Enhancing Patient Care via Co-Creation and Validation of a New and Improved Delivery System for Lanreotide Autogel/Depot: Focus on its Evaluation by US Healthcare Professionals
Daphne Adelman,1 Xuan-Mai Truong Thanh,2 Clémentine Megret.31Northwestern University, Chicago, IL; 2Ipsen, Boulogne-Billancourt, France; 3Ipsen PharmSciences, Dreux, France.
Background: Lanreotide autogel/depot, a somatostatin analog used to treat acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is currently supplied as a sterile, ready-to-use, single-dose prefilled syringe for deep subcutaneous administration. We performed studies to i) gain insights into patient, caregiver, and healthcare professional (HCP) use of the current delivery system (DS) and prototypes, and ii) evaluate use of an improved new DS (NDS).
Methods: Four human factor (HF) formative studies were conducted (06/2015-09/2016) in participants representing patients with acromegaly (n = 33) or GEP-NETs (n = 21), caregivers (n = 3), HCPs (n = 73), and other relevant HCPs (n = 2). These studies identified challenges/areas for improvement with the current DS and evaluated NDS prototypes. Formative study-led improvements to the NDS included: ergonomics, robustness of injection process, intuitiveness of use, needle exposure. Lastly, a HF validation study was performed in the US and Germany (05-06/2017) to demonstrate safe and effective use of the final NDS as intended. Validation study inclusion criteria: patients with acromegaly, or non-diagnosed participants with enlarged hands and fingers/dexterity issues willing to self-inject (acromegaly representatives); a caregiver of/patient with a GEP-NET, or non-diagnosed participants willing to inject self/someone else (GEP-NET representatives/caregivers). Critical tasks were assessed when participants performed two injections with the NDS into a mannequin. Results of the HF validation study are reported.
Results: The US arm of the HF validation study comprised 35 HCPs who did [n = 16] or did not [n = 19] receive training prior to testing. During the testing session, misuses were reported for 21 (60%) participants, 6 (38%) in the trained group and 15 (79%) in the untrained group. The total number of misuses was 7 in the trained HCP group and 37 in the untrained group. No task errors were specific to the NDS.
Conclusion: The ergonomic, robust and intuitive delivery system developed in conjunction with patients, caregivers, and HCPs may further improve patient care.
DIPNECH: The Mayo Experience
Daniel Almquist,1 Arriana Cabrera,1 Heidi Kosiorek,2 Mohamad Sonbol,2 Thorvardur Halfdanarson,2 Helen Ross,1 Dawn Jaroszewski,1 Harshita Paripati.11Mayo Clinic Arizona, Phoenix, AZ; 2Mayo Clinic, Rochester, MN.
Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary disorder with neuroendocrine cell proliferation associated with Lung NET. Optimal diagnostic and treatment strategies have yet to be well defined. Herein, we aim to describe the Mayo Clinic experience with DIPNECH.
Methods: A retrospective analysis was performed of patients diagnosed with DIPNECH within Mayo Clinic between January 2000-Febuary 2019. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, disease characteristics, time of diagnosis, surgery, and last follow up date were extracted. Extent of symptom burden, treatment approaches, disease progression, and disease-free survival (DFS) were evaluated by chart review.
Results: A total of 59 patients were identified with a median age of 63 (43-81) years. The cohort was predominantly female (93.2%) and non-smoking (76.3%). Most patients (86.4%) had symptomatic disease with chronic cough being the most common (71.2%) followed by exertional dyspnea (44.1%). Imaging typically showed bilateral lung nodules (93.2%) with mosaic attenuation noted 69.5% of the time. Surgical resection was frequently completed to confirm diagnosis (94.9%). Most patients received inhaled glucocorticoids combined with a beta agonist (79.7%). Oral steroid use was seen in 49.2% of patients whereas a somatostatin analog was used in 15.3% following the diagnosis of DIPNECH. These medical interventions led to symptom relief in 23.7% of the patients. The median follow up for all patients was 19.5 months. Progression of tumorlets was seen in 48.7% of patients with only 7 (17.9%) patients progressing to a diagnosis of carcinoid tumor. The 3-year DFS was 90.5%.
Conclusion: DIPNECH remains a rare disease more commonly diagnosed in women in their early 60’s. DIPNECH appears to have an indolent course with obstructive symptoms being the most common finding. Overall, DIPNECH appears to have a low risk of progressing to carcinoid tumors based on the observation of this study.
Somatostatin Analog Use in Patients With Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)
Taymeyah Al-Toubah, Mintallah Haider, Jonathan Strosberg. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Background: Diffuse idiopathic pulmonary neuroendocrine cell neoplasia (DIPNECH) is a rare pulmonary condition, characterized by the diffuse proliferation of neuroendocrine cells in the respiratory epithelium. Patients typically present with cough and dyspnea. A diagnosis of DIPNECH is not usually associated with malignant behavior but can be diagnosed in patients with multifocal bronchial neuroendocrine tumors. There are limited data on the management and treatment of DIPNECH; however a few case studies have noted that somatostatin analogs (SSA) may control symptoms.
Methods: We retrospectively reviewed the records of patients treated at a large referral center evaluated between 1/2008 and 9/2018 with a clinical and/or pathological diagnosis of DIPNECH who received treatment with a SSA.
Results: 26 patients were identified, all of whom were female with radiographic (CT) and pathologic confirmation of disease (69% surgical, 31% biopsy). Median age was 60 years (44–78), 7 (27%) had a history of smoking and all symptomatic at baseline with cough, dyspnea, wheezing, and/or palpitations. Patients presented with a history of symptoms ranging from 6 months–40 years, with the majority being less than 5 years (38%) at diagnosis. Median duration of SSA (lanreotide LAR or octreotide LAR) was 17 months (1–145 months). 54% of patients experienced no toxicity with SSA, and the 46% who did, experienced diarrhea, cramping and abdominal pain. 2 patients developed gallstones requiring discontinuation of SSA. 38% of patients did not require additional supportive medications for symptoms; the remainder of patients most frequently also used a steroid inhaler. 21 patients (81%) experienced improvement in their symptoms (10 mildly, 2 moderately, 9 significantly).
Conclusion: SSAs can be used in patients with DIPNECH to control clinical symptoms, and result in palliation in the majority of cases. Further research is warranted in this subset of patients.
Capecitabine and Temozolomide in Advanced Lung Neuroendocrine Neoplasms
Taymeyah Al-Toubah, Brian Morse, Jonathan Strosberg. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Background: Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently demonstrated significant activity in patients with pancreatic NETs, but data in lung NETs are limited.
Methods: We retrospectively reviewed the records of patients treated at a large referral center to identify patients seen between 1/2008 and 9/2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Small cell lung cancer patients were excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression free survival, overall survival, and toxicity.
Results: 20 patients were identified who received treatment with capecitabine/temozolomide. 14 (70%) were typical lung NETs, 5 (25%) atypical carcinoids, and 1 (5%) was defined as a large cell neuroendocrine carcinoma. 19 were evaluable for response. 6 (30%) patients exhibited a best response of PR per RECIST 1.1 criteria, 11 (55%) SD, and 2 (10%) PD; ORR was 30% and DCR was 85%. Median PFS was 13 months (95% CI, 4.4–21.6 months). Median OS was 68 months (95% CI, 35.3–100.7 months). Toxicity profile was mild with mainly grade 1, expected toxicities. 6 patients required dose reduction due to toxicity.
Conclusion: The CAPTEM regimen is associated with a high response rate and a relatively tolerable toxicity profile in lung NENs. This regimen warrants further exploration in a prospective clinical trial.
Primary Neuroendocrine Neoplasms of the Kidney, a Distinct Entity but Classifiable-Like the Gastroenteropancreatic Neuroendocrine Neoplasms
Manik Amin,1 Deyali Chatterjee.21Washington University in St Louis, St Louis, MO; 2Washington University School of Medicine, St Louis, MO.
Background: Primary neuroendocrine neoplasms of the kidney are a distinct and rare entity, but classifiable-like the gastroenteropancreatic neuroendocrine neoplasms. Due to rarity of these tumors, not much is known about histopathology and behaviors of these tumors. We attempted to review pathology of primary kidney neuroendocrine tumor patients at our institution.
Methods: Retrospective chart review identified 8 primary kidney neuroendocrine tumors from Siteman Cancer Registry database from 1/1/2000 until 1/1/2018. Pathology review was done for all the patients to confirm their diagnosis and other pathological features.
Results: In our cohort, we identified eight cases of neuroendocrine neoplasms of the kidney. Three of the cases were poorly differentiated neuroendocrine carcinoma. All cases of well-differentiated neuroendocrine tumor (either grade 1 or grade 2) were identified in females (age range, 44–60). All the tumors characteristically extended to the perirenal fat. These tumors showed diffuse positivity for synaptophysin, variable positivity for chromogranin, and did not stain for markers specific for renal differentiation (PAX-8). The growth pattern in well differentiated neuroendocrine tumors is predominantly trabeculated, but a diffuse plasmacytoid growth is also noted, which is unusual in gastroenteropancreatic neuroendocrine neoplasms. Two patients had primary tumor measuring 9 cm and 14 cm respectively also presented with positive lymph nodes and lymphovascular invasion developed metastatic disease in 2 years.
Conclusion: Primary kidney neuroendocrine tumors are very rare. These tumors also do not stain for markers-like renal cell carcinoma (negative for WT-1, AMACR). The growth pattern in well differentiated neuroendocrine tumors is predominantly trabeculated, but a diffuse plasmacytoid growth is also noted, which is unusual in gastroenteropancreatic neuroendocrine neoplasms.
Understanding the Treatment Preferences of Neuroendocrine Tumor Patients Using Discrete Choice Experiments
Matthew Anaka,1 David Chan,2 Sharon Pattison,3 Alia Thawer,4 Bryan Franco,5 Lesley Moody,4 Christopher Jackson,3 Eva Segelov,6 Simron Singh.41University of Alberta, Edmonton, Canada; 2University of Sydney, Sydney, Australia; 3University of Otago, Dunedin, New Zealand; 4Sunnybrook Health Sciences Centre, Toronto, Canada; 5Queen's University, Toronto, Canada; 6Monash University, Melbourne, Australia.
Background: Neuroendocrine tumors (NETs) are a diverse group of rare malignancies, with significant heterogeneity in terms of prognosis, symptom burden, and impact on quality of life. There is little published information on NET patient preferences and priorities in regards to medical management. Improved understanding of the perspectives and values of the NET patient population in regards to available treatments would facilitate patient-centered care.
Methods: We designed three discrete choice experiments (DCE) which model clinical scenarios where advanced NET patients have several treatment options. The DCEs employ the ‘potentially all pairwise rankings of all possible alternatives’ (PAPRIKA) method as implemented in the 1000minds platform. Data from the randomized clinical trials that support the use of different medical treatments was used to generate the content for the DCE attributes. The online DCEs surveys were trialed in a pilot study as a test of technical issues and face validity, which were assessed through semi-structured interviews.
Results: Based on semi-structured interviews, the DCEs achieved face validity, as they included treatment attributes identified as important by the participants. Participants expressed concern with the length of the DCEs, and on apparent redundancy of the choices between the clinical scenarios. The participant-level partial worth utility data revealed variable willingness to trade off factors like progression free survival (PFS) for side effects rates and method of treatment administration, and variable preference for attribute profiles matching specific treatments for advanced NETs.
Conclusion: We developed and piloted a series of DCEs that model preferences for NET treatment. Preliminary results indicate that patients place variable importance on factors like PFS, and preference for profile matching specific treatments. The DCEs are currently being refined based on feedback from the pilot study, with plans to begin participant recruitment at sites in Canada, Australia, and New Zealand.
Association Between Preoperative Vasostatin-1 and Pathological Features of Aggressiveness in Localized Nonfunctioning Pancreatic Neuroendocrine Tumors (NF-PanNET)
Valentina Andreasi, Stefano Partelli, Marco Manzoni, Francesca Muffatti, Barbara Colombo, Angelo Corti, Massimo Falconi. San Raffaele Scientific Institute, Milan, Italy.
Background: A reliable and accessible biomarker for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) is currently unavailable. Chromogranin A (CgA) represents the best-described neuroendocrine biomarker, but its accuracy is low. Vasostatin-1 (VS-1), a fragment derived from the cleavage of CgA, was recently investigated and found to be more accurate as tumor biomarker in a cohort of patients affected by mainly metastatic small intestinal NET. Aim of the present study was to assess a possible association between preoperative VS-1 plasma levels and pathological features of aggressiveness, in comparison to CgA, in a cohort of patients affected by sporadic localized NF-PanNET.
Methods: Patients submitted to surgery for sporadic localized NF-PanNET at San Raffaele Hospital were included in the study. Preoperative plasma samples were prospectively collected from May 2015. Circulating levels of total-CgA and VS-1 were retrospectively investigated by sandwich Enzyme-Linked ImmunoSorbent Assays (ELISA).
Results: Overall, 50 patients were included. VS-1 value (P = 0.0001) was the only preoperatively retrievable factor independently associated with NF-PanNET size. No significant correlation between CgA and tumor diameter was found (P = 0.057). A VS-1 value of 0.39 nM was identified as the optimal VS-1 cut-off accurately associated with NF-PanNET larger than 4 cm, with a sensitivity of 80% and a specificity of 80%. Patients with VS-1 >0.39 nM had a significantly higher frequency of microvascular invasion (P = 0.005) and nodal metastases (P = 0.027). Median VS-1 plasma level was significantly higher in the presence of microvascular invasion (P = 0.001) and nodal metastases (P = 0.012). Proton pump inhibitors (PPI) assumption significantly increased total-CgA levels, but not those of VS-1 (P = 0.111). No significant correlation was found between total-CgA and VS-1 (P = 0.119).
Conclusion: In localized, non-metastatic NF-PanNET, VS-1 is strongly associated to tumor dimension and its plasma levels are significantly higher in the presence of microvascular invasion and nodal metastases; moreover, VS-1 value is not affected by the use of PPI.
Management of Small Asymptomatic Nonfunctioning Pancreatic Neuroendocrine Tumors: Limitations to Apply Guidelines Into Real Life
Valentina Andreasi, Stefano Partelli, Michele Mazza, Francesca Muffatti, Stefano Crippa, Domenico Tamburrino, Massimo Falconi. San Raffaele Scientific Institute, Milan, Italy.
Background: International guidelines suggest a watchful strategy for small nonfunctioning pancreatic neuroendocrine tumors. The aim of this study was to evaluate the management and indications for surgery in patients with asymptomatic nonfunctioning pancreatic neuroendocrine tumors ≤2 cm.
Methods: Patients with asymptomatic, incidental, sporadic nonfunctioning pancreatic neuroendocrine tumors ≤2 cm without nodal or distant metastases were included (2012–2016). A comparison between active surveillance and surgery groups was performed.
Results: Of the 101 included patients, 72% underwent active surveillance and 28% were surgically treated. Patients submitted to surgery were significantly younger (53 vs 60 years, P = 0.013), had a higher incidence of positive 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) (18% vs 50%, P = 0.003), and a higher incidence of cytologically determined G2 tumor (0% vs 14%, P = 0.008). Conservatively managed patients had a significantly smaller tumor size (12 vs 16 mm, P = 0.0001). The main reasons determining the surgical choice were as follows: patient's preference (32%), positive 18F-FDG PET (21.5%), main pancreatic duct dilation (17.5%), cytologically determined G2 tumor (14.5%), and young age (14.5%). At a median follow-up of 40 months, all of the 73 patients conservatively managed were alive, with no evidence of distant metastases and none underwent surgery. Only 5 patients had a tumor growth >20%.
Conclusion: One third of patients with asymptomatic small nonfunctioning pancreatic neuroendocrine tumors ≤2 cm underwent surgery. Patient's preference, initial tumor size and young age were the main determinants of surgical indication. Preoperative diagnostic workup, including 18F-FDG PET and cytologic grading seem to be poorly accurate in determining malignant features in these small lesions.
Antitumor Efficacy of Concurrent Everolimus With Hepatic Transarterial Bland Embolization (Evero-Embo) in Patients With Metastatic Well Differentiated Neuroendocrine Tumor (NET)
Lowell Anthony, Gaby Gabriel, Riham El Khouli, Aman Chauhan. Markey Cancer Center University of Kentucky, Lexington, KY.
Background: Hepatic transarterial embolization (TAE) is effective loco-regional therapy for neuroendocrine tumor (NET). Systemic targeted therapies, such as everolimus & sunitinib, are typically held 2–4 weeks prior to and after procedures. The safety of evero-embo has been previously reported (GI-ASCO). TAE induces anoxic injury while everolimus effects cell growth, proliferation and survival. Combining these two modalities may result in clinical synthetic lethality effectively debulking significant hepatic disease and/or delaying progression. Historically bland TAE has a median hepatic progression-free survival of ~nine months. In this study, the clinical efficacy of evero-embo is examined.
Methods: Clinical and radiographic data were reviewed for all sequential patients who underwent evero-embo between 9/2016 and 4/2018 at the University of Kentucky Markey Cancer Center. An independent radiologist performed response evaluation criteria in solid tumors (RECIST) measurements. To be included in this study, patients were required to have had systemic everolimus for ≥one month prior to embolization and to be on everolimus immediately post procedure. Patients with at least 12 months post procedure follow-up were included for efficacy review.
Results: Fifty-one TAEs with concurrent systemic everolimus were performed in 34 NET patients. Twenty-one of 24 patients were noted to have a partial response; the remainder had stable disease. Hepatic progression was not observed. Twenty-one of the 34 patients had 12 or more months of follow-up post procedure (median of 17 months). None of these 21 patients had hepatic progression.
Conclusion: Evero-embo results in a partial response rate of 62% and may have significant antitumor activity when compared to bland TAE in NET patients. With a median follow-up of 17 months, hepatic progression has not occurred in any patient. Additional follow-up is necessary to compare the median hepatic progression free survival (PFS) of evero-embo to the historical drug-eluting bead TAE PFS.
ISL-1 Expression as a Potential Prognostic Factor in Patients With Well-Differentiated Pancreatic Neuroendocrine Tumors
Hussein Assi, Kar-Ming Fung, Hassan Hatoum. University of Oklahoma Health Sciences Center - Stephenson Cancer Center, Oklahoma City, OK.
Background: ISL1 is a transcription factor that is expressed in about 77% of well-differentiated pancreatic neuroendocrine tumors (WD-PanNETs). ISL1 has been shown to be implicated in the tumorigenesis of several cancers. Its potential use as a predictor of outcome in WD-PanNETs remains unknown. Our study aim is to evaluate the prognostic implications of the expression of the transcription factor ISL1 in patients with WD-PanNETs. We hypothesize that high expression of ISL-1 in WD-PanNETs confers worse outcome.
Methods: We retrospectively reviewed 37 patients with biopsy-proven WD-PanNETs treated at the Stephenson Cancer Center between 2013–2018. Grade 3 tumors were excluded. Patient’s clinicopathologic characteristics and survival data were analyzed using frequency statistics and Kaplan-Meier curves. Archived tissue blocks from pancreatic tumor samples will be used for immunohistochemistry. Staining with ISL1 antibody will be done per standard staining protocol. A nuclear staining intensity of at least 1+ in at least 5% of tumor cells will be considered positive. The objective of the study is to compare the outcome of patients with WD-PanNETs according to ISL1 expression.
Results: Out of 37 patients, 16 (43.2%) had grade 1 tumor, 17 (45.9%) had grade 2 tumor, with the rest being unknown grade. Fifty-seven percent were males. Median age at diagnosis was 60 (33–78) years. Stage distribution included 9 (25.7%), 10 (28.6%), 5 (14.3%) and 11 (31.4%) patients with stages 1, 2, 3 and 4, respectively. Median follow-up was 37 months. Progression of disease occurred in 12/37 (32.4%) patients. Overall, the 3-year progression-free survival was 66.8%. Median time to progression was 9.8 months. ISL-1 staining of tissue specimens is in progress.
Conclusion: To our knowledge, this is the first study to correlate ISL1 expression with disease and survival outcomes in patients with WD-PanNETs. ISL-1 staining could potentially be used in clinical practice to dictate appropriate management strategies.
Imipridone ONC201 Blocks Tumor Growth by Inhibiting RET/IGFBP2 Pathway in Medullary Thyroid Cancer
Rozita Bagheri-Yarmand,1 Rohinton Tarapore,2 Joshua Allen,2 Steven Sherman,1 Robert Gagel.11The University of Texas MD Anderson Cancer Center, Houston, TX; 2Oncoceutics Inc., Philadelphia, PA.
Background: Medullary thyroid carcinomas (MTC) is a neuroendocrine tumor arising from the calcitonin-secreting C cells. RET tyrosine kinase receptor is a driver oncogene and frequently mutated in MTC. Activating mutation of RET prevents apoptosis through inhibition of ATF4, a transcriptional regulator of endoplasmic reticulum (ER) stress. While tyrosine kinase inhibitors (TKIs) can delay progression, the responses to these agents are incomplete. Innovative drugs are needed that are effective against refractory MTC. ONC201 is a first-in class small molecule with favorable safety profile that activates p53-independent apoptosis through induction of ATF4.
Methods: MTC cells were treated with ONC201 and cell viability was measured by colorimetric assay and cleaved caspase3/PARP staining followed by flow cytometry. MTC xenografts were treated with ONC201 at a weekly dose of 120 mg/kg for 8 weeks. Real-time RT-PCR, western blot, and immunohistochemistry were used to examine mRNA and protein levels.
Results: Here, we report that ONC201 caused apoptosis in MTC cells and abrogated MTC tumor growth in mice without toxicity. ONC201 Induced mRNA levels of apoptotic genes, including ATF4, DDIT3 (CHOP), and BBC3. ONC201 also inhibited RET expression at both mRNA and protein levels. Functional proteomic identified IGFBP2 as a RET target that is known to promote survival, metastasis, and resistance to MAPK inhibitors. The treatment of MTC cells with ONC201 or ATF4 overexpression downregulated IGFBP2 mRNA and protein levels and decreased the secretion of IGFBP2 into the conditioned media. Immunohistochemical and western blot analysis of MTC xenografts demonstrated decreased IGFBP2 protein levels in mice treated with ONC201 that was associated with decreased proliferation. The combination of ONC201 with TKIs inhibited cell survival in a synergistic manner.
Conclusion: These results demonstrate that ONC201 inhibits RET-mediated signaling and support the further investigation of ONC201 as a therapeutic agent for the treatment of MTC alone or in combination with thyrosine kinase inhibitors.
Real-World Effectiveness of Telotristat Ethyl Among Patients With Mild Baseline Diarrhea
Al Benson,1 Vijay Joish,2 Sam Dharba,2 Pablo Lapuerta,2 Dipa Sapre,2 Jonathan Strosberg.31Feinberg School of Medicine, Northwestern University, Chicago, IL; 2Lexicon Pharmaceuticals, Inc., The Woodlands, TX; 3Moffitt Cancer Center, Tampa, FL.
Background: Clinical trials demonstrated the efficacy of telotristat ethyl (TE) in patients with carcinoid syndrome (CS) with ≥4 and <4 daily bowel movements (BM).This subgroup analysis of the TELEPRO study evaluated the real-world effectiveness of TE in patients reporting <4 daily BM at baseline.
Methods: Design and methodology of TELEPRO have been published elsewhere. Patients initiating TE between March–November 2017 who participated in a nurse support program collecting symptom-related data at initiation and at least one follow-up month up to 3 months were included. Pre/post t-tests assessed CS symptom changes from TE initiation through 3 months in a subgroup of patients reporting <4 BM/day at TE initiation using last observation carried forward for missing values.
Results: Approximately 20% (n = 68) of patients participating in the nurse support program reported <4 BM/day at baseline. Demographic and clinical characteristics were similar between patients reporting <4 and ≥4 daily BM, respectively: 50% and 57% female; 6.0 and 5.5 mean years since CS diagnosis; 68% and 64% receiving long-acting somatostatin analog (SSA) therapy but three times higher SSA rescue use (18% vs 6%). CS symptom burden at baseline in patients with <4 BM/day were as follows: BM/day (2.4 ± 0.7) mean urgency (28.7 ± 33.2), stool consistency (5.5 ± 1.8), abdominal pain (22.5 ± 26.6), nausea severity (50.7 ± 28.4), flushing episodes/day (3.6 ± 4.3). At the end of Month 3, patients experienced significant (P < 0.05) improvements in urgency (-13.2), stool consistency (-1.3), abdominal pain (-13.7), nausea (-30.9), and flushing episodes/day (-1.7). Improvements in mean BM/day frequency from baseline were minimal (-0.2, P = 0.12), however 30% (n = 21) of patients reported ≥30% reduction, a meaningful reduction to patients reported elsewhere.
Conclusion: Patients with mild CS diarrhea exhibited improvements in CS symptoms from treatment with TE. Addressing the burden of CS diarrhea beyond BM frequency such as stool consistency and urgency including other concomitant CS symptoms may be warranted.
Randomized Phase II Trial of Pazopanib Versus Placebo in Patients (Pts) With Progressive Carcinoid Tumors (CARC) (Alliance A021202)
Emily Bergsland,1 Michelle Mahoney,2 Tim Asmis,3 Nathan Hall,4 Priya Kumthekar,5 Michael Maitland,6 Donna Neidzwiecki,7 Andrew Nixon,7 Eileen O'Reilly,8 Lawrence Schwartz,9 Jeff Sloan,2 Jonathan Strosberg,10 Jeff Meyerhardt.111University of California, San Francisco, San Francisco, CA; 2Mayo University, Rochester, MN; 3University of Ottawa, Ottawa, Canada; 4University of Pennsylvania, Philadelphia, PA; 5Northwestern University, Chicago, IL; 6Inova Center for Personalized Health and University of Virginia, Fairfax, VA; 7Duke University, Durham, NC; 8Memorial Sloan Kettering Cancer Center, New York, NY; 9Columbia University Medical Center, New York, NY; 10Moffitt Cancer Center, Tampa, FL; 11Dana Farber Cancer Institute, Boston, MA.
Background: Pts with progressive CARC have limited treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor (VEGFR-2,-3, PDGFR-a, and b, and c-KIT) with initial data suggesting efficacy in CARC.
Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive low-intermediate grade CARC with radiologic progressive disease (PD) <12 months (mo). Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint-progression-free survival (PFS). Secondary endpoints-overall survival (OS), objective response rate (ORR) and safety. Trial had 85% power to detect a difference in median PFS 14 v 9 mo (hazard ratio [HR], 0.64) at 1-sided alpha=0.1. Stratified log-rank test based on intention-to-treat (ITT) principle used. Unblinding and crossover allowed if PD confirmed by central review.
Results: 171 (97 PZ, 74 PL) pts randomized 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up 44 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS 11.6 in PZ and 8.5 mo in PL (HR, 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, P = 0.0005), crossing pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS 41 and 42 mo in PZ and PL, respectively (HR, 1.13, 1-sided 90% UCL 1.51, P = 0.70). Notable treatment-related grade 3+ adverse events (PZ vs PL %): hypertension (27 vs 4), fatigue (8 vs 3), ALT (9 vs 0), AST (9 vs 0), and diarrhea (5 vs 4).
Conclusion: PZ compared to PL associated with significant improvement in PFS in patients with progressive CARC. The results confirm VEGF signaling pathway is a valid target for therapy in CARC, but the potential benefit of PZ needs to be considered in the context of the risk of toxicity. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org
Tumor Growth Rate (TGR) to Monitor Growth/Predict Response to Lanreotide Autogel Use Before, During and After PRRT in Advanced GEP-NETS: Data From the PRELUDE Study
Lisa Bodei,1 Raj Srirajaskanthan,2 Chiara Maria Grana,3 Sergio Baldari,4 Tahir Shah,5 Angela Lamarca,6 Frédéric Courbon,7 Klemens Scheidhauer,8 Eric Baudin,9 Gustave Roussy,9 Xuan-Mai Truong Thanh,9 Aude Houchard,9 Vikas Prasad.101Memorial Sloan Kettering Cancer Center, New York, NY; 2Kings College Hospital, London, United Kingdom; 3IRCCS European Institute of Oncology, Milan, Italy; 4University of Messina, Messina, Italy; 5Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 6The Christie NHS Foundation Trust, Manchester, United Kingdom; 7IUCT-Oncopole, Toulouse, France; 8Technical University Muenchen, Klinikum r.d. Isar, Munich, Germany; 9Ipsen, Boulougne-Billancourt, France; 10Universitätsklinikum Ulm, Ulm, Germany.
