Genomic Profiling Distinguishes Gastroenteropancreatic Poorly Differentiated Neuroendocrine Carcinomas (GEP-NEC) from Small Cell Lung Carcinoma (SCLC)
Emily Bergsland,1 Ritu Roy,1 Julia Elvin,2 Fiona Graeme-Cook,2,3 Mark Bailey,2 Phil Stephens,2 Jeffrey Ross,2 Adam Olshen.1,41UCSF; 2Foundation Medicine, Inc.; 3Massachusetts General Hospital; 4UCSF Helen Diller Family Comprehensive Cancer Center.
Background: Optimal therapy for GEP-NEC is not clear. Traditionally treated like SCLC, overall prognosis is poor and new therapies are needed. We examined genomic alterations (GA) in GEP-NEC of different sites compared to SCLC.
Methods: Sequential GEP-NEC cases from a database [Foundation Medicine] of tumors submitted for genomic profiling analyzed after digital pathology images reviewed by two different pathologists. Group 1: 274 cases with “some” component of morphologically apparent NEC −123 pancreas (P), 92 colorectal (CR), and 59 “other GI” sites; Group 2: 159 cases passing an independent, stricter pathology review (>50% NEC with small or large cell histology)- 91 P, 51 CR, and 17 “other GI”. Hybridization-captured libraries of up to 315 cancer-related genes, plus select introns were sequenced (FoundationOne). All classes of GA identified in 192 cancer-related genes shared across 2 different assay versions. “Actionable” alterations were assessed. 593 SCLC cases used for comparison.
Results: There were 9 genes with alterations in >15% of tumors in any group (Group 1). Only TP53 crossed the 15% threshold in every group: MEN1 and DAXX >15% specific to P, APC and KRAS specific to CR, and CCNE1 > 15% specific to “other GI”. Every GEP-NEC group had a lower rate of alteration for TP53 and RB1 than SCLC. Analysis of Group 2 GEP-NEC showed similar findings (“Other GI” excluded due to small N). Pooled P and CR NEC with small cell histology (N = 142) showed significantly different GA compared to SCLC. 37% of Group 2 GEP-NEC harbored potentially “actionable” GA.
Conclusion: Findings indicate underlying drivers of GEP-NEC may depend on site of origin and distinguish GEP-NEC from SCLC. Presence of potentially actionable GA in GEP-NEC suggest additional therapeutic targets. Lack of access to medical record/original tissue precludes correlation of GA with outcome or proliferation index; additional samples required to more fully explore large v small cell subtypes.
Correlation of Angiogenic Markers in Neuroendocrine Tumors and Their Prognostic Implications
David Beyer,1 Yi-Zarn Wang,1 Ramcharan Thiagarajan,1 Robert Ramirez,2 Richard Campeau,1 J. Philip Boudreaux,1 M. Jennifer Ricks,2 Eugene Woltering.11LSU Health Sciences Center; 2Ochsner Medical Center.
Background: Neuroendocrine tumors (NETs) are rare and indolent neoplasms. Two markers, CD31 and Factor VIII, describe the angiogenicity of a tumor and may correlate with tumor growth and metastasis. We hypothesized that these two angiogenic markers are highly correlated. Tumors with higher angiogenic markers may have higher proliferative indices (Ki-67) and poorer prognoses.
Methods: Pathology reports from all NET patients who had surgery performed at our institution from April 2003 to October 2014 were queried for Factor VIII, CD31 and Ki-67 immunohistochemical values. Patient demographics, tumor characteristics and pathology reports were analyzed. For subjects with multiple values, the highest value was used in statistical calculations. Survival from date of diagnosis was calculated via Kaplan-Meier method and statistical significance was defined as p < 0.05.
Results: One-thousand and seventy-two specimens from 534 NET patients were analyzed. CD31 and Factor VIII were statistically significantly correlated (p < 0.0001; r = 0.8663). When individually compared to Ki-67, CD31 and Factor VIII showed no statistical association (p = NS). Survival sorted by Ki-67 was statistically significant (p < 0.05). However, survival, stratified by CD31 and Factor VIII, was not statistically significant (p = NS).
Conclusion: Factor VIII CD31 in NETs are significantly correlated regardless of primary tumor site, high values do not predict a poor prognosis. Further studies are warranted to determine the role of these markers in the diagnosis management of NETs.
Immune Checkpoint Markers and Immune Response in Well Differentiated Neuroendocrine Tumors (NET) of the Small Intestine and Pancreas
Annacarolina da Silva,1 Zhirong Qian,1 Sui Zhang,1 Yohei Masugi,1 Scott Rodig,2 Lauren Brais,1 Trevor Dutton,1 Jennifer Chan,1 Stephen Hodi,1 Shuji Ogino,1 Matthew Kulke.11Dana Farber Cancer Institute, Boston, MA; 2Brigham and Women's Hospital, Boston, MA.
Background: Immune checkpoint (ICP) inhibition has emerged as a promising treatment approach in human malignancies. The potential for neuroendocrine tumors (NET) to respond to ICP inhibitors is unknown, and the immune environment of NET remains relatively unexplored. We aimed to determine the expression profile of PD-1, PD-L1 and PD-L2, in both small intestine neuroendocrine tumors (SINET) and pancreatic neuroendocrine tumors (pNET) and to describe the associated immune response.
Methods: We retrospectively analyzed the clinical and molecular characteristics of 85 well differentiated NET (64 SINET, 21 pNET). We assessed tumor and associated stromal expression of ICP markers using the murine monoclonal antibodies anti-PD-1 (EH33), anti-PD-L1 (9A11) and anti-PD-L2 (9E5). We assessed tumor infiltrating lymphocytes using the T-cell markers CD45RO (UCHL1), CD3 (7.2.38), CD8 (C8/144B) and FOXP3 (206D). We interpreted expression based on published criteria.
Results: Among low grade NET (64 SINET, 21 pNET), tumoral PD-L1 expression was observed in 0/64 (0%) SINET and 2/18 (11%) pNET and tumoral PD-L2 expression in 52/64 (88%) SINET and 19/21(90%) pNET. PD-1-positive stromal lymphocytes were present in 27/60 (45%) SINET and 9/19 (47%) PNET; PD-L1-positive stromal lymphocytes in 33/59 (55%) SINET and 3/18 (17%) pNET, and PD-L2-positive stromal lymphocytes in 52/61(85%) SINET and 19/21 (90%) pNET. T-cell infiltrates, as measured by CD45R0, CD3, CD8 expression, were more abundant in pNET than in SINET. FOXP3+ cells were rare in both. No obvious differences in ICP marker expression or T-cell infiltrates were observed between 5 CDKN1B mutated and 22 wild type SINET.
Conclusion: Expression of the ICP marker PD-L1 is uncommon in pNET and SINET, whereas both tumor types express PD-L2. T-cell immune infiltrates are present in both tumor types, appearing to be more prominent in pNET. CDKN1B mutational status does not appear to influence ICP marker expression or immune response in SINET. Assessment of mutational status of pNET is ongoing.
Loss of UCHL1 Expression Increases Metastatic Potential in Pancreatic Neuroendocrine Tumors
Brendan Finnerty, Maureen Moore, Irene Min, Marco Seandel, Todd Evans, Rasa Zarnegar, Thomas Fahey. New York Presbyterian Hospital – Weill Cornell Medicine, New York, NY.
Background: Well-differentiated pancreatic neuroendocrine tumors (WD-PNET) metastasize even in the setting of low Ki67 index. We have previously identified UCHL1, a post-translational modifier that targets proteins for lysosomal degradation, as differentially expressed in metastatic and localized PNETs. Here we aimed to elucidate how UCHL1 may contribute to the metastatic phenotype.
Methods: Two PNET cell lines, BON (lymph node of metastatic PNET with no UCHL1 expression) and QGP (primary tumor of metastatic PNET with very low UCHL1 expression) were stably transfected with an inducible UCHL1 gene and the cells then studied with and without UCHL1 expression for cell viability, apoptosis, growth, cell-cycle arrest, and cellular invasion. These in vitro assays were compared to the cell lines transfected with an empty vector (BON-EV and QGP-EV) as negative controls.
Results: UCHL1 expression in BON cells (BON-UCHL1) resulted in a higher percentage of BON-UCHL1 cells in the G0/G1 phase of the cell cycle as compared to BON-EV cells (47 ± 4% vs. 37 ± 3%, p = 0.03). Similarly, there was a higher percentage of QGP-UCHL1 cells compared to QGP-EV in the G0/G1 phase (68 ± 6% vs. 61 ± 4%, p = 0.02). BON-UCHL1 cells were also observed to have lower numbers of colonies per low-power field than the BON-EV cells (667 ± 36 vs. 895 ± 43, p < 0.001) in an anchorage independent colony growth assay. In a cell adhesion assay, BON-UCHL1 cells displayed decreased adhesion with a lower fraction of non-adherent cells when compared to BON-EV (63 ± 7% vs. 92 ± 5%, p < 0.001). A modified Boyden chamber assay for cell invasion was also noted to be decreased in BON-UCHL1 cells after 24-hours (12 cells vs. 74 cells per transwell plate, p = 0.03).
Conclusion: Loss of UCHL1 gene expression is associated with metastasis in well-differentiated PNETs. Re-expression of UCHL1 in 2 PNET cell lines was associated with findings consistent with decreased metastatic potential. Further in vivo studies are warranted to confirm these findings.
Development of Non-Metastatic and Metastatic Xenograft Models of Pancreatic Neuroendocrine Disease for Defining the Molecular Landscape Responsible for Progression and Therapeutic Outcome
Sean Glenn, Michael Rusiniak, Daniel Abbotoy, Yanqing Wang, Renuka Iyer, Heinz Baumann, Kenneth. Gross Roswell Park Cancer Institute, Buffalo, NY.
Background: We have generated a unique mouse model of highly metastatic islet cell carcinoma by selectively abrogating floxed alleles of p53 and Rb genes using Cre-recombinase driven by the renin promoter. Incorporation of a multi-colored fluorescent reporter, Confetti, confers the ability to observe clonality of primary tumors and metastases. This ability allows concise identification and excision of metastatic and non-metastatic primary lesions from the spontaneous model for discrete molecular profiling of each tumor as well as implantation into host xenograft animals for longitudinal drug studies.
Methods: Clonal color-matched expansion of the rare cells that progress to primary tumors and metastases allow for rapid identification and excision of non-metastatic and metastatic primaries from the same mouse. Primary tumors are divided into multiple xenograft animals for subsequent proposed drug intervention studies. Next-Generation Sequencing technology is used to define the molecular landscape of each tumor as a basis to stratify non-metastatic vs. metastatic as well as responder vs. non-responder phenotypes.
Results: Dissection of animals of appropriate genetic constitution reveals that most mice harbor multiple primary tumors of different fluorescent color. Remarkably, in the subset of animals that developed metastatic disease, all observed liver metastases are a single color suggesting they derive from only one of multiple primary tumors in each case. Preliminary xenograft experiments show that metastatic primary tumors, when implanted will seed metastases to liver, however non-metastatic primaries do not. Whole Exome Sequencing of DNA from multiple sets of metastatic and non-metastatic tumors, along with identified responses to drug treatment will offer up insight into genes responsible for metastatic progression as well as response to therapy.
Conclusion: Our utilization of our spontaneous neuroendocrine pancreas model combined with multiple fluorescent reporters to dissect out primary tumors for xenograft development, is providing unique insights into pancreatic islet carcinogenesis, metastasis, and feasibility for drug studies.
Met Activation Confers Increased Aggressiveness and Corresponds With Hypoenhancement on Contrast Enhanced Computed Tomography in Pancreatic Neuroendocrine Tumors
Geoffrey Krampitz, Irving Weissman, Jeffrey Norton. Stanford University School of Medicine, Stanford, CA.
Background: Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with variable biological behavior. Previously, we showed that increased tumor aggressiveness was associated with hypo-enhancement on preoperative contrast enhanced computed tomography (CT). However, the molecular rationale for pathogenesis in this cohort of PanNETs is unknown.
Methods: We used snap-frozen tissue from patient PanNETs with either hypo- or hyper-enhancing imaging characteristics on preoperative CT. Using quantitative polymerase chain reaction, mRNA expression for MET, HIF1A, HGF, KDR, SNAI1, CDH2, VIM, CDH1, PECAM1, TEK, FLT4, and LYVE1 was determined and correlated to preoperative imaging characteristics and overall survival. Protein expression of the above genes and activated MET was confirmed by immunofluorescence. For treatment studies, PanNET cell line APL1 cells, previously transduced using lentivirus containing a green fluorescent protein (GFP) and luciferase constructs, were orthotopically injected into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice and treated with MET inhibitor MET-MAb antibody (Genentech).
Results: PanNETs that were hypo-enhancing on preoperative CT had increased expression of MET, HIF, HGF, SNAI1, CDH2, VIM, FLT4, and LYVE1 and decreased expression of CDH1, PECAM1, and TEK compared to hyper-enhancing tumors. Furthermore, blocking MET activation inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo.
Conclusion: Our results demonstrate that PanNETs that are hypo-enhancing on contrast enhanced CT imaging studies and are associated with decreased overall survival have increased tumor hypoxia, increased mesenchymal characteristics, decreased epithelial features, diminished vascularity, and enhanced lymphatics compared to hyper-enhancing tumors. Furthermore, we show the efficacy of anti-MET therapy on PanNETs in animal treatment models. Our findings suggest a molecular mechanism for increased tumor aggressiveness seen in hypo-enhancing tumors compared to hyper-enhancing tumors, and provide a strong preclinical justification for testing blocking anti-MET antibodies in patients with PanNETs.
New Image-guided Alpha Particle Therapy for NETs in Children and Adults
Dongyoul Lee, Mengshi Li, Dijiex Li, Michael Schultz. University of Iowa, Iowa City, IA.
Background: Neuroendocrine tumors (NETs) are a rare form of cancer whose incidence is increasing. In the development of effective therapy, high expression of somatostatin receptor subtype 2 (SSTR2) has been identified as a potential target for drug delivery, including peptide receptor radionuclide therapy using DOTA0-Tyr3-octreotide (DOTATOC). While beta particle therapies using 90Y/177Lu have been extensively examined, the potential advantages of alpha particle therapy have been relatively unexplored. Within this context, we are developing a new image-guided 203Pb(imaging)/212Pb(therapy) approach that we anticipate will impart a higher RBE (relative biological effectiveness) via targeted alpha particle deposition in NETs and improve outcomes compared to current beta particle therapies.
Methods: Pancreatic carcinoid (BON-1) cells were implanted subcutaneously in nude mice and a bio-distribution study was conducted by injecting 1 μCi of 203Pb/212Pb-DOTATOC via tail vein. Mice were euthanized at 1 h, 3 h, and 24 h post-injection (n = 3); tissues of interest were harvested and radioactivity measured. These data were used to inform a SPECT/CT imaging study (180 μCi of 203Pb-DOTATOC was injected via tail vein) at 1 h post injection. A pilot therapeutic study was then conducted in BON-1 tumor bearing mice (3 groups: control, single dose, and 3 fractionated doses; total dose ~120 μCi of 212Pb-DOTATOC). Ongoing survival studies reveal a significant survival benefit and tumor control in 212Pb-DOTATOC treated NET tumor bearing mice relative to untreated mice.
Results: Excellent tumor contrast was observed in the first 203Pb-DOTATOC SPECT/CT images of human NETs obtained in these pilot studies. Biodistribution and imaging studies informed 212Pb-DOTATOC therapy in which significant survival improvement and reduction in tumor growth was observed in human NET bearing mice.
Conclusion: A 203Pb/212Pb theranostic combination is a promising alternative for image-guided radionuclide therapy for NETs and other SSTR2 expressing tumors.
Novel Combinatorial Drug Therapy for MTC
Karine Pozo,1 Keisuke Ishimatsu,1 Rahul Telange,1 Masaya Takahashi,1 Sarah Oltmann,1 Stefan Zahler,2 James Bibb.11The University of Texas Southwestern Medical Center; 2Ludwig-Maximilians-Universität Munich.
Background: Medullary thyroid carcinoma (MTC) originates from the thyroid gland parafollicular cells. Treatment options for progressive, metastatic MTC patients are limited to the recently FDA-approved tyrosine kinase inhibitors (TKIs), Vandetanib and Cabozantinib, which target multiple receptor tyrosine kinases, including VEGFR2. However, the efficacy of TKIs is limited and development of TKI resistance is common. Here we examined, the effect of a combinatorial drug therapy using the TKI, Nintedanib, and the histone deacetylase (HDAC) inhibitor, Romidepsin, on MTC growth and mouse survival.
Methods: We used the NSE/p25-gfp bi-transgenic mouse line, which is an inducible mouse model for MTC. Mice were dosed with either Nintedanib (100 mg/kg/day) or Romidepsin (0.75 mg/kg/day) or [Nintedanib (35 mg/kg/day) + Romidepsin (0.37 mg/kg/day)] or vehicle. Drugs were administered intraperitoneally for a 3-week period. For survival studies, mice were left untreated for 3 more weeks. Tumor progression was monitored weekly using a T2 weighted magnetic resonance imaging on a 7 Tesla system. Tumor tissues were analyzed for oncogenic signaling pathways by immunoblotting. Proliferation and microvessel density were determined by immunostaining tumors with Ki-67 and CD-31 antibodies respectively.
Results: Romidepsin, alone, has no effect on tumor growth. However Nintedanib slows down tumor growth by 50% by disrupting tumor vasculature. This is demonstrated by a 75%, and a 54% reduction in microvessel density in Nintedanib- and [Nintedanib + Romidepsin]-treated mouse tumors, respectively. Importantly Nintedanib has no effect on proliferation. However combining Nintedanib with Romidepsin reduced proliferation by 70%. Mechanistically Nintedanib or the combination of Nintedanib and Romidepsin inhibit RET and VEGFR2 signaling as well as AKT and mTor.
Conclusion: Nintedanib or combinatorial treatments of [Nintedanib + Romidepsin] represent valid strategies to stop MTC progression. We are currently evaluating the effect of these drugs on mouse survival and development of drug resistance.
Enhancing Neuroendocrine (NET) Cancer Therapy Responses via Disruption of Peroxide Balance
Samual Rodman,1,2 Kelly Falls,1,2 Joshua Shoenfeld,1,2 Douglas Spitz,1,2 Melissa Fath.1,21University of Iowa, Iowa City, IA; 2Radiation Oncology.
Background: Cancer cells relative to normal cells are believed to exist in a chronic state of oxidative stress characterized by increased steady-state levels super oxide and peroxide produced as by-products of dysfunctional mitochondrial metabolism. It has also been shown that cancer cells, compared to normal cells, have increased labile iron and copper. These metals can participate in oxidation reactions that result in highly toxic hydroxyl radicals. Our project takes advantage of these differences using drugs that are already deemed safe for human use [ascorbate (ASC), D-penicillamine (DPEN), and disulfiram (DSF)] for killing cancer cells and enhancing traditional therapy responses.
Methods: Peroxide flux after addition of ASC, DPEN or DSF was measured in lung cancer cells using the 3 aminotriazole method. NET cell lines DMS53 (lung small cell), BON and QGP-1 (pancreatic) and H727 (bronchial carcinoid) were treated with ASC, DPEN or DSF + Cu with and without traditional therapies and clonogenic assays were performed. BON cells were grown as xenografts and the mice treated with ASC, DPEN and/or everolimus daily. Tumor volumes were measured using calipers.
