliminary findings of the PRIME-NET study suggest that the addition of MET to treatment with everolimus (EVE) and/or somatostatin analogs (SSAs) can provide clinical benefit in diabetic neuroendocrine tumor (NET) patients. In light of this and other retrospective evidence of MET's anticancer activity in NETs, prospective studies are needed. A pilot, single-arm, open-label, prospective study (MetNET-2 trial, NCT02823691) was designed to evaluate the safety of MET in combination with lanreotide in well-differentiated gastrointestinal (WD GI) and lung NETs.

A population-based study of outcomes in patients with gastrointestinal neuroendocrine tumours.

Neuroendocrine tumours (NETs) are heterogeneous, with varying presentations and treatment options. To our knowledge, there are no randomized and few long-term studies of patient outcomes. The role of surgical and medical therapy for local, regional and metastatic disease continues to be evaluated in the literature. We conducted a population-based search of the provincial cancer registry to identify patients with gastrointestinal NETs from the stomach, small intestine, colon and rectum diagnosed between 1990 and 2005 and assessed their outcomes. We examined clinicopathological information on the outcomes of 530 patients with gastrointestinal NETs. The overall incidence of NETs increased from 11 per million to 19 per million during the study period. Advancing stage and patient age were associated with poor overall or disease-specific outcomes. Surgery, both curative and palliative, was associated with decreased risk of overall (hazard ratio [HR] 0.5, p < 0.001) and disease-specific (HR 0.5, p < 0.001) death. The biggest benefit was observed in patients with distant disease, in whom 5-year disease-specific survival for R0 resections was nearly double that for patients with macroscopic residual disease (92% v. 48%, p = 0.009). Older age was associated with poor 5-year overall and disease-specific survival (p < 0.001). There has been a significant increase in incidence of gastrointestinal NETs, and advancing patient age, but not sex, is linked to poor outcomes in terms of overall and disease-specific survival. Surgery, both curative and palliative, was associated with decreased risk of overall and disease-specific death. Compared with patients with residual macroscopic disease, patients with distant disease were nearly twice as likely to survive 5 years if they had R0 resections. The use of radioisotope therapy and long-acting octreotide therapy was also associated with improved outcomes overall.

Metachronous duodenal neuroendocrine neoplasms after endoscopic mucosal resection

SummaryDuodenal neuroendocrine tumors (D‐NETs) may or may not be associated with a functional clinical syndrome. The term D‐NETs includes all duodenal tumors with neuroendocrine features as determined by histological/ immunohistochemical methods including positivity for neuroendocrine cytosolic markers (neuron‐specific enolase, or secretory vesicle proteins (chromogranin A (CgA), synaptophysin)). More than 90% of all D‐NETs arise in the first and second part of the duodenum. Approximately 20% of D‐NETs occurs in the periampullary region. Most D‐NETs are asymptomatic and incidentally detected during upper gastrointestinal (GI) endoscopy examinations for symptoms unrelated to the carcinoid tumor. D‐NETs account for 2% ‐ 5% of GI neuroendocrine tumors, and usually present as solitary small lesions confined to the duodenal submucosa. Endoscopic treatment is generally recommended for D‐NETs less than 10 mm as it is associated with a low frequency of lymph node invasion and distant metastases. However, the report of metachronous or synchronous concurrence of D‐NETs is scarce. Herein, we present a case of metachronous duodenal neuroendocrine tumor status successfully treated by hybrid endoscopic submucosal dissection.Copyright © 2017, The Gastroenterological Society of Taiwan, The Digestive Endoscopy Society of Taiwan and Taiwan Association for the Study of the Liver.

An elevated serum alkaline phosphatase level in hepatic metastases of grade 1 and 2 gastrointestinal neuroendocrine tumors is unusual and of prognostic value.