Background: 177Lu-DOTATATE is licensed for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). PRELUDE (NCT02788578) is the first international multicenter retrospective study with central radiology reading to describe lanreotide autogel (LAN) with and after 177Lu–peptide receptor radionuclide therapy (PRRT; LAN–PRRT) in advanced NETs. We report effectiveness data and post hoc analyses of TGR as a growth measure/predictive factor of LAN–PRRT response.
Methods: PRELUDE was a retrospective, non-comparative study that analyzed the medical records of patients receiving LAN and 177Lu-DOTATATE/TOC then LAN only. Patients had metastatic/locally advanced G1/2 somatostatin receptor-positive GEP/lung NET; progressive disease on two scans 6 and 12 months before LAN–PRRT; ≥1 LAN injection 8 weeks before LAN–PRRT; continuous LAN during LAN–PRRT; cumulative PRRT activity ≥500 mCi. Primary endpoint: progression-free survival (PFS) rate at end of last LAN–PRRT cycle (RECIST1.1 central review). Key secondary endpoint: objective response rate (ORR; RECIST1.1 central review). TGR (%/months from CT/MRI) was assessed post hoc: prebaseline/baseline (T1), baseline/end of last LAN–PRRT cycle (T2), end of last LAN–PRRT cycle/last follow-up (T3). TGR cut-offs predicting ORR for end of last PRRT/last follow-up were derived from ROC curves.
Results: Overall, there were 24/40 enrolled patients in full analysis set (FAS; GEP-NET n = 23, lung-NET n = 1). In the GEP-NET FAS, median LAN exposure was 37 months. PFS rate and ORR: 91.7% [95% CI 53.9;98.8] and 27.3% [13.2;48.2] at last LAN–PRRT cycle; 95.0% [69.5;99.3] and 36.8% [19.1;59.0] at last follow up. Mean [95% CI] TGR: 0.0% [–1.4;1.5] (T1), –1.6% [–2.7;–0.4] (T2), –0.2% [–1.3;0.9] (T3). Based on the Youden index, optimal T1 TGR cut-offs to predict ORR for end of last PRRT/last follow-up derived from ROC curves: 1.18%/0.33% (sensitivity: 0.75/0.83; specificity: 0.80/0.83; area under curve [95%CI]: 0.75 [0.5013–0.9987]/0.82 [0.6108–1.000]).
Conclusion: TGR suggested tumor regression during LAN–PRRT. Objective response at the end/within 12 months after LAN–PRRT was more likely if baseline TGR was ≤1.18%/≤0.33%.
131I MIBG and 90Y DOTATOC in a Dosimetrically Determined Optimal Combination for Personalized Therapy of Selected Patients With Midgut Neuroendocrine Tumors: A First-In-Man Clinical Trial
Kellie Bodeker, David Bushnell, Mark Madsen, Yusuf Menda, Kristin Gaimari-Varner, Stephen Graves, Thomas O'Dorisio, Joseph Dillon, Chandrikha Chandrasekharan. The University of Iowa, Iowa City, IA.
Background: Targeted radiomolecular therapy (TRT) is effective for metastatic neuroendocrine tumors (NETs). Delivering sufficient tumor radiation dose remains challenging due to the critical organ dose-limitations. 131I MIBG targets approximately 50-60% of midgut NETs, with bone marrow the critical organ. In contrast, the critical organ for 90Y DOTATOC is the kidney. We previously demonstrated this difference can be exploited by combining these agents into a single treatment regimen to yield higher total tumor radiation dose without exceeding critical organ dose limits.
Methods: A first-in-man clinical trial was initiated at University of Iowa (NCT03044977) for patients with non-operable progressive NET. Escalation schema employs organ limiting dose cohorts for marrow and kidneys utilizing a standard 3 × 3 design. Follow-up measures include eGFR, urine protein as well as neutrophil and platelet counts. Tumor targeting and dosimetric evaluation (imaging and blood sampling) were performed prior to therapy using combination administration of 6 mCi of 111In-pentetreotide (as a biodistribution surrogate for 90Y DOTATOC) plus 2.0 mCi of 131I-MIBG. These results were used to determine therapeutic administered activity levels of 90Y DOTATOC plus 131I-MIBG delivered over 2 cycles.
Results: The first dose cohort reported here treated subjects to 1900 cGy kidney and 150 cGy bone marrow. Total administered activities of 90Y DOTATOC and 131I-MIBG are provided (Table 1). Tumor dosimetry estimates from four well defined (CT) liver tumors from subject 1 are shown (Table 1). Dose limiting toxicity has not occurred; thus, dose will be escalated to organ constraints of 2300 cGy kidney and 200 cGy bone marrow.
Conclusion: Initial treatment in this first-in-man study demonstrates the feasibility of using forward-planned dosimetry for a phase 1 escalation trial and suggests the safety of combinatorial TRT for neuroendocrine tumor using 90Y DOTATOC and 131I-MIBG for the initial cohort. The trial remains active.
Lutetium 177-DOTATATE Therapy in Progressive Metastatic Well-Differentiated G1/G2 Neuroendocrine Tumors: Review of the University of Kentucky’s Post-FDA Approval PRRT Program
Charles Andrew Chacko,1 Aman Chauhan,1 Riham El Khouli,2 Lowell Anthony.11Markey Cancer Center University of Kentucky, Lexington, KY; 2University of Kentucky, Lexington, KY.
Background: The US FDA approved peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE in January 2018. Clinical experience/data, although deficient, are emerging.
Methods: We retrospectively reviewed patient medical records who began PRRT 5/2018-6/2019 at the University of Kentucky. 177Lu-DOTATATE was administered at dose 200 mCi over 30 minutes every 8 weeks for 4 doses. An amino acid solution containing Arginine HCL 2.5%/Lysine HCL 2.5% in one-liter NS, infused over 4 hours, 30 minutes prior to radiotherapy treatment, was given with 16mg ondansetron ODT.
Results: Twenty-nine patients received at least 1 of 4 doses, 19/29 completed dose 2, 8/29 completed dose 3, and 1/29 completed all 4 doses. 5/29 (17%) were deceased after dose 1. Currently five patients are not due for dose 2, ten for dose 3, and seven for dose 4. 8/19 were evaluable for radiological responses via NM Tumor Total Body Scan (Luta-Scan). Categorically, 14/29 (48%) had GI NET, 8/29 (28%) pNET (pancreatic), 4/29 (14%) tNET (thoracic), and 3/29 (10%) uNET (unknown primary). Furthermore, 28% had G1 disease, 41% G2, and 31% (9/29) were uncategorized (lacking Ki-67). 17/29 (59%) had received 2 prior non-somatostatin analog systemic therapies and 41% had 1 prior liver-directed therapy. Follow-up after dose 4 was 21 days. Clinical/Luta-Scan response was 63% (5/8) for those completing at least 3 PRRT doses. 14/19 (74%) had stable disease and 1/19 had Luta-Scan progression. Grade 1/2 adverse events (AEs) included fatigue, nausea, edema, and thrombocytopenia. Grade 3/4 AEs prompting treatment discontinuation included generalized weakness (1/29) and thrombocytopenia (1/29). All AE Grade 3/4 patients had baseline progressive disease and ≥3 prior lines of treatment.
Conclusion: Our PRRT experience with 177Lu-DOTATATE has been well-tolerated and effective in the ongoing treatment of progressive metastatic well-differentiated G1/G2 NET. Our results, although limited and ongoing, include a broader spectrum of patients than NETTER-1 and include interim Luta-Scan response data.
Antitumor Efficacy of M3814 as a Radiation Sensitizer in Neuroendocrine Tumor (NET) Preclinical Models
Aman Chauhan,1 Piotr Rychahou,1 Tadahide Izumi,1 John Wu,1 Lowell Anthony,2 Mark Evers,1 Charles Kunos.31University of Kentucky, Lexington, KY; 2Markey Cancer Center University of Kentucky, Lexington, KY; 3NCI CTEP, Rockville, MD.
Background: M3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of Ionizing Radiation (IR) in various solid tumor in-vivo models. M3814 inhibits DNA damage repair mechanisms. Currently antitumor efficacy of M3814 in NETs is unknown.
Methods: The efficacy of M3814 in combination with external beam radiation (IR) was evaluated in the QGP and BON in vitro cell line model as well as QGP (pancreatic NET cell line xenograft) mouse model. Tumor cells were injected s.c. into athymic nude mice for incubation. They were harvested once they attained a large size, they were then dissected and re-implanted into athymic mice. This was done so that the implanted tumor tissue was of equal size. Treatment started when palpable tumors were established (200-300 mm3). M3814 was given orally 30 minutes prior to irradiation. Each mouse was irradiated with 2 gray fractions for 4 consecutive days. IR was applied using a radiation therapy device for small rodents calibrated to deliver 2 Gy. Mice were randomized into 4 groups; XRT alone, M3814 alone, Placebo and XRT+M3814 combination.
Results: Both XRT and XRT+M3814 group showed anti-tumor activity, however, the combination group showed marked anti-tumor activity at both 2 and 3 weeks post-treatment. Of note, the tumors treated with XRT+M3814 were also visibly less vascular as compared to XRT alone and placebo. M3814 alone had no effect on tumor as expected. Both XRT and XRT+M3814 groups noted post-treatment decline in the mice weight, however, weight change was similar between XRT and XRT+M3814 groups.
Conclusion: M3814 is a potential radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in BON and QGP in vitro clonogenic assay and QGP xenograft in vivo model with marked reduction of tumor growth on application of 2-Gy fractions for 4 days with oral M3814.
Clinical Efficacy and Toxicity Data on Phase 1 Study of Fosbretabulin in Combination With Everolimus in Neuroendocrine Tumors
Aman Chauhan,1 Susanne Arnold,1 John Wu,1 Rashmi Nair,1 Stacey Slone,1 Emily Dressler,2 Heather Flynn,1 Val Adams,1 Heidi Weiss,1 Mark Evers,1 Lowell Anthony.31University of Kentucky, Lexington, KY; 2Wake Forest University, Winston-Salem, NC; 3Markey Cancer Center University of Kentucky, Lexington, KY.
Background: Fosbretabulin, a synthetic, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), is the lead compound in a class of agents termed vascular disrupting agents (VDAs) and has shown activity as a single agent in ovarian cancer and GEPNETs. Everolimus, an mTOR inhibitor, is FDA approved for the management of NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D) in metastatic GEPNET patients was conducted.
Methods: Single center, phase I study involving GEPNETs incorporated a partial order continual reassessment method (PO-CRM) to define the dose escalation. Primary objective was to establish the maximum tolerated dose (MTD) in NETs that have progressed after at least one prior regimen for metastatic disease. The secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 months.
Results: Of the 17 patients enrolled, 16 were evaluable. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60 mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients that include increased abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). All evaluable patients except one had stable disease at 3 months. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting.
Conclusion: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. ClinicalTrials.gov Identifier: NCT0301429
A Phase 2 Study Evaluating a Proprietary Amino Acid Based Medical Food (Enterade) in Patients With Quality of Life Limiting Diarrhea Due to Carcinoid Syndrome and Other Neuroendocrine Tumors
Aman Chauhan,1 Mark Evers,2 Heidi Weiss,1 Val Adams,1 Jill Kolesar,1 Donald Cohen,1 Susanne Arnold,1 Lowell Anthony.21University of Kentucky, Lexington, KY; 2Markey Cancer Center University of Kentucky, Lexington, KY.
Background: Diarrhea in neuroendocrine tumor (NET) patients is a major symptom that severely affects the quality of life. Enterade is an amino acid based oral rehydration solution which has been shown to restore intestinal villi and decrease secretory diarrhea and has also shown to improve survival and body weight in preclinical mice model. Retrospective data from NET patients presented at GI ASCO (2018) suggests antidiarrheal clinical activity in NET patients.
Methods: This is an investigator-initiated, single center, open label, phase II study involving well differentiated neuroendocrine tumors with quality of life limiting diarrhea (4 or more stools/day). Two distinct subject cohorts (carcinoid syndrome diarrhea and non-carcinoid syndrome diarrhea) will be enrolled. The primary endpoint is a reduction in the frequency of diarrhea for individual subjects before and after enterade®. Subjects will maintain a daily stool diary. The mean of daily stool frequency between Day 1 and 28 will be considered baseline. The diarrheal frequency of each patient will be compared to their own baseline during the observation period. On day 29 (±3 days), subjects will start enterade® BID for 28 days (D29–D56). On Day 57 ± 3 days) subject will return to clinic for assessment of response. Based on a prior published study (Kulke et al), we will assume that the mean daily reduction in Bowel Movements from baseline is equal to 1.5 (SD of change = 1.5) representing a large effect size = 1.0. A sample of 12 subjects in each cohort will provide over 90% power in detecting this effect size based on a two-sided paired t-test with % significance level. Additional 3 subjects will be added to each cohort to account for potential dropouts. Final sample size will be 15 subjects for each cohort.
Results: Trial is currently accruing.
Conclusion:ClinicalTrials.gov Identifier: NCT03722511
TACE or TARE? Chronic Hepatotoxicity in Patients With Metastatic Neuroendocrine Tumor
Brian Currie, Gregory Nadolski, Jeffrey Mondschein, Mandeep Dagli, Deepak Sudheendra, S. William Stavropoulos, Michael Soulen. Hospital of the University of Pennsylvania, Philadelphia, PA.
Background: The understanding of long-term hepatotoxicity from transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) is evolving. We compared the manifestations of liver injury following TACE and TARE in patients with neuroendocrine tumor (NET).
Methods: IRB-approved single-institution retrospective analysis of all NET patients receiving TACE from 2006-2016 and TARE from 2005-2014 and surviving at least one year from the initial treatment. Patients receiving only TACE (n = 63) or TARE (n = 28) were evaluated for the presence or absence of durable hepatic toxicities occurring at least 6 months after the initial treatment. The definition and grading of liver injury was adapted from the Common Terminology Criteria for Adverse Events Version 4.0 and was characterized by the presence of Grade 3 or above laboratory or clinical toxicities.
Results: Chronic hepatic toxicity occurred in 22% (14/63) of TACE patients with a total of 26 Grade 3-4 events, with elevation of bilirubin being the most common, compared to 29% (8/28) of TARE patients with 16 Grade 3-4 and 2 Grade 5 events, with ascites being the most frequent. There were more laboratory toxicities in the TACE group (65% vs 38% of recorded toxicities, P = 0.11) and fewer Grade 4-5 injuries (6% vs 27% of patients, P = 0.06). There were no significant differences in the number of patients receiving hepatotoxic chemotherapy (6% vs. 7%, P > 0.99), but patients undergoing TACE received more treatments (2.5 vs 2, P = 0.07). There was also a significantly higher number of patients experiencing intrahepatic progression of disease in the TACE cohort compared to TARE (75% vs. 43%, P = 0.005).
Conclusion: Delayed hepatotoxicity from TACE and TARE occurred in 22% and 29% of patients, respectively, 6 months to several years following treatment. TACE-related toxicities on average were less severe and manifested primarily as laboratory derangements, compared to TARE which consisted of clinical abnormalities.
Satisfaction Survey of Administration Modes for Long-Acting (La) Somatostatin Analog (SSA) Therapy in Patients With Neuroendocrine Tumors (NET)
Christina Darden,1 David Ray,2 Grace Goldstein,3 Diana Goss,1 Diana Garbinsky,1 Lee Bennett,1 Mark Price,1 Ramya Thota.41RTI Health Solutions, Research Triangle Park, NC; 2Ipsen Biopharmaceuticals, Inc., Palisades Park, NJ; 3The Carcinoid Cancer Foundation, Inc., Mt. Kisco, NY; 4Intermountain Medical Center, Salt Lake City, UT.
Background: To describe patient experiences and satisfaction with LA-SSA administration modes in a real-world setting.
Methods: A longitudinal, prospective, web-based survey was conducted among US patients with NET treated with lanreotide depot (lanreotide) or octreotide LAR (octreotide) within the last 5 days. Patients recruited by the Carcinoid Cancer Foundation completed surveys on prior/current experience and satisfaction at baseline, 14 days after injection (D14), and 28 days after injection (D28) but before next injection.
Results: Of 202 patients who completed the baseline survey (82 lanreotide, 120 octreotide), 148 completed D14, and 124 completed D28. Patients reported consistently high satisfaction levels with their most-recent LA-SSA treatment (85.1% [D14]-91.1% [baseline]) and disease control (66.9% [D14]-70.2% [D28]; Table 1). More than 90% of patients would recommend their injection to another patient like themselves, and most reported “good” or “very good” experiences overall with their most recent injection (89.5% [D28]-92.1% [baseline]). At baseline, 55 patients receiving lanreotide (67.1%; 95% CI, 0.57–0.77) reported no pain/difficulty sitting/lying down after their most-recent injection compared with 65 (54.2%; 95% CI, 0.45–0.63) patients receiving octreotide. Over the 28 days, 17.1% (95% CI, 0.09–0.25) to 27.5% (95% CI, 0.15–0.40) of patients receiving lanreotide reported no pain/discomfort at the injection site from their most-recent injection compared with 15.2% (95% CI, 0.08–0.23) to 20.5% (95% CI, 0.11–0.30) of patients receiving octreotide. Nearly 69% (95% CI, 0.62–0.75) said injections differed based on the nursing staff/person administering the injection, and 72.7% (95% CI, 0.65–0.80) of those patients said this was due to varying levels of nurse knowledge of injection processes.
Conclusion: Patients are satisfied with their current LA-SSA treatment and reported positive overall experiences with their most-recent injection; however, this study suggests experiences (i.e., pain) may differ by therapy type and person administering the injection. Nurse training (e.g., injection preparation and process knowledge) impacts the overall patient injection experience.
NETS Arising in a Meckel’s Diverticulum: Do They Behave Differently Than Ileal NETS?
James De Andrade, Andrew Blakely, Andrew Nguyen, Gagandeep Singh, Byrne Lee, Phillip Ituarte. City of Hope, Duarte, CA.
Background: Neuroendocrine tumors (NETs) are the most common primary malignancy of the small intestine, most frequently occurring in the ileum. Meckel’s diverticula contain heterotopic tissues from which NETs may arise and may express differing clinicopathologic behavior
Methods: Patients with NETs located in Meckel’s diverticula (n = 162) and ileum (n = 9486) were reviewed in the National Cancer Database (NCDB) between 2004–2014. Patient and tumor characteristics as well as outcomes were examined.
Results: Patients with Meckel’s diverticula NETs were more likely to be male (72.8% vs 46.4%, P < 0.001) and white (95.1% vs 86.6%, P < 0.001). At diagnosis, patients with Meckel’s NETs were less likely to have lymphovascular invasion (6.5% vs 55.3%, P < 0.001) and clinically diagnosed metastatic disease (2.5% vs. 15.5%, P < 0.001). Well-differentiated tumors occurred similarly in both groups (41.4 vs 49.7, P = 0.12). Patients with Meckel’s and ileal NETs underwent open resection at similar rates (54.6% vs. 60.3%), however, patients with Meckel’s NETs were less likely to have any lymph nodes concurrently removed at surgery (30.4% vs. 85.6%, P < 0.001) and when nodes were removed, were less likely to have evidence of nodal metastasis (52.1% vs 82.7%, P < 0.001). Overall survival was similar between the groups (median not met at 140 months follow up, P = 0.54).
Conclusion: Compared to ileal NETs, NETs of Meckel’s diverticula are more likely to have favorable histopathologic characteristics. Lymphadenectomy is less commonly performed and, while nodal disease is less frequent, it is still present in nearly half of patients. Lymphadenectomy should be performed in these patients for adequate staging.
Does Lymphadenectomy Extent Impact Survival in Small Bowel Neuroendocrine Tumors?
James De Andrade, Andrew Blakely, Andrew Nguyen, Phillip Ituarte, Daneng Li, Byrne Lee, Gagandeep Singh. City of Hope, Duarte, CA.
Background: There are no national guidelines for scale of lymphadenectomy for patients with small bowel neuroendocrine tumors (SB-NETs). Recent studies suggest a minimum of 8 nodes for adequate staging.
Methods: The National Cancer Database (NCDB) was reviewed for the years 2004–2013 for all patients with SB-NETs for whom data on lymphadenectomy and outcomes were present. Comparisons were made between patient groups using t-tests, chi-squared, and Kaplan-Meier method. Ranges of lymphadenectomy were examined to identify thresholds at which a possible survival association may exist.
Results: 19,638 patients met inclusion criteria. 7292 (37%) had 0 lymph nodes (LNs) examined, with 1 LN being the next most frequent number of nodes resected (n = 5704, 29%). 11817 (60%) patients had fewer than 8 LNs resected. Patients with well-differentiated tumors (82% of study population) were less likely to have lymphadenectomy compared to those with non well-differentiated tumors (71% vs 75%, P < 0.001). The mean overall survival for all patients was 103 months, with patients undergoing any lymphadenectomy having a mean survival of 108 months vs 92.6 months for those with no lymphadenectomy (P < 0.001). Using stepwise survival comparison, lymphadenectomy of 1-3 nodes was associated with improved survival compared to 0 nodes resected (P < 0.001). However, comparison of 1–3 vs 4–6 LNs removed (P = 0.147), 4–6 vs 7–9 LNs removed (P = 0.629), and 7–9 vs 10–12 LNs removed (P = 0.962) showed no statistical difference in overall survival. On the other hand, comparison between 10–12 vs 13–15 LNs removed (P = 0.043) and 13–15 vs 16+ LNs removed (P = 0.016) were associated with statistical survival improvement.
Conclusion: 37% of patient with SB-NETs underwent no associated lymphadenectomy. Lymphadenectomy is associated with improved overall survival, with the greatest associations seen for 13 lymph nodes or more resected.
First US Prospective Evaluation of Performance of CU-64 DOTATATE PET/CT in Somatostatin Expressing Neuroendocrine Tumors
Ebrahim Delpassand,1 Rodolfo Nuñez,1 David Ranganathan,2 Nilesh Wagh,2 Afshin Shafie,1 Ayman Gaber,1 Ali Abbasi.21Excel Diagnostics, Houston, TX; 2RadioMedix, Houston, TX.
Background: 68Ga-labeled Somatostatin (SST) analogues are highly sensitive and specific PET radiopharmaceuticals for imaging SST expressing neuroendocrine tumors (NET). However, their major shortcomings are short half-life of 68 minutes, dependency on Ga-68 generator, and hence availability only in limited geographical regions. Cu-64 DOTATATE addresses all these shortcomings with half-life of 12.6 hours, cyclotron production, centralized high scale manufacturing and distribution throughout the country. The study aim was to prospectively evaluate the safety and diagnostic performance of 64Cu-DOTATATE PET/CT in detection of SST expressing NET
Methods: All subjects received 4.0 ± 10% mCi of 64Cu-DOTATATE and PET/CT imaging was performed 60 ± 15 minutes after injection. PET/CT images were read by three independent nuclear medicine physicians blinded to clinical information. Separately, Independent oncologist determined disease or no disease as well as local or metastatic status of the subject, from all available Standard of Truth (SOT) pathology, clinical, and conventional imaging studies. A total of 63 subjects were considered for statistical analysis.
Results: All the images were of high quality. The majority of readers had a sensitivity of 91% and specificity of 97%. 3 patients had their tumors surgically resected with no residual disease by any SOT but mistakenly were called “disease” by one of the oncologists. Correcting for this, the sensitivity, specificity, PPV, NPV, and accuracy were calculated to be 100%, 97%, 97%, 100%, and 98%, respectively. All patients tolerated 64Cu-DOTATATE well, with no serious adverse reactions.
Conclusion: 64Cu-DOTATATE PET/CT is a safe imaging technique that provides high quality images and excellent accuracy (98%) for detection of SST expressing NETs.
Trends and In-Hospital Outcomes of Neuroendocrine Tumors (NETS): A National Perspective
Aakash Desai,1 Thorvardur Halfdanarson.21University of Connecticut, Farmington, CT; 2Mayo Clinic, Rochester, MN.
Background: Limited evidence is available on the trends and in-hospital outcomes among patients with various NETs. We measured the trends of hospitalization, demographics, diagnosis at presentation and in-hospital outcomes in patients with NETs.
Methods: We used the National Inpatient Sample (NIS) dataset, a nationally representative weighted sample of all US hospital discharges, from 2008 to 2014 to identify the diagnosis of NETs (ICD-9 code: 209.x). Categorical and continuous variables were tested using Chi-square test and Student t-test.
Results: 38,686 patients with NETs were identified between 2008 to 2014. The NETs subtypes included: Malignant small intestinal carcinoid tumors (11.5%); appendix, large intestine, and rectum (7%); other and unspecified sites (38.7%); malignant poorly differentiated neuroendocrine tumors (12.6%); Benign carcinoid tumors of the small intestine (4%); appendix, large intestine, and rectum (3.7%) and other and unspecified sites (13.8%). 179 of the 38,686 (0.5%) of the patients had carcinoid syndrome on primary presentation. We found a mean age of 62.88 years, female predominance (51.9%) and predominantly white ethnicity (75.70%) among the cohort. The mean length of stay and cost of hospitalization were found to be ~6.60 days and 18,300.90 USD respectively. Furthermore, the in-hospital mortality across all NETs was found to be 4.77%. In general, the trend of hospitalization for NETs generally increased from 2008 to 2010 but has remained relatively unchanged between 2010–2014.
Conclusion: Our study provides evidence that there is a significant cost and in-hospital mortality associated with this cohort of patients. Retrospective analysis, restriction to in-hospital data such as lack of information regarding procedures, use of coding to identify NETs, and variation in documentation practices, limit the ability to use this data. Despite this, the in-hospital outcomes of NETs, often understudied, provide an insight into the epidemiologic and financial burden of this disease.
Improvement in Carcinoid Syndrome-Related Symptoms With Telotristat Ethyl in Patients With 2 or Less Bowel Movements Per Day
Valentina Di Gialleonardo, Eshetu Tesfaye, Ashwin Kittur, Susan Giacalone, Pablo Lapuerta. Lexicon Pharmaceuticals, Inc., The Woodlands, TX.
Background: In the Phase 3 TELECAST randomized, controlled trial (N = 76), telotristat ethyl (TE), a tryptophan hydroxylase inhibitor, was well tolerated and efficacious in patients with carcinoid syndrome (CS). The aim of this analysis was to assess the efficacy and safety of TE in those patients enrolled in TELECAST with ≤2 bowel movements (BMs)/day at baseline.
Methods: Data on BM frequency, flushing episodes, stool form, nausea, and abdominal pain were collected in electronic diaries over the 12-week double-blind (DB) treatment period. The percent change from baseline at Week 12 for TE groups (250 mg three-times daily [tid] and 500 mg tid) versus placebo were described with nonparametric tests.
Results: A total of 28 (placebo, n = 9; TE 250 mg tid, n = 10; TE 500 mg tid, n = 9) out of 76 patients (37%) in the TELECAST study had ≤2 BMs/day at baseline and were included in the analyses. At the end of the DB treatment period, patients treated with TE 250 mg tid exhibited reductions in flushing by 63.3%, fewer BMs (-12.7%), and less abdominal pain (-78.1%). At the end of the DB period, the incidences of constipation were 20% for the 250 mg tid group and 11% for the 500 mg tid group, respectively. Constipation was not reported as a serious adverse event, and TE was not discontinued in any of the cases. Moreover, concomitant medications that induce constipation were present in 87% of the constipation events.
Conclusion: Patients with ≤2 BMs/day at baseline showed improvement in carcinoid syndrome-related symptoms with TE. The minority of patients who reported constipation continued therapy with TE.