Results: Pharmacologically relevant dosing of DSF, DPEN, and ASC resulted in significantly elevated fluxes of H2O2 compared to control. DPEN and DSF combined with copper resulted in a significant decrease in clonogenic cell survival in all four NET cell lines. Traditional NET therapies, everolimus and sunitinib, were both enhanced by ASC in H727, BON and QGP-1 cell. ASC or DSF + Cu significantly increased clonogenic cell death when combined with IR in DMS53 cells. ASC + everolimus delayed xenograft tumor growth without causing toxicity to the mice.
Conclusion: These observations support the hypothesis that the differences in levels of reactive oxygen species and redox active metals in cancer versus normal cells can be exploited to develop effective NET therapy using ASC, DPEN and DSF to enhance responses to standard of care therapy.
RABL6A, A Novel Oncogene Required for Akt-mTOR and Myc Signaling in Pancreatic Neuroendocrine Tumor Cells
Ryan Sheehy, Angela Schab, Jussara Hagen, Ume Salma Shaik Amjad, Benjamin Darbro, Dawn Quelle. University of Iowa, Iowa City, IA.
Background: A better understanding of pathways controlling pancreatic neuroendocrine tumor (PNET) formation and progression is needed to improve patient diagnosis and treatment. The PI3K/Akt/mTOR pathway is aberrantly activated in PNETs resulting in everolimus (mTOR inhibitor)-based therapies. However, sustained mTOR inhibition unfortunately promotes Akt hyper-activation and drug resistance. Our data suggest that RABL6A, a novel oncoprotein required for PNET cell proliferation and survival, is a key regulator of this clinically relevant pathway as well as Myc oncogenic signaling.
Methods: RABL6A, Akt and Myc protein levels were manipulated using viral shRNA and overexpression vectors in BON-1 PNET cells. Transcript levels were assayed by microarray and qRT-PCR, proteins assessed by western blotting, and cell proliferation/survival measured by cell counts, trypan blue exclusion, EdU incorporation and flow cytometry.
Results: RABL6A loss in PNET cells dramatically reduced both Akt1 and c-Myc expression and activity. Given the central role of Akt1 and Myc in promoting tumorigenesis, we hypothesized that reinstating their activity would rescue the growth arrest phenotype caused by RABL6A loss. Individual restoration of Akt or Myc in RABL6A-depleted PNET cells partially rescued the G1 phase arrest and induced S phase entry. This coincided with decreased expression of the cell cycle inhibitor, p27Kip1, and increased levels of CKS1B, a Myc transcriptional target that promotes p27 degradation. Notably, neither Akt nor Myc activation was sufficient to restore proliferation in the absence of RABL6A since cells became arrested in S-G2/M or died via apoptosis.
Conclusion: RABL6A controls multiple cancer pathways necessary for PNET cell cycle progression and survival. We are testing if RABL6A status in PNETs predicts responsiveness to clinical inhibitors of Akt, mTOR and Myc. These studies identify RABL6A as a new essential regulator of Akt1-mTOR and Myc pathways, suggesting its inhibition may have global anti-cancer activity and therapeutic value in PNET patients.
The 2nd Gen mTOR Inhibitor INK128 Overcomes Resistance to Everolimus (1st Gen) in Pancreatic Neuroendocrine Tumors
Yucheng Wang, Byron Hann, Henry VanBrocklin, Kevan Shokat, Robert Warren, David Donner, Emily Bergsland, Eric Nakakura. UCSF, San Francisco, CA.
Background: Dysfunction of the mTOR pathway is a critical event in pancreatic neuroendocrine tumors (pNETs). The 1st Gen mTOR inhibitor (rapalog), everolimus, is approved for the treatment of pNETs, but therapeutic resistance frequently emerges. Using a novel in vivo model of pNETs, we hypothesized that the 2nd Gen mTOR inhibitor (ATP-competitive inhibitor), INK128, can effectively overcome resistance to everolimus.
Methods: We developed a patient-derived xenograft pNET model that exhibits key features of the disease, such as a NE phenotype and mTOR pathway activation. Nude mice bearing pNET xenografts were treated with everolimus (10 mg/kd/d) p.o. until the development of resistance. Secondary or acquired resistance to everolimus was defined as a 100% increase in tumor volume. Resistant tumors were treated with INK128 (1 mg/kg/d) p.o., and tumor volume was measured by caliper twice weekly.
Results: Most (82 %, 28/34) tumors exhibited no change or a decrease in size after everolimus treatment. This data is very similar to what was reported in humans receiving evelorimus in the RADIANT-3 Trial. During the study period, 12 tumors developed resistance to everolimus and were subsequently treated with INK128. Strikingly, treatment of everolimus-resistant tumors with INK128 effectively halted tumor growth or caused tumor shrinkage most of the time (75%, 8 of 12 cases).
Conclusion: As in patients, our pNET model shows that the mTOR pathway is a critical driver of pNET growth and that everolimus effectively inhibits tumor growth initially. However, as in patients, pNETs developed resistance overtime to everolimus in our model. Importantly, INK128 was able to overcome resistance to everolimus in our PNET model. Our findings provide the preclinical rationale to use 2nd Gen mTOR inhibitors, such as INK128, to overcome resistance to everolimus in patients with advanced pNETs.
The Pentarin Miniaturized Drug Conjugate PEN-221 Targets the Potent Cytotoxic DM1 to Somatostatin Receptor 2 Expressing Cancers
Kerry Whalen, Brian White, Kristina Kriksciukaite, Tsun Au Yeung, Patrick Bazinet, Kay Callahan, Michelle DuPont, Jamie Gifford, Benoit Moreau, Sam Perino, James Quinn, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Leilla Alland, Mary Simcox, Mark Bilodeau, Richard Wooster. 1Tarveda Therapeutics, Watertown, MA.
Background: The selective targeting of potent therapeutics to cancer cells has shown promise in delivering patient benefit while limiting the exposure to and toxicity in normal tissues. Most attention has been given to antibody drug conjugates (ADCs) with a handful of new drug approvals and many molecules in clinical development. Despite long plasma half-lives, the size large of ADCs (150 kDa) is known to limit tumor exposure due to the slow penetration of solid tumor tissue leading to inefficient delivery of the cytotoxic payload. Further, the payload on many ADCs is released while in the plasma, resulting in the delivery of the antibody alone and loss of therapeutic activity. In contrast, Pentarins are miniaturized drug conjugates of ~5 kDa that rapidly penetrate deep into solid tumor tissue to specifically deliver potent payloads to tumor cells.
Methods: Somatostatin receptor 2 (SSTR2) is over expressed in multiple types of neuroendocrine cancers including gastroenteropancreatic, lung and thymus neuroendocrine tumors and small cell lung cancer. Tumor expression of SSTR2 can be detected with approved imaging agents such as 111In-pentetreotide and 68Ga-DOTATATE making it possible to identify patients to treat with SSTR2 targeting agents.
Results: PEN-221 is a highly potent and selective Pentarin consisting of a peptide somatostatin analog conjugated to the potent microtubule binding cytotoxic DM1 through a cleavable linker. The affinity of PEN-221 for SSTR2 matches the affinity of somatostatin 14. Upon binding, PEN-221 stimulates SSTR2 internalization, delivering and capturing the Pentarin in SSTR2 expressing tumor cells. The biological consequences of DM1 release from PEN-221 includes the induction of apoptosis as characterized by increased levels of cleaved caspase-3. In multiple SSTR2-expressing human tumor mouse xenograft models, these effects result in complete and sustained tumor regressions.
Conclusion: PEN-221 is the first Pentarin heading towards human clinical studies in patients with SSTR2 expressing tumors.
Distinctive Chromosomal Instability (CIN) Patterns and Its Prognostic Value in Pancreatic Neuroendocrine Tumors (pNET)
James Yao,1 Abhishek Garg,2 David Chen,3 Eric Van Cutsem,4 Jaume Capdevila,5 Wei He,2 Markus Riester,2 Michael Morrissey,2 Maurizio Voi,3 Paul Engstrom,6 Rodney Pommier.71University of Texas MD Anderson Cancer Center, Houston, TX; 2Novartis Institutes for Biomedical Research, Cambridge, MA; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ; 4University Hospitals Gasthuisberg/Leuven and KULeuven, Leuven, Belgium; 5Medical Oncology Department, Gastrointestinal and Endocrine Tumor Unit, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain; 6Fox Chase Cancer Center, Philadelphia, PA; 7Oregon Health and Science University, Portland, OR.
Background: MEN1, DAXX and ATRX are frequently mutated in pNET. Their associations with chromosomal aberrations, disease progression, and efficacy of targeted therapy have not been established. We explored these biomarkers in patients from RADIANT-3, a randomized phase 3 trial of everolimus (EVE) vs placebo in advanced pNET (Yao JC et al, NEJM 2011).
Methods: Mutations and copy number analysis was performed on 65 archival tumor samples (15% of the trial population) using next-generation sequencing. Cox PH modeling was used to assess the association between groups defined by CIN and clinical outcome.
Results: MEN1, DAXX, and ATRX were mutated in 42, 28, and 11% of pNET, respectively. DAXX and ATRX mutations were mutually exclusive; while 60% of DAXX and no ATRX mutation co-exist with MEN1. Three distinct CIN patterns were identified based on 2 mutually exclusive sets of chromosome aberrations; group 1 with loss of heterozygosity (LOH) in 1st set of chromosomes; group 2 with copy-neutral LOH in 1st set and gains in 2nd set of chromosomes; and group 3 with no recurring gains or loss. MEN1/DAXX/ATRX mutations were associated with CIN in group 1 and 2 (P < 1.8 x 10–10; Table 1).
Group 1 and 2 had better prognosis than group 3 (median overall survival, 62.6 vs 37.9 mo; HR 1.86; 95% CI 0.96-3.6). All patients derived similar PFS benefit from EVE over placebo (Table 1), consistent to that observed in overall study population (median PFS, 11.0 vs 4.6 mo; HR 0.35; 95% CI 0.27-0.45, P < 0.001).
Conclusion: pNET showed 3 distinct CIN groups, with two groups tightly associated with commonly mutated genes. These molecular subtypes may have different disease prognosis, but all benefited similarly from EVE. Results upon statistical validation in larger cohorts may have far-reaching clinical applications.
TR4: A Potential Therapeutic Target in NETs
Dongyun Zhang. Anthony Heaney. 1David Geffen School of Medicine, University of California, Los Angeles, CA.
Background: Testicular Nuclear Receptor 4 (TR4) is an orphan nuclear receptor and our recent findings show that it is an important regulator of tumor growth and hormone biosynthesis in pituitary-derived neuroendocrine tumors (NETs). Here we sought to define the broader role of TR4 in the pathogenesis of NETs.
Methods: We employed short hairpin RNA to silence TR4 expression in SHSY-5Y neuroblastoma and PC-12 pheochromocytoma cells and tested actions of TR4 on cell proliferation and differentiation. Simultaneously, we employed a TR4-overexpressing plasmid in gain-of-function studies.
Results: TR4 knockdown in SHSY-5Y cells and PC12 cells inhibited proliferation by 24% and 15% respectively (p < 0.05). TR4 knockdown in SHSY-5Y cells promoted cell morphological changes from a neuronal (N)-type to a substrate adhesive (S)-type as evidenced by real time PCR analysis showing marked reductions in expression of the N-type cell markers, GAP43 and Synaptophysin, and increased expression of the S-type cell markers, Vimentin, Fibronection and alpha-SMA in the TR4 knockdown cells compared with control. Additionally, whereas all-trans retinoic acid (atRA) treatment promoted differentiation of wild type SHSY-5Y cells, atRA did not inhibit cell proliferation or promote differentiation in the TR4 knockdown cells, further indicating that TR4 knockdown readily promoted terminal differentiation of the neuroblastoma cells toward a fibroblast-like phenotype. In contrast, TR4 overexpression led to increased SHSY-5Y cell proliferation. We measured expression of potential downstream targets of TR4 and observed dramatically reduced Chromogranin A (CgA) mRNA and protein expression in the TR4 knockdown cells. CgA knockdown in the SHSY-5Y cells also led to cell differentiation toward an S-type concomitant with potent inhibition of proliferation.
Conclusion: TR4 blockade inhibits cell proliferation and promotes terminal differentiation in neuroblastoma cells by actions that include modulating CgA expression. These findings indicate a potential role for TR4 in the regulation of NETs pathogenesis, and may pave the way for novel TR4-directed therapies in NETs.
CgA Depletion Inhibits Neuroendocrine Tumor Cell Growth and Alters Phenotype
Dongyun Zhang, Anthony Heaney. David Geffen School of Medicine, University of California, Los Angeles, CA.
Background: Chromogranin A (CgA) is an acidic soluble protein of the granin family, and overexpressed in NETs. Serum CgA has been widely used as a biomarker for the diagnosis and prognosis of various NETs. However, the biological function of CgA in modulation of NET growth and differentiation has been largely unexplored.
Methods: We employed shRNA knockdown and CRISPR-Cas9 knockout approaches to deplete CgA in human neuroblastoma SHSY-5Y and human pancreatic neuroendocrine tumor (pNET) Bon-1 cells and monitored the actions of CgA depletion on tumor cell growth.
Results: Using short hairpan RNA (shRNA) targeting sequences to CgA Exon 2, we attained potent CgA knockdown as demonstrated by real-time PCR and Western Blotting. Upon CgA knockdown, two changes in the neuroblastoma phenotype were observed. Firstly, tumor cell growth was inhibited by 70% (Day 5), leading to a 1.5 fold reduction in the doubling time of CgA knockdown cells. Secondly, the cell morphology changed from a neuroblastic (N)-type to a so call “substrate-adhesive” (S)-type. Simultaneously, we demonstrated that treatment with metformin alone inhibited neuroblastoma cell proliferation by ~30% in control nonsense SHSY-5Y cells. Addition of metformin to the CgA knockdown SHSY-5Y cells resulted in further inhibition of proliferation by 80%. These findings show a synergetic action of metformin with CgA knockdown to inhibit NET growth. In support of our findings using CgA shRNA, a marked growth inhibition caused by CRISPR-Cas9-mediated CgA knockout was also observed in SHSY-5Y cells concomitant with differentiation toward an S-type. Additionally, we demonstrated that in pNET Bon-1 cells, CgA knockdown also resulted in marked inhibition of tumor cell growth.
Conclusion: Reducing CgA expression in neuroblastoma cells and pNET Bon-1 cells inhibits cell proliferation, promotes cell differentiation and sensitizes the cells to the anti-proliferative actions of metformin. It further suggests CgA may be a promising target for treatment of neuroblastoma and potentially other NETs.
PRRT 2.0: Definition and Prediction of Efficacy With Circulating Neuroendocrine Tumor Transcripts
Lisa Bodei,1 Mark Kidd,2 Irvin Modlin,3 Stefano Severi,4 Ignat Drozdov,2 Sylvia Nicolini,4 Dik Kwekkeboom,5 Eric Krenning,5 Richard Baum,6 Giovanni Paganelli.41Memorial Sloan Kettering Cancer Center; 2Wren Laboratories; 3Yale University School of Medicine; 4IRST; 5Erasmus Medical Center; 6Zentralklinik Bad Berka.
Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment for neuroendocrine tumors (NETs) and somatostatin receptor imaging (SRI) uptake is used to identify candidates as well as predict therapeutic efficacy. A blood-based 51 multigene NET transcript analysis (NETest) including gene clusters provides a direct measure of tumor behavior. We evaluated whether the NETest was a predictive biomarker in PRRT.
Methods: 177Lu–PRRT treated NETs (n=72; advanced disease: 30% salvage treatment) followed for 33 months. Baseline evaluation included: histological grade, SRI, CgA (ELISA, normal<108ng/ml) and NETest (qPCR with multianalyte algorithmic analyses). A mathematical predictive response index comprising NETest genes regulating metabolism and growth factor signaling integrated with grade was developed as a predictive quotient (PRI). RECIST criteria were used to evaluate disease control (responder vs non-responder). Statistical analyses: multiple regression, Kaplan-Meier survival, Chi2 analyses.
Results: PRRT demonstrated a 68% disease control rate response with median PFS of 21 months (median follow-up 16 months). NETest decreased in 88% of responders; and increased in 90% of non-responders accurately correlating with RECIST-determined responses. Although 77% low grade and 50% high-grade tumors responded, grade alone was not predictive (p=0.12). Neither baseline SRI measurement (p=0.58) nor CgA were predictive (p=0.53). Baseline gene cluster expression for metabolism and growth factor signaling had 76% accuracy for predicting PRRT-response. The predictive response index (PRI: NETest/grade) accurately predicted responders (97%; mPFS undefined) and non-responders (91%: mPFS: 17 months). This was significantly better than SRI (94% vs. 38% accuracy, p<0.0001). Baseline NETest >40% accurately (89%) predicted treatment response and a longer PFS (HR 2.97, p=0.05).
Conclusion: The blood-based NETest provides a predictive multi-molecular biomarker for PRRT. The PRI is highly accurate (94%) in predicting efficacy and significantly outperforms SRI assessment. Alterations in NETest correlate with RECIST responses and assess real time treatment efficacy. NET multigene measurement in blood can predict patients responsive to PRRT.
Circulating Neuroendocrine Gene Transcripts – the NETest – Accurately Identify GEP-NETs, Are Decreased by Surgery and Predict Tumor Progression and Recurrence
Mark Kidd,1 Lisa Bodei,2 Ignat Drozdov,1 Dik Kwekkeboom,3 Eric Krenning,3 Richard Baum,4 Andrea Frilling,5 Jaroslaw Cwikla,6 Vikas Prasad,7 Irvin Modlin.81Wren Laboratories; 2Memorial Sloan Kettering Cancer Center; 3Erasmus Medical Center; 4Zentralklinik Bad Berka; 5Imperial College London; 6University of Warmia and Mazury, Olsztyn; 7Charite-Berlin; 8Yale University School of Medicine.
Background: A blood-based multigene (51) transcript algorithmic analytic test (MAAA) correlates with tumor tissue levels and provides a neuroendocrine tumor (NET) gene signature. Morphologic and functional imaging is the standard of care for NET localization and for assessing therapeutic efficacy. We evaluated the concordance between the NETest and imaging and whether blood transcripts are a prognostic marker.
Methods: GEP-NETs (n=180) of the small intestine: n=93, pancreas: n=52, large intestine: n=11, stomach: n=3, appendix: n=2 and CUP: n=19 were studied. Grading was: G1: n=80, G2: n=86, no data: n=14. Somatostatin receptor imaging (SRI) was available in 103 (57%). Seventy-seven (43%) had CT/MRI and grading assessment (RECIST 1.0: median 251 days follow-up: range 31–422. NETest (qPCR and MAAA) defines disease activity risk: negative <14%, low <40%. CgA (ELISA): normal <109ng/l). Statistical analyses: Chi2, performance metrics analysis and progression-free survival (Kaplan-Meier).
Results: NETest was elevated in 175 (97%) vs CgA in 94 (52%) [X2=94.1, p<0.0001]. NETest was 100% concordant with CT/MRI and 95% with SRI. Twelve patients with CT/MRI-proven absence of disease (5-years post-surgery) exhibited NETest<14% and normal CgA. Metrics for NETest and imaging (n=180): sensitivity: 97%, specificity: 100%, PPV: 100% and NPV: 71%. CgA metrics: 52%, 100%, 100% and 12%. Surgery significantly (p<0.05) decreased NETest levels and correlated with tumor volume (R2=0.29, p=0.02). Post-surgery NETest elevation (>40%) predicted disease recurrence in 100% (<6 months). NETest was concordant with baseline disease status (RECIST) in 87%; CgA=54% (X2=12.3, p<0.001). A low NETest (<40%) accurately predicted progression free survival for and was significantly different (p=0.01, X2=6.57) compared to a NETest>40% (undefined v 253 days; HR=3.36. CgA was non-predictive (p=0.22).