BackgroundIn our clinical practice we have observed that despite a high hepatic metastatic tumor burden, serum alkaline phosphatase (AP) levels are frequently normal in cases of metastatic neuroendocrine tumor (NET).Patients and methodsWe retrospectively reviewed the records of patients with grade 1 and 2 NETs with liver metastases but without bone metastases seen at our institution in 2013. In total, 49 patients were included (22 female), with a median age of 60 years (range: 28 to 84 years). The primary tumors were located in the duodenum/pancreas (n = 29), small bowel (n = 17) or colon/rectum (n = 3); 10 cases were grade 1 and 39 grade 2. Hepatic involvement was bulky, with more than 10 lesions in 23 patients and a tumor burden above 10% of the liver volume in 26 patients.ResultsSerum AP levels were elevated (≥ upper limit of normal (ULN)) in 16 patients. In multiparametric analysis, elevated serum AP levels were not associated with the primary site, grade, or number or volume of metastases. In multiparametric analysis, progression-free survival was only correlated with grade (p = 0.010) and AP level (p = 0.017).ConclusionsSerum AP levels are frequently normal in liver metastases from NET, even in the event of a major tumor burden, and the serum AP level can be of prognostic value.

Everolimus in Neuroendocrine Tumors of the Gastrointestinal Tract and Unknown Primary

Purpose: The RADIANT-4 randomized phase 3 study demonstrated significant prolongation of median progression-free survival (PFS) with everolimus compared to placebo (11.0 [95% CI 9.2-13.3] vs. 3.9 [95% CI 3.6-7.4] months) in patients with advanced, progressive, nonfunctional gastrointestinal (GI) and lung neuroendocrine tumors (NET). This analysis specifically evaluated NET patients with GI and unknown primary origin. Methods: Patients in the RADIANT-4 trial were randomized 2:1 to everolimus 10 mg/day or placebo. The effect of everolimus on PFS was evaluated in patients with NET of the GI tract or unknown primary site. Results: Of the 302 patients enrolled, 175 had GI NET (everolimus, 118; placebo, 57) and 36 had unknown primary (everolimus, 23; placebo, 13). In the GI subset, the median PFS by central review was 13.1 months (95% CI 9.2-17.3) in the everolimus arm versus 5.4 months (95% CI 3.6-9.3) in the placebo arm; the hazard ratio (HR) was 0.56 (95% CI 0.37-0.84). In the unknown primary patients, the median PFS was 13.6 months (95% CI 4.1-not evaluable) for everolimus versus 7.5 months (95% CI 1.9-18.5) for placebo; the HR was 0.60 (95% CI 0.24-1.51). Everolimus efficacy was also demonstrated in both midgut and non-midgut populations; a 40-46% reduction in the risk of progression or death was reported for patients in the combined GI and unknown primary subgroup. Everolimus had a benefit regardless of prior somatostatin analog therapy. Conclusions: Everolimus showed a clinically meaningful PFS benefit in patients with advanced progressive nonfunctional NET of GI and unknown primary, consistent with the overall RADIANT-4 results, providing an effective new standard treatment option in this patient population and filling an unmet treatment need for these patients.

Predictive factors of carcinoid syndrome among patients with gastrointestinal neuroendocrine tumors (GI NETs).

e15690 Background: Carcinoid syndrome (CS) is associated with a significant symptom burden and deleterious impacts on quality of life. Patients may experience delays in CS diagnosis of 5 to 7 years from initial onset of symptoms, as symptoms may be mistaken for other diseases, such as irritable bowel syndrome or menopause. The current study attempts to detect factors predictive of CS prior to CS diagnosis among patients with GI NETs. Methods: Using a US administrative claims database (IMS PharMetrics) and a retrospective case-control study design, patients (≥18 years) who were newly diagnosed with GI NETs without CS (controls) were exactly matched to patients with CS (cases) based on NET diagnosis date (month and year) at a 3-to-1 ratio. For CS patients, the study index date was the first CS diagnosis date. Each control patient was assigned to have the same index month and year as the matched case patient. The most frequently observed conditions other than symptoms/diagnoses known to be associated with CS during the 1 year prior to the index date were assessed. These conditions were entered into a forward-stepwise logistic regression model to derive predictive factors. Similar methods were applied to another administrative claims database (Truven Health Analytics MarketScan) to validate these predictors. Results: In the development database 1,004 patients with GI NETs were identified, among whom 251 (25%) had CS and 753 (75%) were controls. In both databases, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio (95% CI): 3.38 (2.07 - 5.51)], enlargement of lymph nodes [2.13 (1.10 - 4.11)], and abdominal mass [3.79 (1.87 - 7.69)]. Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patients’ medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.

A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-).