Granulomatous Fungal Infection Coexistence With NET: Not All That Lights Up On PET Scan is a NET
Ayca Dundar, Thorvardur Halfdanarson, Ayse Tuba Kendi, Saul Friedman, Michael Bold, Rachel Eiring, Geoffrey Johnson. Mayo Clinic, Rochester, MN.
Background: While F18-FDG PET imaging provides visualization of malignancies by detecting hypermetabolic lesions, Ga68-DOTATATE PET provides visualization of neuroendocrine tumors (NETs) through increased somatostatin receptor related radiotracer uptake. However, granulomatous inflammation can show activity on both types of PET scans and present challenges in interpretation. To highlight key educational points related to interpretation of scans in patients who suffer from both disease processes, we present two cases with NETs and coexisting granulomatous pulmonary fungal infection and correlate imaging findings with pathological and microbiological information.
Methods: PET scans were performed from the orbits through the thighs with CT fusion imaging.
Results: Case 1: A 16-year-old male with bronchial carcinoid tumor and history of histoplasmosis treated with itraconazole underwent F18-FDG PET/CT showing a right hilar mass with mild uptake, and moderate uptake in hilar and mediastinal lymph nodes. Ga68-DOTATATE PET/CT demonstrated intensely DOTATATE-avid (SUVmax 37.6) right hilar mass and no significant activity in the mediastinal lymph nodes. CT showed right hilar mass, calcified right lung granulomas, partially calcified hilar and mediastinal nodes, splenic and liver calcifications. Pathological examination of the resection specimen revealed typical carcinoid tumor, with clear margins. Evidence of histoplasmosis with granulomatous inflammation and fungal organisms was seen in the lung parenchyma and mediastinal lymph nodes. Case 2: A 68-year-old male with partially-resected grade 2 small bowel NET treated with octreotide underwent Ga68 DOTATATE PET/CT showing multiple mediastinal DOTATATE-avid lymph nodes (SUVmax 6.6), concerning for possible metastatic disease. A bronchoscopy with endobronchial nodal biopsies and bronchial washings were done. The nodes were negative for tumor and revealed necrotizing granulomatous inflammation. Bronchial washing revealed Cryptococcus neoformans. The patient was treated with fluconazole.
Conclusion: Granulomatous fungal infections may cause increased DOTATATE and/or FDG uptake on PET scans, mimicking NETs, and should be considered as differential diagnosis in cases of mediastinal adenopathy with DOTATATE and/or FDG avidity.
Method for Establishing and Characterizing Small Bowel Neuroendocrine Tumor Organoids
Po Hien Ear, Guiying Li, Aaron Scott, Meng Wu, Ellen Abusada, Courtney Kaemmer, Dawn Quelle, Andrew Bellizzi, James Howe. University of Iowa, Iowa City, IA.
Background: Small bowel neuroendocrine tumors (SBNETs) are rare cancers originating from enterochromaffin cells of the gut. Research in this field has been limited by the lack of patient-derived SBNET cell lines, which are slow growing and difficult to propagate. The few cell lines that have been established are not readily available and may lose NET cell characteristics after continued propagation in culture. Generating new cell lines requires significant time (years) given the indolent nature of well-differentiated SBNETs and necessity of many enrichment steps to eliminate the rapidly dividing cancer-associated fibroblasts.
Methods: To overcome these challenges, we developed a protocol to culture SBNET cells from surgically removed tumors as organoids in Matrigel with enriched DMEM/F12 medium or stem cell medium. Cultured organoids were tested for NET markers (Chromogranin A, Synaptophysin, and SSTR2) by immunofluorescent microscopy, immunohistochemistry, and gene and protein expression level quantification.
Results: We successfully generated viable SBNET organoid cultures from 8 of 9 tumors, which we have been able to maintain in culture, and verified sustained expression of NET markers and low Ki-67 positivity. Phenotypic analysis of organoids showed that they form spheroid or ellipsoid structures and measure between 20 to 100 μm in diameter. Larger organoids bleb off to the surrounding milieu and form new organoids. For proper expansion, SBNET organoids require new medium every week and splitting every 2 to 4 weeks. They are slow growing and double in surface area every 14 days.
Conclusion: We established an in vitro strategy to grow and propagate cells from patient SBNETs as organoids that maintain NET marker expression. They grow slowly but can be expanded for testing new therapeutics. In addition, they have the potential to establish much needed mouse models of well-differentiated SBNETs for biological investigations and drug testing in vivo.
A Pilot Study Assessing the Cognitive Profile in Neuroendocrine Tumor (NET) Patients With Carcinoid Syndrome (CS)
Rachel Goodwin,1 Horia Marginean,1 Joanna Gotfrit,1 Tim Asmis,1 Michael Vickers,1 Stewart Longman,2 Janice Pasieka.21The Ottawa Hospital Cancer Centre, Ottawa, Canada; 2Alberta Health Services, Calgary, Canada.
Background: There is limited information on cognitive changes over time in NET patients with CS. We are developing a study to assess the effect of treatment with somatostatin analogs (SSAs) on cognitive function in patients with NETs. This pilot study has been designed to test the feasibility of a larger study.
Methods: The pilot study will recruit 10 adult patients from 4 Canadian cancer centers with stage IV NET who manifest CS who are starting long acting SSA therapy. Cognitive performance will be assessed before treatment begins and twice at 3 and 6 months post-SSA injections. Cognitive tests will examine the subjective experience of the patient and family members, and the objective functioning of the patient, including domains of processing speed, auditory attention, sustained attention, executive functioning, and affective awareness.
Results: The pilot study will validate the feasibility of critical components of the full-scale study: recruitment rate, retention levels, eligibility criteria, suitability of time and resources allocated, and will corroborate estimates for sample size calculation. If the main study is feasible without major amendments to the design of the protocol, the pilot study will be considered a ‘run in’ period and the participants will be included in the full-scale study. Pilot study results available at the date of the symposium will be presented.
Conclusion: The proposed research has direct implications for clinical services development to improve quality of life for NET patients with carcinoid syndrome. SSA therapy may help NET patients with carcinoid syndrome, it may result in improved cognitive function which could ameliorate or restore quality of life. This may ultimately help us determine if cognitive testing and cognitive rehabilitation should become standard of care.
Geographic and Demographic Disparities in Neuroendocrine Tumors (NETS): A Population-Based Study
Rohit Gosain,1 Somedeb Ball,2 Navpreet Rana,3 Adrienne Groman,1 Elizabeth Gage-Bouchard,1 Arvind Dasari,4 Sarbajit Mukherjee.11Roswell Park Comprehensive Cancer Center - University at Buffalo, Buffalo, NY; 2Texas Tech University Health Sciences Center, Lubbock, TX; 3University at Buffalo, Buffalo, NY; 4MD Anderson Cancer Center, The University of Texas, Houston, TX.
Background: The incidence and prevalence of Neuroendocrine Tumors (NETs) are rapidly rising. There are very few studies investigating the role of sociodemographic factors on NETs. The aim of our study was to identify the disparities in the NET population.
Methods: We conducted a retrospective analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database, and studied NETs patient population from 1973 to 2015. Univariate and multivariate analyses were performed to evaluate patients’ disease-specific survival (DSS) and overall survival (OS). Different socio-demographic factors including location of residence: urban area (UA) versus rural area (RA), gender, race, insurance status and marital status were included in the analysis.
Results: A total of 53,522 [RA: n = 5517; UA: n = 47,517] patients were included in the analysis. The incidence of NETs was found to be rising in both RA and UA but more rapidly in UA. RA was associated with more advanced stage at presentation in comparison to UA. Cause-specific mortality remained higher in RA than UA throughout the study period. In the multivariate model, RA had a trend towards poorer DSS (HR, 1.02; P = 0.615) and a worse OS compared to UA (HR, 1.05; P = 0.053). Multivariate analysis showed significantly worse DSS and OS in uninsured, single and male patients compared to insured, married and female patients respectively.
Conclusion: Our study identified sociodemographic disparities on NET outcomes. Access to healthcare could be a potential contributing factor although differences in environmental exposure, health behavior and tumor biology could also be responsible. Further population-based studies are required to address these disparities.
Health Related Quality of Life (HRQOL) in Neuroendocrine Tumor: A Systematic Review
Rohit Gosain, Renuka Iyer. Roswell Park Comprehensive Cancer Center - University at Buffalo, Buffalo, NY.
Background: Given the long survival (median 9.3 years) and many new therapies approved for the treatment of neuroendocrine tumors (NETs) we sought to evaluate the impact of currently used therapies on HRQoL. The intent was to identify the common tools used, impact of treatment on patient reported outcomes and assist providers and patients to make appropriate treatment choices.
Methods: We did a thorough review of the literature, utilizing PubMed, The Cochrane Library and EMBASE, utilizing relevant keywords. Publications that were letters, editorials, narrative reviews, case reports, and studies not in English were excluded from our study.
Results: Of the 2375 records found, only 63 met our inclusion criteria. The commonly used QOL instruments used were EORTC QLQ-C30, QLQ GI.NET-21, and FACT-G. HRQoL was assessed in all pivotal trials that led to approval of octreotide, somatuline, everolimus, telotristat, peptide receptor radionucleotide therapy (PRRT), and sunitinib in NET patients. These therapies showed no worsening in QOL compared to control arms, while only PRRT showed benefit in several elements of HRQoL (especially in physical functioning, role functioning, fatigue, pain, diarrhea, disease related worries and body image; Table 1). The trial examining sunitinib versus placebo showed no change in QOL except for diarrhea especially in sunitinib arm. The tool used in the TELESTAR study was developed for the unique indication of carcinoid diarrhea and 67% patients reported improvement with diarrhea control compared to 33% in the control arm.
Conclusion: In addition to survival outcomes, patient centered outcomes are a key element in making appropriate treatment choices. HRQoL data should be readily provided to patients during their pretherapy counseling along with toxicity information, to assist patients in informed decision making. There is a paucity of data when patients are off treatment and impact of access to care, age and socioeconomic and demographic factors in decision making are needed.
SKIE: An Automated Approach to Quantitation of Ki-67 Index From Human Gastrointestinal Neuroendocrine Tumor
Darshana Govind,1 Kuang-Yu Jen,2 Karen Matsukuma,2 Guofeng Gao,2 Kristin Olson,2 Dorina Gui,2 Pinaki Sarder.11The State University of New York at Buffalo, Buffalo, NY; 2University of California Davis, Davis, CA.
Background: Ki-67 index is an established diagnostic factor in gastrointestinal neuroendocrine tumors (GI-NETs). Automated assessment of this index is challenging due to the difficulty in computationally distinguishing tumor from non-tumor regions in standard histopathological images. We propose an integrated approach, termed SKIE (Synaptophyin-Ki-67 index estimator), combining whole slide image (WSI) analysis with double immunohistochemical staining for Ki-67 and synaptophysin (stains tumor regions).
Methods: SKIE detects the tumor regions, extracts five hot-spots based on the Ki-67 positive cell density within the tumor regions, and computes the average index. The index for 50 WSIs of human GI-NETs were compared with four pathologists’ assessment based on Ki-67 staining alone and the gold standard obtained via exhaustive counting by a fifth pathologist based on double stained images. The performance of SKIE was also compared to the current most widely used automated immunostain quantification tool, ImmunoRatio.
Results: Among 50 WSIs, all five pathologists unanimously graded 32, wherein, SKIE achieved 96.87% accuracy. The one discordant case was attributed to staining inconsistencies. The remaining 18 WSIs had discordant grades. Thus, the gold standard was chosen for comparison. 15 WSIs matched with the gold standard, one was assigned a lower, and two were assigned a higher grade by SKIE. Moreover, SKIE outperformed ImmunoRatio by ~3 fold. Also, SKIE displayed 0.80 ± 0.96% index error rate (significant linear weighted Cohen’s kappa, κ = 0.669, while being ~9K times faster in computing the index from a hot-spot. In contrast, the average index among the four pathologists had a moderate Cohen’s kappa, κ = 0.47, which SKIE outperforms. SKIE-estimated hot-spots, when re-graded by the fifth pathologist resulted in the revision of five cases to higher grades than previously anticipated, demonstrating SKIE’s better hot-spot selection capability and ability to improve clinical workflow.
Conclusion: The proposed method is faster, robust and more accurate than existing automated and manual methods.
Tumor Detection Rates Using Standard Screening Protocols in Patients With SDHX Pathogenic Variants
Samantha Greenberg,1 Michelle Jacobs,2 Heather Wachtel,3 Amanda Anson,1 Bonita Bennett,3 Maria Bonanni,3 Luke Buchmann,1 Debbie Cohen,3 Wendy Kohlmann,1 Katherine Nathanson,4 Anne Naumer,1 Amanda Schaefer,2 Tobias Else,2 Lauren Fishbein.51University of Utah Huntsman Cancer Institute, Salt Lake City, UT; 2University of Michigan, Ann Arbor, MI; 3University of Pennsylvania Perlman School of Medicine, Philadelphia, PA; 4University of Pennsylvania Perlman School of Medicine Abramson Cancer Center, Philadelphia, PA; 5University of Colorado School of Medicine, Aurora, CO.
Background: Patients with germline SDHx pathogenic variants are at increased risk for pheochromocytomas, paragangliomas, renal cell carcinomas and gastrointestinal stromal tumors. Most experts recommend SDHx carriers undergo biennial whole-body imaging (neck to pelvis) and annual biochemical testing (plasma or urine metanephrines and catecholamines) beginning in childhood. Minimal data exist regarding screening protocol efficacy. This study aimed to evaluate the tumor detection rate using standard screening protocols of whole-body imaging and biochemical testing in SDHx pathogenic variant carriers.
Methods: An IRB approved multi-center retrospective analysis was conducted at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute. All clinical imaging and biochemical screening data from each center’s start of screening program through March 1, 2018 were abstracted, including subsequent clinical management of patients with tumor(s) detected.
Results: In total, 262 SDHx pathogenic variant carriers completed 498 screens. The mean age was 41.9 years (range, 6.5–90.7 years), and 55.3% were female (n = 145). SDHB pathogenic variant carriers were the most common (n = 188, 71.8%), followed by SDHD (n = 34/13.0%), SDHC (n = 28/10.7%), SDHA (n = 9/3.4%) and SDHAF2 (n = 3/1.1%). The average number of screens per patient was 1.9 (range, 1–8). In total, 19.8% (n = 52) SDHx carriers had a positive screen for SDHx-related tumors (n = 48) or other cancer (n = 4). Across all screens, 11.4% (57/498) were positive and 77.2% (44/57) were from the first screen. Negative bloodwork was seen in 40.4% (23/57) of the positive screens.
Conclusion: The combination of full body imaging and biochemical testing is effective for screening SDHx pathogenic variant carriers and identifies SDHx-related and incidental tumors. Imaging is essential as biochemical testing alone does not detect all disease. Three-fourths of tumors were identified on the first imaging screen, suggesting that it may be possible to increase the suggested imaging interval. Future longer-term studies are needed to determine the appropriate interval for imaging screening for SDHx pathogenic variant carriers
Computing the Cost of Care Per Day for Patients With Metastatic NETs
Divya Gupta, Kristopher Kapphahn, FeiFei Qin, Kathleen Hornbacker, Solomon Henry, Douglas Wood, Douglas Blayney, Pamela Kunz. Stanford University, Palo Alto, CA.
Background: Patients with low grade metastatic neuroendocrine tumors (NETs) usually have a long median survival and require complex but expensive care at multidisciplinary centers. The cost burden for patients and institutions serves as a barrier to care for these patients. Understanding the drivers of these costs and whether intense monitoring adds value will help to optimize value-based care for patients.
Methods: We adapted the cost of care per day (CCPD) method to measure the cost of monitoring while accounting for varying follow-up duration [Blayney JCO 2018]. We queried the Stanford NET Database (derived from the Stanford Cancer Institute Research Database), which aggregates data from the electronic health record and other electronic sources. NET patients diagnosed with metastatic disease between 2010 to 2017 who had two or more surgery, chemotherapy or radiation-related encounters at Stanford within 3 years of metastatic disease diagnosis were studied. Common Procedural Terminology (CPT) codes assigned to each service were tallied and mapped to the corresponding Medicare fee schedule code and date.
Results: 126 patients were studied; mean age 65.5, 50% female, 50% male, 67% white, 8% Asian, 4% black. Primary tumor sites: pancreas (26%), small intestine (26%), lung (13%). 10% of tumors were functional, 11% non-functional, 80% unknown. Stage at diagnosis: 3% T1, 10% T2, 12% T3, 10% T4. Tumor grades: 17% grade 1, 21% grade 2, 15% grade 3, 48% without. Mean CCPD was $140.70, of which chemotherapy was 41%, surgery 7%, radiation 8%, imaging 17%, labs 8%, outpatient 12%, and inpatient 2%.
Conclusion: This study supports that CCPD can be applied to other tumor types beyond breast. This model identifies drivers of cost and where interventions to lower cost would have the greatest impact in decreasing total spending on high-quality oncology care. Future studies should evaluate the correlation between high-cost patients and survival and capture costs beyond those at Stanford.
Symptom Burden at the End of Life for Neuroendocrine Tumors: A Population-Based Analysis of Patient-Reported Outcomes
Julie Hallet, Laura Davis, Alyson Mahar, Calvin Law, Elie Isenberg-Grzeda, Sten Myrehaug, Haoyu Zhao, Kaitlyn Beyfuss, Lesley Moody, Natalie Coburn. Sunnybrook Health Sciences Centre, Toronto, Canada.
Background: How to best support neuroendocrine tumor (NET) patients remains unclear. While the peri-diagnostic period has been investigated, there is no data regarding symptoms at the end of life, when suboptimal symptom control may be particularly burdensome. This study examined symptom trajectories and factors associated with high symptom burden in NET at the end of life.
Methods: We conducted a population-based retrospective cohort study of NET diagnosed from 2004-2015, who died between 2007–2016. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial datasets. Moderate-to-severe symptom scores in 6 months prior to death were presented by 2-week intervals. Multivariable Poisson regression identified factors associated with moderate-to-severe symptoms scores.
Results: Among 677 decedents, 2579 symptom assessments prior to death were analyzed. Overall, moderate-to-severe scores were most commonly reported for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%) at any time. This proportion changed over time, progressively increasing closer to death: 56.8% to 83.9% tiredness, 50.5% to 73.1% wellbeing, 40.9% to 80.6% lack of appetite, and 41.5% to 68.8% drowsiness. The increase was steeper in the 8 weeks before death for lack of appetite, drowsiness, and shortness of breath. On multivariate analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months prior to death and with shorter survival from diagnosis (<6 months). Women reported a higher burden of anxiety, nausea, and pain than men. There was no association between symptom burden and age or primary tumor site.
Conclusion: NET patients suffer a high symptom burden at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptom, this information is important to improve patient-centered and personalized supportive care for NET at the end of life.
Initial Experience With Peptide Receptor Radionuclide Therapy (PRRT) for the Treatment of Neuroendocrine Tumors (NETS) at a Tertiary Care United States Center
Jason Heckert,1 Samuel Botterbusch,2 Sarit Kipnis,1 Bonita Bennet,3 Caroline Creamer,3 Alice Alderson,3 Jennifer Eads,3 Michael Soulen,3 Daniel Pryma,3 David Mankoff,3 David Metz,3 Bryson Katona.31Hospital of the University of Pennsylvania, Philadelphia, PA; 2University of Pennsylvania, Philadelphia, PA; 3Perelman School of Medicine, Philadelphia, PA.
Background: The recent NETTER-1 trial showed that PRRT is effective for treating mid-gut NETs, leading to FDA approval of Lutetium 177 DOTATATE for the treatment of gastroenteropancreatic NETs. The purpose of this study was to examine the implementation of PRRT at a tertiary referral center by characterizing the patients selected for treatment, tolerance of therapy, and early toxicity.
Methods: Medical records of all NET patients receiving PRRT from August 2018 through April 2019 were reviewed to obtain demographic data, tumor characteristics, prior non-PRRT NET treatments, adverse events, and laboratory values prior to and following PRRT. PRRT was administered according to the NETTER-1 protocol every 8 weeks.
Results: 51 patients (24 female) were scheduled for PRRT over the study period. Mean (±SD) age and duration of disease prior to therapy were 60.1 ± 10.9 and 6.3 ± 5.2 years, respectively. Primary NET location was small bowel (45%), pancreas (27%), unknown (8%), colon (8%), lung (4%), and other (8%). NET grade was 1 in 34%, 2 in 53%, 3 in 13%, and unknown in 8%. 50 patients (98%) had received somatostatin analogue (SSA) therapy, and 37 (73%) had undergone primary tumor resection. 33 patients (65%) had received non-SSA systemic therapy, including capecitabine/temozolomide (20 patients, 39%). 28 patients (55%) had received liver directed therapy (TACE, TARE, bland embolization, RFA, and/or wedge resection). Of the 51 scheduled patients, 39 received at least one dose of PRRT during the study period. Two of 86 cycles of PRRT (2%) were delayed due to fatigue and nausea, and 4 (5%) were delayed due to thrombocytopenia (Table 1).
Conclusion: Our early experience with PRRT in heavily pretreated, predominantly grade 2 patients including 4 with off label primary tumor locations only revealed transient toxicities in a minority of patients with few cases of treatment delay.
Prediction of Survival for Pancreatic Neuroendocrine Tumors: A Systematic Review of Clinical Tools
George Ho,1 Kaitlyn Beyfuss,2 Sten Myrehaug,1 David Chan,3 Victoria Zuk,2 Calvin Law,1 Alyson Mahar,4 Julie Hallet.11University of Toronto, Toronto, Canada; 2Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada; 3University of Sydney, Sydney, Australia; 4University of Manitoba, Winnipeg, Canada.
Background: Individual prognostication can support the management of pancreas neuroendocrine tumors (PNETs). Little is known about PNETs prediction tools’ accuracy and utility. We sought to evaluate the quality of prediction tools in PNETs.
Methods: We systematically searched the literature for studies reporting development or validation of tools predicting survival for PNETs. We evaluated the tools using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies guidelines and the American Joint Committee on Cancer (AJCC) acceptance criteria for risk models.
Results: We identified 7 tools to predict survival in PNETs that all addressed resected tumors. All were developed on patients diagnosed back to 1980–90s. They included 2 to 5 prognostic factors; the majority excluded key factors such as age and sex. Tumor grade was most commonly included. Five tools were designed to predict overall survival, and two for both disease-specific and recurrence-free survival. Two tools underwent bootstrapping internal validation with one showing “good” discrimination (C-statistic: 0.74). Two tools were externally validated: calibration was evaluated with inspection of survival curves and estimates, but discrimination was not assessed. Validation samples relied on unknown or small (<100) number of events. No tool met AJCC acceptability criteria for risk models.
Conclusion: Existing tools cannot be confidently used for PNETs prognostication in current clinical practice. Patient-level and non-pathologic disease factors should be included for more personalized prognostication. Better quality tools should be developed and validated following best methodology practices for predictive tools development and validation.
The Telepath Phase 3 Study: An Analysis of Long-Term Treatment With Telotristat Ethyl in Patients With Carcinoid Syndrome Symptoms
Dieter Horsch,1 Lowell Anthony,2 David Gross,3 Juan Valle,4 Staffan Welin,5 Marta Benavent,6 Kenneth Kassler-Taub,7 Polina Binder,7 Phillip Banks,7 Pablo Lapuerta,7 Matthew Kulke.81Center for Neuroendocrine Tumors, Bad Berka, Germany; 2Markey Cancer Center University of Kentucky, Lexington, KY; 3Hadassah-Hebrew University Medical Center/ENETS CoE, Jerusalem, Israel; 4University of Manchester/The Christie, Manchester, United Kingdom; 5Uppsala University Hospital, Uppsala, Sweden; 6Hospital Universitario Virgen del Rocío / Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain; 7Lexicon Pharmaceuticals, Inc, Princeton, NJ; 8Boston Medical Center, Boston, MA.
Background: TELEPATH (NCT02026063) is an open-label extension phase 3 study that evaluated the long-term safety and changes in patient reported outcomes of telotristat ethyl (TE) in patients enrolled in prior Phase 2 (NCT00853047, NCT01104415) or Phase 3 (NCT01677910, NCT02063659) trials.
Methods: Patients continued receiving open-label TE 250 or 500 mg three times per day for treatment of carcinoid syndrome (CS) symptoms as administered in the original study they were enrolled in. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and the secondary endpoint was evaluation of long-term changes in patient-reported outcomes over the first 84 weeks of TELEPATH treatment (i.e., during continuation of TE therapy).
Results: 124 patients were enrolled and 53.2% completed the study. Mean cumulative duration of exposure was 102.6 weeks (max, 234 weeks) and treatment compliance was 88.2%. TEAEs were reported in 98.4% of patients (serious in 53.2% with 2.4% [n = 3 patients] experiencing treatment related SAEs). Study drug discontinuation due to TEAEs was required in 17.7% of patients. Death due to TEAEs was reported in 16.1% (n = 20 patients) of patients, 12 were due to progressive disease/underlying malignancy and only 1 was considered possibly related to treatment. The most frequent TEAEs by preferred term were diarrhea (35.5%), nausea (33.1%), and abdominal pain (32.3%). There was no significant change in the proportion of patients reporting adequate relief of CS symptoms associated with gastrointestinal events. A minimal (-0.9, P = 0.29) change was reported in the EORTC QLQ-30 Global Health Status score at Week 84. The mean severity score of patients overall with CS generally remained stable.
Conclusion: Long-term administration of TE was well-tolerated in majority of patients and AEs were consistent with the known safety profile. In general, benefits in quality of life and relief of CS symptoms experienced in the prior studies were maintained with extended therapy.
GA-DOTATATE Cardiac Uptake in Carcinoid Heart Disease Patients
Malak Itani, Manik Amin, Joyce Mhlanga, Nikolaos Trikalinos. Washington University in St Louis, St. Louis, MO.
Background: Carcinoid heart disease (CHD) diagnosis and management relies on echocardiographic measurements and clinical symptoms. We explored the diagnostic utility of myocardial uptake of Ga-68 Dotatate in patients with neuroendocrine tumors (NETs) with and without CHD.
Methods: We reviewed the Ga-68 Dotatate images of all NET patients with CHD who were seen in the clinic between 6/1/2016 (date of FDA approval of Ga-68 Dotatate) and 6/1/2019. For controls, we reviewed images of a second group of patients with carcinoid symptoms (CS) without CHD, and a third group of patients without CHD and with no CS. For semiquantitative evaluation of myocardial uptake of Ga-68 Dotatate, we placed regions of interest (ROI) with an area of 1 cm2 over 5 regions in the myocardium (mid anterior wall, apical and mid lateral wall, mid and basal septal wall). For internal standardization, sum of mean standardized uptake value by body weight (SUV) over 5 myocardial regions was divided by SUV of the cardiac blood pool, and will be referred to as myocardial uptake score (MUS).
Results: A total of 20 patients were included, all with well differentiated tumors (13 small bowel primary) with a mean age of 60 years (range, 30–84). Twelve patients had carcinoid syndrome and 5 of these had carcinoid heart disease (group 1), while eight patients had no CHD or CS (group 3). Group 1 MUS was 10.9 (7.3–15, SD 2.8), Group 2 (CS with no CHD) was 7.7 (5.1–11.9, SD 2.2) and Group 3 was 8.7 (4.5–16, SD 4.1). Two patients in group 3 had elevated MUS (more than 10) and both had evidence of non-CHD cardiac disease.
Conclusion: Ga-Dotatate PET/CT myocardial uptake is higher in patients with CHD and non-carcinoid heart disease. This can aid identification of NET patients at risk for cardiac disease.
Novel Mouse Models of Pancreatic Neuroendocrine Tumor Metastasis
Courtney Kaemmer,1 Umesalma Shaik,1 Chandra Kumar Maharjan,1 Devon Moose,1 Goutham Narla,2 Benjamin Darbro,1 Andrew Bellizzi,1 Micheal Henry,1 Dawn Quelle.11The University of Iowa, Iowa City, IA; 2University of Michigan, Ann Arbor, MI.