Conclusion: A blood-based NET transcript test has threefold clinical utility: diagnosis (97%), identification of residual disease (100%) and disease progression (100%). It accurately correlated with image-proven NET disease and surgical resection. NETest has clinical utility in the monitoring of NET disease.
A Prognostic Model for Pulmonary Carcinoid Tumors Based on Large Chromosomal Alterations
Konstantinos Leventakos,1 Sarah Johnson,1 Sarah Kerr,2 Marie Christine Aubry,2 Dennis Wigle,3 George Vasmatzis,2 Thanyanan Reungwetwattana,3,4 Julian Molina.4Departments of 1Medicine; 2Laboratory Medicine and Pathology; and 3Surgery; Mayo Clinic, Rochester, MN; 3Ramathibodi Hospital, Mahidol University, Thailand; 4Department of Medical Oncology, Mayo Clinic, Rochester, MN.
Background: Previous mutational analyses have failed to identify a predictive or prognostic marker for pulmonary carcinoid tumors (PCT). We sought to use high-throughput next-generation sequencing to detect potential driver translocations and improve prognostication.
Methods: A total of 39 PCTs were selected for structural variant analysis including 18 clinically benign and 21 more clinically aggressive PCTs (+ for node +/− distant metastasis +/− recurrence). Macrodissection was followed by genomic DNA isolation and next-generation sequencing was performed using an Illumina Mate Pair library protocol.
Results: A total of 414 unique genomic breakpoints were detected. Only 6/39 (15%) had no genetic rearrangements identified and all of them were clinically benign tumors. We observed aneuploidy in 16 patients, 12 of which were present in patients with more aggressive tumors. Gains and deletions are frequent in carcinoids and there is a different profile in good/bad prognosis cases. Deletions in Chromosome 3 are more common in bad prognosis carcinoids. We observed a group of 5 gene deletions that were present only in bad prognosis cases. All of these genes were located in cytogenetic locus 3p12.3. We calculated a score as Sum of junctions + number of deletions/100MBs + number of gains/100MB. This was found to be prognostic of good or bad clinical behavior with bad prognosis cases having a higher score (P=0.04). For this score AUC was 0.759.
Conclusion: This study revealed different profiles in chromosomal alterations between good and bad prognosis cases. Aneuploidy a prognostic factor associated with bad prognosis and 3p.12.3 deletion is present only in bad. Bad prognosis carcinoids tend to have more junctions, more breakpoints per gene, more deleted genes, more genes with gain. A score including number of junctions, deletions and gains is prognostic of clinical behavior.
Blood Gene Transcript Analysis Diagnoses Bronchopulmonary NETs and Identifies Progressive Disease
Anna Lewczuk,1 Mark Kidd,2 Kyung Min Chung,2 Agnieszka Kolasinska-Cwikla,3 Jaroslaw Cwikla,4 Lisa Bodei,5 Irvin Modlin.61Medical University of Gdansk; 2Wren Laboratories; 3Institute of Oncology, Warsaw; 4University of Warmia and Mazury; 5Memorial Sloan Kettering Cancer Center; 6Yale University School of Medicine.
Background: Bronchopulmonary (BP) NETs comprise ~30% of all NETs and are classified into 4 groups: typical (TC); atypical carcinoid (AC); large cell NEC and small cell cancer. Differentiating between atypical (AC) and typical (TC) can be challenging. Ki67 (high grade NECs) and somatostatin receptor (SSTR) expression is of some value in guiding therapy. Biomarkers remain of equivocal value and limited clinical utility.
Methods: BP-NETs (n=94; complete resection; disease free: n=6, stable disease (SD): n=39; progressive disease (PD): n=49); other lung disease (non-neoplastic: n=33; neoplastic: n=3); normal controls n=84). PD was established by clinical and RECIST criteria. NETest measurement utilized qPCR: risk scale 0-100%; low (<40%) and high activity risk cutoffs (>80%). Multianalyte algorithmic analysis included 51 genes with inclusion of SSTRs (SSR1,3,5) “omic” was undertaken. CgA measured by ELISA (normal <109ng/ml). Analysis by X2 tests and ROC (area under curve [AUC]).
Results: In all BP-NETs irrespective of TC or AC, NETest was positive (88/88, 100%). Other neoplastic and non-neoplastic lung disease (3/36, 8% positive) (AUC: 0.88±0.03, p<0.001) as were controls (30/33, 90%) (AUC: 0.97±0.01, p<0.0001). A NETest value of >40% defined progressive disease (PD) vs stable disease (SD) in 80% (p<0.0001, AUC: 0.87±0.04). Surgical cures and controls were all negative (NETest<14%). Combination of NETest and SSTR “omic” gene defined clinico-histological groups in 94%: PD/AC (92%; 35/38), PD/TC (100% 11/11), SD/AC (67%, 6/9), SD/TC (100%, 30/30). Only 50% of BP-NETs were CgA positive (X2=20.1, p<0.001). CgA increase did not predict progression.
Conclusion: A blood-based NETest positively identified BPNETs (100%) and negatively controls and lung disease (<10%). Progressive disease, stable disease and no disease (curative surgical resection) can be accurately identified (94%). BP-NET clinico-histological groups can be accurately identified by NETest+SSTRomic analysis in 94%. Blood-based genomic information will facilitate precise lung NET characterization and provide molecular information of clinical utility.
Neuroendocrine Tumor Blood Transcript Analysis, the NETest, Predicts Gastroenteropancreatic Neuroendocrine Tumor Disease Status and is Prognostic for Progressive Disease
Marianne Pavel,1 Henning Jann,1 Vikas Prasad,1 Ignat Drozdov,2 Irvin Modlin,3 Mark Kidd.21Charite-Berlin, Berlin, Germany; 2Wren Laboratories, Branford, CT; 3Yale University School of Medicine, New Haven, CT.
Background: A key issue in GEP-NET management is early identification and prediction of disease progression. Clinical strategies are insensitive; no accurate biomarkers exist and imaging is limited (variable sensitivity/disease indolence). We evaluated whether a blood-based multigene transcript analysis (NETest) was a predictive and prognostic marker of progression in a long-term, follow-up study.
Methods: Well-differentiated GEP-NETs (n=34): small intestine (n=24), pancreatic (n=7), MEN-ZES (n=2), CUP (n=1) followed longitudinally for a median of 4 years (2.2-5.4). Grade I: n=15, Grade II: n=17; (no grade in 2). Baseline imaging and biomarkers were available in all. Subsequent imaging (restaging median 7 times; 3–15) and blood sampling (median 3 times: 2–5) were acquired (clinical management protocols). Progression was defined by RECIST 1.0 criteria. NETest measurement utilized qPCR and multianalyte algorithmic analysis: risk scale 0-100% with low (<40%) and high activity risk cutoffs (>80%). CgA was measured by RIA (normal <150μg/l, abnormal >300μg/l). PFS was assessed by Kaplan-Meier curve analysis and Cox-proportional modeling was undertaken.
Results: At baseline, all were NETest positive; CgA was positive in 50%. Median PFS was 2.59 years. Neither grade nor baseline CgA were associated with progressive disease (PD). Baseline NETest>80% was significantly associated (p=0.01) with PD: median PFS=0.68 years vs. 2.78 years (NETest<40%). NETest was the only predictive marker by multivariate analysis (p<0.012). Alterations in NETest were more informative than CgA for PD (96% vs 40% p<2x10-5, X2=18.1) and exhibited an earlier time-point change (1.02±0.15 years vs 0.72±0.11 years, p=0.03). CgA levels >300ng/ml were non-informative. Low NETest values (<40%) accurately predicted disease stability over a 5 year period (p=0.05, Chi2=3.8 vs. CgA).
Conclusion: A blood-based NET multigene analysis measurement correlates with clinical disease status in well-differentiated GEP-NETs. Elevated levels accurately predicted GEP-NET progression occurring ~1 year before image-based evidence of disease progression. The NETest has predictive and prognostic utility for GEP-NETs.
Next-Generation Sequencing (NGS) in Pancreatic Neuroendocrine Tumors (panNETs): Defining Differentiation and Grade Genetically
Nitya Raj, Anastasia Hrabovsky, Derek Alexander, Ronak Shah, Olca Baturk, Laura Tang, David Klimstra, Diane Reidy-Lagunes. Memorial Sloan Kettering Cancer Center, New York, NY.
Background: Advances in tumor sequencing technology have improved our understanding of the genetic basis of NETs. Specifically, whole exome sequencing of well differentiated (WD) panNETs demonstrated an increased number of mutations in chromatin remodeling genes; in poorly differentiated (PD) neuroendocrine carcinomas, alterations along the TP53/RB signaling pathways have been observed. We sought to validate these observations in clinical practice.
Methods: This prospective study (NCT01775072) used the MSK-IMPACT assay to do NGS on panNETs in a routine practice setting. MSK-IMPACT is an assay providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number and select gene rearrangements.
Results: Results are available in 56 patients (mean age 55, 45% female); 21 patients (38%) with low grade tumors, 23 patients (41%) with intermediate grade tumors, and 12 patients (21%) with high grade tumors; 5 patients (9%) with PD tumors and 51 patients (91%) with WD tumors. RB1 alterations were identified in 3 tumors (5%); all of these tumors were PD and high grade. TP53 alterations were identified in 5 tumors (9%); 3/5 tumors (60%) were PD and high grade and 2/5 tumors (40%) were WD and intermediate grade, but exhibited aggressive clinical behavior. Alterations in chromatin remodeling genes were only observed in WD tumors of low/intermediate grade; MEN1 alterations in 31 tumors (55%), DAXX alterations in 19 tumors (34%), ATRX alterations in 12 tumors (21%), and SETD2 alterations in 9 tumors (16%).
Conclusion: In line with prior work in panNETs, using an institutional NGS platform, we demonstrated tumor grade/differentiation genetically. Changes in chromatin remodeling genes were exclusive to WD, low/intermediate grade tumors. To contrast, alterations in RB1/TP53 were seen either in PD, high grade tumors, or in aggressively behaving WD, intermediate grade tumors. We will further categorize these genetic alterations and present updated results at the meeting.
Impact of Prior Somatostatin Analogue (SSA) Use on Progression-free Survival (PFS) in Patients With Advanced Nonfunctional Neuroendocrine Tumors (NET) of Lung or Gastrointestinal (GI) Origin: A Secondary Analysis from the RADIANT-4 Study
Roberto Buzzoni,1 Carlo Carnaghi,2 Rodney Pommier,3 Nicola Fazio,4 Simron Singh,5 Maurizio Voi,6 Lida Pacaud,7 Antonia Ridolfi,8 James Yao,9 Edward Wolin,10 Marianne Pavel,11 Jonathan Strosberg.121Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy; 2IRCCS Istituto Clinico Humanitas, Rozzano, Italy; 3Oregon Health and Science University, Portland, OR; 4Istituto Europeo di Oncologia, IRCCS, Milano, Italy; 5Sunnybrook Health Sciences Centre, Toronto, Canada; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ; 7Novartis Pharma AG, Basel, Switzerland; 8Novartis Pharma S.A.S., Rueil-Malmaison, France; 9University of Texas/MD Anderson Cancer Center, Houston, TX; 10Cedars-Sinai Medical Center, Los Angeles, CA; 11Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany; 12Moffitt Cancer Center, Tampa, FL.
Background: In the RADIANT-4 study, EVE reduced the risk of disease progression or death by 52% vs placebo (PBO; P<0.00001) in patients (pts) with advanced, well-differentiated, progressive, nonfunctional NET of lung/GI tract. This subgroup analysis assessed the impact of prior SSA on PFS in the RADIANT-4 study.
Methods: Pts were randomized (2:1) to receive EVE 10 mg/d or PBO. This analysis reports baseline characteristics, PFS, and safety by prior SSA use.
Results: Of 302 pts randomized, 163 (54%) had any prior SSA use (mostly for tumor control; EVE vs PBO: 53% vs 56%). Baseline characteristics were similar in pts with or without prior SSA. Primary tumor sites in prior SSA group: Lung (23%), GI (65%), and NET of unknown primary (12%). Pts received ≥1 type of SSA, which included octreotide LAR (77%), octreotide SC (14%), lanreotide (14%). Median duration of exposure to prior SSA was 15 mo (range, <0.1-103.5). Median PFS (central review; EVE vs PBO) in prior SSA group was 11.1 (95% CI, 9.2-13.3) mo vs 4.5 (3.6-7.9) mo (HR 0.56; 95% CI, 0.37-0.85); in SSA naïve pts, 9.5 (8.2-16.7) mo vs 3.7 (2.4-8.1) mo (HR 0.57; 95% CI, 0.36-0.89). The most common drug-related adverse events (AEs) in EVE arm (prior SSA vs SSA naive) included stomatitis (60% vs 50%), diarrhea (34% vs 28%), and peripheral edema (28% vs 23%).
Conclusion: EVE improves PFS in pts with advanced, progressive, nonfunctional NET of lung/GI tract regardless of prior SSA use. AEs were manageable and consistent with the overall population.
Escalated Dose Somatostatin Analogues (SSA) in Management of NETs: A Systematic Review
David L Chan,1 Diego Ferone,2 Manuela Albertelli,2 Simron Singh.11Odette Cancer Centre, Toronto, Canada; 2IRCCS AOU San Martino-IST, University of Genoa, Italy.
Background: SSAs are effective in controlling NET symptoms and more recently have been shown to have anti-proliferative properties. PROMID and CLARINET have established “standard” doses of octreotide and lanreotide, but dose escalation is often employed both for symptom relief and tumor control.
Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL and abstracts of major conferences. Studies investigating patients treated with doses of octreotide higher than 30mg/28d or lanreotide higher than 120mg/28d were eligible for inclusion. Data extracted included patient population, interventions and prior SSA use. The primary endpoint was disease control rate; secondary endpoints included response rate, symptom control, biochemical response, progression-free survival and toxicity.
Results: 22 studies (13 prospective; 1019 patients) were identified from 609 search results. Of the 13 studies that mandated prior treatment, the reasons for dose escalation were tumor progression (5), symptoms (3), either (2) and not listed (3). SSAs used were octreotide LAR (11), lanreotide ATG (1), short-acting octreotide (3), short-acting lanreotide (6), and mixtures (2). Significant heterogeneity existed in dosing schedules as well as reporting of efficacy data.
Disease control rate ranged from 40-100% (pooled rate 327/515) with response rates from 0-42% (pooled rate 28/515). Dose escalation was associated with improvement in carcinoid symptoms in at least 50% of patients. Biochemical response was variably defined but reported rates ranged from 33% to 100% (pooled rate 56/79). PFS ranged from 7 months to 32 months. Dose escalation was generally well tolerated with side effect profile and frequency comparable to normal dose SSA.
Conclusion: Escalated dose SSA is well tolerated and results in significant rates of disease control and symptomatic improvement. Compared to a prior systematic review (Broder WJG 2015), this review adds review of lanreotide, includes 6 new studies with 600 additional patients, and restricts inclusion to clinical studies. Prospective randomized trials of escalated SSA therapy are warranted.
Efficacy and Safety of Everolimus in Advanced, Progressive, Nonfunctional Neuroendocrine Tumors (NET) of the Lung: A Subgroup Analysis of the Phase 3 RADIANT-4 Study
Nicola Fazio,1 Roberto Buzzoni,2 Gianfranco Delle Fave,3 Margot E. T. Tesselaar,4 Edward Wolin,5 Eric Van Cutsem,6 Paola Tomassetti,7 Jonathan Strosberg,8 Maurizio Voi,9 Lida Pacaud,10 Antonia Ridolfi,11 Simron Singh,12 Marianne Pavel,13 Matthew Kulke,14 James Yao.151Istituto Europeo di Oncologia, IRCCS, Milano, Italy; 2Fondazione IRCCS, Istituto Nazionale dei Tumori, Milano, Italy; 3Azienda Ospedaliera Sant'Andrea, Università La Sapienza, Roma, Italy; 4Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, Netherlands; 5Cedars-Sinai Medical Center, Los Angeles, CA; 6University Hospitals Gasthuisberg/Leuven and K U Leuven, Leuven, Belgium; 7Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 8Moffitt Cancer Center, Tampa, FL; 9Novartis Pharmaceuticals Corporation, East Hanover, NJ; 10Novartis Pharma AG, Basel, Switzerland; 11Novartis Pharma S.A.S., Rueil-Malmaison, France; 12Sunnybrook Health Sciences Centre, Toronto, Canada; 13Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany; 14Dana Farber Cancer Institute, Boston, MA; 15University of Texas MD Anderson Cancer Center, Houston, TX.
Background: In the phase 3, RADIANT-4 study, everolimus (EVE) improved median progression-free survival (PFS) by 7.1 months in patients (pts) with advanced, progressive, nonfunctional NET of lung or GI tract compared to placebo (PBO); HR, 0.48; 95%CI, 0.35-0.67; P<0.00001. This subgroup analysis evaluated efficacy and safety of EVE in pts with lung NET from RADIANT-4.
Methods: In RADIANT-4 study, pts were randomized (2:1) to EVE 10 mg/d or PBO, both with best supportive care. The present analysis reports subgroup of lung NET.
Results: Of 302 pts, 90 had lung NET (EVE, n=63 and PBO, n=27). Median age, 65 years; males: 52%; most pts (99%) had well-differentiated disease; WHO PS 0/1/2: 71%/28%/1%; Caucasian: 86%. Prior therapies (EVE vs PBO) included: somatostatin analogues (mostly for tumor growth control; 43% vs 41%), surgery (52% vs 67%), and chemotherapy (40% vs 48%).
Median PFS (95% CI) by central review (EVE vs PBO) was 9.2 (6.8-10.9) vs 3.6 (1.9-5.1) months with tumor progression risk-reduction by 50% in EVE (HR, 0.50; 95% CI, 0.28-0.88). Most frequent (≥5%) G3/4 adverse events irrespective of drug-relationship (EVE vs PBO) were stomatitis (11% vs 0), hyperglycemia (10% vs 0), diarrhea (7% vs 0), hypophosphatemia (7% vs 0), dyspnea (5% vs 7%), and hypertension (0 vs 7%).
Conclusion: EVE treatment improved PFS by 6 months and reduced tumor progression risk by 50% in pts with advanced, progressive, nonfunctional lung NET compared to PBO. EVE safety profile was similar to overall RADIANT-4 population.
Efficacy of Lanreotide Depot/Autogel for Symptomatic Control of Carcinoid Syndrome (CS) in Neuroendocrine Tumor Patients: Follow-up Analysis of the ELECT Prospective, Randomized, Double-blind and Open-label Phases
George A Fisher, Jr,1 Edward M Wolin,2 Pamela L Kunz,1 Nilani Liyanage,3 Beloo Mirakhur,4 Susan Pitman Lowenthal,4 Rodney F Pommier,5 Montaser Shaheen,6 Aaron Vinik.71Stanford University School of Medicine; 2Montefiore Einstein Center for Cancer Care; 3Ipsen Boulogne-Billancourt; 4Ipsen Biopharmaceuticals Inc - Basking Ridge, NJ; 5Oregon Health & Science University; 6University of New Mexico Cancer Center;7Eastern Virginia Medical School.