TPS4146 Background: NENs include a heterogeneous group of tumors with different behavior. Despite immunomodulators such as interferon are approved for the management of grade 1-2 NENs, the low mutation tumor load and PD-1/PDL-1 expression have limited the development of immune check-point inhibitors in this setting. The rational for immunotherapy in high grade NENs is stronger compared with low grade NENs based on the results observed in small cell lung cancer. However, the combination of an antiPDL-1 and antiCTLA-4 could increase the probability of success regardless of tumor growth rate, mutational tumor load or PDL-1 expression in low grade NENs. Methods: This prospective, multi-center, open label, phase II study (EudraCT:2016-002858-20) will evaluate the efficacy and safety of durvalumab plus tremelimumab in 126 pts within four different cohorts, including well-moderately differentiated lung NENs (Cohort 1), grade 1-2 gastrointestinal NENs (Cohort 2), grade 1-2 pancreatic NENs (Cohort 3) and grade 3 GEP NENs (Cohort 4). To optimize the efficacy of immunotherapy in low grade NENs, pts included in the trial must have progressed to all standard approved therapy in each setting, including somatostatin analogues, targeted agents and chemotherapy for lung and GEP grade 1-2 NENs up to 4 prior lines. For pts included in cohort 4, progression to standard platinum-based chemotherapy is mandatory. All pts will receive durvalumab 1500 mg every 28 days for 12 months, and tremelimumab 75 mg Q4W up to 4 doses/cycles. Retreatment is allowed after disease progression in the follow-up period. The primary endpoint of the study for cohorts 1-3 is disease control rate at 9 months including the percentage of pts achieving complete response, partial response, or stable disease according to RECIST v1.1; Median overall survival will be the primary endpoint for cohort 4. Primary endpoints will be assessed by investigators and confirmed by central radiological review. Secondary endpoints include median progression-free survival, safety and tolerability and a wide panel of biomarkers in blood samples and tumor tissue. Clinical trial information: 2016-002858-20.

Reduction of immune inhibitory myeloid derived suppressor cells by low dose sunitinib combined with a cancer vaccine to provide therapeutic benefit to tumor-bearing mice.

e23084 Background: Sunitinib is a receptor tyrosine kinase inhibitor (RTK) approved as a monotherapy for the treatment of advanced RCC, gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. At the approved doses, it inhibits angiogenesis in tumors and targets RTKs (PDGF receptor, VEGF receptor, KIT, FLT-3, and RET) involved in tumor cell growth. Sunitinib also has been shown in murine studies and patients, to exhibit immunomodulatory properties that reduce a heterogeneous population of cells termed myeloid derived suppressor cells (MDSCs) and restore the immune stimulatory Th1 cytokine profile of T cells. The approved anti-angiogenic sunitinib dosing regimens in RCC have a safety profile that is overall manageable with the most commonly reported sunitinib-related grade 3 adverse events including hypertension, fatigue, diarrhea and hand-foot syndrome. Although the tolerability of sunitinib as monotherapy was acceptable in advanced stage diseases, the drug’s side effect profile could potentially pose challenges for use in combination with other oncology therapies. Thus, if the dose of sunitinib could be lowered to improve the side effect profile without impacting its immune modulatory properties, it could be combined with cancer vaccine regimens, offering a better tolerated and highly potent immunotherapy for patients with cancer of all stages. Methods: To evaluate the relationship of dose of sunitinib on its immunomodulatory properties, the pharmacokinetic profile, the frequency of MDSCs, cytokine profile, vaccine induced immune responses and anti-tumor efficacy were monitored in a subcutaneous tumor bearing BALB-neuT mice in the presence or absence of a cancer vaccine. Results: The data suggested that sunitinib doses below the approved daily dose of 50 mg may maintain the drug’s immune modulatory properties and improve overall survival when given concurrently with a cancer vaccine. Conclusions: The data suggested that low dose sunitinib can be administered as an immunomodulator to reduce MDSCs safely in combination with potent, multi-component cancer vaccine regimens.

Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary.

e15696 Background: Neuroendocrine tumor of unknown primary constitutes about 10-15 % of all neuroendocrine tumors. Identification of primary site can helps alter the management. Sunitinib is FDA approved for management of pancreatic neuroendocrine tumors, everolimus is approved for gastroenteropancreatic and bronchial NETs, immune checkpoint inhibitors are active in Merkel cell carcinoma and MIBG treatment is standard of care for pheochromocytoma. Methods: Patients with neuroendocrine tumor with unknown primary were identified from Markey Cancer Center database over a five-year period (2012-2016). Patient who underwent 92-gene reverse transcriptase polymerase chain reaction cancer classification assay (BioTheranostics Tissue Type ID) were analyzed. IRB approval was obtained. Results: 56 patients with neuroendocrine tumors with unknown primary were identified. Median age of cohort was 61 years. 28/56 patients were males. 92 gene cancer ID assay was used in 38 out of 56 patients. Primary site of tumor was identified with &gt; 95% certainty in 36 out of 38 patients. The test reported pancreatic NET as the primary site for 10 patients, gastrointestinal NETs for 14 patients, bronchial carcinoid for 5, large call NEC for 3, Merkel cell carcinoma for two and pheochromocytoma in one patient. Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).

Current status in morphological imaging in adrenal and gastrointestinal neuroendocrine tumours

Current status in morphological imaging in adrenal and gastrointestinal neuroendocrine tumours

The Evolving Landscape of Systemic Therapy for Well-Differentiated Neuroendocrine Tumors of the Lung

James Yao*, MD, is professor and chairman of gastrointestinal medical oncology at the MD Anderson Cancer Center (TX, USA). He is the chair emeritus of the North American Neuroendocrine Tumor Society (NANETS). He has numerous awards including the American Society of Clinical Oncology Career Development Award 2003, and the Carcinoid Cancer Foundation Research Award 2006, MD Anderson Distinguished Alumni Award 2009, Irwin H. Krakoff Excellence in Clinical Research Award 2011, and The Murray Brennan Distinguished Lecturer, Memorial Sloan-Kettering Cancer Center, 2012. In 1995, Dr. Yao received his doctorate of medicine at Baylor College of Medicine (TX, USA). His credentials include board of certification in internal medicine (ABIM) in 1999 and board of certification in medical oncology (ABIM) in 2003. Dr. Yao has special interests in neuroendocrine tumors and gastric cancer and has authored over 100 manuscripts including practice-changing articles in New England Journal of Medicine and The Lancet. He has also been a principal investigator in numerous investigator initiated and multicenter clinical studies. He led the development of everolimus in neuroendocrine tumors from first patient treated through FDA approval for pancreatic neuroendocrine tumors in 2011 and lung and gastrointestinal neuroendocrine tumors in 2016.

18F]FDG PET/CT predicts progression-free survival in patients with idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by an unpredictable course. Prognostic markers and disease activity markers are needed. The purpose of this single-center retrospective study was to evaluate the prognostic value of lung fluorodeoxyglucose ([18F]-FDG) uptake assessed by standardized uptake value (SUV), metabolic lung volume (MLV) and total lesion glycolysis (TLG) in patients with IPF.MethodsWe included 27 IPF patients (IPF group) and 15 patients with a gastrointestinal neuroendocrine tumor without thoracic involvement (control group). We quantified lung SUV mean and SUV max, MLV and TLG and assessed clinical data, high-resolution CT (HRCT) fibrosis and ground-glass score; lung function; gender, age, physiology (GAP) stage at inclusion and during follow-up; and survival.ResultsLung SUV mean and SUV max were higher in IPF patients than controls (p <0.00001). For patients with IPF, SUV mean, SUV max, MLV and TLG were correlated with severity of lung involvement as measured by a decline in forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) and increased GAP score. In a univariate and in a multivariate Cox proportional-hazards model, risk of death was increased although not significantly with high SUV mean. On univariate analysis, risk of death was significantly associated with high TLG and MLV, which disappeared after adjustment functional variables or GAP index. Increased MLV and TLG were independent predictors of death or disease progression during the 12 months after PET scan completion (for every 100-point increase in TLG, hazard ratio [HR]: 1.11 (95% CI 1.06; 1.36), p = 0.003; for every 100-point increase in MLV, HR: 1.20 (1.04; 1.19), p = 0.002). On multivariable analysis including TLG or MLV with age, FVC, and DLCO or GAP index, TLG and MLV remained associated with progression-free survival (HR: 1.1 [1.03; 1.22], p = 0.01; and 1.13 [1.0; 1.2], p = 0.005).ConclusionFDG lung uptake may be a marker of IPF severity and predict progression-free survival for patients with IPF.

Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States

The incidence and prevalence of neuroendocrine tumors (NETs) are thought to be rising, but updated epidemiologic data are lacking. To explore the evolving epidemiology and investigate the effect of therapeutic advances on survival of patients with NETs. A retrospective, population-based study using nationally representative data from the Surveillance, Epidemiology, and End Results (SEER) program was conducted to evaluate 64 971 patients with NETs from 1973 to 2012. Associated population data were used to determine annual age-adjusted incidence, limited-duration prevalence, and 5-year overall survival (OS) rates. Trends in survival from 2000 to 2012 were evaluated for the entire cohort as well as specific subgroups, including distant-stage gastrointestinal NETs and pancreatic NETs. Analyses were conducted between December 2015, and February 2017. Neuroendocrine tumor incidence, prevalence, and OS rates. Of the 64 971 cases of NETs, 34 233 (52.7%) were women. The age-adjusted incidence rate increased 6.4-fold from 1973 (1.09 per 100 000) to 2012 (6.98 per 100 000). This increase occurred across all sites, stages, and grades. In the SEER 18 registry grouping (2000-2012), the highest incidence rates were 1.49 per 100 000 in the lung, 3.56 per 100 000 in gastroenteropancreatic sites, and 0.84 per 100 000 in NETs with an unknown primary site. The estimated 20-year limited-duration prevalence of NETs in the United States on January 1, 2014, was 171 321. On multivariable analyses, the median 5-year OS rate varied significantly by stage, grade, age at diagnosis, primary site, and time period of diagnosis. The OS rate for all NETs improved from the 2000-2004 period to the 2009-2012 period (hazard ratio [HR], 0.79; 95% CI, 0.73-0.85). Even larger increases in OS between these periods were noted in distant-stage gastrointestinal NETs (HR, 0.71; 95% CI, 0.62-0.81) and distant-stage pancreatic NETs (HR, 0.56; 95% CI, 0.44-0.70). The incidence and prevalence of NETs are steadily rising, possibly owing to detection of early-stage disease and stage migration. Survival for all NETs has improved over time, especially for distant-stage gastrointestinal NETs and pancreatic NETs in particular, reflecting improvement in therapies. These data will help to prioritize future research directions.

Synaptophysin-Ki67 double stain: a novel technique that improves interobserver agreement in the grading of well-differentiated gastrointestinal neuroendocrine tumors

A common problem in the assessment of Ki67 proliferative index in well-differentiated gastrointestinal neuroendocrine tumors is distinguishing tumor from non-tumor. This is because background stromal lymphocytes, entrapped non-neoplastic glands, and the delicate vascular network characteristic of neuroendocrine tumors frequently contain a subset of proliferating cells. Furthermore, in small biopsies, crush and cautery artifact can alter the morphologic appearance of tumor cells, making the Ki67 proliferative index more difficult to assess. To address these issues, we developed a synaptophysin-Ki67 double stain using a commercially available immunohistochemistry kit, allowing simultaneous visualization of tumor and proliferating nuclei. To test this method, three gastrointestinal pathologists individually graded 50 gastrointestinal neuroendocrine tumors first using synaptophysin-Ki67 double-stained slides and then, after a washout period, using Ki67-only stained slides (along with routine hematoxylin- and eosin-stained slides). Interobserver agreement on Ki67 proliferative index was moderate using the Ki67-only stained slides (intraclass correlation 0.51, 95% confidence interval: 0.35–0.66) and improved using the synaptophysin-Ki67 double stain (intraclass correlation 0.79, 95% confidence interval: 0.69–0.86). Similarly, interobserver agreement on tumor grade was fair with Ki67-only stained slides (κ=0.39, P<0.001) and improved with the double stain (κ=0.58, P<0.001). Analysis of individual pathologists' scores revealed that fewer total number of tumor cells counted correlated with higher grade designation and appeared to contribute to grade discordance. In tumors cited as particularly challenging to assess by the pathologists, three of four tumors were grade discordant with the Ki67-only stain, whereas all four tumors were grade concordant with the synaptophysin-Ki67 stain. The synaptophysin-Ki67 double stain is the first technique to address specifically the histomorphologic challenges of evaluating Ki67 proliferative index in well-differentiated gastrointestinal neuroendocrine tumors. Although further validation is needed, this study provides evidence that the synaptophysin-Ki67 double stain can improve interobserver agreement.