Background: Pancreatic neuroendocrine tumors (PNETs) are rare, slow growing cancers that lack effective treatments once they become metastatic. Unfortunately, 60% of PNET patients have distant metastatic disease (mainly in the liver) at diagnosis and current therapies fail to improve overall survival. Pre-clinical models of PNET metastasis are greatly needed to advance our understanding of mechanisms driving NET metastasis and to develop/test novel therapeutic interventions.
Methods: PNET cell lines stably expressing luciferase (BON1.luc and Qgp1.luc) were generated and transwell assays performed to measure in vitro migration. Bioluminescent cells were introduced into NSG immunodeficient mice by intravenous (IV, tail vein) or intracardiac (IC) injection. Tumor growth was monitored longitudinally on a weekly basis by non-invasive bioluminescence imaging (BLI). Animals with tumor burden exceeding 109 photons/sec or low body conditioning scores were euthanized, and tumor bearing tissues subjected to ex vivo BLI, histopathology and genetic analyses.
Results: One hundred percent tumor incidence was achieved for both IV and IC metastasis models. Qgp1.luc cells preferentially metastasized to the liver regardless of delivery route, mimicking the predominant site of PNET metastasis observed in patients. By comparison, BON1.luc cells always formed tumors in the lung regardless of administration route and colonized a wider variety of tissues compared to Qgp1.luc, including liver but also adrenal glands, kidney and ovaries with high frequency. Pre-clinical studies evaluating drugs with predicted anti-metastatic activities are ongoing.
Conclusion: We successfully developed new bioluminescent mouse tumor models of PNET metastasis. Qgp1.luc cells preferentially formed tumors in the liver while BON1.luc cells displayed a broader metastatic distribution. This system represents a rapid and relatively inexpensive platform for testing candidate metastasis genes and novel PNET therapies.
Prognostic Impact of a Large Mesenteric Mass >2 cm in Ileal Neuroendocrine Tumors
Yosuke Kasai, Kelly Mahuron, Kenzo Hirose, Carlos Corvera, Grace Kim, Thomas Hope, Brandon Shih, Robert Warren, Emily Bergsland, Eric Nakakura. University of California, San Francisco, San Francisco, CA.
Background: Ileal neuroendocrine tumors (i-NETs) frequently metastasize to mesenteric lymph nodes and the liver. Regional lymphadenopathy is associated with desmoplasia of the mesentery causing a large mesenteric mass (LMM). Although the latest AJCC TNM staging (8th edition) defined LMM >2 cm as N2, the prognostic impact of LMM is ill-defined. We evaluated whether LMM is prognostic for patients with i-NETs.
Methods: This single-institution, retrospective cohort study included 106 patients who underwent resection of i-NETs between 2007 and 2018. LMM was defined as a mesenteric mass >2 cm on preoperative imaging. Overall survival (OS) and liver-progression-free survival (LPFS) were compared between patients with and without LMM.
Results: LMM was present in 62 patients (58%). LMM did not correlate with the presence/absence of liver metastasis (P = 0.680) or the extent of liver involvement (P = 0.962). OS and LPFS differed significantly between patients with and without LMM (5-year OS rates of 63.6% and 94.9%, respectively, P = 0.022; 3-year LPFS rates of 42.4% and 67.0%, respectively, P = 0.031). In multivariate analysis, LMM (hazard ratio, 4.59; 95% confidence interval, 1.52–17.6), liver involvement ≥25% (5.69, 1.71–16.8), and grade 2 (5.48, 2.06–16.5) were independent prognostic factors for OS, while LMM (1.94, 1.09–3.60), presence of liver metastasis of any extent (3.78, 1.76–9.06), and grade 2 (2.22, 1.23–4.01) were independent prognostic factors for LPFS.
Conclusion: LMM >2 cm is prognostic for OS and LPFS, and represents aggressive tumor biology.
Differential Diagnosis (DDX) of Carcinoid Syndrome Diarrhea (CSD): A Systematic Literature Review (SLR)
Mohid Khan,1 Thomas Walter,2 Amy Buchanan-Hughes,3 Lucie Keeber,4 Marion Feuilly,5 Enrique Grande.61University Hospital of Wales, Cardiff, Wales; 2Centre Hospitalier Universitaire de Lyon, Lyon, France; 3Costello Medical, Cambridge, United Kingdom; 4Ipsen Ltd., Nottingham, United Kingdom; 5Ipsen Pharma, Boulogne-Billancourt, France; 6Medical Oncology Department, MD Anderson Cancer Center Madrid, Madrid, Spain.
Background: CSD is related to serotonin secretion by neuroendocrine tumors (NETs). Although CS is often the cause of diarrhea among NET patients, alternative causes should be considered as these may require different treatment. However, there is no guidance on DDx of CSD in NET patients.
Methods: MEDLINE/Embase/Cochrane Library were searched in September 2018 with terms for NETs, CS and diarrhea. Congress abstract books/bibliographies/ClinicalTrials.gov were hand-searched. Two independent reviewers screened articles at title/abstract and full text stage. Relevant studies reported quantitative or qualitative evidence relating to DDx of CSD; framework synthesis was used to synthesize heterogeneous evidence from these studies.
Results: 46 publications were included. Most reported on pancreatic enzyme insufficiency (PEI) in NET patients. Other causes include bile acid malabsorption, small intestinal bacterial overgrowth, short bowel syndrome and infection. Diagnostic approaches include fecal elastase (FE) test, hydrogen breath test, SeHCAT scan and stool culture. Other approaches include assessment of patient history, diarrhea characteristics, and trials of treatment modification. There are limited data on effectiveness of approaches; quantitative evidence on FE tests was conflicting. If diarrhea is misdiagnosed, treatment may be deemed ineffective and underlying conditions could remain undetected.
Conclusion: Evidence on DDx of CSD is limited. PEI is a common topic of discussion, with little data available on other causes of diarrhea in NET patients. While the necessity of DDx of CSD is recognized in the literature, the most effective diagnostic algorithm is unclear.
64Cu-DOTATATE Somatostatin Receptor Imaging in Neuroendocrine Tumor Patients: Experience From More Than 600 Patients
Andreas Kjaer, Tina Binderup, Camilla Johnbeck, Esben Carlsen, Mathias Loft, Seppo Langer, Birgitte Federspiel, Ulrich Knigge. Righospitalet (National University Hospital) & University of Copenhagen, Copenhagen, Denmark.
Background: We introduced 64Cu-DOTATATE in 2009. The potential benefits compared to 68Ga-labeled tracers include better spatial image resolution and longer half-life of 64Cu (13h) making logistics easier, in particular in high-throughput centers. Here we present our experience of with 64Cu-DOTATATE in >600 neuroendocrine tumor patients.
Methods: Description of performance and practical workflow based on the first 600 patients.
Results: The PET tracer 64Cu-DOTATATE is produced in batches for up to ten patient doses. These batches are released in the morning and the product has an approved shelf life of 24h. Accordingly, for practical purposes the patients may be scanned during the day and evening on the day of tracer production. Due to the long half-life, patients showing up late are no longer a major concern with regard to PET tracer use. Compared to 68Ga-labeled tracers, which we used previously and that typically were produced for 1–2 patients at a time, we have freed up substantial radiochemist time at our department. Imaging with 64Cu-DOTATATE is typically performed 1h after injection of approximately 200 MBq of 64Cu-DOTATATE but head-to-head comparison has demonstrated that that image acquisition may be performed any time between 1 and 3h post injection. With regard to diagnostic performance, we have undertaken head-to-head comparison studies with 111In-DTPA-octreotide and 68Ga- DOTATOC, respectively. Lesion detection rate of 64Cu-DOTATATE was superior to both 111In-DTPA-octreotide and 68Ga-DOTATOC. Sensitivity and specificity calculated on basis of the first 112 patients when using a composite standard of truth (CT only, follow up on imaging/biopsy) were 97% (CI, 91–99%) and 100% (CI, 96–100%), respectively. Following PET/CT scans of 600 patients with 64Cu-DOTATATE , we have so far observed no major side-effects.
Conclusion: 64Cu-DOTATATE is a sensitive and logistically convenient somatostatin receptor imaging PET tracer for routine use in neuroendocrine tumors patients.
Survey of Challenges in Access to Diagnostics and Treatment for NET Patients (SCAN)
Teodora Kolarova,1 Simone Leyden,2 Catherine Bouvier,3 Dirk Van Genechten,4 Ronald Hollander.11International Neuroendocrine Cancer Alliance, Boston, MA; 2Unicorn Foundation, Blairgowrie, Australia; 3NET Patient Foundation, Warwickshire, United Kingdom; 4vzw NET & MEN Kanker Belgium, Blankenberge, Belgium.
Background: Neuroendocrine Tumors (NETs) are uncommon and complex neoplasms, with increasing incidence and prevalence. This survey (SCAN) aims to measure the global readiness to provide access to diagnostics and treatments for NET patients in terms of awareness, availability, quality of servicing and affordability. An earlier assessment of unmet needs carried out among NET patients and healthcare professionals identified significant disparities in what patients consider available to them in terms of the latest diagnostic tools and treatments, compared to what their healthcare systems actually offer.
Methods: The survey is to be conducted by two online questionnaires among NET patients and healthcare professionals. Both questionnaires would be available in 10 of the most spoken languages globally: Arabic, English, German, French, Japanese, Hindi, Italian, Mandarin (Chinese), Russian, Spanish. To draw statistically reliable conclusions, this survey would use quotas based on patient registries wherever available, national registries of the medical professionals by expertise and NET medical societies’ registries by region.
Results: SCAN results will measure awareness of NETs and level of access to diagnostics and optimal treatment. The findings will also allow calculating the financial burden for NET patients globally, per region and nationally, based on their socio-economic profile. SCAN aims to capture the reasons for the existing gaps in diagnostics and care for NET patients in the different parts of the world.
Conclusion: The survey would be the first to incorporate the perspectives of all key stakeholders, part of the healthcare system, who could be in a position to communicate and provide services to the NET patient, addressing all medical professionals involved in multidisciplinary care, including: oncologists, surgeons, gastroenterologists, endocrinologists, nuclear medicine specialists, pathologists, radiologists, psychiatrists, nurses, and general practitioners. Data would be crossed with the NET patients’ perspective.
Efficacy Update on the First Real World Experience of Peptide Receptor Radionuclide Therapy (PRRT) in Neuroendocrine Tumors (NET) Since US FDA Approval
Bhavana Konda,1 Sherry Mori Vogt,1 Sherise Rogers,1 Cassandra Grenade,1 Claire Verschraegen,1 Ye Zhou,1 Ashima Goyal,1 Mona Natwa,2 Chadwick Wright,2 Akram Hussein,2 Hallie Barr,2 Dramane Konate,2 Andrew Brown,2 Rochelle Batdorf,2 Bonnie Williams,2 Lai Wei,2 Manisha Shah.21The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2The Ohio State University, Columbus, OH.
Background: Real-world data on 177Lu-DOTATATE in the US is lacking. We recently reported the first real-world experience of PRRT in NET (Konda et al, E-Abstract ASCO 2019). Here, we present updated efficacy data after a median follow-up of 10.2 months.
Methods: We reviewed medical records of patients who began PRRT between 03/14/18-10/01/18 at the Ohio State University. 177Lu-DOTATATE was administered at 200 mCi over 20–30 min every 8 weeks for 4 doses. Arginine-lysine 25 g/25 g in 1 L saline and intravenous palanosetron 0.25 mg were infused over 4 h, starting 30 min pre-treatment. Clinical evaluation occurred 2 weeks before and after each PRRT dose, and radiographic assessment using contrast CT/MRI was performed following 2 and 4 doses. Patients who received ≥2 PRRT doses were considered evaluable for efficacy.
Results: 46 patients received ≥2 PRRT doses and 42/46 were evaluable for response (RECIST v1.1). 50% were female and median age was 63 (range, 39–84) years. 33/42 (79%) completed 4 doses, 1/42 (2%) had 3 doses (on active therapy at this time), and 8/42 (19%) discontinued treatment after 2 or 3 doses. Treatment discontinuation was due to toxicities (4/8), progressive disease (PD; 1/8), or patient/physician preference unrelated to toxicities (3/8). Primary site was GI (62%), pancreas (12%), lung (10%), unknown (10%), GI and pancreas (5%), and ampullary (2%). 31% had grade 1 (G1), 56% G2, 7% G3 (2/42; Ki-67: 25% and 40%), and 7% unknown grade. 9% were systemic therapy naïve, 55% received ≥1 prior systemic therapies (excluding somatostatin analogs), and 43% had ≥1 prior liver-directed therapies. Median follow-up from first PRRT to last clinic visit/death was 10.2 months. Objective response rate (partial response) was 17% (7/42; Table 1). 76% (32/42) had stable disease, and 5% (2/42) had PD.
Conclusion: 177Lu-DOTATATE is an effective treatment in advanced NET, and our results are consistent with the NETTER 1 data.
Toxicity Update on the First Real World Experience of Peptide Receptor Radionuclide Therapy (PRRT) in Neuroendocrine Tumors (NET) Since US FDA Approval
Bhavana Konda,1 Sherry Mori Vogt,2 Sherise Rogers,1 Cassandra Grenade,1 Claire Verschraegen,1 Ye Zhou,1 Ashima Goyal,1 Mona Natwa,2 Chadwick Wright,2 Akram Hussein,2 Hallie Barr,2 Dramane Konate,2 Andrew Brown,2 Rochelle Batdorf,2 Bonnie Williams,2 Lai Wei,2 Manisha Shah.21The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2The Ohio State University, Columbus, OH.
Background: Real-world toxicity data on 177Lu-DOTATATE in the US is lacking. We recently reported the first real-world experience of PRRT in NET (Konda et al, E-Abstract ASCO 2019). Here, we present updated toxicity data in these patients.
Methods: We reviewed medical records of patients who began PRRT between 03/14/18-10/01/18 at the Ohio State University. 177Lu-DOTATATE was administered at 200 mCi over 20–30 min every 8 weeks for 4 doses. Arginine-lysine 25 g/25 g in 1 L saline and intravenous palonosetron 0.25 mg were infused over 4 h, starting 30 min pre-treatment. Clinical evaluation occurred 2 weeks before and after each PRRT dose, and radiographic assessment using contrast CT/MRI was performed following 2 and 4 doses. Patients who received ≥1 PRRT doses were considered evaluable for adverse events (AEs).
Results: 52 patients were evaluable for toxicity. All patients had metastatic disease. Primary site was GI (65%), pancreas (12%), lung (8%), unknown (8%), GI and pancreas (4%), ampulla (2%), and 1 patient (2%) had paraganglioma. 31% of patients had grade 1 (G1), 54% G2, 6% G3 (Ki-67: 25%, 29%, and 40%), and 10% unknown grade of tumor. 8% of patients were systemic therapy naïve, 31% received ≥2 prior systemic therapies (not including a somatostatin analogs), and 38% had ≥1 prior liver-directed therapy. Most TRAEs were grade 1/2 including fatigue, nausea/vomiting, abdominal pain, transaminase elevation, and cytopenias. 9/52 (17%) had Grade 3/4 TRAEs that led to treatment discontinuation (Table 1). Attribution of AEs for patients #1–8 in Table 1 was possibly related to PRRT and likely/possibly related to disease and for patient #9 was likely related to PRRT and unlikely to disease.
Conclusion: 177Lu-DOTATATE is generally well tolerated. Caution is needed in patients with high tumor burden in the liver or peritoneum, intestinal luminal compression by tumor, or with mesenteric ischemia from underlying tumor.
Ocular Metastases of Neuroendocrine Tumors
Shria Kumar, Jason Heckert, Bonita Bennett, Bryson Katona, David Metz. University of Pennsylvania, Philadelphia, PA.
Background: Advances in somatostatin receptor scintigraphy with 68G-dotatate PET scanning can identify metastases in unusual locations, including ocular metastases (OMs) and provide information on response to therapy. Here, we report our experience with OM patients at a neuroendocrine referral center.
Methods: We identified 6 NET patients with OM seen from April 2012 to April 2019. Charts were reviewed for demographics, clinical syndromes, symptoms, NET history, and follow-up after receipt of Institutional Review Board approval.
Results: Table 1 describes the patients. Median time from initial NET diagnosis to OM was 13.8 years one had OM diagnosed 15 months before identification of the primary lung tumor. 5 were symptomatic with strabismus +/- visual loss. The asymptomatic patient was incidentally found to have OM on MRI after routine ophthalmologic exam suggested OM. None were identified with gallium scan alone. Five (83%) had other metastases. 4 (67%) received systemic chemotherapy for NET, 5 (83%) received somatostatin analogue treatment. Two patients (33%) underwent PRRT. One (pancreatic primary) received everolimus/CAP-TEM, TACE for liver metastases, EBRT to bone metastases and 2 cycles PRRT after distal pancreatectomy/splenectomy. The second (lung primary) received carboplatin / etoposide, EBRT of lung and bone, and 3 cycles PRRT. Both underwent EBRT to OMs, with significant improvement despite systemic progression. Of the other 4, 1 had OM surgically resected, without recurrence on MRI and controlled systemic disease. Two had EBRT to OM, with one being definitively treated of both systemic and OM disease, and the other with worsening of disease, including OM. The last was asymptomatic, imaging showed stable lesion despite progressing systemic disease (patient expired).
Conclusion: This is the first series to describe NET OM in the era of PRRT. OM is usually diagnosed after identification of the primary tumor in the setting of widespread disease, requiring systemic and metastatic directed therapies.
Operative Resection of Duodenal Carcinoid Tumors: A Single Center Experience
Shria Kumar, Nadim Mahmud, Bryson Katona, Robert Roses, Gregory Ginsberg, David Metz. University of Pennsylvania, Philadelphia, PA.
Background: Duodenal carcinoids (DC) reflect <3% of intestinal carcinoids and can be removed by operative (OR) or endoscopic resection (ER). We previously found no differences between ER techniques regarding margin positivity and local tumor recurrence. How OR compares with ER is unclear.
Methods: 18 patients underwent dedicated DC ORs between 2006 and 2017. We compared tumor and patient characteristics within types of OR and with ER (n = 28). Primary endpoints were margin and nodal status, recurrence, and survival. Standard descriptive statistical analyses were performed using Stata/IC 15.1.
Results: 8 patients underwent Whipple, 8 targeted resection and 2 Billroth II gastrectomy. Median age was 54, 56% female, 76% white, 81% without genetic syndrome. 63% underwent surgery for concerning features 19% not amenable to ER 19% due to other factors. There were no differences in tumor size, margins, penetration or differentiation among OR subtypes. More Whipple patients had G2 tumors (P = 0.03). Median post-op stay of 7 days, no major complications. 89% patients alive at 3.8 years. Of 4 patients with positive lymph nodes, all low grade, tumor size was 10.5mm (5 mm for ER, P = 0.01), all survived. Comparing OR and ER, there was no difference in tumor differentiation, grade, patient demographics, or survival (Table 1). There was a trend for tumor size (OR 8 mm ER 5 mm, P = 0.09). ER left more positive margins (69 vs 0%, P < 0.01). Local recurrence confirmed in 3/28 ERs after 1, 3, and 7 months vs. distant recurrence in 3/19 ORs, at 17, 18, and 37 months (P = 0.61). There was an increased use of ER vs OR over time (P < 0.01).
Conclusion: Operative resection of DC is rare, even in our tertiary care referral center, but has excellent resection margins and survival. Outcomes appear similar to ER. Patients with larger tumors are appropriate for surgery. There has been a trend towards ER over time.
Intra-Arterial Peptide Receptor Radionuclide Therapy Using Y-90 DOTATOC for Hepatic Metastases of Gastroenteropancreatic Neuroendocrine Tumors
Courtney Lawhn Heath, Nicholas Fidelman, Emily Bergsland, Thomas Hope. University of California San Francisco, San Francisco, CA.
Background: Intravenous Lu-177 DOTATATE (a form of peptide receptor radionuclide therapy, PRRT) delays progression in metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Up to 75% of GEP-NET patients have liver metastases. We aimed to determine whether direct intra-arterial (IA) injection of 90Y-based PRRT into the liver would achieve higher intratumoral concentrations of PRRT, thus maintaining efficacy while reducing systemic toxicity.
Methods: PRRT-naïve GEP-NET patients with liver-predominant metastases involving <70% of the liver were enrolled in this pilot, single-center, open-label study. Patients underwent baseline PET/CT imaging using intravenous 68Ga-DOTATOC. On a subsequent date, 94.7 ± 5.4 mCi 90Y-DOTATOC was administered into the proper hepatic artery over 30 minutes. The first five patients concurrently received IA 68Ga DOTATOC and underwent PET imaging within 1 hour. All patients were followed for response (RECIST1.1) and toxicity (CTCAE v4.0) (median, 44 weeks, range, 24–52).
Results: Of 10 enrolled patients, 30% (3/10) pts experienced grade 3 adverse events (AEs) (2/10 bilirubin, 1/10 anemia). During the follow-up period, best response was SD in 70% (7/10) and PD in 30% (n = 3/10). No PR or CR was observed. Patients who received IA 68Ga DOTATOC failed to demonstrate increased uptake by hepatic metastases compared to IV, with average IA:IV SUVmax ratio 0.86 ± 0.24. However, extrahepatic metastases and background demonstrated expected decreased uptake between IA and IV (ratio, 0.68 ± 0.19).
Conclusion: Our study demonstrated that administration of PRRT via the proper hepatic artery is generally safe and well tolerated. However, a single treatment resulted in minimal disease response. In addition, in contrast to previous reports, there was no increased uptake of 68Ga DOTATOC in hepatic metastases when delivered IA compared to IV. One possible reason is somatostatin receptor saturation, as the imaged 68Ga-DOTATOC was administered alongside a much larger dose of 90Y-DOTATOC than diagnostic doses of somatostatin receptor agonists used in prior studies.
Dosimetry and Potential Toxicities of 212Pb-DOTATOC in a Preclinical Model: Towards Personalized Dosimetry Based Alpha-Particle Therapy for Neuroendocrine Tumors
Dongyoul Lee, Stephen Graves, Dijie Liu, Hsiang Wen, Diana Zepeda-Orozco, Mark Madsen, Susan Walsh, G. Watkins, Yusuf Menda, Michael Schultz, David Bushnell. The University of Iowa, Iowa City, IA.
Background: Emerging evidence suggests that alpha particle therapy has the potential to improve tumor response compared to beta particle therapy. However, concerns regarding potential toxicities to normal organs and tissues mandate development of personalized dosimetry approaches. In this study, a dosimetry-based dose escalation study was performed with 212Pb-DOTATOC in an animal model to examine the relationship between localized alpha dose and pathological changes in kidneys.
Methods: 203Pb-DOTATOC was administered to eight CD1-Elite (SOPF) mice and SPECT/CT images were obtained at 1.5h and 20h post-injection. The mice were divided into four groups and injected with escalating activities of 212Pb-DOTATOC (0.037–0.178 MBq/g). Absorbed doses arising from 212Pb-DOTATOC were estimated by OLINDA software. Blood or urine were collected up to 16 weeks for analyses of nephrotoxicity parameters NGAL (neutrophil gelatinase-associated lipocalin) and cystatin C, and kidneys were harvested at 7 months post-injection for histopathological analyses. Four mice were injected with the highest dose (0.178 MBq/g), and hematological toxicity was evaluated by complete blood counts.
Results: Escalated 212Pb-DOTATOC activities linearly increased alpha dose in kidneys (6.6 Gy to 35.2 Gy) with minimal contributions from beta particles (<4%). We found evidence for acute tubular injury and renal function reduction by 50% (5 of 8 treated mice) with higher prevalence in males. Chronic renal toxicity was observed in the treated mice with a higher degree of tubular/glomerular damages in males compared to females. 50% and 40% average declines were observed in platelets and white blood cells respectively within 2–3 weeks in mice, which returned to baseline levels at 5 weeks post administration.
Conclusion: 203Pb imaging-based dosimetry can inform personalized dosimetry-guided therapy with 212Pb-based therapeutics. Administration of 212Pb-DOTATOC (0.037–0.178 MBq/g) resulted in acute/chronic renal toxicity and reversible hematological toxicity. NGAL is a sensitive biomarker for acute tubular injury, but observed levels were not proportional to increased alpha doses in this study.
Application of Chromogranin A and Chromogranin B in Advanced Neuroendocrine Tumors
Yuanliang Li,1 Huangying Tan.21Beijing University of Chinese Medicine, Beijing, China; 2China-Japan Friendship Hospital, Beijing, China.
Background: Chromogranin A (CgA) is a general marker for neuroendocrine tumors (NETs), which is affected by many factors and has limited diagnostic value for rectal NET. Chromogranin B (CgB) can be used as a tumor marker for NETs, but its research is less, and its diagnostic role needs to be further elucidated.
Methods: Patients were recruited in China-Japan Friendship Hospital from May 2018 to March 2019. Serum CgA and CgB were detected by ELISA.
Results: 15 non-tumor patients and 10 patients with advanced rectal NETs, 31 patients with advanced pancreatic NETs were enrolled in this study. Compared to those in non-tumor patients, serum CgA in patients with advanced rectal NETs were not significant elevated (P = 0.462), while serum CgA in patients with advanced pancreatic NETs were elevated (P = 0.05). Serum CgB were significantly higher in patients with advanced rectal and pancreatic NETs than those in non-tumor patients (P = 0.037, P = 0.012, respectively). In patients with advanced rectal NETs, serum CgA were not elevated significantly, while serum CgB were elevated in 90% of patients. The levels of serum CgA and CgB in the advanced pancreatic NETs were significantly higher than those in the non-tumor group. The area under the curve (AUC) of serum CgA and CgB were 0.673 (P = 0.059), 0.733 (P = 0.011) respectively, the cutoff value of CgB was 632.03 pg/ml (sensitivity: 83%; specificity: 60%). The AUC of serum CgA & CgB was 0.93 (95% CI, 0.843–1.000; P < 0.001).
Conclusion: Compared with serum CgA, serum CgB has a better diagnostic value and could be used as an effective tumor biomarker. Combination of serum CgA and CgB may help to improve the diagnosis of advanced rectal and pancreatic NETs.
Upregulation of Immune Signaling Pathways Differentiates Metastatic From Localized Pancreatic Neuroendocrine Tumors
Jessica Limberg, Akanksha Verma, Timothy Ullmann, Maureen Moore, Dessislava Stefanova, Brendan Finnerty, Toni Beninato, Rasa Zarnegar, Olivier Elemento, Thomas Fahey, III, Irene Min. NYP-Weill Cornell Medical Center, New York, NY.
Background: Metastases may be present at diagnosis of pancreatic neuroendocrine tumors (PNETs), which is associated with decreased overall survival. Furthermore, the high heterogeneity of PNETs makes treatment particularly difficult. Here we aimed to determine whether there is differential expression of immune system genes between localized and metastatic PNETs.
Methods: Bulk RNA sequencing was performed on samples of sporadic well-differentiated primary PNETs resected from 2000–2016 at our institution. Differentially expressed genes were compared between localized and metastatic tumors. Immunohistochemistry was used for validation.
Results: 22 primary tumors were sequenced: 15 localized and 7 metastatic [to liver (n = 5) or to lymph nodes (n = 2)]. Patients were demographically similar. The Ki-67 proliferation index was higher in metastatic tumors, although not statistically significant [median, 10 (range, 4–20) vs 4 (1–10), P = 0.055]. There were 188 genes that were significantly differentially expressed (FDR < 0.05) between localized and metastatic PNETs: 64 upregulated and 124 downregulated genes. A gene set enrichment analysis indicated several pathways involved in immune and inflammatory responses (i.e. T cell recruitment and signaling) that were significantly upregulated in metastatic tumors (all FDR < 0.05). Additionally, immunohistochemical analysis showed high expression of CD3+ T cells more frequently in metastatic lesions compared to localized tumors (57% vs 0%, P = 0.026).
Conclusion: Upregulation of immune and inflammatory system specific pathways appears to be associated with metastatic PNETs as compared to localized tumors. Further investigation into the specific tumor immune microenvironment of metastatic PNETs is warranted to analyze its role in disease progression and identify potential therapeutic targets.