Background: In ELECT, lanreotide significantly reduced rescue medication use for symptomatic control of CS in Neuroendocrine tumor (NET) patients vs PBO in the 16-week double-blind (DB) phase. Patient-reported symptoms during DB and initial open-label (IOL) treatment are presented.
Methods: Adults with NETs and CS history, with/without prior somatostatin analog (SSA) use, were randomized to DB Lanreotide (LAN) 120 mg or PBO every 4 weeks for 16 weeks, followed by a 32-week IOL phase on lanreotide. Each patient recorded daily the frequency and severity of diarrhea and flushing by Interactive Voice (Web) Response System for 1 month pre-randomization until study end. Analysis of covariance models incorporated baseline symptoms, prior SSA, and country. Given high variability of urinary 5HIAA, values were log-transformed.
Results: Of 115 patients randomized (n=59 LAN, n=56 PBO), 56 LAN- and 45 PBO-treated patients switched to LAN, continued in IOL (LAN-LAN and PBO-LAN). During DB phase, least square (LS) mean percentage of days with moderate/severe diarrhea and/or flushing were significantly lower for LAN (23.4%) vs placebo (35.8%) (LS mean difference [95% CI] -12.4 [−20.73,-4.07]; p=0.004) Among LAN-LAN patients in IOL, composite (frequency x severity) diarrhea scores improved significantly from DB to IOL and were not significantly different for flushing or diarrhea and flushing (Table 1). Composite symptom scores improved significantly from DB to IOL for PBO-LAN patients. Mean (95% CI) differences in changes from baseline in urinary 5HIAA between DB week12 and IOL week48 were −14.75μmol/d (−27.02, 56.51) for LAN-LAN and 73.96μmol/d (−11.77,159.7) for PBO-LAN. Adverse event frequency during IOL by DB group (LAN, PBO) was 70% vs 71%. The safety profiles observed during IOL and DB were similar.
Conclusion: Lanreotide improved control of diarrhea and flushing in carcinoid patients during initial 16weeks of treatment, and was sustained for an additional 32 weeks through week 48 of this phase 3 study.
Pharmacokinetic (PK) Differences Between Subcutaneous and Intramuscular Administration of Lanreotide: Results From a Phase I Study
Amandine Manon,1 Edward Wolin,2 Christophe Chassaing,3 Laurent Bertocchi,3 Joel Richard,3 Alexandria Phan.41Ipsen Innovation; 2Montifiore Einstein Center for Cancer Care; 3Beaufour Ipsen Industrie; 4Houston Methodist Hospital.
Background: Recent data have shown that ~38% of intended gluteal intramuscular (IM) injections with long-acting release octreotide were mistakenly given subcutaneously (SC); in carcinoid syndrome patients, this significantly increased the rate of flushing (P=0.005; Boyd 2013, Pancreas). Lanreotide depot (LAN) recently became the first somatostatin analogue FDA-approved for the treatment of gastroenteropancreatic neuroendocrine tumors (120 mg Q4W) as a deep SC injection. Since LAN efficacy and pharmacokinetics have been demonstrated, including rapid initial release and long half-life of 23–30 days, we report pharmacokinetic parameters of SC vs IM routes of administration.
Methods: In a phase I study, healthy adult volunteers received 1 mg lanreotide immediate release formulation (IV bolus) followed by 60 mg 0.246 mg/mg deep SC or IM lanreotide depot. Serial blood samples were analyzed.
Results: Of 42 volunteers (mean [SD] age 25±6 years, weight 66±10 kg), 11 received the same LAN dose (60 mg 0.246 mg/mg) as SC (n=5) or IM (n=6), 30 received other doses/concentrations, and 1 was excluded. Between 14 and 112 d, comparable mean concentration-time profiles were observed for both routes. The mean Cmax (5.8±4 vs 6.8±3 μg/L) and mean T1/2 (33±14 vs 23±9 d) were deemed comparable, as were median Tmax (8 vs 16 hours) and median residence time (last) in serum (28 vs 20 d). Slightly lower AUClast (1651±54 vs 2007±172 h•μg/L) and AUCinf (1843±134 vs 2100±193 h•μg/L) were observed with SC vs IM injections.
Conclusion: For long-acting octreotide, intended gluteal IM injections are often given SC. Lanreotide depot 60 mg 0.246 mg/mg SC and IM injection had similar PK profiles in this small cohort, leading to further development of SC, due to more lanreotide availability in the late-release phase after SC injection.
Capecitabine and Temozolomide (C/T) Combination Therapy in Patients (pts) With Advanced Neuroendocrine Neoplasms (aNEN) and the Role of O6-methylguanine-methyltransferase (MGMT) as a Potential Biomarker for Response
Dwight Owen, Andrew Alexander, Lai Wei, Jessica Hemminger, Manisha Shah. The Ohio State University Comprehensive Cancer Center, Columbus, OH.
Background: Tumor O6-methylguanine-methyltransferase (MGMT) reverses temozolomide-induced DNA injury, and low MGMT tumor expression is a predictor of response to temozolomide in glioblastoma. C/T therapy induces partial responses in up to 70% of pts with grade 1–2 pancreatic NEN but the role of MGMT expression as a predictor is unclear. We evaluated C/T combination therapy in patients with aNEN of all grades and primary sites, and assessed MGMT expression by immunohistochemistry (IHC) as a prognostic and predictive biomarker.
Methods: A retrospective review was carried out at Ohio State University of 38 pts with aNEN receiving C/T therapy from 2009 to 2013, with 29 pts evaluable for RECIST response. Tumor MGMT expression was assessed in 20 pts by IHC to evaluate whether low MGMT expression (<10%) predicted response to C/T therapy vs high levels (≥10%).
Results: Primary NEN site was pancreas in 18 pts, and non-pancreas in 11 pts. Objective response, progression-free survival (PFS) and overall survival (OS) data are outlined in Table 1. Partial response (PR) rate was 50% in pts with pancreas primary vs 18% for non-pancreas primary. High PRs were observed in pts with grade 3 NEN (57%). Median PFS in the MGMT-low group was 16.6 months vs 9.5 months in the MGMT-high group (p=0.19). Median OS in the MGMT low group was 42.9 months vs 18.1 months in the MGMT-high group (p=0.16). There was a trend toward higher rate of PR (63%) in pts whose tumors had low levels of MGMT expression compared to those with high levels (17%) (p=0.18).
Conclusion: We observed a trend towards increased PR, median PFS, and median OS in aNEN pts whose tumors had low MGMT protein expression by IHC. Results of this trial serve as strong rationale for future prospective trials to clarify role of MGMT expression in choosing C/T therapy for pts with NET.
Efficacy and Safety Results of Telotristat Ethyl in Patients With Carcinoid Syndrome During the Double-blind Treatment Period of the TELECAST Phase 3 Clinical Trial
Marianne Pavel,1 David Gross,2 Marta Benavent,3 Martyn Caplin,4 Petros Perros,5 Raj Srirajaskanthan,6 Juan Valle,7 Richard Warner,8 Matthew Kulke,9 Lowell Anthony,10 Pamela Kunz,11 Dieter Hörsch,12 Kjell Öberg,13 Pablo Lapuerta,14 Shanna Jackson,14 Phillip Banks,14 Talia Biran,14 Rocio Garcia-Carbonero.151Charité-Universitätsmedizin Berlin, CVK, Med. Klinik m. Schwerpunkt; 2Hadassah-Hebrew University Medical Center; 3Hospital Universitario Virgen del Rocío; 4Royal Free Hospital; 5Royal Victoria Infirmary; 6Kings College Hospital; 7The Christie NHS Foundation Trust; 8Mt. Sinai School of Medicine; 9Dana–Farber Cancer Institute; 10University of Kentucky; 11Stanford University; 12Klinik für Innere Medizin; 13Uppsala University Hospital; 14Lexicon Pharmaceuticals Inc; 15Hospital Universitario Doce de Octubre.
Background: Serotonin overproduction by neuroendocrine tumors is a feature of carcinoid syndrome (CS), which is characterized by diarrhea, flushing, and valvular heart disease. In a previous pivotal Phase 3 trial (TELESTAR) in patients with CS experiencing on average ≥4 bowel movements (BMs)/day despite stable-dose somatostatin analog (SSA) therapy, the tryptophan hydroxylase inhibitor telotristat etiprate (TE) reduced BM frequency and urinary 5-hydroxyindoleacetic acid (u5-HIAA), a serotonin metabolite. TELECAST was another double-blind, placebo-controlled, Phase 3 study evaluating safety and efficacy of TE in SSA-treated and SSA-naïve patients with less-severe gastrointestinal symptoms than TELESTAR patients.
Methods: All eligible patients (N=76) were experiencing ≥1 prespecified CS-associated symptom; SSA-treated patients were required to have <4 BMs/day. Patients were randomly assigned (1:1:1) to receive placebo (n=26), TE 250 mg (n=25), or TE 500 mg (n=25) orally 3x/day for 12 weeks. Safety and change from baseline in u5-HIAA at Week 12 were co-primary endpoints. Responders were predefined as patients experiencing ≥30% reduction in BM frequency for ≥50% of days.
Results: At baseline, across all groups, mean BM frequency was 2.5 BMs/day (range: 2.2–2.8) and mean u5-HIAA was 78 mg/day (range: 66–86); ≥92% of patients were receiving SSA therapy. Estimated treatment differences in mean u5-HIAA compared with placebo were −30 mg/day (−54%; P<0.001) for TE 250 mg and −41 mg/day (−90%; P<0.001) for TE 500 mg.
On each TE dosage, 10 (40%) patients were BM responders versus 0 on placebo.
Serious adverse events and study discontinuations were infrequent (Table 1). The incidence of gastrointestinal-related adverse events (AEs) was similar across groups. Mild or moderate hepatic enzyme elevations were observed in TE-treated patients, and depression-related AEs occurred in 2 placebo and 2 TE patients (1/dosage); none of these AEs led to study discontinuation.
Conclusion: TE significantly reduced u5-HIAA and BM frequency and was well tolerated.
Impact of Prior Chemotherapy (Chemo) on Progression-free Survival (PFS) in Patients (Pts) With Advanced, Nonfunctional Lung or Gastrointestinal (GI) Neuroendocrine Tumors (NET): A Secondary Analysis From the Phase 3 RADIANT-4 Study
Rodney Pommier,1 Jonathan Strosberg,2 Simron Singh,3 Edward Wolin,4 James Yao,5 Maurizio Voi,6 Lida Pacaud,7 Antonia Ridolfi,8 Nicola Fazio,9 Marianne Pavel,10 Roberto Buzzoni,11 Carlo Carnaghi.121Oregon Health and Science University, Portland, OR; 2Moffitt Cancer Center, Tampa, FL; 3Sunnybrook Health Sciences Centre, Toronto, Canada; 4Cedars-Sinai Medical Center, Los Angeles, CA; 5University of Texas/MD Anderson Cancer Center, Houston, TX; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ; 7Novartis Pharma AG, Basel, Switzerland; 8Novartis Pharma S.A.S., Rueil-Malmaison, France; 9Istituto Europeo di Oncologia, IRCCS, Milano, Italy; 10Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany; 11Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy; 12IRCCS Istituto Clinico Humanitas, Rozzano, Italy.
Background: In the phase 3 RADIANT-4 study, everolimus (EVE) improved PFS by 7.1 months (mo) compared to placebo (PBO; P<0.00001) in pts with advanced, progressive, nonfunctional NET of lung or GI tract. This sub group analysis evaluated impact of prior chemo use on PFS in RADIANT-4.
Methods: In RADIANT-4, pts were randomized (2:1) to EVE 10mg/d or PBO, both with best supportive care. A subgroup analysis of the RADIANT-4 study by prior chemo use is presented.
Results: Of 302 pts, 77 (25%) had received chemo (EVE, n=54 & PBO, n=23) and 225 (75%) were chemo-naïve (EVE, n=151 & PBO, n=74) prior to study entry. Baseline characteristics were comparable between subgroups. Primary tumor sites (prior chemo vs chemo-naïve): Lung (49% vs 23%), GI (38% vs 65%), NET of unknown primary (13% vs 12%). Median PFS (95%CI) in prior chemo group (EVE vs PBO) was 9.2 (5.6-11.7) mo vs 2.1 (1.9-3.7) mo (HR 0.35; 95%CI 0.19-0.64). In chemo-naïve group (EVE vs PBO), median PFS (95%CI) was 11.2 (9.2-16.6) mo vs 5.4 (3.7-9.0) mo (HR 0.60; 95%CI 0.42-0.86). Most frequent drug-related G3/4 AEs (EVE vs PBO) in prior chemo group: stomatitis (9% vs 0), anemia (8% vs 4%) & diarrhea (6% vs 0); chemo-naïve group: diarrhea (8% vs 3%) & stomatitis (7% vs 0).
Conclusion: EVE improved PFS in pts with advanced, well-differentiated, progressive, nonfunctional NET of lung or GI origin irrespective of prior chemo use. EVE safety profile was similar to overall RADIANT-4 population.
The Efficacy and Safety of Sunitinib in Patients With Advanced Well-differentiated Pancreatic Neuroendocrine Tumors
Eric Raymond,1 Matthew Kulke,2 Shukui Qin,3 Michael Schenker,4 Antonio Cubillo,5 Wenhui Lou,6 Jiri Tomasek,7 Espen Thiis-Evensen,8 Jianming Xu,9 Karoly Racz,10 Adina Croitoru,11 Mustafa Khasraw,12 Eva Sedlackova,13 Ivan Borbath,14 Paul Ruff,15 Paul Oberstein,16 Tetsuhide Ito,17 Kathrine Fernandez,18 Brad Rosbrook,18 Nicola Fazio.191Paris Saint-Joseph Hospital Group; 2Dana-Farber Cancer Institute; 3PLA Cancer Center of Nanjing Bayi Hospital; 4Centrul de Oncologie Sf. Nectarie, Oncologie Medicala; 5Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal; 6Zhongshan Hospital, Fudan University; 7Masarykuv onkologicky ustav/Klinika komplexní onkologické péče; 8Oslo University Hospital, Department of Gastroenterology; 9No.307 Hospital, Academy of Military Medical Sciences; 10Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine; 11Fundeni Clinical Institute, Department of Medical Oncology; 12Andrew Love Cancer Center, Geelong Hospital; 13Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika;14Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology; 15University of the Witwatersrand, Faculty of Health Sciences; 16Columbia University Medical Center, Division of Hematology/Oncology; 17Kyushu University Hospital; 18Pfizer Inc; 19IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors.
Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) on the basis of a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings.
Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with confirmed, progressive, well-differentiated, unresectable advanced or metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is still ongoing.
Results: Sixty one treatment-naïve and 45 previously-treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG performance status 0, 65.1% or 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously-treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously-treated patients (Table 1). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%).
Conclusion: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib.
Lanreotide Autogel/Depot (LAN) Post-Octreotide Long-Acting Release (OCT) for Safe and Tolerable Treatment of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
M. Wasif Saif,1 Julie Fu,1 Melissa Smith,1 Antonia Maloney,1 Valerie Relias,1 Barbara J Weinstein,2 Yvelisse N Suarez,2 Martin D Goodman,3 Kevin P Daly.4Departments of 1Medicine; 2Pathology; 3Surgery, and 4Radiology, Tufts Medical Center, Boston, MA.
Background: The Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET) demonstrated LAN provides significantly prolonged progression-free survival for unresectable, well/moderately differentiated, locally advanced or metastatic GEP-NETs. However, assessment of LAN after OCT treatment among GEP-NET patients is still needed. This case series measured LAN tolerability for GEP-NETs patients who had disease progression, lack of OCT tolerance, or changed therapy.
Methods: This is a retrospective chart review of GEP-NETs patients at Tufts University Medical Center who received LAN post-OCT. Information obtained included demographic data, tumor stage/grade, somatostatin analog treatment/dose, baseline/current levels of biochemical markers (chromogranin [CgA], urinary 5-hydroxyindoleacetic acid [5-HIAA, seratonin]), radiological response, and adverse events (AEs).
Results: Patients (n=15; 43–81 yrs; 5 men) with non-functional, low-grade GEP-NETs receiving OCT 30-60mg were switched to LAN. Metastatic sites, locations, grades of primary tumors, and reasons for switching are presented in Table 1. LAN started at 120mg (n=13), 90mg (n=1), or 60mg (n=1) based on renal dysfunction, and median number of LAN cycles=5.23 (range 2–10). 5-HIAA values were obtained (n=5, baseline: 3.6-8.7mg/L, post-LAN: 3.1-4.1mg/L). Both serum serotonin (<10-1280 to <10-533ng/mL) and CgA levels (7–38,200 to <5-660nmol/L; normal ≤15nmol/L) decreased. Gastrin declined (n=1; 239 to 76pg/mL; normal: ≤100pg/mL), PPP declined (n=1; 1401 to 387pg/mL; normal: 60–69 yrs: <312pg/mL), and ACTH decreased (n=1; 92 to 10pg/mL; normal: 6-50pg/mL). Concomitant therapies included chemotherapy (n=2), targeted agents (n=3), surgery (n=2), and liver-directed therapy (n=5). Radiological responses were SD (n=7), PR (n=4), PD (n=1), CR (n=1), or not reported (n=2). Treatment-related AEs included fatigue (n=3) and constipation, diarrhea, nausea, hyperglycemia (all n=1).
Conclusion: Among these post-OCT GEP-NET patients who experienced disease progression and poor OCT tolerance, LAN alone or with concomitant therapies was well tolerated. LAN was also associated with biochemical and radiological responses.
Use of Alklyating Chemotherapy in High Grade Neuroendocrine Tumors: Evaluation of Real World Data
Arani Sathiyapalan, Suzanne Richter, Michael Sanatani, Stephen Welch, Walter Kocha. London Health Sciences Centre, London, Canada.
Background: High grade neuroendocrine tumors (NETs) are believed to have activity to certain alkylating agents. These regimens include streptozocin (STZ) (used in combination with doxorubicin or 5-fluorouracil) and dacarbazine (DTIC). Current series report variable responses between 6 – 69%. Our objective was to evaluate our real world data to better understand treatment decision-making and clinical outcomes with alkylating agents in advanced high grade NETs.
Methods: We reviewed the medical records of 36 patients with metastatic NETs who received alkylating systemic chemotherapy with either a DTIC regimen (n=15) or STZ based regimen (n=21). Patient cases were evaluated for age, time on treatment, time to progression (TTP), overall survival (OS), and reason for discontinuation by two sample t-test.
Results: Observed time on treatment was slightly prolonged with DTIC (77.5 days vs STZ: 64.0 days). STZ had a prolonged TTP of 7.0 months with STZ vs. 5.5 months with DTIC (p=0.778). There was no significant difference in OS with a mean of 9.1 months (DTIC) vs. 12.4 months (STZ) (p=0.355). The predominant cause of treatment discontinuation in both groups was progressive disease; DTIC (71%) versus STZ (42%). Toxicity resulted in treatment discontinuation in 19% for STZ vs 7% for DTIC.
Regression analysis based on the Ki67 index revealed a significantly prolonged TTP of 11 months with a Ki67<20 as compared to 2.6 months with a Ki67>20 (p=0.014).