CXCR4 as Radio-Theranostic Target for High Grade Lung NETS and NECS
Dijie Liu, Mengshi Li, Ying Hong, Claudia Robles-Planells, Edwin Sagastume, Evan Balk, Andrew Bellizzi, Sue O'Dorisio. University of Iowa, Iowa City, IA.
Background: High grade lung neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are currently incurable. CXCR4 has been closely involved in tumor proliferation and metastases indicating poor prognosis. Preliminary data has demonstrated: 1) high CXCR4 expression in poorly-differentiated NETs and NECs as compared to well-differentiated low-grade NETs in patients’ specimens 2) and specific targeting of 68Ga-Pentixafor (CXCR4 antagonist) to CXCR4 positive tumor xenografts in mice by PET/CT imaging and biodistribution. In this study, we investigated the radio-theranostics of CXCR4 antagonists targeting CXCR4 in high-grade atypical lung NET carcinoid and lung NECs.
Methods: The expression of SSTR2 and CXCR4 was assessed in a panel of typical, atypical lung neuroendocrine carcinoid and NECs cell lines by qPCR and flow cytometry. Mice tumor xenografts and patient tissue microarray were evaluated for CXCR4 expression by immunohistochemistry and graded for staging by Ki-67. PET/CT imaging and biodistribution profile of 68Ga-Pentixafor was acquired in mice bearing CXCR4-positive tumor xenografts. In vitro cytotoxicity of 90Y-, 177Lu- and 212Pb-Pentixather was evaluated by alarma blue test. Toxicity of 177Lu-Pentixather was assessed in mice to determine the maximum tolerated dose (ongoing).
Results: qPCR and flow cytometry demonstrated that 1/3 of the typical, 1/1 atypical bronchial/lung neuroendocrine carcinoid, and 5/5 lung NEC cell lines expressed CXCR4, while the SSTR2 expression was relatively low in all the NEC cell lines. PET imaging using 68Ga-pentixafor in mouse xenograft models verified that the radionuclide was targeted to the tumors. 90Y-, 177Lu- and 212Pb-Pentixather demonstrated time- and dose- dependent in vitro cytotoxicity. Mice treated with 9.25, 17.5, and 25.9 MBq of 177Lu-pentixather did not demonstrate weight loss or a change in body conditioning indicating the treatment was well-tolerated.
Conclusion: CXCR4-targeted theranostics can be used in mouse models to identify high grade lung NETs and NECs. And further radionuclide therapy targeting CXCR4 will be conducted in tumor-bearing mice.
Safety and Response of an Evans Blue-Modified Radiolabeled Somatostatin Analogue 177LU-Dota-Eb-Tate with Increased Effective Dose in the Treatment of Metastatic Neuroendocrine Tumors: A Pilot Prospective Study
Qingxing Liu,1 Yuejuan Cheng,1 Jie Zang,1 Hao Wang,1 Huimin Sui,1 Jingjing Zhang,1 Orit Jacobson,2 Zhaohui Zhu,1 Xiaoyuan Chen.21Chinese Academy of Medical Science and Peking Union Medical College, Peking Union Medical College (PUMC) Hospital, Beijing, China; 2Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD.
Background: The aim of this study was to evaluate the safety and efficacy of 177Lu-DOTA-EB-TATE, a novel radiolabeled somatostatin analogue modified by Evans Blue to increase tumor retention in patients with progressive metastatic neuroendocrine tumors (NETs).
Methods: Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: Group A (n = 6, 43±12 y) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTATATE as controls Group B (n = 7, 55 ± 7 y) administered approximately 1.11 GBq (30 mCi) 177Lu-DOTA-EB-TATE Group C (n = 6, 55 ± 10 y) administered approximately 1.85 GBq (50 mCi) 177Lu-DOTA-EB-TATE Group D (n = 14, 50 ± 10 y) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0. 68Ga-DOTATATE PET/CT were performed at baseline and 2–3 months after treatment for response evaluation.
Results: Administration was well tolerated as outlined in Table 1. No CTC 3 or 4 hematotoxicity, nephrotoxicity or hepatotoxicity was observed during or after treatment in group A-C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ%=-17.4 ± 29.3%) and group D (Δ% = -15.1 ± 39.1%), but greatly increased in Group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). According to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in group A, B, C and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax decreased in group B (Δ% = -7.3 ± 24.5%), group C (Δ% = -34.9 ± 12.4%) and group D (Δ% = -17.9 ± 19.7%), but mildly increased in group A (Δ% = 8.4 ± 48.8%) (P = 0.009). Suvmax significantly decreased in EBTATE group (group B plus C and D) (Δ% = -19.0 ± 21.5%) than TATE group (P = 0.045).
Conclusion: 177Lu-DOTA-EB-TATE is well tolerated and is more effective than 177Lu-DOTA-TATE. Both 1.85GBq (50mCi) and 3.7 GBq (100mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of 177Lu-DOTA-EB-TATE treatment and longer follow-up is warranted.
Currarino Syndrome: A Rare Condition With Potential Connection to Neuroendocrine Tumors
Alex Liu, Mohamad Sonbol, Thorvardur Halfdanarson. Mayo Clinic, Rochester, NY.
Background: Currarino syndrome (CS) is a congenital disorder that consists of a triad of anomalies: presacral mass, sacral dysgenesis, and anorectal malformations. It is an autosomal dominant condition that has been associated with mutations in the MNX1 gene. There have been few reports in the literature regarding the association of CS with neuroendocrine tumors (NETs). In this study, we sought to determine the incidence and clinical characteristics of NET in patients with CS.
Methods: Mayo Clinic electronic medical records were searched for patients with CS. Data on demographics, CS diagnosis (made clinically or genetically), NET diagnosis, family history of NET, were extracted.
Results: A total of 26 patients were identified. Genetic testing was confirmed in 11/26 patients. Only 3/26 (11.5%) of patients were found to have a concomitant diagnosis of NET with ages ranging from 22 years to 75 years at time of NET diagnosis. 3/26 patients had family history of NET. Out of the three patients with CS and NET, two had confirmed primary NET from the pre-sacral mass. The remaining patient demonstrated focal uptake within a pre-sacral mass with metastatic liver lesions, currently pending surgical evaluation for pre-sacral mass resection. Two patients received octreotide and then subsequent peptide receptor radionuclide therapy due to progression of the metastatic disease. The third patient was not treated due to complete resection of pre-sacral mass with negative margins, and currently undergoing surveillance scans.
Conclusion: In our cohort of patients with Currarino syndrome, the incidence of neuroendocrine tumors is estimated at 11.53%. The coexistence of two very rare conditions, CS and presacral primary NETs and the absence of association with NETs arising in other locations, suggests there may be an etiological connection between CS and presacral primary NETs.
Accuracy of Ki-67 Index Obtained From FNA Specimens in the Diagnosis and Grading of Pancreatic Neuroendocrine Tumors
Austin Livingston, Erin Strong, Kathleen Christians, Susan Tsai, Abdul Khan, Kulwinder Dua, Bryan Hunt, Catherine Hagen, Douglas Evans, Callisia Clarke. Medical College of Wisconsin, Milwaukee, WI.
Background: Proliferative index as determined by Ki-67 immunostaining of histology sections (IHC) carries significant prognostic and therapeutic relevance for patients with pancreatic neuroendocrine tumors (pNETs). However, the experience with assessment of Ki-67 from needle biopsy specimens (endoscopic ultrasound-guided fine-needle aspiration EUS-FNA) is not well defined. Importantly, FNA biopsy is the most common form of tissue acquisition used to confirm the diagnosis of a potentially malignant neuroendocrine tumor.
Methods: We performed a retrospective of all patients with suspected pNET referred for diagnostic EUS-FNA at the Medical College of Wisconsin between 2009 and 2018. We compared the Ki-67 index obtained from FNA biopsies (cytology) and tumor histology.
Results: EUS-FNA of pNETs was performed in 80 consecutive patients and was diagnostic in 69 (86%). Of the 11 (14%) non-diagnostic samples, 9 had insufficient tissue, 1 was unable to be classified by cytomorphology, and 1 was unsuccessful due to tumor anatomy. Surgical specimen were available for comparison with the FNA biopsies in 51 (73.9%) of the 69 patients. Cytologic Ki-67 correlated with histologic Ki-67 (Pearson’s coefficient r = 0.92). Using histology as the gold standard, 43 (84%) of 51 tumors were accurately graded by cytology. Of the 26 histologic G1 tumors, 25 (96%) were accurately identified by cytology and 1 was inaccurately classified G2. Of 17 G2 tumors, 11 (65%) were correctly classified on cytology and 6 (35%) were inaccurately classified as G1. All 7 G3 tumors were accurately graded on cytology. Overall accuracy in classification was 44 (86%) of 51. 49 (98%) tumors were accurately deemed well–differentiated on cytology, while 1 G3 well differentiated pNET was in accurately reported to be poorly differentiated.
Conclusion: Ki-67 index as determined on cytology by EUS-FNA biopsy correlates with the histologic assessment of Ki-67. G2 tumors at the lower end of Ki-67 are at highest risk of being misclassified.
Real-World Comparative Analysis of Lanreotide and Octreotide Long-Acting Release (Lar) Use for Neuroendocrine Tumors (NETS) in Canada
Jonathan Loree,1 Marion Feuilly,2 Callahan Laforty,3 Anna Liovas,2 Heather McKechnie,2 Winson Cheung.41BC Cancer, Vancouver, Canada; 2Ipsen Pharma, Boulogne-Billancourt, France; 3IQVIA, Toronto, Canada; 4University of Calgary, Calgary, Canada.
Background: Somatostatin analogues (SSAs) provide symptomatic control and anti-proliferative activity in NETs. Data comparing the two currently available long-acting SSAs lanreotide and octreotide LAR are limited.
Methods: Claims data from the IQVIA Private Drug Plan, Ontario Drug Benefit program and Régie de l’assurance-maladie du Québec in Canada were compiled for patients receiving their first SSA between 09/2015-06/2018. Injection burden, rescue medication use, treatment persistence, and costs were compared over a 12-month period from first SSA prescription. Averages were compared by t-test and persistence on therapy was evaluated by log-rank test.
Results: A total of 908 patients were included: 375 received lanreotide 120 mg subcutaneously and 533 received octreotide LAR 30 mg intramuscularly. During the first 30 days of therapy, octreotide LAR use was associated with increased use of rescue medications, such as short acting octreotide, as compared to lanreotide (0.22 vs 0.03 claims/patient, P < 0.0001), but this difference disappeared after Day 30 and by Day 360 decreased to 0.03 vs 0.02 claims/patient P = 0.43. The combination of short-acting octreotide as rescue medication and octreotide LAR resulted in more injections/year for patients versus lanreotide (13.4 vs 12.5, P < 0.0001). More patients remained on lanreotide than octreotide LAR after 1 year (70% vs 55%, log-rank P = 0.0005). Reasons for discontinuation were not documented in administrative data. Mean total annual costs that also considered rescue medications were lower for lanreotide than octreotide LAR ($27,829.35 versus $31,255.49 CAD/patient, respectively, P < 0.0001).
Conclusions: In the absence of clinical trials directly comparing lanreotide and octreotide LAR, factors driving the selection of SSA are unclear. Our real-world study using administrative data suggests that treatment with lanreotide appears less burdensome and less costly and results in greater treatment persistence than octreotide LAR.
Care Excellence: A Survey of American NET Centers for Self-Assessment by Established Criteria
Cindy Lovelace,1 Margaret Bean,1 Eric Liu,2 George Fisher,3 Thomas O'Dorisio.41The Healing NET Foundation, Nashville, TN; 2Rocky Mountain Cancer Centers, Denver, CO; 3Stanford Health Care, Palo Alto, CA; 4University of Iowa Health Care, Iowa City, IA.
Background: The Healing NET Foundation (HNF) is interested in optimizing care for NET patients. One way to do this is to inspire NET centers to expand their expertise and services based on identified components that contribute to care excellence. HNF built a survey to help neuroendocrine cancer programs at American medical centers self-assess against the criteria for the ENETS Center of Excellence (CoE) designation.
Methods: A task force at the 3rd HNF Summit analyzed the ENETS CoE requirements and presented key components to the 60-member faculty of NET experts. The ARS response to the presentation was that 85% would consider trying to become an “Advanced NET Center” and 76% preferred an external audit to self-study for the designation. Based on that feedback, HNF developed a survey around the ENETS CoE criteria in partnership with Thomas O’Dorisio, MD, of the University of Iowa, the only American center to be designated an ENETS CoE. The HNF survey was sent to Summit faculty representing twenty-five US medical centers offering NET care. Nineteen centers completed surveys between October 2018 and May 2019.
Results: A majority of surveyed centers claimed to meet ENETS criteria in some basic measures, such as enough new GEP-NETs patients yearly, NET expertise in necessary disciplines, and regular tumor board meetings. A majority of centers report falling below ENETs criteria in new patients discussed in tumor board, standard operating procedures across disciplines, and patients enrolled in clinical trials. See the data presented in Table 1.
Conclusion: Because details vary from center to center, a possible future HNF project is to develop an online profile of centers listing key measures, such as are outlined in this survey, that are voluntarily provided by centers as a resource for patients seeking advanced care and as a resource for centers striving to improve care.
Patterns of Care and Outcomes in Localized, Grade 3, Gastroenteropancreatic Neuroendocrine Neoplasms: A 10-Year Experience in a Tertiary Center
Ivan Lyra Gonzalez, Stephanie Moignard, Charles Lim, Osvaldo Espin Garcia, Ozgur Mete, Carol-Anne Moulton, Monika Krzyzanowska, Raymond Jang. Princess Margaret Cancer Centre, Toronto, Canada.
Background: High-grade Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN) represent 5% of all GEP-NEN. Few high grade GEP-NEN present with localized disease, and therefore evidence is lacking on the best treatment approach for these patients.
Methods: A retrospective analysis of patients diagnosed with a localized high-grade GEP-NEN (defined as having a Ki-67 of > 20%) at Princess Margaret Cancer Centre between 2008 and 2017 was conducted. Kaplan-Meier and Cox proportional hazards methods were used to analyze progression free survival (PFS) and overall survival (OS) with treatment modality (surgery or chemotherapy ± other therapy), Ki-67 and age as covariates in multivariate analysis.
Results: Among 640 GEP-NENs treated during this timeframe, 32 (5%) presented with localized disease. The most common primaries were colon (31.3%) and pancreas (21.9%). Poorly differentiated tumors accounted for 15 (46.9%) patients, well-differentiated for 5 (15.6%), and either mixed/not reported for 12 (37.5%). The Ki-67 was 21-60% in 34.4% patients and >60% in 62.5%. Surgery was the most frequent modality in 23 (71.8%) patients, followed by chemotherapy in 19 (59.4%) patients. Half of the patients were assigned to a multimodality treatment, of which surgery with chemotherapy was the most common (N = 10, 31.3%). Median OS was not reached, and median PFS was 22.2 months. The estimated 3-year OS and PFS rates were 69% (95% CI, 55–88%), and 34% (95% CI, 19–59%) respectively. In multivariate analysis, only surgery was associated with an improved PFS (HR 0.27 [95% CI, 0.08–0.98]) with a HR of 0.29 [95% CI, 0.05–1.45] for OS.
Conclusion: Surgery followed by chemotherapy were the most commonly used treatment modalities for localized, high grade GEP-NENs. Patients who had surgery had better PFS compared with those treated non-surgically, highlighting the importance of surgery in this patient population. Although the absolute number of patients is small, our experience represents some of the largest, contemporary cohorts examining localized high grade GEP-NENs.
RABL6A Promotes PNET Angiogenesis and Development In Vivo
Chandra Kumar Maharjan, Courtney Kaemmer, Casey Bauchle, Samuel Stephens, David Meyerholz, Dawn Quelle. The University of Iowa, Iowa City, IA.
Background: Pancreatic neuroendocrine tumors (PNETs) progress slowly but relentlessly, invariably resulting in untreatable metastatic disease. A better understanding of mechanisms driving PNET pathogenesis will guide more effective and more targeted therapies. We recently discovered a novel oncogenic driver of tumor cell survival and proliferation, named RABL6A, that promotes clinically relevant pathways (AKT-mTOR and VEGFR) in PNET cells. Genetic and proteomic tumor analyses show RABL6A is highly expressed and activated in patient PNETs. Here, we use genetically altered mouse models to test the hypothesis that RABL6A drives PNET formation and angiogenesis in vivo.
Methods: RIP/Tag2 (RT2) mice express oncogenic SV40 large T-antigen (Tag) under the rat insulin promoter (RIP), resulting in islet β cell transformation and development of hyperplastic islets, angiogenic islets, and insulinomas in a time-dependent fashion. RT2 mice were crossed with RABL6A knockout (KO) mice to generate four cohorts: WT, RT2, RABL6A KO, and dual targeted RT2-RABL6A KO. Tumor formation was tracked via weekly assessment of plasma insulin by ELISA. Pancreata of euthanized mice were either perfused with collagenase to isolate islets for molecular analyses or fixed in paraformaldehyde for histopathological studies at specific time points.
Results: RT2 mice developed high-grade angiogenic PNETs whose development was effectively tracked by increases in plasma insulin levels. We are still expanding the RT2-RABL6A KO cohort of animals, but initial results for female RT2 vs RT2-RABL6A KO mice are compelling. RABL6A loss led to significant reductions in PNET tumor number and size (endocrine area), number of angiogenic islets, and number of mitoses within islets. Those changes correlated with extended survival in RT2 females lacking RABL6A.
Conclusion: Studies are ongoing. However, early data suggest RABL6A promotes PNET development in vivo by increasing tumor cell proliferation and promoting the angiogenic switch.
Clinicopathological, Molecular and Genetic Characteristics of Thymic Tumors in Multiple Endocrine Neoplasia 1 Syndrome
Adel Mandl,1 James Welch,1 Jaydira Del Rivero,2 Craig Cochran,1 Roxanne Merkel,1 David Schrump,2 William Simonds,1 Robert Jensen,1 Lee Weinstein,1 Sunita Agarwal,1 Jenny Blau,1 R. Ripley,3 Vaishali Parekh,1 Gayathri Veeraraghavan,1 Zahraa Sater.11National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; 2National Cancer Institute, Bethesda, MD; 3National Institutes of Health, Bethesda, MD.
Background: Thymic carcinoids associated with multiple endocrine neoplasia 1 (MEN1) are rare yet highly aggressive tumors that have a high mortality rate. The goal of this study was to analyze the clinicopathological, genetic, and molecular features of thymic tumors in MEN1 patients at our institution.
Methods: In our longstanding prospective natural history study, we identified thymic tumors in 14/350 (4%) germline MEN1mutation patients (12 carcinoids, 2 thymomas). We evaluated demographic characteristics, MEN1 related diseases as well as recurrence, and overall survival. We analyzed tumor histopathology and isolated DNA to evaluate for loss of heterozygosity at the MEN1 locus and performed RNA sequencing to help further understand the characteristics of the tumors.
Results: Thymic carcinoids occurred exclusively in men 2 females had thymomas. Median age of diagnosis was 43 years old (range, 29–65), 7/14 (50%) of the patients were smokers, and the mean tumor diameter was 7.18 cm (range, 2.5–15 cm). ACTH production was not detected in any of the cases. Tumor recurrence occurred in 8 patients. Familial clustering was identified in 6 patients within 5 families. MEN1 mutations did not show any specific clustering within the MEN1 gene but a preponderance of protein truncating mutations was observed. Loss of heterozygosity analysis is currently in progress. RNA-sequencing has helped to determine subtypes of MEN1-associated thymic tumors as well as to identify potential therapeutic targets for small molecule inhibitors.
Conclusion: We present the clinicopathological, genetic, and molecular features of 14 thymic tumors in MEN1 patients. Familial clustering of thymic tumors within MEN1 families suggests the need for increased surveillance in affected male family members. Histopathological analysis and characterization of RNA-sequencing data have helped to determine subtypes of MEN1-associated thymic tumors as well as to identify potential therapeutic targets for small molecule inhibitors.
Development of Anti-SSTR CAR T Cells for Future Treatment of NETS
Barbara Mandriani,1 Mauro Cives,1 Eleonora Pelle',1 Davide Quaresmini,1 Maria Ramello,2 Jonathan Strosberg,2 Daniel Abate-Daga,2 Franco Silvestris.11University of Bari Aldo Moro, Bari, Italy; 2H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Background: Neuroendocrine tumors (NETs) overexpress somatostatin receptors (SSTRs). Here, we investigate the antitumor activity of chimeric antigen receptor (CAR)-T cells directed against SSTRs.
Methods: We developed a second-generation CAR-like construct containing two molecules of octreotide in the extracellular moiety and CD28 as costimulatory module. The construct was cloned in a pMSGV1-28Z retroviral vector and then transduced in CD8+ T cells from a healthy donor. BON1, CM, and QGP1 NET cell lines were transduced to express luciferase (Luc) and were thus screened for membrane SSTR1-5 expression by Western blot (WB). Co-culture experiments were performed at effector/target (E/T) ratios ranging from 10:1 to 1:10 for up to 48 hrs. Tumor cell cytotoxicity was then assessed by bioluminescence imaging, while the release of IFN-γ, IL-2 and TNF-α by activated CAR-T cells was assessed by ELISA. NSG female mice (n = 6/group) were subcutaneously injected with 4x106 Luc+ NET cells, and were then subjected to either intratumor or intravenous administration of anti-SSTR CAR-T cells, or untransduced (UT) T cells.
Results: CM and BON1 cells appeared to overexpress SSTRs, whereas low amounts of these receptors were detected in QGP1 cells. Following WB confirmation of the CAR expression by transduced lymphocytes, anti-SSTR CAR-T cells were co-incubated with target cells, and induced tumor cell death in up to 40% (±8%) of CM cells when an E/T ratio of 1:1 was used. The tumoricidal effect of CAR-T cells was time-dependent and peaked at 48 hrs. When compared with UT T cells, CAR-T cells secreted significantly higher levels (P < 0.01) of IFN-γ (up to 1057 pg/ml), IL-2 (up to 845 pg/ml) and TNF-α (up to 1048 pg/ml) after co-incubation with CM cells. Experiments in mice are currently underway.
Conclusion: Anti-SSTR CAR-T cells exhibit antitumor activity against NET cell lines. The tumoricidal activity of CAR-T cells is critically influenced by the density of membrane expression of SSTRs.
High Ki-67 Index is Indicative for Lymph Node Metastasis in Small Non-Functioning Pancreatic Neuroendocrine Neoplasms
Toshihiko Masui, Kazuyuki Nagai, Takayuki Anazawa, Kenzo Nakano, Yuichiro Uchida, Akitada Yogo, Norio Emoto, Kyoichi Takaori, Shinji Uemoto. Kyoto University, Kyoto, Japan.
Background: Small PanNEN is not rare. The Surveillance Epidemiology and End Results database demonstrated that a large proportion of PanNEN are attributable to tumors ≤2 cm. These imply the necessity of identifying risk factors as well as the ranges of lymph node metastasis in such small tumors. This study evaluated clinicopathological factors associated with lymph node metastasis in patients with non-functioning pancreatic neuroendocrine neoplasms (PanNEN) and specifically analyzed the risk factors and range of lymph node metastasis for tumors ≤2 cm in diameter.
Methods: Consecutively diagnosed PanNEN patients at our hospital from January 2000 to June 2018 were evaluated in this study. We analyzed 69 non-functioning sporadic PanNEN patients in whom R0 resection with no distant metastasis as well as 43 patients with tumors ≤20 mm in radiological diameter.
Results: Nineteen PanNEN patients (27.5%) had lymph node metastasis, including seven patients (16.3%) with small PanNEN. Large radiological diameter, high Ki-67 as well as cyst formation correlated significantly with positive lymph node metastasis. In patients with tumors ≤20 mm in diameter, high Ki-67 index correlated significantly with lymph node metastasis. When we set the cut-off Ki67 index as 3.3%, 2 out of 43 patients had lymph node metastasis. Tumors in the uncinate process readily metastasized to the region around the superior mesenteric artery.
Conclusion: These findings indicate that high Ki-67 index suggests a necessity of lymphadenectomy in tumors ≤20 mm and lymphadenectomy should be applied to the region spatially adjacent to the primary tumor.
Novel Use of a CLIA-Certified CDKN2C Loss Assay in Sporadic Medullary Thyroid Carcinoma
Jessica Maxwell, Maria Gule-Monroe, Vivek Subbiah, Mimi Hu, Nancy Perrier, Maria Cabanillas, Jeffrey Lee, Paul Graham, Gilbert Cote, Naifa Busaidy, Elizabeth Grubbs. UT MD Anderson Cancer Center, Houston, TX.
Background: The cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma (sMTC) tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in MTC patients, independent of RET status. We evaluated CDKN2C loss in a prospective clinical environment using a novel CLIA-certified assay to confirm its association with aggressive disease and interrogate response to targeted therapy.
Methods: Patients with advanced sMTC underwent tumor genotyping for the purpose of management of targeted therapy and prognostication.
Results: Tumors from 83 patients with advanced sMTC were evaluated for CDKN2C loss from 5/2017 to 5/2019. Thirty-three patients had haploid loss (1n) (51%), 32 (49%) were diploid wildtype (2n), and the test was indeterminate in 15 cases (18%). Forty-five patients (70%) had a somatic RET mutation and 38% had alteration of both genes. Thirteen (20%) patients presented with M1 disease and 47 (73%) eventually developed distant metastasis. Patients with CDKN2C loss had a shorter time-to-distant-metastasis compared to those with wildtype CDKN2C (1.7 versus 6.6 years P = 0.01). Patients with fewer genetic alterations had longer time-to-distant-metastasis, but this did not reach statistical significance (P = 0.06, Table 1). Of the 34 patients treated with targeted therapies, median time from diagnosis to initiating therapy was 1.8 years in those with CDKN2C loss versus 6.1 years in wildtype patients (P = 0.02).
Conclusion: This is the first evaluation in the clinical setting of CDKN2C haploinsufficiency in sMTC. Although a larger cohort and longer follow-up will be required, loss of CDKN2C is frequent and loss seems to be associated with more aggressive disease. Additionally, loss may indicate patients that might receive benefit from treatment with a CDK inhibitor.
Real-World Comparison of Lanreotide and Octreotide LAR Use for Neuroendocrine Tumors (NETS) in British Columbia, Canada
Shehara Mendis,1 Justin Jao,1 M.K.C. Lee,1 Sharlene Gill,1 David Schaeffer,2 Daniel Renouf,1 Jonathan Loree.11BC Cancer, Vancouver, Canada; 2Vancouver General Hospital, Vancouver, Canada.
Background: Long-acting somatostatin analogues (LA-SSAs) have symptomatic and anti-proliferative effects in well differentiated NETs of the pancreas and small bowel. However, no head-to-head trials comparing efficacy of LA-SSAs exist.
Methods: We evaluated prescribing pattern and efficacy of lanreotide and octreotide LAR in patients diagnosed with pancreatic or small bowel NETs between 1990 and 2015 in a population-based cohort from British Columbia, Canada. Prescribing patterns, progression free survival (PFS), overall survival (OS), and time to treatment failure (TTF: cessation of LA-SSA for any reason) were compared between agents. Lanreotide funding began in 2015, and octreotide LAR funding began in 1999 locally. Patients who discontinued an SSA for reasons other than progression (ie post surgical debulking) were censored from PFS.
Results: Of 770 cases identified, 305 received LA-SSA. Baseline characteristics are in Table 1. In the first line, 30 received lanreotide, of whom 2 switched to octreotide LAR (7%) during therapy, and 275 patients received octreotide LAR, of whom 37 (13%) switched to lanreotide (P = 0.29). There were no differences in age (P = 0.95), gender (P = 0.54), primary site (P = 0.51) or grade (P = 0.69) between groups. Use of dose escalation (7% vs 35%, P < 0.001) was higher with octreotide LAR but rescue short acting octreotide use did not differ (0% vs 10%, P = 0.09). Median PFS (Hazard Ratio [HR], 0.48 95% confidence interval (95% CI), 0.30-0.78) and OS (HR, 0.38; 95% CI, 0.21-0.68) were longer with lanreotide than octreotide LAR in first line. TTF was comparable between groups (P = 0.57) median follow-up was longer with octreotide LAR (P < 0.001).
Conclusion: Lanreotide was associated with longer PFS, OS, and less use of dose escalation versus octreotide LAR. This may be due to small numbers of patients receiving lanreotide due to later approval and differences in follow-up. Validation in larger cohorts and greater follow up is needed to directly compare efficacy.
Role of Functional Imaging for Response Assessment of Lu177-Dotatate Therapy
Erik Mittra, Nadine Mallak, Adam Brown, Bree Murphy, Rodney Pommier. Oregon Health & Science University, Portland, OR.
Background: Since the approval of Lu177-DOTATATE, many patients with progressive neuroendocrine tumor (NET) have now been treated. But, the role of functional imaging for response assessment is not well established and is the goal of this study.
Methods: This is an IRB-approved, prospective study of 45 patients (20 women, 25 men, age range, 33–82) who had Lu177-DOTATATE therapy for NETs at our institution. All patients had a baseline Ga68-DOTATATE PET/CT. To date, 17 patients have completed 4 cycles, 10 patients 3 cycles, 8 patients 2 cycles, and 10 patients 1 cycle of therapy. All patients received a whole-body planar gamma scan 3-4 hours after their therapy, as well as a repeat Ga68-DOTATATE PET/CT 3 months after completion of all 4 cycles. We evaluated the relative uptake on the scans in comparison to each other as well as to clinical outcomes.
Results: The distribution of Lu177 on the planar scans were highly concordant with the baseline Ga68-DOTATATE PET/CT, accounting for differential resolution. Each of the successive post-therapy Lu177 whole-body scans were usually similar to each other (stable disease) per patient, with some showing reduction in number or degree of uptake (partial response). None showed worsening disease. Seven patients have received a post-therapy Ga68-DOTATATE PET/CT scan to date. In comparison to the baseline PET, the findings are variable, with some showing mild improvement, others with stable disease, and others with mild increase in size and/or uptake of lesions.
Conclusion: The post-therapy Lu177 whole-body scan can be used to confirm biodistribution of the therapeutic isotope to the same sites of disease seen on the pre-therapy Ga68-DOTATATE PET/CT and as a quick assessment of disease status between cycles of therapy. The post-therapy Ga68-DOTATATE PET/CT shows variable changes in comparison to the baseline scan and does not necessarily correlate to clinical response in the same time-frame, but may to longer-term outcomes.
Single-Institution Clinical Experience of Toxicity With LU177-DOTATATE Therapy
Erik Mittra, Bree Murphy, Adam Brown, Nadine Mallak, Rodney Pommier. Oregon Health & Science University, Portland, OR.
Background: With the FDA-approval of Lu177-DOTATATE in 2018, we are now gaining real-world experience with this therapy, which may be different than results from clinical trials. It is important to share these results and learn about institutional variations. This project focuses on the toxicity from Lu177-DOTATATE.
Methods: This is an IRB-approved, retrospective study of 45 patients (20 women, 25 men, age range, 33–82) who have had at least one Lu177-DOTATATE therapy for NETs at our institution. To date, 17 patients have completed 4 cycles, 10 patients 3 cycles, 8 patients 2 cycles, and 10 patients 1 cycle of therapy. All but three patients had GEP-NETS. The others had renal or lung primaries or paraganglioma. We compiled data on all types of toxicity relative to the number of cycles of therapy given.
Results: Of the 45 patient started on the therapy, 9 died before completing the therapy due to progressive disease. Five died after 1 cycle, two after 2 cycles, one after 3 cycles, and one after 4 cycles. Another 10 patients stopped therapy due to persistent CTCAE Grade 2 or higher toxicity. In all cases, thrombocytopenia was the issue, but without a correlation to the extent of bone disease or another factor. The average baseline platelets for those 10 patients was 176 (±70), and their nadir was 41 (±17). The average baseline platelets for those that completed all 4 cycles successfully was 240 (±98), and the nadir was 189 (±82). No patients experienced significant renal or hepatotoxicity.
Conclusion: In our experience, thrombocytopenia is the major toxicity seen, with 22% experiencing a significant reduction in platelets disrupting therapy. Other toxicity was not seen and a specific predictive pattern could not be identified. Additionally, starting the therapy sooner would likely prevent patients from not completing the therapy due to rapidly progressive disease.
Evaluation of Small Bowel Neuroendocrine Tumor Metastases by 68Ga-DOTATATE PET/CT: A Single Institution Review
Hannah Monahan, Ajit Goenka, Michael Wells, Stephen Broski, Annie Packard, Thorvardur Halfdanarson. Mayo Clinic, Rochester, MN.
Background: Gastrointestinal neuroendocrine tumors (GI-NETs) are malignancies with varied pathologic and clinical behaviors. Most GI-NETs involve the small intestine (38%) and approximately 50% of patients demonstrate regional or distant metastatic disease at the time of diagnosis. Increased incidence in recent years has mainly been attributed to physician awareness alongside advancements in endoscopy and radiologic imaging. One such imaging advancement is 68Ga-DOTATATE PET/CT, which provides greater sensitivity of tumor detection compared to CT and MRI, thus impacting clinical management. The purpose of this study was to review the prevalence and pattern of small bowel NET metastases identified on 68Ga-DOTATATE PET/CTs performed at our institution.
Methods: A retrospective review of 68Ga-DOTATATE PET/CTs from November 2016 through December 2017 was performed. Two board certified nuclear radiologists independently reviewed the imaging, documenting the presence of metastases: liver, spleen, bone, peritoneum, lymph nodes (mesenteric, retroperitoneal, upper abdominal, iliac chain) and distant (beyond the abdominal cavity). The reviewers were blinded to other imaging modalities, and discrepancies after initial interpretation were revisited to establish agreement.
Results: Seventy eight 68Ga-DOTATATE PET/CT exams evaluating small bowel NETs were included in this study, with 29.5% (N = 23) performed for initial staging. Of initial staging exams, 52.2% (N = 12) demonstrated metastatic disease and the overall rate of metastatic disease, staging and re-staging) was 72%. Metastatic locations are shown in Table 1. Atypical metastases included cardiac (n = 2) and breast (n = 1).
Conclusion: This study demonstrates a similar prevalence of liver (53%) and higher prevalence of bone (19%) metastases compared to current knowledge. Additionally, the prevalence of peritoneal metastases (36%) was significantly higher than previously reported. By reviewing the common and uncommon patterns of metastatic disease in GI-NETs, an informed radiologist can provide accurate staging and facilitate appropriate patient management.
Incidence Patterns of Adrenocortical Carcinomas and Malignant Pheochromocytomas and Paragangliomas in California
Claire Mulvey, Alan Paciorek, Brandon Shih, Meg McKinley, Dawn Pearson, Iona Cheng, Ann Griffin, Quan-Yang Duh, Sanziana Roman, Julie Sosa, Insoo Suh, Chienying Liu, Katherine Van Loon, Emily Bergsland. University of California, San Francisco, San Francisco, CA.
Background: Pheochromocytomas (PHEO), paragangliomas (PGL), and adrenocortical carcinomas (ACC) are rare endocrine malignancies with limited data regarding risk factors. We sought to characterize the burden of malignant PHEO, PGL, and ACC in California.
Methods: Using the population-based California Cancer Registry, we identified all new diagnoses of malignant PHEO, PGL, and ACC in California from 1992–2016 (ICD-O-3 codes 8700/3, 8680/3, and 8393/3). We estimated age-adjusted incidence rates (AIR) standardized to the 2000 United States census. We compared AIRs by sex, race/ethnicity, and county of residence categorized as urban versus suburban/rural using SEER*Stat and generated IR ratios (IRR).
Results: Between 1992-2016, there were 261 incident cases of malignant PHEO, 271 of malignant PGL, and 866 of ACC in California. Overall AIR per 100,000 person-years were 0.03 for PHEO, 0.025 for PGL, and 0.10 for ACC. Incidence differed by both sex and race/ethnicity (Table 1). Men had a higher incidence of PGL than women (P < 0.05) and tended towards higher incidence of PHEO (P = 0.09), while men had a lower incidence of ACC than women (P < 0.05). Compared with non-Hispanic White Californians, non-Hispanic Black Californians had higher PHEO incidence, whereas PGL incidence was lower for Hispanic and Asian/Pacific Islander Californians (P < 0.05). Compared with non-Hispanic White Californians, ACC incidence was lower in non-Hispanic Black, Hispanic, and Asian/Pacific Islander Californians (all P < 0.05). There were no differences in incidence of either PHEO, PGL, or ACC for urban versus suburban/rural counties.
Conclusion: Malignant PHEO, PGL, and ACC remain rare cancers in California, with disease-specific differences in incidence by sex and race/ethnicity but not by urban versus suburban/rural county of residence. We report novel findings of a higher incidence of malignant PHEO in non-Hispanic Black Californians and a lower incidence of malignant PGL in Hispanic and Asian/Pacific Islander Californians. We also confirm higher incidence of ACC in women and non-Hispanic White Californians.
Autophagy Inhibition Induces Apoptosis on Low-Grade Pancreatic Neuroendocrine Tumor Mouse Model
Kenzo Nakano, Toshihiko Masui, Norio Emoto, Akitada Yogo, Yuichiro Uchida, Kazuyuki Nagai, Takayuki Anazawa, Kyoichi Takaori, Yoshiya Kawaguchi, Shinji Uemoto. Kyoto University, Kyoto, Japan.
Background: Autophagy is an intrinsic pathway through which cells digest organelles or foreign proteins to supply amino acids. Autophagy inhibition has been shown inhibitory effect on cancer cells, and clinical trials using autophagy inhibitor chloroquine (CQ) or hydroxychloroquine (HCQ) are ongoing in several cancers. The aim of this study is to investigate the mechanism how CQ induces apoptosis on PanNET cell lines and to test whether HCQ shows inhibitory effect on PanNET models in vivo.
Methods: PanNET cell lines MIN6 and QGP-1 were used. Genetically engineered mice with heterozygous mutation in Men1 gene (Men1+/ΔN3-8) were bred for 18 months and then HCQ 10 mg/kg or saline was intraperitoneally administered for 21 consecutive days. On day 22, mice were sacrificed and whole pancreas were sectioned and histologically analyzed.
Results: CQ treatment resulted in reduced proliferation and apoptosis induction on both PanNET cell lines. With CQ treatment, endoplasmic reticulum (ER) stress was induced and unfolded protein response was activated through the PERK-eIF2α-ATF4 pathway resulting in the expression of pro-apoptotic protein CHOP, indicating the ER stress-mediated apoptotic cell death. 18-month-old Men1+/ΔN3-8 mice had pancreatic tumors with low Ki-67 labeling indexes. HCQ administration decreased mean tumor size, but there was no significant change in the number of tumor or Ki-67 labeling index. Histological analyses showed more TUNEL positive apoptotic cells and more CHOP positive cells in HCQ group.
Conclusion: Autophagy inhibition induced apoptosis on PanNET cell lines and Men1+/ΔN3-8mouse PanNET model. Inhibitory effect of HCQ might be beneficial on PanNET patients.
MicroRNA-Based Classification of Neuroendocrine Neoplasms
Jina Nanayakkara,1 Kathrin Tyryshkin,1 Xiaojing Yang,1 Justin Wong,1 Thomas Tuschl,2 Neil Renwick.11Queen's University, Kingston, Canada; 2The Rockefeller University, New York, NY.
Background: Neuroendocrine neoplasms (NENs) are clinically diverse tumors that lack a single defining molecular marker. microRNAs (miRNAs) are small RNA molecules that are excellent biomarkers due to their stability, abundance, cell-type- and disease-stage specificity. To date, there are no comprehensive miRNA profiling studies of multiple NEN pathological types. Given their utility in cancer classification, we hypothesized that miRNAs can be used to define and classify NENs.
Methods: Comprehensive miRNA expression profiles for 221 archived NEN samples, representing 15 different pathological types, and 114 non-NEN controls were generated through barcoded small RNA sequencing. Following data quality control, we compared miRNA expression in NEN and non-NEN samples through high expression analyses and built a hierarchical machine-learning model for NEN classification.
Results: miR-375 was abundantly expressed in all NENs and significantly higher in NEN compared to non-NEN tissues. Within NENs, machine learning models identified 17 miRNAs that could accurately discriminate all 15 pathological types. These miRNAs were subsequently used in a multi-layer machine-learning model that separates NENs on developmental (epithelium vs neuroectoderm) and anatomic origin, with 97–100% accuracy at each layer of the classifier.
Conclusion: We provide compelling evidence that miR-375 is a universal mono-analyte marker of NEN tissue differentiation. We also show that NENs can be accurately classified through high quality miRNA expression profiling and machine-learning models. We plan to leverage our findings to improve NEN detection and to advance our knowledge of neuroendocrine tumorigenesis.
Gastro-Entero-Pancreatic Neuroendocrine Tumors in Young Adults - Fare Better Than Older Patients
Andrew Nguyen, Camille Stewart, Christopher Larocca, James De Andrade, Phillip Ituarte, Byrne Lee, Sue Chang, Jonathan Kessler, Daneng Li, Gagandeep Singh. City of Hope, Duarte, CA.
Background: While patients who are treated for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) tend to be in their 6th and 7th decades of life, there is a distinct subset of patients who face this diagnosis earlier. Herein, we query in a population-based study, clinical and pathologic features and survival of patients of ages 18–35 with a diagnosis of a primary GEP-NET.
Methods: A retrospective study of the NCDB including patients from 2004 to 2014 with a primary gastrointestinal or pancreatic neuroendocrine tumor was performed. Patients were stratified by age. Kaplan-Meier and multivariate Cox proportional hazards analyses were performed.
Results: We identified 31,983 patients with a diagnosis of a primary GEP-NETs in the NCDB. The median age of diagnosis was 59 years and 5% of patients were under the age of 35. While 5-year overall survival for all patients was 66%, for those patients of ages 18-35, it was 84%, which was higher than any other age group (P < 0.001). We looked at distributions of stage and grade across age groups. 55.9% of patients ages 18–35 had stage 1 disease, whereas those in groups ages 36–70, and ≥70, had frequencies of stage 1 disease of 36.2%, and 27.8%, respectively. Young patients had lower grade of disease as 78.5% of patients ages 18–35 had well-differentiated grade, whereas those in groups ages 36–70, and ≥70, had frequencies of well-differentiated grade of 72.4%, and 64.4%, respectively. Multivariate analysis for overall survival found that young age, low grade, and early stage to be associated with lower risk of mortality.
Conclusion: Five percent of patients with GEP-NETs are under the age of 35. These patients tend to have earlier stage disease and lower grade tumors, which contribute to a much better survival compared to older patients. These findings suggest that younger patients are ideal candidates for an aggressive surgical approach when deemed resectable.
Renal Neuroendocrine Tumors: Definitive Surgery is the Cornerstone of Longevity
Andrew Nguyen, James De Andrade, Christopher Larocca, Camille Stewart, Phillip Ituarte, Jonathan Kessler, Gagandeep Singh, Sue Chang, Daneng Li. City of Hope, Duarte, CA.
Background: While pancreatic, lung, and gastrointestinal primary neuroendocrine tumors are uncommon, renal neuroendocrine tumors are many times rarer with less than 100 cases reported in the literature. The natural history of these tumors has not been well characterized. We performed the first population-based study that describes patient and tumor characteristics as well as survival patterns of patients diagnosed with renal neuroendocrine tumors.
Methods: A retrospective study from the SEER database including patients from 1973 to 2014 with a histologic diagnosis of a primary renal neuroendocrine tumor was performed. Patients were stratified by stage and operative versus non-operative management. Kaplan-Meier and multivariate Cox proportional hazards analyses were performed.
Results: 114 patients were identified with primary renal neuroendocrine tumors. For all patients, 5-year overall survival was 62% and disease-specific survival was 67%. Median age at diagnosis was 56, where patients who were managed operatively were younger (operative, median age 53 versus non-operative, median age 65, P = 0.0019). Those who underwent operative management had a 5-year overall survival of 78% and a disease-specific survival of 82%, whereas those with non-operative management had a 5-year overall survival of 28% and disease-specific survival of 34%. In addition to being younger, patients who underwent operative management had earlier stage disease (63/80, 78.8% patients with local or regional disease). In the 34 patients who did not have an operation, 26 patients (76.5%) had distant disease at presentation. On univariate analysis, operative management reduced risk of all-cause mortality (HR, 0.19; 95% CI, 0.11–0.34; P < 0.001), yet in the multivariate model, this risk reduction was no longer significant. Younger age, lower tumor grade, local disease was associated with reduced risk of mortality in both univariate and multivariate analyses.
Conclusion: Renal neuroendocrine tumors are rare. Surgery remains the cornerstone for longevity. Increased survival was observed in patients of younger age, earlier stage and lower grade tumors.
Incidence and Survival Patterns of Gastroenteropancreatic Neuroendocrine Neoplasms in California
Alan Paciorek, Brandon Shih, Meg McKinley, Iona Cheng, Li Zhang, Claire Mulvey, Ann Griffin, Eric Nakakura, Katherine Van Loon, Emily Bergsland. University of California San Francisco, San Francisco, CA.
Background: Neuroendocrine neoplasms (NEN) are a heterogeneous group of rare tumors that typically account for <5% of tumors in any organ. There is a paucity of epidemiologic data regarding risk factors. We aimed to characterize the burden of NENs in California with its diverse racial populations.
Methods: Using California Cancer Registry, we identified all newly diagnosed NEN from gastroenteropancreatic (GEP) sites in years 1992–2015. Age-adjusted incidence rates (AIR) were compared according to year using annual percent change (APC) and according to sex, race-ethnicity, primary tumor site, stage, and type of county of residence (urban, suburban, rural) using incidence rate ratios (IRR). Kaplan-Meier survival estimates from diagnosis to death by any cause were compared using log-rank tests stratified the same ways.
Results: There were 23,983 GEP NEN cases and 9,910 deaths. All AIRs increased over the 24 years, with the greatest increase in Hispanics with pancreatic NEN (APC 8.9). Table 1 compares AIRs from the last 5 years. The greatest discrepancies (>4-fold) were for non-Hispanic (NH) blacks or NH whites vs Asians with small intestine or appendiceal NEN. Longer median survival estimates were seen in women (13.1 years) vs. men (11.6), and in Asians (20.7) and Hispanics (16.7) vs. NH blacks (12.3) and NH whites (9.6). No significant survival differences were detected according to county type. Median survival estimates were significantly different according to primary tumor site: colorectal (19.9 years), appendiceal (16.0), small intestine (10.1), stomach (9.7), and pancreatic (4.4).
Conclusion: Incidence rates of GEP NENs in California steadily increase from 1992 through 2015 for all populations. Survival estimates differ significantly by primary tumor site of origin, sex, race-ethnicity, and stage, but not by county. These findings show higher incidence rate and longer survival than in previous publications and add information about NENs in Hispanic and Asian populations in California.
Clinical Implications of Pathogenic Germline Variants in Small Intestine Neuroendocrine Tumors
Kimberly Perez,1 Matthew Kulke,2 Lauren Brais,1 Rujuta Gadgil,1 Holly Alexander,1 Jonathan Nowak,3 John Garcia,4 Shan Yang,4 Ed Esplin,4 Sapna Syngal,1 Judy Garber,1 Jennifer Chan.11Dana-Farber Cancer Institute, Boston, MA; 2Boston Medical Center, Boston, MA; 3Brigham and Women's Hospital, Boston, MA; 4Invitae Genetics, San Francisco, CA.
Background: Hereditary susceptibility for NET tumors (NET) has been well-described in patients with rare, inherited genetic syndromes, including MEN1, von Hippel Lindau or tuberous sclerosis complex syndromes. An inherited basis for presumed “sporadic” NET has been suggested by evidence of familial clustering of NET tumors, and a documented higher incidence of second malignancies in patients and families with NET tumors.
Methods: We performed germline analysis with an 83-gene, next generation sequencing panel using DNA from 90 individuals with SI-NET. Participants were identified from the clinically annotated Dana-Farber Cancer Institute Neuroendocrine and Carcinoid Tumors Program’s prospectively collected database which includes over 1800 patients. The patients were selected based on patient-reported family and past medical history. The high risk features were categorized as diagnosis of SI-NET under the age of 40, personal history of a second cancer, and those with family history meeting National Comprehensive Cancer Network Guideline criteria for genetic testing. In those with identified pathogenic germline mutations, analysis of the tumor DNA for loss of heterozygosity will be performed utilizing the DFCI custom targeted next-generation sequencing platform.
Results: Of the 90 patients evaluated, a pathogenic germline variant was identified in 8 patients (Table 1): 4 had a personal history of a second cancer 5 had a family history and met clinical criteria to undergo genetic testing. One patient had a family history and a personal history of a second cancer. Pathogenic variants were identified in the following genes: CHEK2, RAD51C, BLM, RET, ATM, FH, and TP53. Somatic testing results are pending at the time of submission.
Conclusion: We demonstrate a 9% incidence of pathogenic germline variants in moderate to low penetrance genes associated with inherited susceptibility for malignancy not previously described in association with SI-NET.
A Personalized Remote Radiation-Tracking Vest for At-Home Monitoring of LU-177 DOTATATE Therapy
Larry Pierce, Robert Harrison, Hubert Vesselle, Robert Miyaoka. University of Washington, Seattle, WA.
Background: The FDA has approved the Peptide Receptor Radionuclide Therapy (PRRT), Lutathera (177Lu-DOTATATE) with package instructions dictating 4 doses of 200 mCi each for all Neuroendocrine Tumor (NET) patients. This universal prescription may be too much for some patients, leading to radiation damage in kidneys or other organs-at-risk (OARs). For others, 4 doses may be significantly less than can be safely tolerated, leading to sub-optimal treatment and shortened progression-free and overall survival. Tailoring the number of doses to each patient requires repeated nuclear medicine scans (e.g., multiple SPECT or SPECT plus planar) over the course of several days to perform OAR dosimetry. These scans are expensive and burdensome on the patient, often requiring hotel stays near the imaging facility.
Methods: To alleviate the cost and burden of longitudinal SPECT/planar dosimetry for PRRT, we have developed a low-cost Personalized Remote Radiation-Tracking (PRRT) vest for at-home dosimetry. The PRRT vest contains radiation-monitoring sensors that can compute OAR dosimetry measurements that are reported wirelessly to the healthcare provider. The vest is personalized for each patient, using the patient’s qualifying PET/CT scan to determine the optimal placement of sensors within the vest. Our methods mitigate the confounding effects of organ motion, vest mis-positioning, and other effects to ensure accurate dosimetry. We have created accurate computer models of patients wearing the PRRT vest under a variety of physical and biological conditions. The virtual vest was “worn” for 2 minutes each day over the course of several days post-injection. The OAR and NET washout rates were then computed.
Results: The PRRT vest estimated washout rates were within 5% of truth for OARs and within 8% for NETs.
Conclusion: Accurate washout rate measurements from the vest mean that accurate at-home dosimetry is possible with the PRRT vest. The PRRT vest is a low-cost dosimetry solution that will enable individualized 177Lu-DOTATATE therapy.
Identification of Subtype-Specific Therapeutic Targets for Precision Medicine Applications in Small Cell Lung Cancer
Karine Pozo, Rahul Kollipara, Kathia Rodarte, Adi Gazda, John Minna, Jane Johnson. UT Southwestern Medical Center, Dallas, TX.
Background: Small cell lung cancer (SCLC) is an incurable neuroendocrine cancer for which targeted therapies are lacking. Heterogeneity between tumors is evident and may underlie apparent failures in clinical trials. Therefore, personalized treatments based on tumor subtype are needed. Four SCLC subtypes have been described based on NE marker and transcription factor (TF) expression. SCLC-A is the preponderant subtype and is characterized by the TF Achaete-scute homolog 1 (ASCL1). The goal of the current study is to identify vulnerabilities specific to the SCLC-A subtype.
Methods: We developed an innovative approach integrating epigenetics and proteomics. We identified super enhancers, which are cell type-specific genomic regions thought to regulate oncogene expression. They are enriched in the histone epigenetics mark H3K27ac. Therefore we performed H3K27ac ChIP-seq on 12 SCLC cell lines and 4 SCLC patient-derived xenografts (PDX) representing 3/4 known subtypes. This approach was complemented with proteomics to identify ASCL1 interactors in the SCLC-A subtype. Here, ASCL1 was immunoprecipitated from SCLC-A cells and immune pellets were analyzed by mass-spectrometry.
Results: 1) All super enhancers identified for all cell lines and PDX models distribute across 3 groups, which is consistent with the current SCLC subtype classification. 2) Unique and shared super enhancer-associated genes were identified for SCLC-A and other subtypes. These represent potential subtype-specific therapeutic targets. 3) 247 ASCL1-interacting proteins were detected in the SCLC-A subtype, including the TFs NKX2.1 and PROX1. 4) ASCL1, PROX1 and NKX2.1 co-immunoprecipitate in SCLC-A cells. 5) They bind ~2000 common regulatory regions on the SCLC-A genome. 6) ASCL1, PROX1 and NKX2.1 downstream targets include the ion channels SCN3A and KCNB2 7) siRNA-mediated knock-down of ASCL1, PROX1 and NKX2.1 results in loss of SCN3A, KCNB2, and reduction in SCLC-A cell survival.
Conclusion: Overall, we demonstrate a strategy that stratifies tumors and identifies candidate tumor subtype-specific therapeutic targets.
Xermelo Patient Registry: Improvements in Clinical Outcomes, Patient Satisfaction, and Weight With Telotristat Ethyl in the Real-World
Mark Price,1 Vijay Joish,2 Steven Schwartz,3 Ann Fish-Steagall,4 Lee Bennett,1 Christina Darden,1 Eshetu Tesfaye,2 Karie Arnold,2 Sumon Wason,2 Pablo Lapuerta.21RTI Health Solutions, Research Triangle Park, NC; 2Lexicon Pharmaceuticals, Inc., Somerset, NJ; 3Diplomat, Plymouth, MI; 4Biologics McKesson, Inc., Raleigh, NC.
Background: This ongoing registry evaluates clinical and patient-reported outcomes in a larger cohort of patients receiving telotristat ethyl (TE) for carcinoid syndrome (CS) diarrhea over a longer duration of treatment than observed in clinical trials.
Methods: The RELAX registry offers online surveys to patients with CS when they initiate TE and every 6 months for up to 3 years. Baseline assessments include demographic and clinical characteristics and satisfaction with current treatment before starting TE. Follow-up assessments include overall and specific CS symptom control, patient global impression of change (PGIC), weight change, TE treatment satisfaction, and somatostatin analog (SSA) use. Demographic, clinical characteristics and 6-month treatment satisfaction and clinical outcomes were evaluated using descriptive statistics.
Results: This cohort included 109 patients who initiated TE (baseline) and 51 patients with 6-month follow-up data. Mean (SD) age was 60.9 (11.1), 5.3 (4.5) years since CS diagnosis 56% female 66% primary tumor in small intestine. Background treatment included SSA, radionuclide therapy, chemotherapy, radiation, and embolization. Overall, patients reported improved CS symptoms and increased satisfaction with CS treatment after 6 months of TE (Table). The majority of patients reported reductions in daily bowel movements (41/51, 80%) and 75% (95% CI, 63–87%) showed weight gain or maintenance over 6 months of TE treatment, a clinically relevant indicator of health for patients with CS. Use of short-acting SSA rescue therapy and long-acting SSA decreased or stayed the same for nearly all patients (Table 1).
Conclusion: These findings are consistent with previous demonstrations of the effectiveness of TE. Improvement in clinical outcomes despite diverse treatment histories, including maintenance of weight and background SSA therapy, together with patient satisfaction suggest benefits of TE in clinical practice.
Analysis of Factors Related to Gallstones in Patients With Neuroendocrine Tumors Treated With Long-Acting Somatostatin Analogues
Zhirong Qi,1 Xudong Qiu,1 Yuanliang Li,2 Dou Dou,1 Jie Luo,1 Fei Su,1 Huangying Tan.11China-Japan Friendship Hospital, Beijing, China; 2Beijing University of Chinese Medicine, Beijing, China.