Conclusion: STZ containing regimens demonstrated a trend toward prolonged PFS in comparison to DTIC, but there was no difference in OS between the two groups. Despite STZ appearing to have an increased toxicity rate, the rate of cessation between the groups was similar. There was a significant improvement in PFS in tumors with a Ki67<20 regardless of therapy. This real world evaluation suggests similar efficacy with improved tolerability of DTIC based chemotherapy as a potential alternative to other alkylating agents.
Everolimus for Advanced, Progressive, Nonfunctional Neuroendocrine Tumors (NET) of the Gastrointestinal (GI) Tract: Efficacy and Safety from a RADIANT-4 Subgroup Analysis
Simron Singh,1 Carlo Carnaghi,2 Roberto Buzzoni,3 Markus Raderer,4 Harald Lahner,5 Juan Valle,6 Maurizio Voi,7 Lida Pacaud,8 Jeremie Lincy,8 Natsuko Okita,9 Matthew Kulke,10 Jonathan Strosberg,11 James Yao,12 Marianne Pavel,13 Nicola Fazio.141Sunnybrook Health Sciences Centre, Toronto, Canada; 2IRCCS Istituto Clinico Humanitas, Rozzano, Italy; 3Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy; 4Univ. Klinik f. Innere Medizin I, AKH, Wien, Austria; 5Universitaetsklinikum Essen, Zentrum f. Innere Medizin, Essen, Germany; 6Institute of Cancer Studies, University of Manchester, The Christie Hospital, Manchester, UK; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ; 8Novartis Pharma AG, Basel, Switzerland; 9National Cancer Center Hospital, Chuo-ku, Tokyo, Japan; 10Dana Farber Cancer Institute, Boston, MA; 11Department of Medicine, Moffitt Cancer Center, Tampa, FL; 12University of Texas/MD Anderson Cancer Center, Houston, TX; 13Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany; 14Istituto Europeo di Oncologia - IRCCS, Milano, Italy.
Background: Everolimus (EVE) demonstrated progression-free survival (PFS) benefit of 7.1 months compared to placebo in the phase 3 RADIANT-4 study in patients (pts) with advanced, well-differentiated, progressive, nonfunctional NET. This subgroup analysis evaluated the efficacy and safety of EVE in GI NET subset of RADIANT-4.
Methods: In RADIANT-4, pts were randomized (2:1) to EVE (10 mg/d) or PBO. The present analysis included pts with GI NET (stomach, colon, rectum, appendix, caecum, ileum, duodenum, jejunum, or small intestine).
Results: Of 302 pts, 175 had GI NET (EVE [n=118], PBO [n=57]). Median age was 63 years; females: 55%; G1/G2: 75%/25%; WHO PS 0/1: 78% or 22%; Caucasian: 73%. Ileum (41%), rectum (23%) and jejunum (13%) were the most common locations. Prior therapies (EVE vs PBO) included: surgery (70% vs 84%), somatostatin analogues (59% vs 63%), and chemotherapy (19% vs 12%). Median PFS (95% CI) by central review (EVE vs PBO) was 13.1 (9.2-17.3) mo vs 5.4 (3.6-9.3) mo with an estimated 44% risk-reduction in favor of EVE (HR, 0.56; 95%CI, 0.37-0.84). The most frequent G3/4 adverse events irrespective of drug-relationship reported in ≥5% pts (EVE vs PBO) included diarrhea, hypertension, and stomatitis.
Conclusion: EVE demonstrated improvement in PFS for pts with GI NET with an estimated 44% reduction of risk in disease progression or death in favor of EVE vs PBO. Safety profile for EVE was consistent with that previously reported.
Phase I, Multi-center, Open-label, Dose-escalation Study of Pasireotide LAR (PAS) in Patients With Advanced Neuroendocrine Tumors (NET)
Jonathan Strosberg,1 Jennifer Chan,2 Alain Mita,3 Madan Kundu,4 Karina Hermosillo,5 Ke Hu,4 Edward Wolin,3 James Yao.61Department of Medicine, Moffitt Cancer Center, Tampa, FL; 2Dana Farber Cancer Institute, Boston, MA; 3Cedars-Sinai Medical Center, Los Angeles, CA; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ; 5Novartis Pharma AG, Basel, Switzerland; 6University of Texas/MD Anderson Cancer Center, Houston, TX.
Background: Pasireotide, a novel somatostatin analog, has been previously investigated but the maximum tolerated dose (MTD) has not been determined in pts with advanced NET. We report results of a planned interim analysis of a phase I dose-escalation (DE) study to determine the MTD, characterize safety, tolerability, PK, and efficacy trends in pts with advanced NET.
Methods: Pts were enrolled in 2 phases: DE phase at a starting dose of 80mg PAS i.m. followed by a dose expansion (DX) phase. Associations between PK parameters and clinical outcomes were evaluated using regression analysis. Bradycardia is defined as heart rate < 40 bpm.
Results: As of July-2015, 29 pts (15, DE; 14, DX) were treated with 80 mg (13pts) and 120 mg (16pts) doses. No protocol defined dose-limiting toxicities were observed in the study; however in a post hoc analysis a higher incidence of bradycardia was seen with 120 mg (31.3%) vs 80 mg (0%). Treatment discontinuations (Table) were primarily due to disease progression (44.8%) or adverse events (AEs; 27.6%). In the PK analysis, probability of bradycardia showed a moderate increase with increasing PAS concentration that was not statistically significant [Odds ratio for every 1.5x increase (95% CI): daytime, 1.672 (0.381-7.338); nighttime, 2.024 (0.494-8.292)]. No significant association was observed between PAS concentrations and glucagon levels. Two partial radiographic responses (PRs) were observed, both in the 120mg dose. PAS concentrations correlated with % tumor shrinkage although the association was not statistically significant (P = 0.08). The most common AEs are listed in the Table 1.
Conclusion: MTD was defined at 120 mg for PAS in pts with advanced NET. Although objective radiographic responses are rarely observed with SSA, 2 PRs were observed among 16 pts in the 120mg cohort. Bradycardia appears to be a dose-limiting effect; however the mechanism and clinical significance are uncertain.
Long-Term Safety/Tolerability of Lanreotide Autogel/Depot (LAN) in Neuroendocrine Tumors (NETs) Patients With Carcinoid Syndrome (CS): The ELECT Long-Term Open-label Extension
Aaron Vinik,1 George Fisher, Jr,2 Pamela Kunz,2 Nilani Liyanage,3 Beloo Mirakhur,4 Susan Pitman Lowenthal,4 Rodney Pommier,5 Montaser Shaheen,6 Edward Wolin.71Eastern Virginia Medical School, Norfolk, VA; 2Stanford University School of Medicine, Stanford, CA; 3Ipsen, Boulogne-Billancourt; 4Ipsen, Basking Ridge, NJ; 5Oregon Health & Science University, Portland, OR; 6University of New Mexico Cancer Center, Albuquerque, NM; 7Montefiore Einstein Center for Cancer Care, Bronx, NY.
Background: The ELECT study demonstrated that LAN treatment for CS in NET patients reduced rescue medication use vs placebo (PBO) during a 16-wk double-blind (DB) phase, and sustained symptomatic control during a 32-wk initial open-label (IOL) phase. Here we present final results of a long-term open-label extension (LTOLE).
Methods: Adult patients with NETs and a history of CS with/without prior somatostatin analog use were randomized to DB LAN 120mg or PBO every 4 wks for 16 wks, followed by an initial 32 wk IOL phase on LAN. Patients could then enter a LTOLE on LAN for up to 2 yrs (at sites where LAN was not already approved for symptom control). The LTOLE focused only on safety assessments.
Results: Of the 115 patients who took part in the DB phase (LAN, n=59; PBO, n=56) and 101 who then entered the IOL, 57 also entered the LTOLE on LAN. The overall adverse event (AE) profile of LAN is summarized in Table 1. The duration (median [IQR]) of LAN treatment for the 57 patients who entered the LTOLE was 109.6 (64.0–134.6) wks during this phase alone. During the LTOLE, the most common AEs reported by patients were abdominal pain (n=14 [25%]), fatigue (n=9 [16%]), diarrhea, hyperglycemia and back pain (each n=8 [14%]). The treatment related AEs most frequently reported by patients were cholelithiasis (n=4 [7%]), hyperglycemia and fatigue (both n=2 [4%]). Few patients (n=2[4%]) reported serious AEs considered treatment-related (hyperglycemia and glucose intolerance) but none led to study withdrawal.
Conclusion: These results on long-term use are consistent with the established safety/tolerability of LAN and extend the evidence base supporting the use of LAN 120mg in patients with NETs.
Everolimus (EVE) in Advanced, Nonfunctional, Well-differentiated Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin: Second Interim Overall Survival (OS) Results From the RADIANT-4 Study
James Yao,1 Nicola Fazio,2 Simron Singh,3 Roberto Buzzoni,4 Carlo Carnaghi,5 Edward Wolin,6 Jiri Tomasek,7 Markus Raderer,8 Harald Lahner,9 Maurizio Voi,10 Lida Pacaud,11 Jeremie Lincy,11 Juan Valle,12 Gianfranco Delle Fave,13 Eric Van Cutsem,14 Do-Youn Oh,15 Jonathan Strosberg,16 Matthew Kulke,17 Marianne Pavel.11University of Texas/MD Anderson Cancer Center, Houston, TX; 2Istituto Europeo di Oncologia - IRCCS, Milano, Italy; 3Sunnybrook Health Sciences Centre, Toronto, Ontario; 4Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy; 5IRCCS Istituto Clinico Humanitas, Rozzano; 6Cedars-Sinai Medical Center, Los Angeles, CA; 77Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Univ. Klinik f. Innere Medizin I, AKH, Wien, Austria; 9Universitaetsklinikum Essen, Zentrum f. Innere Medizin, Essen, Germany; 10Novartis Pharmaceuticals Corporation, East Hanover, NJ; 11Novartis Pharma AG, Basel, Switzerland; 12Institute of Cancer Studies, University of Manchester, The Christie Hospital, Manchester, UK; 13Azienda Ospedaliera Sant'Andrea - Università La Sapienza, Roma, Italy; 14Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KULeuven, Leuven, Belgium; 15Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 16Department of Medicine, Moffitt Cancer Center, Tampa, FL; 17Dana Farber Cancer Institute, Boston, MA; 18Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
Background: The RADIANT-4 study met its primary end point with a median progression-free survival (PFS) of 11.0 months (mo) for EVE vs 3.9 mo for placebo (PBO; HR=0.48 [95% CI 0.35-0.67]; P < .00001) in patients (pts) with advanced, progressive, well-differentiated NET of lung or GI origin. A planned first interim OS analysis favored EVE but did not cross the boundary for significance (HR=0.64; 95% CI 0.40-1.05; P = .037). We report survival results from preplanned second interim OS analysis.
Methods: 302 pts with advanced, progressive, well-differentiated, nonfunctional lung/GI NET were randomized (2:1) to EVE (10 mg/d) or PBO, each with best supportive care. Pts were stratified by tumor origin, WHO performance status, and prior somatostatin analogue use. Primary end point was PFS; OS was the key secondary end point.
OS was estimated using the Kaplan–Meier method and the treatment groups were compared using a one-sided log-rank test. The Lan-DeMets method with O’Brien-Fleming type stopping boundary was used to control the cumulative type I error rate. HR was estimated by a stratified Cox proportional hazards model.
Results: By data cutoff (Nov 30, 2015), 101 pts died; 66 of 205 (32%) in the EVE group and 35 of 97 (36%) in the PBO group. Median duration of study follow-up was 33.4 mo. EVE was associated with a 27% reduction in the estimated risk of death compared to PBO (HR=0.73; 95% CI 0.48-1.11; P = .071 [the P-value threshold to claim significance for OS was 0.001982]). Estimated survival rate at 2 years was 77% with EVE and 62% with PBO (Table 1).
Conclusion: The findings from this second interim OS analysis also suggested a trend for survival benefit with EVE, although statistical significance was not achieved. The final OS analysis will be performed when approximately 191 deaths have occurred.
Pitfalls in the Response Evaluation After Peptide Receptor Radionuclide Therapy With [177Lu-DOTA0,Tyr3]Octreotate
Tessa Brabander, Jaap Teunissen, Boen Kam, Eric Krenning, Dik Kwekkeboom. Erasmus MC, Rotterdam, Netherlands.
Background: Peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) is a treatment with good results, especially for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEPNETs). However, there are some pitfalls that should be taken into consideration when evaluating the treatment response after PRRT.
Methods: We performed a retrospective study of 354 Dutch patients with GEPNETs that were treated with 177Lu-octreotate between March 2000 and December 2011. Liver function tests and chromogranin A were measured before each therapy and in follow-up. Imaging was performed before therapy and in follow-up after 6 weeks, 3 months and 6 months and thereafter every 6 months.
Results: An increase of more than 20% from baseline values of the aminotransferases was observed in 83 of 351 patients (24%). There was no difference between patients who eventually had PD and patients who had CR/PR/SD. An increase of chromogranin A compared to baseline was observed in 76 patients (29%). This was present in 34% of patients who eventually had PD and 27% of patients who had CR/PR/SD. In the majority of patients these biochemical markers normalized after therapy. On imaging, an increase in the sum of diameters of lesions was seen in 40 patients (19%) with stable disease. Progressive disease on imaging was based on new lesions in 94% of patients.
Conclusion: An increase of liver enzymes and chromogranin A is not uncommon after therapy with 177Lu-octreotate. In the vast majority of patients this will resolve in follow-up and is therefore not due to progression. Also on imaging the lesions can show a temporary increase. Clinicians should be aware that these changes are more frequently due to radiation induced inflammation than to disease progression and that repeated measurements over time are necessary to differentiate between the two.
Physiological Uptake in the Pancreatic Head on SRS Using 111In-DTPA-octreotide: Incidence and Mechanism
Tessa Brabander, Jaap Teunissen, Dik Kwekkeboom. Erasmus MC, Rotterdam, Netherlands.
Background: Physiological uptake in the uncinate process or pancreatic head has been described with Gallium-68 labeled PET tracers for somatostatin receptor imaging. 111In-DTPA-octreotide is the only registered radiopharmaceutical for the imaging of neuroendocrine tumors. We studied the uptake in this region of the pancreatic head on somatostatin receptor scintigraphy (SRS) using 111In-DTPA-octreotide in a large group of patients.
Methods: 407 patients underwent SRS using 111In-DTPA-octreotide in our department in 2014. After excluding patients with a known malignancy in or close to the pancreas, as well as all scans without SPECT/CT of the upper abdomen, we reviewed 178 scans in total. The uptake was graded on a 4-point scale that correlates the uptake in the pancreatic head to physiological uptake in the liver.
Results: Uptake in the region of the pancreatic head, including the uncinate process, was seen in 46/178 patients (26%) on SPECT-CT and in 12 patients (7%) on planar imaging. On SPECT/CT uptake was lower than the liver in 26 patients (15%), equal to the liver in 17 patients (10%) and higher than the liver in three patients (2%). In patients with diabetes mellitus the incidence of uptake in the pancreatic head was 50% on SPECT/CT.
Conclusion: Physiological uptake in the pancreatic head is seen on SPECT/CT with 111In-DTPA-octreotide in 26% of patients and the incidence is doubled in patients with diabetes mellitus. Previous case reports showed uptake in the pancreatic head due to histologically proven pancreatic polypeptide (PP) cell hyperplasia. Also, patients with DM have elevated serum PP concentrations, which is likely due to PP-cell hyperplasia. Since 90% of PP-cells are present in the pancreatic head, PP-cell hyperplasia is the most likely explanation for visualization of the pancreatic head on SRS in a substantial number of patients.
Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3] Octreotate in Patients With Gastroenteropancreatic and Bronchial Neuroendocrine Tumors
Tessa Brabander, Jaap Teunissen, Boen Kam, Wouter de Herder, Gaston Franssen, Eric Krenning, Dik Kwekkeboom. Erasmus MC, Rotterdam, Netherlands.
Background: Bronchial and gastroenteropancreatic neuroendocrine tumors are slow-growing tumors, which often present the somatostatin receptor on the cell membrane. This receptor is a target for therapy with radiolabeled somatostatin analogues. We have treated a large group of patients and present the results of efficacy, survival and toxicity.
Methods: Patients were included for analysis of efficacy and survival if treated with a cumulative dose of at least 600 mCi (22.2 GBq) [177Lu-DOTA0,Tyr3]octreotate. For safety analysis 610 patients with a cumulative dose of at least 100 mCi (3.7 GBq) were included. For efficacy analysis 522 patients were included.
Results: The objective response rate in the total group of patients was 34%. Stable disease was observed in 37% of patients, resulting in a disease control in 71% of all patients. Overall survival (OS) and progression free survival (PFS) were 63 months (95% CI 57-75 months) and 23 months (95% CI 20-25 months) respectively. Long-term toxicity included acute leukemia in 4 patients (<1%) and myelodysplastic syndrome in 9 patients (1.5%).
Conclusion: Peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate is a therapeutic option for bronchial and gastroenteropancreatic neuroendocrine tumors with good response rates and few side-effects. Compared to other therapeutic options for neuroendocrine tumors this therapy is safe and both OS and PFS are favorable for PRRT.
Tumor Growth Rate (TGR) in Intestinal/Pancreatic Neuroendocrine Tumors: Post Hoc Exploratory Analysis of Data From the CLARINET Study
Martyn Caplin,1 Marianne Pavel,2 Philippe Ruszniewski,3 Nilani Liyanage,4 Christine Massien,4 Clarisse Dromain.51Royal Free Hospital; 2Charité University Medicine Berlin; 3Beaujon Hospital; 4Ipsen; 5Gustave Roussy Cancer Campus.
Background: The phase III CLARINET study showed significantly improved progression-free survival (PFS) with lanreotide autogel/depot (LAN) vs. placebo (PBO) in intestinal and pancreatic neuroendocrine tumors (NETs). This exploratory analysis evaluated TGR, a novel measure of tumor response, in NET patients from CLARINET.
Methods: Patients with metastatic intestinal/pancreatic NETs received LAN 120 mg or PBO every 4 weeks for 96 weeks. Target lesions were assessed by central radiologic review based on RECIST v1.0. TGR (% variation of tumor volume per month) was calculated from sum-of-longest-diameters (SLD) of original target lesions (excluding new ones) on two CT scans during defined periods: 12–24 weeks prior to randomization vs. baseline (pretreatment); and baseline vs. each visit or between consecutive visits. TGR pre- and post-treatment were compared between treatment groups.
Results: Almost all patients were classified as stable on RECIST after 12 weeks of treatment (LAN, 90/96; PBO, 94/98), whereas a large proportion exhibited TGR changes. An early reduction in mean TGR was observed after only 12 weeks treatment with LAN but not with PBO, resulting in a significant difference in TGR between treatments which was maintained at subsequent study visits. (Table 1). ROC analysis showed that pretreatment TGR≤/>4% was the best cut-off value for predicting risk of progression, independently of treatment; TGR > 4% resulted in a 4-fold higher risk of progression than TGR ≤ 4% (HR 4.1; [95%CI 2.5, 6.5]; p < 0.001). Regardless of pretreatment TGR, LAN was more effective than PBO in delaying progression.
Conclusion: These results suggest TGR may provide an early and more precise characterization of treatment activity than RECIST criteria in NET patients. The potential clinical utility of TGR requires validation in prospective studies as a pre-specified outcome measure.