Background: To evaluate gallstone disease incidence and associated factors in a series of patients treated with long-acting somatostatin analogs for neuroendocrine neoplasms.
Methods: A prospectively-collected database of patients with a diagnosis of neuroendocrine neoplasms, treated with somatostatin analogs at our Institution between 2010 and 2018, was retrospectively analyzed. Patients’ demographics and disease characteristics were analyzed to evaluate the incidence and the factors related to biliary stone disease.
Results: Eighty-three patients were included, among 60 patients with gallbladder in situ and no history of stone disease, 26 (43.3%) developed gallstones after a mean of 32.3months (range, 4–154) from treatment start. The incidence of gallstone is related to duration of receiving somatostatin analogs treatment (P < 0.05). Previous cholecystectomy was associated with a lower incidence of development of gallstones. Among 11 patients who underwent cholecystectomy before the start of SSA, 1 (9.1%) patient developed common bile duct stones during SSA therapy.
Conclusion: We observed a high incidence of gallstone disease in patients treated with long-acting somatostatin analogs-treated for neuroendocrine neoplasm, somatostatin analogs treatment duration is related to the occurrence of gallstones.
Study on the Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors: Traditional Chinese Medicine Combined With Somatostatin Analogues
Xudong Qiu, Zhirong Qi, Yuanliang Li, Huangying Tan. China-Japan Friendship Hospital, Beijing, China.
Background: At present, there are few reports on the treatment of GEP-NET with traditional Chinese medicine. The purpose of this study is to observe the efficacy of traditional Chinese medicine combined with SSA in the treatment of advanced GEP-NET.
Methods: From June 2012 to January 2019, 50 patients with advanced GEP-NET who were treated regularly by traditional Chinese medicine combined with SSA in Chin-Japan Friendship Hospital were retrospectively analyzed, including 26 males and 24 females, with a median age of 53 (20–81). Fifteen patients received first-line treatment with traditional Chinese medicine combined with SSA, and 35 patients received other therapy before. The primary site including 23 cases of pancreas, 23 cases of gastrointestinal tract, and 4 cases with unknown primary site. Seven cases were NET G1, 37 cases were NET G2, 5 cases were NET G3, and 1 case was unknown. All patients were treated with traditional Chinese medicine. They were also treated with octreotide LAR 20–40 mg/21–28 d, or lanreotide LAR 40 mg/10–14 d. RESIST 1.1 was used to evaluate the tumor response every 2-4 months. The main end point was PFS.
Results: As of February 28, 2019, only 6 of 50 patients died, with a median follow-up of 29.0 months (5.6–86.5). The median OS and PFS were not reached. Thirty-two patients received SSA combined with traditional Chinese medicine only, and the other 18 patients received other treatments. A total of 14 patients developed disease progression, 11 patients turned to other treatment after stable disease, the remaining 25 patients with stable disease still receiving SSA combined with traditional Chinese medicine. No CR or PR was observed, with an objective response rate of 0%. 44 patients had SD, and the SD rate was 88.0%.
Conclusion: Compared with SSA alone, traditional Chinese medicine combined with SSA can significantly prolong PFS in patients with advanced GEP-NET.
PD-1 Blockade in Advanced Adrenocortical Carcinoma
Nitya Raj,1 Youyun Zheng,1 Virginia Kelly,1 Seth Katz,1 Joanne Chou,1 Richard Do,1 Marinela Capanu,1 Dmitriy Zamarin,1 Leonard Saltz,1 Charlotte Ariyan,1 Brian Untch,1 Eileen O'Reilly,1 Anuradha Gopalan,1 Michael Berger,1 Elly Olino,2 Neil Segal,1 Diane Reidy.11Memorial Sloan Kettering Cancer Center, New York, NY; 2Yale School of Medicine, New Haven, CT.
Background: Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options.
Methods: Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary endpoint was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 (PD-L1) expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates.
Results: We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4–34.7). The objective response rate to pembrolizumab was 23% (9 patients, 95% confidence interval [CI], 11–39) and the disease control rate was 52% (16 patients 95% CI, 33–69). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of 6 patients with MSI-H/MMR-D tumors responded. The other 7 patients with objective responses had microsatellite stable (MSS) tumors. The median progression-free survival was 2.1 months (95% CI, 2.0–10.7) and median overall survival was 24.9 months (95% CI, 4.2 to not reached). Thirteen percent (N = 5) of patients had treatment-related grade 3/4 adverse events. Tumor PD-L1 expression and MSI-H/MMR-D status were not associated with objective response.
Conclusion: MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is MSS, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile. (ClinicalTrials.gov number, NCT02673333)
Duodenal Neuroendocrine Tumors Exhibit Distinct Transcriptome and Mutations Compared to Pancreatic Neuroendocrine Tumors and Ileal Carcinoids
Karen Rico,1 Sulaiman Sheriff,1 Suzann Duan,1 Sammed Mandape,1 Ritu Pandey,1 Bryson Katona,2 David Metz,2 Juanita Merchant.11University of Arizona, Tucson, AZ; 2University of Pennsylvania, Philadelphia, PA.
Background: Approximately seventeen neuroendocrine cell types in the GI tract may give rise to Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs). However, even when the tumors arise from the same cell type, they may behave differently. MEN1 mutations occur in 40% of pancreatic neuroendocrine tumors (PNETs) but not in small bowel NETs, suggesting additional mechanisms of pathogenesis. To determine if GEP-NETs exhibit a distinct transcriptome and whether MEN1 and somatic mutations influence tissue-specific differences.
Methods: Blood and tumor whole exome sequencing was performed in three PNETs, three duodenal neuroendocrine tumors (DNETs), and two ileal carcinoids (ICs). Somatic indels and single nucleotide variations (SNVs) were compared across tumor types. RNA-Seq was performed on two DNETs and two PNETs. We conducted a western blot and IHC of menin to determine if mutations led to loss of protein or change in subcellular localization.
Results: Duodenal gastrinomas had elevated transcripts of genes related to gastrin-cell specification (NKX6-3, NKX2-2). In PNETs, increased transcripts were related to the early stages of enteroendocrine cell differentiation (ASCL-1, IRX2). DNETs had MEN1 mutations in the C-terminus of menin near the nuclear localization signals. By contrast, the PNETs had MEN1 mutations closer to the N-terminus of the protein. Menin protein was detected in GEP-NETs and was cytoplasmic. The molecular mass of menin was smaller than the protein expressed from MEN1 gene transfected in Men1-/- mouse embryonic fibroblasts, suggesting differential post-translational modification of menin. Indels were found in DNETs (MAP3K9), PNETs (RBM5) and ICs (ESRRA). The SNVs identified were PNETs (RHPN2), DNETs (MUC20) and ICs (APC).
Conclusion: The transcriptome and mutations in GEP-NETs are reflective of their respective tumor locations. The presence of mutations in other genes suggests that MEN1 mutations may not be sufficient to initiate tumorigenesis. Thus, the identification of altered genes and gene functions provides a promising avenue for targeted treatment of tumor-specific GEP-NETs.
CLARINET FORTE Baseline Characteristics: Lanreotide Autogel 120 mg (LAN) Every 14 Days in Patients With Progressive Pancreatic or Midgut Neuroendocrine Tumors During a Standard First-Line LAN Regimen
Philippe Ruszniewski,1 Jarosław Ćwikła,2 Catherine Lombard-Bohas,3 Ivan Borbath,4 Tahir Shah,5 Ulrich-Frank Pape,6 Xuan-Mai Truong Thanh,7 Aude Houchard,7 Marianne Pavel.81University of Paris, Beaujon Hospital, Clichy, France; 2University of Warmia and Mazury, Olsztyn, Poland; 3Edouard-Herriot Hospital, Lyon, France; 4Cliniques Universitaires Saint-Luc, Woluwe-Saint-Lambert, Belgium; 5Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 6Charité – Universitätsmedizin Berlin, Berlin, Germany; 7Ipsen, Boulogne-Billancourt, France; 8Universitätsklinikum Erlangen, Erlangen, Germany.
Background: Lanreotide autogel (LAN) is a long-acting somatostatin analog used to treat somatostatin receptor-positive (SSTR+), gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In CLARINET, LAN 120 mg every 28 days (q28d) significantly improved progression-free survival (PFS) versus placebo in metastatic, SSTR+ GEP-NETs. CLARINET FORTE (NCT02651987) is an ongoing phase 2 study assessing the safety and efficacy (centrally assessed median PFS) of a reduced LAN 120 mg dosing interval (q14d) in progressive pancreatic NETs (panNETs) and midgut NETs.
Methods: Eligible patients had well-differentiated, metastatic/locally advanced, unresectable, functional or non-functional G1/G2, panNETs or midgut NETs with Ki-67 ≤20%. Patients had radiological progressive disease ≤2 years prior to study inclusion (centrally assessed) while receiving first-line LAN 120 mg at standard treatment intervals (q28d) for ≥24 weeks. Following a 28-day screening interval, LAN 120 mg was administered q14d.
Results: Ninety-nine enrolled patients from 10 countries received LAN 120 mg q14d (panNET, n = 48 midgut NET, n = 51). In the panNET group, 22.9% and 77.1% of patients had G1 and G2 tumors (according to WHO classification), respectively this was 54.9% and 45.1% in the midgut NET group. n/N (%) of patients with a Ki-67 of 2–10% was 28/48 (58.3%) and 18/50 (36%) in the panNET and midgut NET groups, respectively. Median (range) duration of LAN treatment (standard dosing interval) prior to study enrolment was 21.7 (5–103 panNET) and 16.4 (5–198 midgut NET) months. In the panNET group, diarrhea and flushing were present in 16.7% and 8.3% of patients in the midgut NET group, this was 41.7% and 28.0%, respectively.
Conclusion: Baseline CLARINET FORTE data highlight the high rate of G1 in progressive midgut NET and of G2 in panNET. The cohort is representative of typical patients requiring treatment intensification due to progressive panNET or midgut NET. Final analyses in Q1 2020 will provide efficacy and safety data for LAN 120 mg at q14d.
Differential Gene Expression in Metastatic Pancreatic Neuroendocrine Tumors Predicts Novel Therapeutic Agents
Aaron Scott,1 Michelle Weitz,2 Patrick Breheny,2 Po Hien Ear,2 Benjamin Darbro,2 Bart Brown,2 Terry Braun,2 Guiying Li,2 Ume Salma Shaik Amjad,2 Courtney Kaemmer,2 Chandra Kumar Maharjan,2 Dawn Quelle,2 Andrew Bellizzi,2 Joseph Dillon,2 Thomas O'Dorisio,1 James Howe.21University of Iowa Hospitals and Clinics, Iowa City, IA; 2University of Iowa, Iowa City, IA.
Background: Pancreatic neuroendocrine tumors (PNETs) are uncommon malignancies noted for their indolent growth, propensity to metastasize, and comparatively favorable prognosis. Although both the number of treatment options and the median survival have increased in the last several decades, most patients will die of metastatic disease, and new systemic therapies are needed. We analyzed differential gene expression in PNET metastases to identify novel therapies for these tumors.
Methods: Tissue samples were obtained from primary tumors, lymph node and liver metastases from 43 patients with sporadic, well-differentiated PNETs. RNA-Seq was performed and gene expression was compared between primary tumors and metastases. Genes which were selectively overexpressed at only one metastatic site were filtered out to reduce the influence of tissue-specific genes unrelated to metastasis. Ingenuity Pathway Analysis (IPA) and the Connectivity Map (CMap) were used to identify potentially effective drugs based upon comparisons to expression profiles from tumor cells treated with these agents. Promising drugs were tested using two PNET cell lines (BON1, QGP1).
Results: A total of 841 genes were significantly differentially expressed in metastases compared to the primary tumors, 565 of which remained in the common metastatic profile after filtering. IPA predicted altered activity of several transcriptional regulators involved in cell survival, differentiation and proliferation. Drugs targeting these regulators, including mTOR, PI3K, CDK, NF-kB, topoisomerase, and HDAC, were identified through CMap and IPA, and nine were selected for validation (Table 1). All but one compound tested demonstrated complete or near complete inhibition of proliferation in PNET cell lines.
Conclusion: We employed a complementary bioinformatics approach to identify novel therapeutic agents for PNETs by analyzing gene expression changes in metastatic tumors. The validity of this strategy was supported in vitro using two PNET cell lines. Additional in vivo evaluation of these compounds using PNET models of metastasis will be important for confirming their clinical utility.
Presacral Neuroendocrine Tumors Associated With the Currarino Syndrome
Aaron Scott,1 Jonathon Tessmann,1 Terry Braun,1 Bart Brown,1 Patrick Breheny,1 Benjamin Darbro,1 Andrew Bellizzi,1 Joseph Dillon,1 Thomas O'Dorisio,2 Alice Alderson,3 Bonita Bennett,4 John Bernat,5 David Metz,4 James Howe.11University of Iowa, Iowa City, IA; 2University of Iowa Health Care, Iowa City, IA; 3Perelman School of Medicine, Philadelphia, PA; 4University of Pennsylvania, Philadelphia, PA; 5University of Iowa Hospitals and Clinics, Iowa City, IA.
Background: Currarino Syndrome (CS) is an autosomal dominant syndrome caused by mutations in MNX1 and characterized by anorectal abnormalities, partial sacral agenesis and presacral masses. The presacral masses are typically benign, however malignant degeneration can occur, and presacral neuroendocrine tumors (NETs) have been reported in three cases. We report two families affected by CS in which two individuals developed presacral NETs.
Methods: Exome sequencing was performed on genomic DNA, and tumor DNA in patients with presacral NETs and MNX1 mutations. Sequencing reads were aligned using Burrows Wheeler Aligner. Variants were generated using the Genome Analysis Toolkit, Varscan, and annotated using Variant Effect Predictor. Consistency of variant candidates was assessed using the Integrative Genomics Viewer. Mutations in MNX1 were confirmed by commercial testing.
Results: Family 491 had 6 members with features of CS including two siblings who presented with presacral, grade 2 NETs, one of which had metastasized to bone and lymph nodes. A germline c.874C>T (p.Arg292Trp) mutation was found in a highly conserved region of MNX1 in three affected members who underwent sequencing (Table 1). A second somatic variant/deletion in MNX1 was not detected in either patient’s tumor. In family 342, two patients had presacral NETs, and sequencing did not reveal an MNX1 mutation or copy number variants.
Conclusion: We describe four new patients with CS and NETs, highlighting the variable presentation of CS, and the potential for malignancy in these patients. MNX1 is a transcription factor which is important for caudal embryogenesis. Mutations in this gene lead to CS, which in rare cases has been associated with presacral NETs. The lack of a second, somatic mutation in the tumor argues against MNX1 acting as a tumor suppressor, and the absence of a germline MNX1 mutation in family 342 suggests that other genetic and anatomic factors contribute to the development of presacral NETs.
Prevalence of Hereditary Pheochromocytoma and Paraganglioma and Associated Genotypes Within a Pediatric and Adolescent Population: A Review of Patients Presenting to Familial Cancer Services Within NSW, Australia, Between 1993–2018
Amanda Seabrook,1 Roderick Clifton-Bligh,1 Judy Kirk,2 Janine Smith,3 Allan Spigelman,4 Diana Benn,1 Katherine Tucker.51Royal North Shore Hospital, Kolling Institute of Medical Research, St. Leonards, Australia; 2Westmead Hospital, Westmead, Australia; 3The Children’s Hospital at Westmead, Westmead, Australia; 4St. Vincent’s Hospital, Darlinghurst, Australia; 5Prince of Wales Hospital, Randwick, Australia.
Background: Phaeochromocytoma and paraganglioma (PC/PGL) syndromes associated with germline mutations are highly morbid. Published data has consistently demonstrated a high occurrence of tumors due to hereditary PC/PGL in childhood with a predominance of cluster 1 mutations. This cluster is associated with more aggressive features including bilateral, multiple and extra-adrenal tumors. As the occurrence of these tumors are scarce, data has not been systematically captured in the Australian Paediatric Cancer Registry. The objective of our study was to establish prevalence of hereditary PC/PGLs in patients under the age of 21 y who were investigated through Familial Cancer Services in New South Wales (NSW), Australia between 1993–2018.
Methods: Information was collected through the state-wide online genetic database known as ‘TrakGene’ which comprised of a network of 7 adult and 2 pediatric tertiary hospitals. Data collected included patient demographics and tumor features.
Results: Of 31 patients assessed in our cohort 81% (25/31) harbored a germline mutation in one of the driver genes associated with hereditary PC/PGL: SDHB (n = 11), VHL (n = 12), NF1 (n = 1) and MAX (n = 1). The average age of PC/PGL in those with SDHB mutations was 14 y (range, 7–21) and in those with VHL mutations was 14 y (range, 5–18) the patients with NF1 or MAX mutations were aged 13 y and 21 y respectively. Of the SDHB group, eight presented with extra-adrenal PGL and two with PC. All tumors in patients with VHL were PCs. Longitudinal follow-up data demonstrated 23% (4/17) developed metachronous disease and 18% (3/17) developed metastatic disease.
Conclusion: Pediatric and adolescent patients with PC/PGL are highly likely to harbour a germline driver mutation, particularly in VHL or SDHB. Patients diagnosed with a PC/PGL at a young age should be referred to specialist services for comprehensive work-up to detect bilateral, multifocal or metastatic disease, and family counselling.
Prevalence of Bone Metastases in Neuroendocrine Neoplasms by 68Ga DOTATATE PET Scan
Shagufta Shaheen, Rebecca Gardner, Vandana Sundaram, Kathleen Hornbacker, Farshad Moradi, Joy Wu, Pamela Kunz. Stanford University, School of Medicine, Palo Alto, CA.
Background: Neuroendocrine neoplasms (NEN) are rare tumors, accounting for only 0.5% of all tumors. These tumors are heterogeneous and their prognosis and long-term survival are not well known. NENs have the propensity to metastasize to liver, bone, lymph nodes and lung. Bone metastasis initially thought to be a rare feature of NEN, are now a well-recognized clinical complication causing significant morbidity and mortality. Bone metastasis portends poor prognosis with poor outcomes. Prevalence of bone metastasis in NEN varies considerably, with most studies reporting a 12–15% range. With the advent of more sensitive imaging modalities such as 68Ga DOTATATE PET, we hypothesize that the prevalence of bone metastases is higher than previously reported.
Methods: Data for sex, age, tumor, and metastasis diagnosis dates, primary tumor site, WHO grade, and metastasis site were extracted from the Stanford Neuroendocrine tumor database. We included patients who had 68Ga DOTATATE PET and metastatic disease patients with second malignancies were excluded. We classified patients with bone metastasis (BM) or not (non-BM) based on results from 68Ga DOTATATE PET. Patient characteristics reference (Table 1) were compared using chi-square and t-tests.
Results: Of the 2175 NEN patients, we included 131 patients: 50 (38%) with bone metastasis and 81 (62%) with non-bone metastasis. Primary tumor site and grade were not statistically significantly different between BM and non-BM patients (P = 0.271). However, lung metastasis and metastasis at other sites were higher in BM patients (P = <0.001, 0.021, respectively). There were 10 deaths in the BM cohort and two in the non-BM cohort.
Conclusion: Prevalence of bone metastasis in our study was 38.2% which is higher than reported in most other studies. Further studies are needed to characterize and evaluate therapeutic options for bone metastasis.
CDK-Targeted Combination Therapies of Pancreatic Neuroendocrine Tumors (PNETS) Guided by RABL6A-Dependent Regulation of the PNET Kinome and Phosphoproteome
Ume Salma Shaik Amjad,1 Courtney Kaemmer,1 Chandra Kumar Maharjan,1 Jordan Kohlmeyer,1 Laura Herring,2 Dennis Goldfarb,2 E. Wilkerson,2 Ryan Sheehy,1 Mariah Leidinger,1 David Meyerholz,1 Tim Ginader,1 Gideon Zamba,1 Andrew Bellizzi,1 Lee Graves,2 Benjamin Darbro,1 Dawn Quelle.11University of Iowa, Iowa City, IA; 2University of North Carolina, Chapel Hill, NC.
Background: More effective therapeutics are needed to improve survival of advanced PNET patients. RABL6A is a novel oncoprotein that drives PNET proliferation and survival through multiple pathways, including suppression of the retinoblastoma (RB1) tumor suppressor via cyclin-dependent kinase (CDK) activation. In recent PNET clinical trials, overall patient survival has not been improved by CDK4/6 monotherapy, warranting the development of combination targeted therapies. Here, we examined the global PNET kinome and phosphoproteome to identify other kinases regulated by RABL6A whose inhibition may synergize with CDK4/6 inhibitor therapy.
Methods: Quantitative proteomics (kinome and phosphoproteome analyses) of PNET cells that express or lack RABL6A was performed. Effects of altered RABL6A expression on cellular protein (immunoblotting), proliferation & survival (trypan blue exclusion, cell counting, colony formation), drug sensitivity (AlamarBlue), and tumor growth/drug response in vivo (mouse xenografts) were measured.
Results: RABL6A depletion in PNET cells caused significant downregulation of >1100 cellular phosphoproteins and reprogramming of the global kinome. Expression of RABL6A was required for activity of many cell cycle, mitotic and tumor-promoting kinases, including CDKs 1/2/6, Aurora kinases A and B, Polo-like kinase 1 and select tyrosine directed and MAP kinases. Cellular analyses verified PNET cell sensitivity to CDK4/6 inhibitors (e.g., palbociclib) was dependent on RABL6A expression. The combination of drugs targeting CDK4/6 and CDK1/2, which more fully activates RB1 tumor suppressive activity, was more effective against PNET growth than either inhibitor alone. Ongoing studies are examining the efficacy of other innovative, rational therapies that combine inhibitors of CDKs with drugs targeting other RABL6A regulated kinases.
Conclusion: Quantitative kinome and phosphoproteomic analyses, which have not been performed before in NETs, identified a global kinase signature associated with PNET proliferation / survival and RABL6A signaling. This approach allows rational design of novel kinase-targeted combination therapies for NET patients.
Comparison of GI Toxicity Associated With AA Formulations Co-Infused With PRRT: Commercial Parenteral Nutrition Formula Versus Compounded L-Lysine/L-Arginine
Dhiraj Sikaria,1 Jose Jesurajan,1 Johnna Smith,2 Jonathan Strosberg,2 Ghassan El-Haddad.21University of South Florida Morsani College of Medicine, Tampa, FL; 2H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Background: Renal reabsorption of radiolabeled somatostatin analogs can be decreased by co-infusion of positively charged amino acids (AA). Different AA solutions have been used with Peptide receptor radionuclide therapy (PRRT) for that purpose. We hypothesized that AA infusion containing only the essential L-Lysine and L-Arginine would be significantly less toxic than the AA-containing solutions used for parenteral nutrition.
Methods: Retrospective study of two cohorts of patients with metastatic GEP-NETs treated at our center with PRRT using 177Lu-DOTATATE: one cohort receiving treatment on an early access program (EAP) using Clinisol® 15% sulfite AA 2 L (9 essential and 8 non-essential AA) and another cohort treated subsequent to FDA approval who received the compounded formulation Aminoprotect® containing only L-Lysine HCl 2.5%/L-Arginine HCl 2.5%, 1L. Clinical information related to gastrointestinal symptoms during administration of AA infusion and MAR were reviewed to identify adverse reactions and PRN medications given. Chi Squared tests were used to compare AEs.
Results: 20 patients treated on the EAP program with Clinisol® 15% were compared to the first 29 consecutively treated patients who received Aminoprotect®. There were 69 infusions in the Clinisol group and 115 infusions in the Aminoprotect group. Most common GI side effect during AA infusion in each group was nausea. In the Clinisol group, 75.4% (52/69) of infusions caused nausea, 69.6% (48/69) requiring antiemetics, while in the Aminoprotect group 5.2% (6/115) of AA infusions caused nausea, 2.6% (3/115) requiring antiemetics (P < 0.05). All 20 patients in Clinisol group experienced nausea during at least one of their AA infusions. In the Aminoprotect group, 20.7% (6/29) of patients had nausea during any AA infusion with 10.3% (3/29) needing medication.
Conclusion: AA infusion containing L-lysine/L-arginine has significantly better GI tolerance than commercial parenteral nutrition formulas containing numerous AA. We recommend the use of L-lysine/L-arginine infusions during PRRT in order to decrease acute GI toxicity.
Liquid Biopsy Metabolomic Profiling of Neuroendocrine Cancer Patients
Nicholas Skill,1 Elliott Campbell,1 Tanja Milosavljevic,2 Elise Chouest,2 Brianne Voros,2 Eugene Woltering,2 Mary Maluccio.11Indiana University, Bloomington, IN; 2LSU Heath New Orleans, New Orleans, LA.
Background: Metabolomics is the study of small molecule metabolites in biofluids and tissue. These small molecules are exquisitely sensitive to different biological states and therefore represent a promising approach to identify changes in biopathology over time and over the course of treatment. Investigating metabolomic signatures associated with NET will highlight unrecognized metabolic aberrancies that contribute to symptoms and performance status. The expectation is that this technique will also identify biomarkers of a response to treatment that will guide the timing and frequency of intervention.
Methods: Serum samples collected from patients with confirmed neuroendocrine cancer were subjected to high performance liquid chromatography (HPLC) coupled with dual mass spectroscopy to quantitate 309 metabolites spanning multiple metabolomic pathways.
Results: Principal component analysis (PCA) was used to identify key metabolomics differences among NET patients. Living related donor serum was used as controls. Elevated alpha-ketoglutaric acid, tyrosine, and lactate, alongside depressed arginine and adenosine was characteristic of NET patients. Small-bowel primaries displayed elevated cortisol, pyruvate, and glutamine as compared to pancreatic primaries. The three groups were easily distinguished when plotted against eigenvectors 1 and 2 of the PCA. The identified metabolites were used to construct a linear prediction model by partial least squares-discriminant analysis, which identified NET status and primary location with 100% accuracy in jackknife cross-validation.
Conclusion: Metabolic aberrancies associated with function identified pathways that likely explain differences in symptoms between pancreatic and intestinal NET. Further Investigation into the metabolic consequences linked to each defect will allow us to better personalize treatment of symptoms.
Incidence and Survival Patterns of Pancreatic Neuroendocrine Tumors Over the Last Two Decades: A SEER Database Analysis
Mohamad Sonbol, Gina Mazza, Jason Starr, Timothy Hobday, Thorvardur Halfdanarson. Mayo Clinic, Rochester, MN.
Background: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with outcome varying by stage, grade, and clinical presentation. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs over the last two decades using a large population-based database.
Methods: Using 2000–2016 data from the SEER 18 registry, we identified patients with PNETs using a combination of ICD-O-3 and histology codes. Age-adjusted incidence rates were calculated using SEER*Stat 8.3.5. Using SAS 9.4, overall survival (OS) was analyzed using the Kaplan–Meier method, and prognostic factors were investigated using a multivariate Cox proportional hazards model.
Results: We identified 8,944 pts with PNETs. Annual incidence rates increased over study period from 0.27 to 1.00 per 100,000. This was largely explained by a significant increase in number of pts diagnosed with localized disease in recent years (2012-2016). Median OS (mOS) for the entire cohort was 68 months (95% CI, 64–73) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for pts diagnosed between 2009-2016 (mOS, 85 months) compared to those diagnosed between 2000–2008 (mOS, 46 months) (HR, 0.66; P < 0.001). In addition, patients with grade I/II metastatic disease who underwent surgery experienced significantly longer OS (mOS, 84 months) compared to those who did not undergo surgery (mOS, 18 months) (HR, 0.31; P < 0.001). In the multivariate analysis, more recent diagnosis, younger age, female sex, surgery, early stage, and lower grade favorably predicted OS (Table 1). On the other hand, functional status and race did not predict OS.
Conclusion: There has been a steady increase in the incidence of PNETs with notable stage migration as most patients are diagnosed in early stages of disease in recent years. Additionally, this increase in incidence is accompanied by a significant improvement in survival across different disease stages.