Evaluation of Uncinate Process Uptake on DOTA-TOC PET/MRI
Thomas Hope,1 Miguel Pampaloni,2 Eric Nakakura,1 Katherine Van Loon,1 Emily Bergsland.11University of California, San Francisco; 2Department of Radiology and Biomedical Imaging
Background: Physiologic uptake in the uncinate process is a common finding when imaging patients with neuroendocrine tumors using somatostatin receptor PET imaging. PET/MRI is a new simultaneous imaging modality that allows for the acquisition of PET and MRI data in the same imaging session. We set forth to evaluate the utility of PET/MRI for the characterization of uncinate process uptake seen on PET.
Methods: 30 consecutive patients imaged using DOTA-TOC PET/MRI we included for evaluation. Patients were injected with an average of 5.4 mCi of Gallium-68 DOTA-TOC and imaged 113 after injection. All imaging was acquired using a gadolinium containing hepatobiliary contrast agent (gadoxetate disodium, Eovist). Images were retrospectively reviewed and compared to additional comparison imaging studies. Uptake was characterized as either being focal or diffuse. SUVmax values were calculated when uptake was noted.
Results: 21 of the 30 patients imaged demonstrated uptake in the uncinate process, with 13 of the 21 patients demonstrating focal uptake. In 20 of the 21 patients, a confident imaging interpretation could be made when comparing to additional studies, and 10 patients were determined to have physiologic uptake, 7 to have nodal disease and 3 to have pancreatic masses. The average SUVmax in negative patients was 15.5, while in patients with disease, the average was 27.9. Diffusion weighted imaging was negative in two patients with pathologic uptake, but was positive in the remaining 8 patients.
Conclusion: Preliminary analysis of DOTA-TOC PET/MRI suggests that MRI imaging can be used to adequately distinguish physiologic uptake for pathologic uptake in the uncinate process. Understanding the role of cross sectional imaging in characterizing uptake is important, given that this is a common finding in patients being imaged using somatostatin receptor PET.
Peptide Receptor Radionuclide Therapy (PRRT) for Metastatic Neuroendocrine Tumors (NETs): A United States Experience
Bryson Katona,1 Brian Riff,2 Michael Soulen,1 Daniel Pryma,1 Bonita Bennett,1 Damian Wild,3 Guillaume Nicolas,3 Ursina Teitelbaum,1 David Metz.11Perelman School of Medicine, University of Pennsylvania; 2Icahn School of Medicine at Mount Sinai; 3University Basel Hospital.
Background: The phase III NETTER-1 trial showed that PRRT serves as effective therapy for low to intermediate grade progressive metastatic small bowel NETs but little is known about its general utility in real-world United States (US) practice. We therefore examined the efficacy and toxicity of PRRT in a US-based population.
Methods: Data was analyzed on all University of Pennsylvania patients with metastatic NETs who underwent PRRT therapy for progressive disease between July 2005 and March 2016 (n = 24). Tumor progression was determined by RECIST 1.1. Laboratory and clinical data was analyzed using CTCAE criteria, to determine hematologic toxicity, nephrotoxicity, and hepatotoxicity. Kaplan-Meier plots were created to estimate progression free survival (PFS) and overall survival (OS).
Results: Mean age, duration of disease and number of prior therapies at first PRRT was 58 years, 5 years, and 2.6 treatments, respectively. 58% were male, 29% had small bowel primary tumors and 29% had grade 3 tumors. During follow-up (range 3–129 months), 17 of 24 patients (71%) progressed, 5 (21%) had stable disease, 2 (8%) have not yet obtained post-treatment imaging, and there were 11 deaths. Median PFS was 13 months and median OS was 36 months. New onset nephrotoxicity, anemia, leukopenia, and thrombocytopenia developed in 36%, 50%, 30%, and 28%, respectively. Acute liver injury occurred in 11 patients (46%) including 5 (21%) with biochemical injury, 11 (46%) with new onset ascites, and 3 (13%) deaths due to liver-related complications.
Conclusion: In this US population of metastatic NETs, PRRT provided a median PFS of 13 months. The PRRT-associated toxicities and lower PFS compared to the NETTER-1 trial may be due to extensive pre-treatment, higher grade tumors, inclusion of non-small bowel primary sites, and later use of PRRT, all of which may have implications regarding where PRRT should fit in the treatment algorithm of NET patients.
Personalized Dosimetry Based Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors With 90Y-DOTATOC
Yusuf Menda,1 Mark Madsen,1 Thomas O'Dorisio,1 John Sunderland,1 Leonard Watkins,1 Molly Martin,1 Joseph Dillon,1 Michael Schultz,1 James Ponto,1 David Biushnell,1,2 Sue O'Dorisio.11University of Iowa Carver College of Medicine; 2University of Iowa; 3VAMC Iowa City.
Background: Peptide Receptor Radionuclide Therapy (PRRT) with 90Y-DOTATOC is typically administered with a fixed-dosage approach. However, personalized dosimetry can guide the amount of administered activity to maximize tumor dose while not exceeding toxic levels to the kidneys. The goal of this study is to evaluate the feasibility and impact of dosimetry-based adaptive approach in determination of the administered activity of 90Y-DOTATOC.
Methods: Patients with non-resectable or metastatic neuroendocrine tumors are enrolled in a prospective clinical trial with PRRT. 90Y-DOTATOC is produced in a synthesis unit (ModularLab PharmTracer, Eckert & Zeigler, Berlin, Germany) using GMP grade DOTATOC and 90Y-Chloride utilizing a GMP-certified cassette. Patients are treated with 3 cycles separated by 6 weeks. Adult subjects receive 4.44 GBq and pediatric patients receive 1.85 GBq/m2 for the 1st cycle. Renal and blood dosimetry obtained from the 1st and 2nd cycles determine the administered activity for subsequent cycles. PET-CT is used to quantify the initial renal uptake of 90Y-DOTATOC. This is immediately followed by bremsstrahlung SPECT-CT, repeated at 24, 48 and 72 hours, to measure the renal residence time of 90Y-DOTATOC. Administered activities of 90Y-DOTATOC are deescalated up to 50% or escalated up to 25% constrained by a cumulative kidney threshold dose of 23 Gy and blood dose of 2 Gy.
Results: 18 patients were treated with at least one cycle of 90Y-DOTATOC. The kidney dose ranged from 0.6 to 2.7 mGy/MBq; blood dose was between 0.04 to 0.24 mGy/MBq. The administered activity was changed by more than 10% from baseline in 17 adult patients for the 2nd and/or 3rd cycle, with the activity ranging between 2.3 - 5.6 GBq. The administered activity was reduced in 6 and increased in 20 administrations.
Conclusion: A hybrid dosimetric approach using PET-CT and bremsstrahlung SPECT-CT allows for individualized adaptive dosage administrations for PRRT with 90Y-DOTATOC.
Magnetic Resonance Imaging of Neuroendocrine Tumor Hepatic Metastases: Evaluation of Lesion Conspicuity and Interobserver Agreement of Lesion Measurements on Various Sequences
Brian Morse,1 Dalanda Diallo,2 Daniel Jeong,1 Kerry Thomas,1 Jonathan Strosberg.11Moffitt Cancer Center, Durham, NC; 2University of South Florida, Tampa, FL.
Background: Prior work by Dromain et al showed that the best MR sequences to evaluate metastatic disease in the liver from NET were T2-weighted and arterial phase dynamic postcontrast (Dromain et al, Am J Roentgenol. 2003 Jan;180:121–8). There are newer MR sequences which may outperform T2-weighted and arterial phase images for evaluation of NETs. The goal of this study was to determine which magnetic resonance sequences provide the highest lesion conspicuity (measured using signal intensity and contrast to noise ratios) and produce lesion measurements with the highest interobserver agreement (measured using concordance correlation coefficient) for hepatic metastases from gastrointestinal neuroendocrine tumors.
Methods: Patients with metastatic NETs who had magnetic resonance imaging exams with both gadoxetate disodium and gadopentetate dimeglumine contrast within a six month span were identified, and 23 metastatic hepatic lesions were selected. Three radiologists and one medical oncologist measured greatest axial diameter of each lesion on the following sequences: T2-weighted (with and without fat suppression), T1-weighted (gradient-recalled echo and fat-suppressed), postcontrast (dynamic, delayed, and hepatobiliary phase) and diffusion-weighted. Signal intensity ratio (SIlesion/SIliver) and contrast to noise ratio ([SIlesion – SIliver]/noise) were calculated for all lesions on each sequence. Interobserver agreement for lesion measurements on each sequence was calculated utilizing concordance correlation coefficient.
Results: Diffusion-weighted sequences had the highest signal intensity ratio with percent change in signal intensity ranging from 147-187% (versus a range of 19.6-130% for other sequences). One hepatobiliary sequence had the highest contrast to noise ratio with a value of 41 (versus a range of 3.2-28.1 for other sequences). All sequences showed high interobserver agreement for lesion measurements, regardless of observer experience.
Conclusion: These results show that diffusion weighted and hepatobiliary phase sequences outperform most other MR sequences with regard to lesion conspicuity, but there is no improvement in interobserver agreement of lesion measurements.
Improved Survival in Stage IV NETs Treated With High Dose I-131 MIBG is Predicted by Response at Initial Follow-up and by Multiple Rounds of Therapy
Michael Morse, Ari Kane, Matthew Thorpe, Jorge Oldan, Jason Zhu, Salvador Borges-Neto. Duke University School of Medicine, Durham, NC.
Background: Peptide receptor radionuclide therapy (PRRT) has promising activity in advanced somatostatin receptor (SSTR)-expressing neuroendocrine tumors (NETs); however, 20 % of NETs lack sufficient SSTR expression (1). An alternative is iodine-131-meta-iodobenzylguanidine (I131-MIBG), a radiolabeled norepinephrine analog that can be taken up by NETs, including some negative on somatostatin receptor scintigraphy.
Methods: We performed a retrospective review of the medical charts of all patients treated with I131-MIBG for NETs (excluding pheochromocytoma/paraganglioma) at Duke University Hospital from 1991–2014 (n = 211).
Results: Primary site: Unknown 39%, small bowel 32%, lung 10%, other 19%. Prior therapy: surgery 63%, radiation 10%, embolization 6%, chemotherapy 27%, SSA 72%. 81% received one treatment; the remainder received multiple treatments over their lifetime. At first follow up, 71% reported improvement in pre-treatment symptoms such as GI symptoms, fatigue, flushing, and pain. Median time to symptomatic progression was 1.4y ± SE 0.3. Initial follow up imaging demonstrated 2% CR, 18% PR, 60% SD and 20% PD. Median TTP was 1.7y ± 0.2. Laboratory (CgA, 5HIAA) response: 34%; stable lab results: 48%; Median survival post treatment was 2.4y ± 0.2. Improved survival was predicted by: multiple MIBG treatments vs. one treatment; stable/response vs. progression at first imaging follow up; symptomatic response vs. non-response to MIBG; response/stability vs. progression in labs.
Conclusion: Response to I131-MIBG is associated with survival benefit for NETs.
NETTER-1 Phase III in Patients With Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate: Efficacy, Safety, QoL Results, and Subgroup Analysis
Jonathan Strosberg,1 Edward Wolin,2 Beth Chasen,3 Matthew Kulke,4 David Bushnell,5 Martin Caplin,6 Richard Baum,7 Pamela Kunz,8 Timothy Hobday,9 Andrew Hendifar,10 Kjell Öberg,11 Maribel Lopera Sierra,12 Dik Kwekkeboom,13 Philippe Ruszniewski,14 Eric Krenning.131H. Lee Moffitt Cancer Center; 2Markey Cancer Center, University of Kentucky; 3The University of Texas MD Anderson Cancer Center; 4Dana-Faber Cancer Institute; 5University of Iowa; 6Royal Free Hospital; 7Zentralklinik, Bad Berka; 8Stanford University Medical Center; 9Mayo Clinic College of Medicine; 10Cedars Sinai Medical Center; 11Oncology; 12Advanced Accelerator Application Inc.; 13Erasmus Medical Center; 14Hopital Beaujon.
Background: Therapeutic options for patients are currently limited with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy.
Methods: NETTER-1 is the first phase III, randomized trial evaluating 177Lu-DOTA0-Tyr3-Octreotate (Lutathera®) in patients with progressive, somatostatin receptor positive midgut NETs. 230 patients were randomized to receive Lutathera 7.4 GBq every 8 weeks (x4 administrations) versus Octreotide LAR 60 mg every 4 weeks. The primary endpoint was PFS (RECIST 1.1). Secondary objectives included ORR, OS, toxicity, and quality of life (QoL) based upon EORTC QLQ-C30 and QLQ-G.I.NET21 questionnaires. Subgroup analysis of PFS was performed to assess impact of potential prognostic factors.
Results: Centrally confirmed disease progressions or deaths were 23 in the Lutathera arm and 68 in the Octreotide LAR 60 mg arm. The median PFS was not reached for Lutathera and was 8.4 months with control, P < 0.0001, HR 0.21. At the time of the NDA/MAA submission, interim OS analysis (14 deaths in Lutathera group and 26 in control group; P = 0.0043) suggested an improvement in OS. Subgroup analyses for PFS confirmed consistent benefits of Lutathera irrespective of stratification and prognostic factors including tumor grade, age, gender, tumor marker levels, and levels of radiotracer uptake. Grade 3 or 4 neutropenia, thrombocytopenia and lymphopenia occurred in 1%, 2% and 9% of patients in Lutathera arm vs. none in controls. Health related QoL surveys indicated a moderate improvement in the global health status in the Lutathera treatment arm, demonstrating that the treatment benefit of Lutathera is not offset by a negative impact on patient quality of life.
Conclusion: The phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS, and suggests an OS benefit in patients with advanced midgut NETs treated with Lutathera. Subgroup analysis demonstrates consistent benefit across prognostic factors. The Lutathera safety and QoL profile was found to be favorable.
Does Receptor Status Impact Survival of Patients With Neuroendocrine Tumors?
Yi-Zarn Wang, David Beyer. LSU Health Sciences Center, New Orleans, LA.
Background: Neuroendocrine tumors (NETs) are rare neoplasms increasing in incidence due to greater awareness among patients and physicians. The most reliable diagnostic imaging study has been the 111-In-pentetreotide scan which binds to somatostatin receptors of the tumor. It is known that breast cancer treatment outcome is tightly correlated with degree of tumor cell differentiation and receptor status. We hypothesize that receptor status determined by 111-In-pentetreotide (Octreoscan) and 123-I-Metaiodobenzylguanidine (MIBG) imaging results can predict prognosis for small bowel NETs.
Methods: A database with all patients seen at the LSU/Ochsner NET Program was queried for nuclear medicine scan results. Included patients had a histologically confirmed ileal, jejunal, or small intestinal NET and Octreoscan and MIBG imaging results. Kaplan-Meier survival analysis was performed and statistical significance was determined by Log-rank test (P < 0.05).
Results: 110 patients diagnosed between July 1994 and September 2013 were included. There were 64 females (64/110, 58%) and 46 males (46/110, 42%). Seventy-three (73/110, 66%) and sixty-three (63/100, 57%) patients had positive Octreoscan and MIBG imaging results, respectively. 5- and 10-year survival was calculated and sorted into four groups based on imaging positivity (Table 1).
Conclusion: Most midgut NETs present with positive Octreoscans which reflect positive receptor status; a favorable feature in prognosis based on the well-established breast cancer treatment experience. Unexpectedly, our data have shown receptor scintigraphy studies result has no baring in short term survival. More surprisingly, patients with double positive scan demonstrate a substantial survival disadvantage over a longer interval. Further longitudinal studies are required to determine if NET receptor status can reliably predict patient prognosis and the mystery of the reversal relation of the receptor status of NET patients and their prognosis.
Prospective Experience With Routine SSTR2A Immunohistochemistry in Neuroendocrine Epithelial Neoplasms
Deema Alkapalan, Jessica Maxwell, Thomas O'Dorisio, James Howe, Andrew Bellizzi, Iowa NET SPORE. University of Iowa Hospitals and Clinics.
Background: Neuroendocrine epithelial neoplasms (NENs) express high levels of somatostatin receptors, the basis of octreotide therapy and somatostatin receptor imaging (SRI). In the Fall of 2014 we began routine immunohistochemistry (IHC) testing of all neuroendocrine tumors (NETs) for SSTR2A, using the monoclonal antibody UMB-1. Cases are scored based on criteria proposed by Korner and Reubi (AJSP 2012). We also test neuroendocrine carcinomas (NECs) upon request. Herein, we report our first year's prospective experience.
Methods: We searched the pathology database for all SSTR2A IHC orders. Most stains (>90%) had been interpreted by a single pathologist in the context of routine care. The following clinicopathologic data were obtained: SSTR2A result, SSTR2A H-score (extent*intensity), age, gender, anatomic site, differentiation (well, poor), WHO 2010 grade (G1-3), SRI results, prior somatostatin analogue treatment.
Results: We performed 214 IHC in 203 patients (M:F, 1:1; mean/median age 57/59). SSTR2A IHC was positive in 91% of 192 NETs and 26% of 19 NECs; 91% of 85 G1 and 90% of 97 G2 tumors; and 100% of 10 morphologically well-differentiated but G3 neoplasms. While 97% and 99% of pancreatic and ileal NETs were positive, only 38% of lung tumors were. 64% and 33% of patients with a negative OctreoScan or DOTA-scan, respectively, were IHC-positive.
Conclusion: Routine SSTR2A in NENs is clinically feasible. As expected, SSTR2A is highly expressed in NETs. Of interest, expression appears less common in lung. There is no significant difference in SSTR2A-positivity between G1 and G2 tumors. A surprising number of poorly differentiated and G3 tumors are positive, with follow up imaging and treatment implications. Patients with negative SRI are also often positive, opening up somatostatin-based therapy in these patients.
Identification of Recurrence Predictors in Stage I-III Midgut NETs After Curative Surgery
Mauro Cives, Jonathan Strosberg. Moffitt Cancer Center, Tampa, FL.
Background: Surgery represents the only curative treatment for stage I-III midgut neuroendocrine tumors (NETs). There is very little data on post-operative recurrence risk and therefore few evidence-based guidelines for long-term surveillance. This study is aimed at evaluating risk of recurrence and identifying predictors of recurrence which will facilitate generation of risk-based surveillance guidelines.
Methods: 150 patients with stage I-III midgut NET who underwent R0-R1 surgical resection between 1985 and 2011 were retrospectively evaluated for relapse and survival outcomes. Demographic (sex, age), clinical (NET primary site, tumor size, uni- or multifocality, presence of symptoms at diagnosis, type of surgery) and pathological features (tumor grading, differentiation, presence or absence of perineural or angiolymphatic invasion, degree of parietal invasion, presence of nodal metastases, margin clearance) were assessed as potential predictors of recurrence. Disease-free survival (DFS) was calculated using the Kaplan-Meier method.
Results: After a median follow-up of 82 months (range 1–325), 61/150 patients (41%) relapsed. The median DFS was 125 months (95% CI, 87–139 months). Amongst patients who recurred, the rate of relapse was stable after second year and the median time to recurrence was 61 months (95% CI, 51–73 months). Liver (64%), mesentery (23%) and pelvic lymph nodes (13%) were the most common sites of recurrence. No relapse was observed amongst patients (n = 5) with stage I midgut NET. Tumor size predicted recurrence (P < 0.05), while a borderline increased risk of relapse was observed in tumors with perineural invasion (P = 0.07).
Conclusion: The risk of relapse is substantial in patients with resected local and locally advanced midgut NETs, with the possible exception of stage I disease. Given the long median relapse-free survival, guidelines should recommend long term (beyond 5 year) surveillance; however frequent scans may not be necessary.