Randomized Embolization Trial for Neuroendocrine Tumors (RETNET): First Safety Report
Michael Soulen,1 Rony Avritscher,2 Ghassan El-Haddad,3 Nicholas Fidelman,4 Ricardo Garcia-Monaco,5 Sarah White,6 E. Paul Wileyto.11University of Pennsylvania, Philadelphia, PA; 2MD Anderson Cancer Center, Houston, TX; 3Moffit Cancer Center, Tampa, FL; 4University of California San Francisco, San Francisco, CA; 5Hospital Italiano, Buenos Aires, Argentina; 6Medical College of Wisconsin, Milwaukee, WI.
Background: Embolotherapy of progressive or symptomatic neuroendocrine tumor (NET) liver metastases is standard of care in international guidelines, without recommendation regarding embolization technique. RETNET (NCT02724540) is a prospective randomized controlled trial comparing bland, cTACE, and DEB-TACE. Interim safety analyses are planned following accrual of 10 and 30 subjects in each arm. The first safety review is reported here.
Methods: Society of Interventional Radiology (SIR) QI guidelines for embolization and TACE set the performance threshold for major complications at 8%, and for any complications 15%. For RETNET, a 20% incidence of serious adverse events as defined by the SIR (D = unplanned increase in level of care, E = permanent adverse sequelae, F = death) would be grounds for closing an arm. This provides a probability of halting of 62% at the first safety review if the true event rate is 20%. Blinded review was performed by an independent DSMB consisting of three senior interventional oncologists at non-participating institutions after a minimum of 10 subjects in each arm had one-month follow-up after their first embolization cycle.
Results: Two subjects in the bland arm had SIR Category D events (pain unrelated pancreatitis 6 months post-embo). The subject with pain required re-hospitalization and withdrew from the study. Two subjects in the cTACE arm had SIR Category D events (unrelated renal infection, hyponatremia), none resulted in study discontinuation. 4 subjects in the DEB arm had Category D (hyponatremia, carcinoid crisis, both requiring ICU admission) or E (hepatobiliary necrosis biloma) events, two of which resulted in study discontinuation.
Conclusion: 4/10 NET subjects embolized with DEB had serious adverse events, two permanent and two resulting in study discontinuation. Based on the trial stopping rule, the DSMB closed the DEB arm.
Neoadjuvant Capecitabine/Temozolomide for Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors
Malcolm Squires,1 Patrick Worth,2 Bhavana Konda,3 Manisha Shah Mary Dillhoff,1 Sherif Abdel-Misih,1 Timothy Pawlik,1 Carl Schmidt,1 George Poultsides,2 Jordan Cloyd.11The Ohio State University, Columbus, OH; 2Stanford University, Palo Alto, CA; 3The Ohio State University Comprehensive Cancer Center, Columbus, OH.
Background: Recent evidence has demonstrated the efficacy of the chemotherapy regimen capecitabine and temozolomide (CAPTEM) in the treatment of metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs). However, the role of CAPTEM in the neoadjuvant setting has not been established.
Methods: All patients with locally advanced or resectable metastatic PNETs who received CAPTEM with neoadjuvant intent between 2009–2017 at 2 high-volume academic centers were retrospectively reviewed. Radiographic response was assessed according to RECIST 1.1 criteria and predictors of response were measured by logistic regression.
Results: Thirty patients with either locally advanced PNET (n = 10) or pancreatic neuroendocrine hepatic metastases (n = 20) underwent neoadjuvant CAPTEM therapy, receiving a median of 4 cycles (IQR, 3–8 cycles). Overall, 13 patients (43%) exhibited a partial response (PR) whereas 16 (54%) had stable disease and 1 patient (3%) developed progressive disease. Twenty-six (87%) patients underwent resection (pancreatectomy [n = 12], combined pancreatectomy and liver resection [n = 8], or major hepatectomy alone [n = 6]) 3 (18%) declined surgery despite experiencing a PR, and 1 (3%) underwent an aborted pancreatoduodenectomy due to cirrhosis. Median PNET primary tumor size on final pathology was 5.5cm (IQR, 3.3–9.3 cm), and the median Ki-67 index was 3.5% (IQR, 1–8%). Rates of PR were similar (P = 0.24) across WHO tumor grades (Table 1): Grade 1 (58%), Grade 2 (31%), and Grade 3 (40%). At a median follow-up of 49 months for the cohort, the median progression-free survival for all patients was 28.2 months, and the 5-year overall survival was 63%. A decrease of >50% in the pre-treatment serum value of the tumor markers pancreatic polypeptide or pancreastatin was associated with PR (P = 0.02), while Ki-67 and tumor grade were not significantly associated with radiographic response.
Conclusion: Neoadjuvant CAPTEM is associated with a favorable radiographic response rate for locally advanced or metastatic PNET and may facilitate the selection of patients appropriate for surgical resection.
Factors Associated With Dying from Pancreatic Neuroendocrine Tumor
Erin Strong, Austin Livingston, Susan Tsai, Kathleen Christians, Ben George, Paul Ritch, James Thomas, Kulwinder Dua, Abdul Khan, Brian Hunt, William Hunt, Beth Erickson, Douglas Evans, Callisia Clarke. Medical College of Wisconsin, Milwaukee, WI.
Background: Survival outcomes in patients with pancreatic neuroendocrine tumors (PNETs) are dichotomous some experience rapid disease progression and death, others a more indolent course. The purpose of this study is to identify clinicopathologic factors that predict death from disease (DOD) in patients undergoing curative resection of PNET.
Methods: We performed a retrospective review of patients undergoing curative resection for PNET at our institution over 10 years to determine factors associated with death from disease. Patients undergoing palliative resection were excluded.
Results: 125 patients met inclusion criteria. Median follow-up was 41 months (IQR, 23–67). 11 patients (8.8%) died from disease with a median overall survival (OS) of 30 mos (IQR, 8–41] versus 47 mos (IQR, 24–70) in those still alive. DOD patients were younger (52 yrs vs 57 yrs, P = 0.05) and more likely to present with metastatic disease at diagnosis (54% vs 23%, P = 0.02) have positive final margin resection (27% vs 7%, P = 0.03) have poorly-differentiated histology (22% vs 3%, P = 0.02) and have high grade disease (33% vs 4%, P < 0.001). DOD patients had shorter RFS with 12 mos (IQR, 4–29) vs 37 mos (IQR, 19–65), P = 0.018. On univariable analysis, metastatic disease at diagnosis with HR, 3.151 (95% CI, 0.950–10.456; P = 0.061) positive final margin status with HR, 4.917 (95% CI, 1.269–19.050; P = 0.021) Ki-67 (%) with HR, 1.045 (95% CI, 1.019–1.071; P = 0.001) and mitotic rate with HR, 1.058 (95% CI, 1.006–1.113; P = 0.028) were significantly associated with OS to P < 0.10. On multivariable analysis including these variables, positive final margins remained independently associated with OS with HR, 5.346 (95% CI, 1.071–26.693; P = 0.041) to P < 0.05 (Table 1).
Conclusion: Patients with PNET have favorable prognosis when compared to other pancreatic malignancy. While most have an indolent course, inability to achieve negative margins, early disease recurrence after curative resection, and high grade or poorly differentiated tumors confer higher risk of dying from disease.
Analyses of Patient Diaries in the Netter-1 Study of 77LU-Dotatate Versus High Dose Octreotide in Progressive Midgut Neuroendocrine Tumors
Jonathan Strosberg,1 Edward Wolin,2 Beth Chasen,3 Matthew Kulke,4 David Bushnell,5 Caplin Martin,6 Richard Baum,7 Timothy Hobday,8 Andrew Hendifar,9 Paola Santoro,10 Per Broberg,10 Arnaud Demange,10 Kjell Öberg,11 Philippe Ruszniewski,12 Eric Krenning.131Moffitt Cancer Center, Tampa, FL; 2Tisch Cancer Institute Mount Sinai School of Medicine, New York, NY; 3The University of Texas MD Anderson Cancer Center, Houston, TX; 4Boston Medical Center, Boston, MA; 5University of Iowa, Iowa City, IA; 6Royal Free Hospital, London, United Kingdom; 7Zentralklinik, Bad Berka, Germany; 8Mayo Clinic, Rochester, MN; 9Cedars Sinai Medical Center, New York, NY; 10Advanced Accelerator Applications, a Novartis Company, Reading, MA; 11University Hospital, Uppsala University, Uppsala, Sweden; 12Hopital Beaujon and Paris Diderot University, Clichy, France; 13Erasmus Medical Center, Rotterdam, Netherlands.
Background: The primary statistical analysis for the NETTER-1 trial showed a clinically and statistically significant PFS benefit with 177Lu-DOTATATE vs high-dose octreotide. 177Lu-DOTATATE treatment was also correlated with a significant delay in time to deterioration in HRQoL. In addition to HRQoL questionnaires, patients were asked to record presence or absence of a range of symptoms in a daily diary.
Methods: A Mixed Model Repeated Measures (MMRM) was used to analyze the change, compared to baseline, of the occurrence of abdominal pain, diarrhea, and flushing of the skin as these symptoms were regarded as the most relevant to judge the overall status of the disease. For each visit (week = 0, 4, 8, etc.) the number of days with symptoms during the previous period was calculated. At baseline the number of days with symptoms was counted over the previous 6 weeks whereas the time frame between visits lasted 4 weeks.
Results: The estimated number of days with symptoms declined significantly more in the LUTATHERA arm compared to the Octreotide arm. The difference in change and the confidence intervals for the symptoms abdominal pain, diarrhea and flushing of skin are, respectively: -3.11 [-4.88 to -1.34], -3.11 [-5.04 to -1.18] and -1.98 [-3.88 to -0.08].
Conclusion: Analysis of symptom diaries confirms that 177Lu-DOTATATE can palliate clinically relevant symptoms when compared to high-dose octreotide.
Impact of Baseline Liver Tumor Burden, Alkaline Phosphatase (ALP) Elevation, and Target Size Lesion on Therapeutic Effect of 177LU-DOTATATE Treatment: Analysis of Progression Free Survival, and Safety in NETTER-1 Study
Jonathan Strosberg,1 Pamela Kunz,2 Andrew Hendifar,3 James Yao,4 David Bushnell,5 Matthew Kulke,6 Richard Baum,7 Caplin Martin,8 Philippe Ruszniewski,9 Ebrahim Delpassand,10 Timothy Hobday,11 Chris Verslype,12 Al Benson,13 Berna Polack,14 Beilei He,14 Paola Santoro,14 Eric Krenning.151Moffitt Cancer Center, Tampa, FL; 2Stanford University, Palo Alto, CA; 3Cedars Sinai Medical Center, Los Angeles, CA; 4Univ-Texas MD Anderson Cancer, Houston, TX; 5University of Iowa, Iowa City, IA; 6Boston Medical Center, Boston, MA; 7Zentralklinik, Bad Berka, Germany; 8Royal Free Hospital, London, United Kingdom; 9Hopital Beaujon and Paris Diderot University, Paris, France; 10Excel Diagnostics, Houston, TX; 11Mayo Clinic, Rochester, MN; 12University Hospitals and KU Leuven, Leuven, Belgium; 13Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 14Advanced Accelerator Applications, a Novartis company, Reading, MA; 15Erasmus Medical Center, Rotterdam, Netherlands.
Background: To assess the impact of baseline liver tumor burden (LTB), alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-DOTATATE in the NETTER-1 study population.
Methods: Patients (pts) were randomized to receive either 177Lu-DOTATATE (Lu) (n = 117) or high-dose octreotide 60 mg (Oct) (n = 114). At the time of the primary PFS analysis, 229 pts had been enrolled. Baseline LTB was categorized as low (<25%), moderate (25%-50%), or high (>50%) according to estimated liver tumor volume divided by the total liver volume by computed tomography (CT) or magnetic resonance imaging (MRI). PFS was stratified by baseline LTB, ALP elevation and presence or absence of a large target lesion (>30 mm) at any site of the body on CT or MRI.
Results: Table 1 shows median PFS (months) in pts with low, moderate and high LTB, normal and elevated ALP, and with and without large target lesion. PFS was significantly prolonged with Lu compared with Oct regardless of LTB elevated ALP, or presence of a large target lesion. Within the Lu arm, no significant difference in PFS was observed among pts with different baseline LTB or with normal or elevated baseline ALP, but the absence of a large target lesion at baseline was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and not associated with high baseline LTB in either arm of the study and resolved without sequela.
Conclusion: 177Lu-DOTATATE demonstrated significant prolongation in PFS compared with high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumor burden, elevated ALP, or the presence of a large target lesion.
Effect of Metastatic Site On Survival in Patients With Neuroendocrine Neoplasms (NENS): An Analysis of SEER Data From 2010-2014
Nikolaos Trikalinos, Benjamin Tan, Manik Amin, Jingxia Lu, Ramaswamy Govindan, Daniel Morgensztern. Washington University in St Louis, St Louis, MO.
Background: Neuroendocrine neoplasms (NENs) display variable behaviors based on origin and grade. We assumed that both tumor origin and the location of metastasis may play a role in survival.
Methods: We queried the SEER database (2010–2014) for patients with an established diagnosis of NENs and documented site of metastasis and identified 2235 patients. Overall survival (OS) at the time points were estimated by the Kaplan-Meier method Cox proportional-hazards models were used to evaluate the relationship of the interested variables and OS.
Results: Lung, liver, bone and brain metastases were observed in 9, 74, 8, and 8 percent of metastatic patients respectively. In the multivariate model, metastasis locations were significantly and independently associated with worse survival (bone metastasis HR, 1.334 [0.964–1.848]; brain HR, 1.731 [1.283–2.336]; liver HR, 1.584 [1.195–2.098]). We produced a scoring system that can stratify metastatic NEN patients in low, intermediate and high-risk categories to help physicians with decision making.
Conclusion: Site of metastasis plays an important role in survival of metastatic NEN patients independent of commonly described prognostic factors.
Metastatic Potential of Small Pancreatic Neuroendocrine Tumors: Not as Innocent as They Seem
Eduardo Vega,1 Onur Kutlu,2 Omid Salehi,1 Daria James,1 Olga Kozyreva,3 Jennifer Chan,4 Claudius Conrad.11St Elizabeth Medical Center and Tufts University, Brighton, MA; 2Miller School of Medicine, University of Miami, Miami, FL; 3Saint Elizabeth Medical Center and Dana Farber Cancer Institute, Brighton, MA; 4Dana Farber Cancer Institute, Brighton, MA.
Background: It is well accepted that appropriately selected patients with T2-T3 pancreatic neuroendocrine tumors (pNET) should undergo surgical resection. The optimal management of T1 (≤2 cm) tumors remains unclear. While observation of T1 tumors is an accepted practice due to their presumed lower risk of metastasis, the precise metastatic potential of pNETs ≤2 cm and clinical factors associated with metastatic progression are not well defined.
Methods: We identified patients from the SEER registry diagnosed with pNET between 1998–2014 whom underwent surgery with a primary tumor size ≤2 cm. Additional inclusion criteria included complete information regarding age, sex, grade, location, number of lymph nodes dissected and nodal status, and complete survival and follow-up data. Binary logistic regression analyses were performed to evaluate the factors affecting nodal and systemic metastatic disease.
Results: We identified 612 patients with T1 pNET. Mean age was 55 years 48% were female. 72 (11.7%) had nodal metastasis, and 35 (5.7%) had M1 disease. In the multivariable analysis, tumor location in the body (OR, 1.903; P = 0.03) or tail (OR, 1.258; P = 0.04), tumor grade III-IV (OR, 2.042; P = 0.022), and age (OR, 0.963; P = 0.01) were associated with presence of nodal metastases. Patient age (OR 0.919, P = 0.009), tumor location in body (OR, 1.407; P = 0.038) or tail (OR, 1.612; P = 0.021) and tumor grade III-IV (OR, 5.379; P < 0.001) were associated with presence of M1 disease.
Conclusion: Despite a notion that pNET ≤2 cm have a low metastatic potential, the data presented here suggests that individualized risk stratification for optimal treatment management is required. Moreover, patients with high grade tumors and location in the body/tail should undergo closer surveillance and potentially be considered for surgical removal.
Effect of Telotristat Ethyl on Cardiac Valve Degeneration
Xinmei Wang,1 Danielle Kuban-Johnston,2 Pablo Lapuerta,2 Carla Lacerda.11Texas Tech University, Lubbock, TX; 2Lexicon Pharmaceuticals, Inc, The Woodlands, TX.
Background: Myxomatous mitral valve degeneration increases in prevalence with age. An increasing body of evidence suggests that serotonin signaling is a regulator of valvular degenerative processes. Telotristat ethyl (TE) is an inhibitor of tryptophan hydroxylase 1, the rate-limiting enzyme in serotonin synthesis, and is used in patients with carcinoid syndrome diarrhea. We examined the impact of TE on cardiac valve degeneration.
Methods: A hypertensive mouse model was established by angiotensin II (A2) delivery. Immunohistochemistry was used to identify myxomatous changes inducible by A2. Telotristat ethyl was administered in two settings: 1) in parallel with A2 treatment, as a preventive approach 2) after A2 treatment, as a reversal approach. Both settings had four groups: control, control plus TE, A2, and A2 plus TE.
Results: In both settings, A2 increased blood pressure, mitral valve thickness, and mitral valve expression of MMP1, α-SMA, and TGFβ compared to control. In both settings, A2 plus TE reduced circulating serotonin, mitral valve thickness, and mitral valve expression of MMP1 and α-SMA, but not TGFβ compared to A2.
Conclusion: Markers of myxomatous degeneration increased in animals treated with A2 and decreased with TE. Clinical research is warranted to examine the impact of TE on cardiac valves.
A Pilot Phase 2 Study of S-1 and Temozolomide as Second-Line Treatment in Patients With Advanced or Metastatic Neuroendocrine Carcinoma
Xin Wang,1 Zhirong Qi,2 Huangying Tan.21Beijing University of Chinese Medicine, Beijing, China; 2China-Japan Friendship Hospital, Beijing, China.
Background: Neuroendocrine carcinoma (NEC) is a group of highly malignant and invasive rare tumors with few treatment options. Due to its malignancies, many patients missed the opportunity of surgery at the time of diagnosis. For the patients with advanced or metastatic NEC, platinum-based chemotherapy is often used as first-line treatment. There is no standard second-line treatment for patients with disease progression or intolerance to platinum-based first-line treatment. According to our clinical observation, some patients with NEC are effectively treated with S-1 combined with temozolomide regimen. The goal of this phase 2 pilot study is to evaluate the utility of S-1 and temozolomide treatment in NEC.
Methods: This study is a prospective, single arm, single institution pilot phase 2 study to evaluate the efficacy and safety of S-1 (40–60 mg orally twice daily, days 1–14 )and temozolomide (200 mg orally once daily, days 10–14) every 21 days as second-line treatment in patients with advanced or metastatic NEC. Patients will be treated until disease progression. Tumor response will be assessed by CT/MRI at baseline then every 6 weeks until progression or intolerance of the toxicity. The primary endpoint is overall response rate (ORR) measured by RECIST 1.1. This study will enroll 40 patients with ECOG performance status of 0-2. The key eligibility criteria is measurable unresectable or metastatic disease of NEC. Patients must have progressed or have been intolerant to platinum-based chemotherapy.
Results: This study is now active and open for enrollment. The anticipated enrollment period is 12 months.
Conclusion: This pilot phase 2 study may show evidence of promising safety and efficacy of S-1 and temozolomide in NEC patients who progressed on or failed platinum-based chemotherapy.
Outcomes After Cessation of Therapy With Alkylating Agents (AA) for Pancreatic Neuroendocrine Tumors (PanNETS)
Y. Linda Wu,1 Diane Reidy,2 Agata Bielska,2 Virginia Kelly,2 Nitya Raj.21New York Presbyterian - Weill Cornell Medical Center, New York, NY; 2Memorial Sloan Kettering Cancer Center, New York, NY.
Background: Treatment-related toxicity precludes the use of all therapies available for panNETs. AA are an effective therapy in panNETs but can cause irreversible bone marrow suppression. For this reason, our institutional approach is to treat patients with AA for a defined time period of up to 12 months prior to a treatment holiday anecdotally, we observed continued disease shrinkage or stability after drug cessation. We aimed to identify and characterize these exceptional responders.
Methods: We retrospectively evaluated patients with well differentiated panNETs treated at MSKCC with AA from 2007 to 2019, and identified those who were placed on a treatment holiday after response to therapy. Patients with continued disease response by radiographic report (tumor shrinkage or stable disease) for greater than 9 months while on a treatment holiday were considered exceptional responders (ER).
Results: 124 patients were evaluable, with 104 patients (84%) receiving temozolomide and 18 (15%) receiving dacarbazine. 40 (32%), 57 (46%), and 22 (18%) patients had low, intermediate and high-grade tumors, respectively. Fifty-eight patients (47%) had either stable disease or disease response to AA and entered a treatment holiday 39/58 patients (67%) were ER and 16/58 patients (28%) had progression in <9 months. No significant differences in tumor grade (P = 0.85) were seen between ER and those who had disease growth in <9 months. Next generation sequencing results were available in 17 tumors of patients classified as ER 14/17 (82%) with alterations in chromatin remodeling genes (MEN1/DAXX/ATRX). Upon disease progression, 11 ER were reintroduced to alkylating agents 9/11 (82%) had progressive disease or death after reintroduction of drug, and 2/11 (18%) responded and went on a second treatment break.
Conclusion: We observed durable responses to AA after cessation of therapy. Many of the ER tumors harbored alterations in chromatin remodeling genes. Reintroduction of AA upon disease progression was generally ineffective.
Lymphovascular Invasion, Tumor Growth Pattern and Fibrosis in Pancreatic Neuroendocrine Tumors: Qualitative Imaging Correlates on Preoperative CT/MRI in a Series of 136 Cases
Motoyo Yano, Nikolaos Trikalinos, Greg Williams, Amber Salter, Samantha Lancia, Chet Hammill, William Hawkins, Deyali Chatterjee. Washington University School of Medicine, St. Louis, MO.
Background: Lymphovascular invasion (LVI), infiltrative growth pattern, and fibrosis in resected pancreatic neuroendocrine tumors (NET) are some of the pathologic risk factors for tumor recurrence and decreased survival. The goal was to determine if these pathological variables have qualitative imaging correlates on preoperative imaging.
Methods: In this single institution retrospective study, a surgical database of resected pancreatic NET was queried and those cases with preoperative contrast enhanced CT and/or MRI were included. Pathological assessment of LVI, growth pattern (circumscribed or infiltrative), and intratumoral fibrosis (classified into no significant fibrosis, predominantly collagenous/mature fibrosis, or active fibroblastic stromal response/immature fibrosis) was performed. Radiological assessment for tumor enhancement (homo- or heterogeneous enhancement hyper, hypo, or isoenhancement progressive enhancement), tumor contour (round, lobulated, ill-defined), ductal dilatation, calcification, cystic components, tumor thrombus, vascular occlusion, and upstream atrophy was performed. Chi-square/Fisher’s exact tests were performed to evaluate for associations.
Results: One hundred thirty-six tumors were included. LVI was present in 56 of 133 cases. Circumscribed growth pattern was seen in 98 of 124 cases. No substantial fibrosis was present in 68 cases, mature fibrosis was present in 38 cases, and immature fibrosis was present in 18 cases. LVI was associated with round contours and absence of LVI was associated with lobulated contours (62.5% vs 42.1% and 51.3% vs 28.6%, P = 0.032). An infiltrative, rather than circumscribed, growth pattern on pathology was associated with ill-defined contours on imaging (19.2% vs 5.1%, P = 0.048. No/mature fibrosis, rather than immature fibrosis, was associated with calcifications (24.3% vs 0%, P = 0.038). No significant associations were found with other qualitative variables.
Conclusion: Tumor contour on preoperative imaging is associated with LVI and growth pattern. Presence of calcifications indicates absence of immature fibrosis.
CT and MRI of Pancreatic Neuroendocrine Tumors Reveal More Than Just a Round, Enhancing Mass: Associations Between “Atypical” Imaging Features
Motoyo Yano,1 Deyali Chatterjee,1 Greg Williams,1 Amber Salter,1 Samantha Lancia,1 Chet Hammill,1 William Hawkins,1 Nikolaos Trikalinos.21Washington University School of Medicine, St. Louis, MO; 2 Washington University in St. Louis, St. Louis, MO.
Background: Pancreatic neuroendocrine tumors (NET) are classically considered round, homogeneously hyperenhancing lesions. “Atypical” features are increasingly appreciated in the literature. The goal was to determine the associations between enhancement patterns and other qualitative features of the tumor.
Methods: This single institution retrospective study was populated using a surgical database of resected tumors. Patients with preoperative CT/MRI were included and images reviewed for qualitative features. Enhancement of the solid portion of the tumors was assessed for homo- or heterogenous enhancement. Degree of enhancement relative to the pancreas was characterized as hyper, hypo, or isoenhancing. For multiphase exams, progressive enhancement was assessed. Tumor contour was categorized as round, lobulated, or ill-defined. Calcifications and cystic components within the tumor were recorded. Secondary findings such as infiltration into adjacent structures, ductal dilatation, tumor thrombus, vascular occlusion, and upstream atrophy were assessed. Chi-square/Fisher’s exact tests were performed to evaluate for associations.
Results: Most tumors (n = 72/131) were hyperenhancing and compared to hypo or isoenhancing tumors were less likely to be infiltrative (7% vs 38.5% vs 24.2%, P < 0.001) and demonstrate vascular occlusion (6.9% vs 30.8% vs 21.2%, P < 0.008). Hypoenhancing tumors (n = 26/131) were more likely to show heterogeneous enhancement than hyper or isoenhancing tumors (84.6% vs 53.5% vs 53.6%, P = 0.016). Homogeneously enhancing tumors were associated with round contours (60% vs 42.9%, P = 0.004). Heterogeneously enhancing tumors (n = 77/127) were more likely to show hypoenhancement (29.3% vs 8%, P = 0.016), progressive enhancement (39.4% vs 4.4%, P < 0.001), lobulated contour (53.2% vs 26%, P = 0.004), calcifications (29.4% vs 4.7%, P = 0.001), cystic components (36.4% vs 14%, P = 0.006), tumor thrombus (9.2% vs 0%, P = 0.041) and vascular occlusion (22.4% vs 8%, P = 0.034) than homogenously enhancing tumors.
Conclusion: Heterogeneous enhancement in pancreatic NET is common and is associated with other “atypical” features such as hypoenhancement, progressive enhancement, lobulated contours, calcifications, cystic components, tumor thrombus, and vascular occlusion.
Meta-Analysis of Prognostic Biomarkers for Pancreatic Neuroendocrine Tumors (PNETS)
Mojun Zhu,1 Thorvardur Halfdanarson,1 Bonnie Rothberg.21Mayo Clinic, Rochester, NY; 2Yale New Haven Hospital, New Haven, CT.
Background: PNETs are marked by histological heterogeneity and variable clinical outcomes. Other than Ki-67 index, reliable circulating or tissue biomarkers for prognosis do not exist.
Methods: PubMed was searched through January 31, 2017. Inclusion criteria were: 1) prospective or retrospective cohort design with a clearly defined source population, boundary dates, and justifications for all excluded eligible cases 2) assay of primary tumor specimens 3) clear descriptions of methods, experimental techniques, and choice of positive and negative controls 4) statistical analysis using multivariate proportional hazards modeling that adjusted for clinical prognostic factors including but not limited to stage or grade and 5) reporting of the resultant adjusted hazard ratios with 95% confidence intervals and corresponding P values. Studies with <50 % PNETs were excluded. Emails were sent to 40 investigators for clarification and responses were received from 16 groups. PNET-specific data was summarized in the table below.
Results: A total of 2958 manuscripts were identified and 462 manuscripts were reviewed in detail. Only 23 multivariate studies met all inclusion criteria. PNET-specific data was summarized in Table 1. These altogether analyzed 24 unique targets and 14 of them were associated with survival.
Conclusion: This meta-analysis identified 14 markers associated with survival of PNET patients. Future studies should adhere to the REMARK criteria and incorporate the 2017 WHO grading system for multivariate analysis.