Multiple and Secondary Hormone Secretion in Patients With Metastatic Pancreatic Neuroendocrine Tumors
Joakim Crona,1 Olov Norlén,2 Pantelis Antonodimitrakis,1 Staffan Welin,1 Peter Stålberg,2 Barbro Eriksson.11Department of Medical Sciences; and 2Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Background: Neuroendocrine tumors secrete many different peptide hormones, yet hitherto each NET patient is thought to produce one hormone that causes a distinct hormonal syndrome. A minority of patients have multiple hormones at diagnosis and may also develop secondary hormone secretion at a later stage. The aim of the study was to determine the frequency and impact of multiple and secondary hormone secretion in sporadic pancreatic NETs.
Methods: A retrospective analysis of patients (n = 323) with pancreatic NETs treated at Uppsala University Hospital, Uppsala, Sweden, was performed. Patients with these characteristics were identified and studied in further detail.
Results: In pancreatic NETs (PNETs) a total of 19/23 (6%) had secretion of multiple hormones at diagnosis and 14/23 (4%) had secondary changes during the disease course. These phenomena occurred exclusively in patients with advanced disease and secondary changes were detected in close timespan with progressive disease. Patients with secondary insulin secretion had increased morbidity and reduced survival (P < 0.002).
Conclusion: Diversity of PNET hormone secretion at diagnosis or during the disease course occurred in a minority of patients (9.3%). These phenomena had a major impact on patient outcome both through increased morbidity and mortality. Our results support that patients with metastatic PNETs should be monitored for clinical symptoms of secondary hormone secretion during the disease course.
Identification of Primary Tumors in Patients Presenting With Metastatic Gastroenteropancreatic Neuroendocrine Tumors
Kendall Keck, Jessica Maxwell, Yusuf Menda, Andrew Bellizzi, Joseph Dillon, Thomas O'Dorisio, James Howe. University of Iowa Carver College of Medicine.
Background: Patients with gastroenteropancreatic neuroendocrine tumors (GEPNETs) often present with metastases. Identification of the primary tumor is important for surgical management, and therefore we sought to determine our success at identifying primary tumors with diagnostic testing and surgical exploration.
Methods: A clinical NET database was reviewed to identify patients presenting with metastases and primary tumors in situ. Results of radiologic, endoscopic, and operative procedures were evaluated to determine which correctly identified the primary tumor. Imaging was deemed positive if a discrete mass or thickening was identified; mesenteric lymphadenopathy was also considered an indicator of small bowel NET (SBNET) primary.
Results: There were 197 patients presenting with metastases and unresected primaries; 134 underwent surgical exploration while 63 were managed non-operatively. Primaries were identified by preoperative diagnostic in 168 (84%), at surgical exploration in 7, and were not found in 22 patients. Overall, CT found 150/197 primary tumors, somatostatin-receptor scintigraphy (SRS) 88/155, and endoscopy 43/107. In the operative group, where the primary sites were verified, CT was statistically better than SRS and endoscopy (P < 0.01;Table 1). The sensitivity of CT for pancreatic NETs (PNETs) in this group was 97%. Mesenteric lymphadenopathy was identified on imaging in 68/90 SBNET patients who underwent resection and was the only indication of the primary site in 35/90 (39%), giving an overall sensitivity of 82% for CT in SBNETs. SRS identified 8 tumors not seen by CT and conversely CT identified 30 tumors not seen on SRS. Surgical exploration identified 6/10 unknown primaries.
Conclusion: CT was the most sensitive diagnostic modality, identifying 76% of all primary tumors. The addition of SRS and endoscopy improved the identification of the primary site to 84% for all patients, and 93% for patients who underwent exploration. Mesenteric lymphadenopathy was found to be a valuable indicator for the preoperative identification of occult SBNETs.
Higher Tumor Grade in Neuroendocrine Tumor Metastases Negatively Impacts Survival
Kendall Keck, Allen Choi, Jessica Maxwell, Guiying Li, Thomas O'Dorisio, Andrew Bellizzi, James Howe. University of Iowa Carver College of Medicine.
Background: Tumor grade is an important predictor of survival in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), as determined by the percentage of cells expressing Ki-67 and mitotic rate. NETs generally grow indolently, but some cells may acquire traits facilitating metastasis. It is currently unclear how frequently metastases differ in grade from their primary tumors, and whether increasing grade in metastases affects prognosis.
Methods: Ki-67 immunohistochemistry was performed on GEPNETs; data from 270 resected patients were reviewed to identify cases with Ki-67 results for both primary tumors and concurrent metastases. Grade was determined using a modified WHO classification (Ki-67: G1 = 0-2%; G2 > 2-20%; G3 > 20%).
Results: Ki-67 was performed on both the primary tumor and metastases (90 lymph nodes, 61 liver metastases) in 103 patients. Tumor grade was higher in metastases from 25 (24%) patients, 24 from G1 to G2, and 1 from G2 to G3; 68(66%) patients had no change in grade (42 G1 and 26 G2) and 10 (10%) decreased from G2 to G1. No clinicopathologic factors were predictive of higher grade in metastases. The median progression free survival (PFS) and overall survival (OS) for patients with G1 primaries was significantly improved for patients with stable versus increased grade (Table 1). The 5-year PFS was 54.5 % for patients with stable grade vs. 7.8% with increased grade, while 5-year OS was 92% and 54%, respectively. The 5-year OS of patients who had G2 primaries and stable grade was similarly decreased at 64%.
Conclusion: The Ki-67 grade of GEPNETs is an important prognostic tool. One-third of patients had a metastasis with a different grade than their primary, and when grade increased, both PFS and OS significantly decreased. These results suggest the importance of determining grade in both primaries and metastases and reinforce the assertion that increasing grade is related to increasing biological aggressiveness.
Outcome of Surgical Resection After Neoadjuvant Peptide Receptor Radionuclide Therapy (PRRT) for Pancreatic Neuroendocrine Neoplasms: A Case-Matched Analysis
Stefano Partelli,1 Carolina Perali,1 Emilio Bertani,2 Mirco Bartolomei,3 Francesca Muffatti,1 Chiara Maria Grana,2 Giuseppe Zamboni,4 Claudio Doglioni,1 Nicola Fazio,2 Massimo Falconi.11San Raffaele Scientific Institute; 2European Institute of Oncology; 3"M.Bufalini" Hospital; and 4Sacro Cuore-Don Calabria" Hospital.
Background: Peptide receptor radionuclide therapy (PRRT) can be an option for advanced pancreatic neuroendocrine neoplasms (PNENs) to allow patients undergo resection. Whether or not neoadjuvant PRRT increases postoperative morbidity remains unclear.
Methods: Patients with initially metastatic and/or locally advanced PNEN who underwent neoadjuvant PRRT (neoadjuvant group) were compared with a group of patients who underwent upfront surgery (control group). Patients were matched for tumor size, grading, staging, and intent of resection.
Results: 20 patients underwent sequential PRRT and pancreatic resection. The reason for neoadjuvant PRRT was liver metastases in 6 patients and organ/vascular infiltration in the remaining 14. After PRRT tumor size decreases from 59 mm to 50 mm (P = 0.047). The rate of curative resection was 65%. Histology revealed a PNEN-G1 in 10 cases, a PNEN-G2 in 7 patients, and a PNEC-G3 in 3 patients. Pre- and postoperative tumor grading was concordant in 13 patients whereas 5 were upstaged and 2 were downstaged. Patients who underwent neoadjuvant PRRT had a lower risk of pancreatic fistula (25% versus 65%, P = 0.011) although the rate of complications was similar (45% versus 60%, P = 0.342). The two groups had similar distribution of tumor grading, T stage, TNM stage, R2 resection, microvascular invasion, perineural invasion, and necrosis. Patients who underwent upfront surgery were more likely to have nodes metastases (80% versus 35%, P = 0.004). The 2-year progression free survival rate was 67% for the neoadjuvant group versus 58% in the control group (P = 0.319). Predictors of progression free survival were PNEC-G3 and stage IV tumor.
Conclusion: Pancreatic resection for PNEN after neoadjuvant PRRT is safe and is associated with a lower risk of developing pancreatic fistula.
Number of Positive Nodes and Their Localization Correlate With Recurrence in Pancreatic Neuroendocrine Neoplasms: Implications for Surgery, Staging, and Surveillance
Stefano Partelli,1 Francesca Muffatti,1 Valentina Andreasi,1 Gianpaolo Balzano,1 Giuseppe Zamboni,2 Claudio Doglioni,1 Massimo Falconi.11San Raffaele Scientific Institute; and 2Sacro Cuore-Don Calabria Hospital.
Background: Nodal involvement is an adverse factor for pancreatic neuroendocrine neoplasms (PNEN). The prognostic value of the number and localization of positive lymph-nodes (PLN) is unknown.
Methods: Among 370 patients with PNEN who underwent resection, those who underwent radical pancreaticoduodenectomy (PD) (2000–2014) were identified. Patients with functioning neoplasms, inherited syndrome and distant metastases were excluded.
Results: 53 patients were included. Of those, 31 patients (58.5%) had node metastases (N1). The median number of examined lymph nodes (ELN) and positive lymph nodes (PLN) were 20 and 1, respectively. The median number of ELN was higher among N1 tumors (23 versus 17.5, P = 0.048). N1 PNEN had a significantly worse 3-year DFS compared with N0 PNEN (69% versus 94%, P = 0.013). Patients with PLN > 1 had a better DFS compared with patients who had 0 or 1 PLN (62% versus 90%, P = 0.005). On multivariate analysis, age > 60 years, G3 PNEN versus G2-G1 PNEN, and PLN > 1 were independent predictors of recurrence. No differences were found in terms of DFS among patients with N0 PNEN according to different cut-offs of ELN. PLN were localized in posterior and anterior pancreaticoduodenal stations (13 and 17) in all 31 patients with N1 NF-PNEN. Superior mesenteric artery nodes (station 15) and hepatoduodenal ligament nodes (station 12) were involved in 5 and 3 cases, respectively. Metastatic involvement of station 12 was associated with a significant poorer DFS (HR 2.5, P = 0.005).
Conclusion: The number of PLN and their localization are associated with the risk of recurrence after PD for NF-PNEN. An adequate lymphadenectomy including station 12 and 15 should be performed. This study suggests preliminary findings to support a revision of the current TNM-based staging systems for PNEN.
Liver Needle Biopsies Are Poor Predictors of Histologic Tumor Grade for Midgut Neuroendocrine Tumors
Robert A. Ramirez,1 David T. Beyer,2 Yi-Zarn Wang,2 Irma Oliva,2 Ramcharan Thiagarajan,2 Mary J. Ricks,1 J. Phillip Boudreaux,2 Eugene A. Woltering.21Ochsner Medical Center; and 2Louisiana State University Health Sciences Center.
Background: Our group has previously shown than neuroendocrine tumors (NETs) are heterogeneous neoplasms having histologic and functional differences between their primary tumor, lymph node, and hepatic metastases. Due to the heterogeneity of these malignancies, we hypothesized that there would be discordance between histologic grade of surgical specimen predicted by preoperative biopsies.
Methods: Twenty consecutive patients diagnosed with NETs of the ileum and hepatic metastasis were included. Ki-67 proliferative index and WHO 2010 histologic grade were recorded for preoperative hepatic needle biopsy and subsequent tissue-matched surgical specimens. Concordance between sample values was determined.
Results: Ten males and 10 females were included in this analysis. Five and fifteen patients had fine-needle aspirate (FNA) and core needle biopsies, respectively. Preoperative biopsies predicted the histologic grade of subsequent tissue-matched surgical specimens in only 65% of samples (13/20). Of the 7 values that changed grade (7/20, 35%), 4 went from intermediate (G2) to low (G1) grade [1 FNA and 3 core biopsies] and 3 went from low (G1) to intermediate (G2) grade [1 FNA and 2 core biopsies]. The corresponding inter-rater agreement statistic (K) was 0.251 ± 0.230 (95% CI: −0.199-0.702), with 0.21 < K < 0.40 indicating fair strength of agreement.
Conclusion: Preoperative fine-needle aspirates and core needle biopsies of hepatic metastasis have a 35% error rate in predicting the histologic grade from subsequent tissue-matched surgical NET specimens. Clinicians should be cognizant of this error rate when making decisions on systemic treatment and consider repeat needle biopsy or open biopsy if actual clinical course.
Outcomes for Patients With Surgically Resected Thymic Neuroendocrine Tumors
Eric Sceusi, Scott Ata, Arlene Correa, Stephen Swisher, Ara Vaporciyan, Jack Roth, Garrett Walsh, Wayne Hofstetter, Reza Mehran, David Rice, Boris Sepesi, Mara Antonoff. MD Anderson Cancer Center, Houston, TX.
Background: Thymic neuroendocrine tumors (NETs) are rare and outcomes after surgical resection are poorly described. Adjuvant therapies are advocated by some, but with unclear prognostic impact. We reviewed our experience with surgically resected thymic NETs to identify factors influencing outcomes and develop best practice treatment guidelines for these patients.
Methods: Patients treated at a single institution, from 1975–2015, with surgically resected thymic NETs were retrospectively reviewed. Institutional tumor registry and departmental database data was supplemented by chart review. Tumor size, stage, histology, date and extent of surgery, margins, and adjuvant and neoadjuvant therapy were reviewed. Univariate and multivariate analyses examined predictors of survival and recurrence. Kaplan-Meier analyses calculated survival.
Results: We identified 27 patients with surgically resected thymic NETs, including 7 (25.9%) with MEN1. Mean and progression-free survival were 129 +/− 25.7 months (95% CI 78.6-179.5 months) and 75.0 +/− 15.0 months (95% CI 45.6 – 104.4 months), respectively. Univariate analysis showed that sex, age, tumor size, tumor grade, margins, nodal status, and MEN1 diagnosis did not influence survival or recurrence. 3 (11.1%) patients underwent induction chemotherapy, 7 (25.9%) adjuvant chemotherapy and 13 (48.1%) adjuvant radiation. Induction chemotherapy significantly predicted mortality (HR 33.4, 95% CI 3–373, P = 0.004) on univariate analysis. Upon multivariate modeling, induction therapy resulted in worse progression-free survival (HR 9.21, 95%CI 1.52-55.8, P = 0.016). Neither adjuvant chemotherapy nor radiation affected overall survival (P = 0.452, P = 0.652) or recurrence (P = 0.962, P = 0.856).
Conclusion: Our review, representing the largest single institution North American series of surgically resected thymic NETs, shows that adjuvant chemotherapy and radiation did not affect outcomes. Induction therapy in 3 patients resulted in increased mortality; however this may reflect extensive preoperative disease and is limited by sample size. Additionally, no preoperative or tumor factors were associated with prognosis. Surgical resection remains the mainstay of treatment thymic NETs, without clear evidence supporting adjuvant therapies.
Neoplasia in Patients With Atrophic Metaplastic Autoimmune Gastritis (AMAG): Screening and Surveillance Endoscopy Should Become Standard of Care
Kristen Stashek, Rashmi Tondon, Stuti Shroff, Robert Roses, Emma Furth, David Metz. University of Pennsylvania, Perelman School of Medicine.
Background: AMAG is an autoimmune condition in which antibodies attack oxyntic mucosa leading to intestinal metaplasia (IM), hypergastrinemia, and type 1 well-differentiated neuroendocrine tumors (WDNET). While IM is a well-established risk factor for adenocarcinoma in the esophagus, the risk of neoplastic progression in AMAG is thought to be low (2-3x general population). In contrast to Barrett esophagus (BE), current guidelines do not call for surveillance upper endoscopy in this population. We report the clinical/pathologic characteristics of AMAG patients who underwent evaluation at our center over a five year period to determine frequency/timing of neoplasias.
Methods: A database search (1/2010-11/2015) revealed 151 patients with AMAG. Patients with a previous history/histologic evidence of H.pylori, and patients with BE/gastric cardiac tumors were excluded. Clinical/pathologic data was recorded.
Results: See Table 1. Of the 151 patients, 13 (8.6%) had a biopsy with dysplasia and/or carcinoma, with 11 (7.3%) developing invasive adenocarcinoma. Of the 11 patients with adenocarcinoma, 3 (27%) had a prior biopsy of dysplasia before developing carcinoma (78, 82, and 144 months after initial biopsy, respectively), while the remaining 8 (73%) were diagnosed on first biopsy. In all, 85% of patients (11/13) were diagnosed with dysplasia and/or carcinoma on first biopsy, despite some having a long-standing history of pernicious anemia (range of 0–20 y). 36/151 (24%) patients were diagnosed with at least one WDNET, with 2/36 developing lymph node and/or liver metastases. Overall, 9.9% (15/151) of patients had an adverse neoplastic event (dysplasia/carcinoma and/or metastasizing NET).
Conclusion: Our study shows that patients with AMAG have a clinically relevant incidence of developing adenocarcinoma. Similar to patients with BE, the risk of finding neoplasia is highest at first biopsy. Also, while most Type 1 WDNETs behave indolently, some cases metastasize. Given the high rate of adverse neoplastic events in AMAG, more stringent screening is recommended.
Economic Burden of Illness of Malignant Gastrointestinal Neuroendocrine Tumors (NET)
Beilei Cai,1 Maureen P. Neary,1 Michael S. Broder,2 Eunice Chang,2 Elya Papoyan,2 Al B. Benson.31Novartis Pharmaceuticals Corporation; 2Partnership for Health Analytic Research, LLC; and 3Northwestern University.
Background: NETs comprise a broad set of tumors that are rare and slow-growing. Almost two-thirds of NETs arise in the gastrointestinal (GI) tract. The objective of this study is to describe the economic burden of GI-NET patients.
Methods: This cohort study used 2 claims databases to describe healthcare utilization and costs of GI-NET patients. Adults with ≥1 inpatient or ≥2 outpatient claims for GI-NET and with a claim for malignant NET or liver malignancy in 2014 were included. Patients not continuously enrolled in 2014 were excluded.
Results: 2,968 GI-NET patients were identified. Mean (SD) age was 52.7 (9.1), 55.0% were female, 25.2% had a claim with diagnosis codes for carcinoid syndrome (ICD-9-CM: 259.2). 33.0% (n = 978) of patients received systemic therapy and 8.0% (n = 237) liver directed therapy. Among the 978 patients who received systemic therapy, 82.4% (n = 806) used somatostatin analogs, 23.5% (n = 230) cytotoxic chemotherapy, and 8.8% (n = 86) targeted therapy. Overall, patients had mean (SD) 16.6 (14.2) office visits, 33.5% had ≥1 ED visit, and 40.5% ≥1 hospitalization. Mean (SD) LOS was 10.7 (17.4) days among hospitalized patients. Annual costs were $70,179, comprising $6,967 pharmacy and $63,212 medical ($41,425 outpatient, $21,088 inpatient, $698 ED).
Conclusion: Resource use and costs for treatment of malignant GI-NET patients were high. Mean annual cost was > $70,000 compared to a national average of ~ $38,000 among all cancers in the first year. While 40% of patients were admitted to the hospital, the majority of costs were from the outpatient setting. One-third of patients received systemic therapy, most commonly somatostatin analogs, but medication costs represented only <10% of total. About 24% of patients were treated with cytotoxic chemotherapy, despite evidence of suboptimal response rates. The availability of more effective therapies providing better outcomes and management of this disease may help to mitigate some of these resource use and/or cost burdens.
Economic Burden of Illness of Malignant Lung Neuroendocrine Tumors (NET)
Beilei Cai,1 Maureen P. Neary,1 Michael S. Broder,2 Eunice Chang,2 Elya Papoyan,2 Al B. Benson.31Novartis Pharmaceuticals Corporation; 2Partnership for Health Analytic Research, LLC; and 3Northwestern University.
Background: Lung NETs, including well- and poorly-differentiated, comprise 1-2% of lung cancers and 20-30% of NETs. The objective of this study is to describe the economic burden of lung NETs.
Methods: This was a cohort study using analyses of 2 claims databases to describe health care utilization and costs for lung NET. Patients were adults with ≥1 inpatient or ≥2 outpatient claims for lung NET and a claim for malignant NET or liver malignancy in 2014. Patients not continuously enrolled in 2014 were excluded.
Results: 736 lung NET patients were identified. Mean (SD) age was 54.1 (8.1), 65.4% were female. 13.9% had a claim with a diagnosis codes for Carcinoid Syndrome (ICD-9-CM: 259.2). 13.0% (n = 96) of patients had liver directed therapy (e.g., surgery, embolization) and 15.2% (n = 112) systemic therapy. Among the 112 patients who received systemic therapy, 82.1% (n = 92) used somatostatin analogs, 20.5% (n = 23) cytotoxic chemotherapy, and 17.9% (n = 20) targeted therapy. Overall, patients had a mean (SD) 21.1 (17.4) office visits, 37.1% had ≥1 ED visit, and 58.4% ≥1 hospitalization. Mean (SD) LOS was 9.2 (11.5) days among hospitalized patients. Annual costs were $80,002, comprising $7,068 in pharmacy and $72,934 in medical costs ($43,084 outpatient, $28,867 inpatient, $983 ED).
Conclusion: Mean annual cost for patients with malignant lung NET (>$80,000/year) were double the national average of ~ $38,000 among all cancers in the first year. More than half of patients were admitted to the hospital, with mean stays of 9.2 days, leading to mean inpatient costs of almost $30,000/year. Interventional treatments such as surgery and chemoembolization were common. One-third of patients received systemic therapy, most commonly with somatostatin analogs, but medication costs represent <10% of the total. New developments in the treatment of lung NET may help reduce some costs associated with this disease.
Epidemiology of Gastrointestinal Neuroendocrine Tumors (GI-NET) in the US: Analysis of 2 Large Insurance Claims Databases
Beilei Cai,1 Michael S. Broder,2 Eunice Chang,2 Caroline Burk,1 Krzysztof J. Grzegorzewski,1 Maureen P. Neary.11Novartis Pharmaceuticals Corporation; and 2Partnership for Health Analytic Research, LLC.
Background: U.S. incidence of all NET increased from 10.9 cases per million person-years (PMPY) in 1973 to 52.5 PMPY in 2004 as reported in SEER (Yao et al, 2008). Prevalence was reported as 216 per million per year for GI NET. It is anticipated that incidence and prevalence may be increasing, but trends beyond 2004 are unknown.
Methods: Retrospective, cross-sectional study using 2010–2014 data from 2 US claims databases: MarketScan and PharMetrics. Patients were 18–64, and had ≥1 inpatient or ≥2 outpatient claims with NET of GI tract (excluding pancreas), identified by ICD-9 codes. Prevalence was number of GI-NET patients divided by number of enrollees/year. Incidence was number of patients with first observed NET diagnosis who were disease-free for 2 years prior, divided by number of enrollees.
Results: For years 2010–2014, there were 1,898-2,808 and 1,507-1,895 GI-NET cases/year in MarketScan and PharMetrics respectively. Prevalence increased 90.8-131.2 per million per year between 2010 and 2014 in MarketScan and 71.1-108.9 in PharMetrics; increased with age and was highest (146.5-281.5 depending on year and data source) in 55–64 year olds; and was 74.3-141.6 in females and 67.7-119.7 in males. Incidence increased in both datasets from 2011 to 2014: 67.0-79.1 PMPY in MarketScan and 47.4-58.2 PMPY in PharMetrics.
Conclusion: In both databases, incidence and prevalence of GI-NET increased considerably from 2010 to 2014. This increase may be due to better diagnostic methods, increased awareness of NET among clinicians and pathologists, and/or an actual increase in disease occurrence in the US population. These results suggest the need for awareness of the clinically effective and safe treatment options available for GI NET patients among healthcare providers.
N.B. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted at the 2016 ASCO Annual Meeting. All rights reserved.
Epidemiology of Neuroendocrine Tumors (NET) of the Lung in the US: Analysis of 2 Large Insurance Claims Databases
Beilei Cai,1 Michael S. Broder,2 Eunice Chang,2 Caroline Burk,1 Krzysztof J. Grzegorzewski,1 Maureen P. Neary.11Novartis Pharmaceuticals Corporation; and †Partnership for Health Analytic Research, LLC.
Background: U.S. incidence of all NET increased from 10.9 cases per million person-years (PMPY) in 1973 to 52.5 PMPY in 2004 as reported in SEER (Yao 2008). Prevalence was reported as 350 per million/year for all NET. Bronchopulmonary or lung NETs represent approximately 20%–25% of primary NETs (Wolin 2015). It is anticipated that incidence and prevalence may be increasing, but trends beyond 2004 are unknown.
Methods: Retrospective, cross-sectional study using 2010–2014 data from 2 US claims databases: MarketScan and PharMetrics. Patients were 18–64, and had ≥1 inpatient or ≥2 outpatient claims with NET of bronchus or lung, identified by ICD-9 codes. Prevalence was number of lung NET patients divided by number of enrollees/year. Incidence was number of patients with a first observed NET diagnosis who were disease-free for 2 years prior, divided by number of enrollees.
Results: For years 2010–2014, there were 397–617 and 393–507 lung NET cases/year in MarketScan and PharMetrics, respectively. Prevalence increased 19.0-30.4 per million/year between 2010 and 2014 in MarketScan and 18.9-26.2 in PharMetrics; increased with age and was highest in 55–64 year olds (45.0-79.0); and was greater in females (22.6-39.3) than in males (13.8-20.6). Incidence increased in both datasets from 2011 to 2014: 15.9-19.2 PMPY in MarketScan and 13.1-16.0 PMPY in PharMetrics.
Conclusion: In both databases, the incidence and prevalence of lung NET have increased considerably from 2010 to 2014. This increase may be due to better diagnostic methods, increased awareness of NET among clinicians and pathologists, and/or an actual increase in disease occurrence in the US population. These results suggest the need for awareness of the clinically effective and safe treatment options available for lung NET patients among healthcare providers.
N.B. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstractwas accepted at the 2016 ASCO Annual Meeting. All rights reserved.
Neuroendocrine Tumor Incidence Over 18 Years: Kentucky Cancer Registry vs SEER
Aman Chauhan,1 Neha Ray,2 Bill Huang,3 Eric B. Durbin,3 Lowell Brian Anthony,1 Thomas Tucker.31Markey Cancer Center, University of Kentucky; 2University of Cincinnati School of Medicine; and 3Kentucky Cancer Registry.
Background: Neuroendocrine tumors (NETs) have a low incidence but a relatively high prevalence. Over the last three decades, NETs incidence has risen 5-fold. Greater awareness, pathological re-classification and improved diagnostics may account, at least in part, for this increase. We conducted an observational study to test the hypothesis that NETs incidence in Kentucky is comparable to that reported in SEER.
Methods: Kentucky Cancer Registry (KCR) and SEER databases between 1995 and 2012 were reviewed. State and local institutional review boards approved access to KCR. Incidence data were adjusted for population and plotted. A ‘best fit’ regression analysis and ANOVA were performed using SAS with p < 0.05 considered statistically significant.
Results: KCR recorded 5,641 individuals with newly diagnosed NETs between 1995–2012. The incidence of NETs in KCR increased from 3.8 (1995) to 10.7 (2012) per 100,000 cases, while it increased from 4.0 (1995) to 6.4 (2012) in the SEER database. The incidence rates in both KCR and SEER databases between 1995–2012 were linear with R2 values of 0.95 and 0.90, respectively. The incidence slopes were defined by the following equations: y = 0.4219x-838 (KCR) and y = 0.1407x-277 (SEER). The difference between these incidence rates was statistically significant (P < 0.0001).
Conclusion: NETs incidence between 1995–2012 showed a linear increase in both KCR and SEER databases. However, the rate of increase was noted to be significantly higher in Kentucky when compared with national data. Specifically, for 2012, the incidence of NETs in Kentucky approached almost twice to that reported in SEER.
The Prognostic Value of Lymph Node Status and Extent of Lymphadenectomy in Pancreatic Neuroendocrine Tumors Confined to and Extending Beyond the Pancreas
Claudius Conrad,1 Onur Kutlu,2 Arvind Dasari,1 Jeffrey Lee.11The University of Texas MD Anderson Cancer Center; and 2Medical University of South Carolina.
Background: The prognostic value of lymph node status and extent of lymphadenectomy in pancreatic neuroendocrine tumors confined to and extending beyond the pancreas.
Methods: SEER was queried for pNET between 1998–2012. (1) Binary-logistic-regression for factors associated with N-status, (2) Kaplan Meier for impact of T-stage, grade and nodal status on DSS and OS and (3) Cox Survival analyses for independent predictors of DSS and OS was performed. Extent of LA was evaluated by comparing >10 vs. <10 nodes dissected.
Results: 981 of 5349 patients fit the inclusion criteria. For T1-T2 tumors, N-status was affected only by tumor size. Cox-survival-analyses demonstrated that N-status (P = 0.001), grade (P < 0.001), patient age (P = 0.001) and sex (P = 0.007) were associated with OS, while tumor size (P = 0.260) and tumor location (P = 0.331) did not impact OS. For T3-T4 tumors, grade (P < 0.001), sex (P = 0.004), tumor size (P = 0.013) and patient age (P = 0.007) impacted OS; for this group N-status was not associated with OS (P = 0.789). Specifically, for T1-T2 tumors, DSS (P = 0.003) and OS (P = 0.008) was longer for N0 vs N1, while N0 vs. Nx had similar OS and DSS. For T3-T4 patients, N-status did not affect outcome. For all T- and N-status, extended LA was not associated with an improved survival.
Conclusion: For T1-T2, N1-status is a significant predictor of negative OS. The comparable outcome of N0 vs. Nx supports limited resection without LA (including enucleation) for selected T1-T2 tumors. However, the inferior outcome of N1-status in T1-T2 tumors highlights the importance of focused preoperative assessment of regional lymph nodes with high quality imaging for this subgroup. Extended LA is unlikely to be helpful in T3-T4 tumors.
Comparative Study of Pulmonary and Extrapulmonary High Grade Neuroendocrine Carcinomas: A SEER Database Analysis of 210195 Cases
Arvind Dasari,1 Kathan Mehta,2 Lauren Byers,1 Halfdan Sorbye,3 James Yao.11University of Texas MD Anderson Cancer Center; 2University of Pittsburgh Medical Center; and 3Haukeland University Hospital and Department of Clinical Science, University of Bergen.
Background: High-grade neuroendocrine carcinomas (NECs) are anatomically grouped into lung (L-NECs) or extra-pulmonary (EP-NECs) and histologically sub-typed into small-cell or large-cell NEC. EP-NECs are managed similar to L-NECs per current guidelines irrespective of site of origin or histological sub type. However, recent small studies show important clinical and epidemiological differences between these subgroups.
Methods: We performed an analysis of the Surveillance, Epidemiology, and End Results (SEER) program of NEC cases from 1973–2012 to describe the differences in NECs based on anatomic location, stage and histological sub-type.
Results: We identified 210195 cases (91.3% L-NECs; 8.7% EP-NECs). Based on relative proportions, we classified EP-NECs into gastroenteropancreatic (GEP-NECs, 34.4%), unknown primary (UP-NECs 32.6%) and other sites (Other-NECs 33%) with varying proportions of histological subtypes (small cell, large cell and other histologies) noted at each site. While L-NECs and UP-NECs increased in incidence from 1973 to 1988 before declining, GEP-NECs and other EP-NECs have increased. Stage at diagnosis varied according to primary tumor site with distant stage varying from 24% for Other-NECs to 40% for GEP-NECs. Survival varied significantly per stage with a substantial proportion of localized cases being alive at 5-year (range: 29% of L-NEC to 45% of Other-NECs) and according to histological sub-type with other histologies having best survival at most sites. Survival according to site ranged from 2.4 months for UP-NEC to 6.5 months for GEP-NECs. Primary site remained highly statistically significant for survival even after multivariate analysis with other prognostic variables (P <0.0001).
Conclusion: We observed significant differences in incidence trends over time and large variations in outcomes depending on anatomical site and histological sub type. Our data do not support the current approach of grouping all NECs as one entity.
Survival Trends of Neuroendocrine Tumors and Associated Prognostic Factors
Arvind Dasari, Chan Shen, Daniel Halperin, Shouhao Zhou, Ying Xu, Yiyi Chu, Tina Shih, James Yao. University of Texas MD Anderson Cancer Center.
Background: Neuroendocrine tumors (NETs) although slow growing can be fatal when advanced. In this population-based study, we aimed to evaluate the clinicopathological factors associated with survival of NET patients and also to examine changes in survival trends over time.
Methods: We identified NET cases diagnosed between 1973 and 2012 from the Surveillance, Epidemiology, and End Results (SEER) data. Patients were staged and assigned histological grades according to the SEER classification systems.
Results: 64,971 NET cases were included in the study. Median overall survival (OS) varied significantly by stage, grade, and age at diagnosis in addition to primary site and time interval of diagnosis (log rank P < 0.001 for all). Local stage was associated with better median OS (range in months: > 360 for appendix to 168 for small intestine) than regional (>360 for appendix to 33 for unknown primary) or distant stage (70 for small intestine to 4 for colon). Grade 1 NETs had better OS (>360 for appendix and rectum to 123 for cecum) compared to grade II (>360 for appendix to 43 for colon) or grade 3/4 NETs (33 for small intestine NETs to 8 for cecum and colon). OS of all NETs improved from 2000–2004 to 2009–2012 (hazard ratio, HR 0.79, 95% CI 0.73 – 0.85). Stronger trends were noted in subgroups of distant stage gastrointestinal NETs (HR 0.71, 95% CI 0.62 – 0.81) and pancreatic NETs (HR 0.56, 95% CI 0.44 – 0.70) over this period.
Conclusion: Age, grade, stage and primary site are strong prognostic factors for OS in NETs. Survival for all NETs has improved over time, especially for distant stage gastrointestinal and pancreatic NETs reflecting improvement in therapies for them.
Understanding a Rare Disease’s Impact on Health Systems: A Population-Based Analysis of Patterns and Drivers of Costs for Neuroendocrine Tumors Costs
Julie Hallet,1,2 Calvin Law,1,2 Matthew Cheung,2,3 Hadas Fischer,4 Ning Liu,4 Nicole Mittmann,5 Simron Singh.1,21The Susan Leslie Multidisciplinary Neuroendocrine Tumors, Odette Cancer Centre - Sunnybrook Health Sciences Centre; 2University of Toronto; 3Odette Cancer Centre - Sunnybrook Health Sciences Centre; 4Institute for Clinical Evaluative Sciences; and 5Sunnybrook Research Institute.
Background: Neuroendocrine tumors (NET) prevalence is increasing. Little is known on resource utilization in NET care. We sought to define patterns of costs in NET management and compare them to a more common malignancy, colon cancer (CC).
Methods: We identified all NET in a cancer registry (2004–2012). They were matched to CC patients (1:3). 2012 CND$ costs were obtained for 4 phases of care around diagnosis: pre-diagnostic (PrDx: −2 years to −181 days), diagnostic (Dx: −180 days to +180 days), post-diagnostic (PDx: +181 days to +3 years) and prolonged post-diagnostic (PPDx: +181 days to +9 years). Mean costs per patient were compared. Costs predictors were analyzed with quantile regression.
Results: 3355 NET were matched to 9320 CC. Mean NET cost was higher in PrDx phase ($5877 Vs $5368; P = 0.05), driven by higher non-drug costs including physician encounters, emergency room visits. Mean NET costs were lower in Dx and PDx phases (both P < 0.01). In PPDx, drug costs were significantly higher in NET ($26788 Vs $7827; P < 0.01), accounting for 41% of costs compared to 16% for CC. CC had a high initial increase in costs, which then decreased PDx. NET had steady increases between each phase, more pronounced in PrDx and PPDx. Older age, lower income, and comorbidities were predictors of higher NET costs in the 4 phases. Gastro-enteric primary site was associated with higher costs in PrDx (parameter estimate – PE $62), and lower costs in Dx (PE $13644). Pancreatic site was associated with higher costs in PDx (PE $3348) and PPDx (PE $1548).
Conclusion: NET cost pattern is unique and differs from CC, with maximal costs during PrDx and PPDx phases. Primary NET site affected costs differently at different time points. Defining these cost patterns now allow for tailoring the use of healthcare resources to tumor type and timing in the patient journey.
Access to Care and Outcomes for Neuroendocrine Tumors: Does Socio-Economic Status Matter? A Population-Based Analysis
Julie Hallet,1,2 Kaitlyn Beyfuss,3 Serge Koujanian,3 Ning Liu,4 Simron Singh,1,2 Refik Saskin,4 Calvin Law.1,21The Susan Leslie Multidisciplinary Neuroendocrine Tumor Clinic, Odette Cancer Centre - Sunnybrook Health Sciences Centre; 2University of Toronto; 3Sunnybrook Research Institute; and 4Institute for Clinical Evaluative Sciences.
Background: Despite rising incidence, Neuroendocrine Tumors (NET) are a poorly understood malignancy lacking standardized care. Differences in socioeconomic status (SES) may further worsen the impact of non-standardized care. We examined the impact of SES on NET peri-diagnostic care patterns and outcomes.
Methods: We conducted a population-based cohort study, within a universal heatlthcare system, of adults with NET. NET cases identified from a provincial cancer registry (1994–2009) were divided into low (1st and 2nd income quintiles) and high SES (3rd, 4th, 5th quintiles). Utilization Band (RUB) captured expected healthcare need based on baseline comorbidities. We compared peri-diagnostic healthcare utilization (−60 days to +6 months), metastatic recurrence, and overall survival (OS) between groups.
Results: Of 4966 NET patients, 38.3% had low SES. Age, gender, and RUB did not differ among groups (P = 0.13). Neither primary NET sites (P = 0.15) nor metastatic presentation differed (P = 0.31). Patients with low SES had higher mean number of physician visits (20.1 ± 19.9 vs 18.1 ± 16.5; P=) and imaging studies (56 ± 50 vs 52 ± 44; P = 0.009) leading to NET diagnosis. Primary tumor resection (P = 0.14), hepatectomy (P = 0.45), systemic therapy (P = 0.38), and liver embolization (P = 0.13) rates did not differ with SES. Metastatic recurrence was more likely with low SES (41.1% vs 37.6%; P = 0.01) over a 61.7 months median follow-up. 10-year OS was inferior with low SES (47.1% vs 52.2%; P < 0.01). Low SES was associated with worse OS (HR 1.16; 95%CI: 1.06-1.26) after adjustment for age, gender, comorbidity burden, primary NET site, and rural living.
Conclusion: Low SES was associated with need for more physician visits and imaging to reach NET diagnosis, but not with more common advanced stage presentation or impact on patterns of therapy. Long-term outcomes were inferior for low SES patients, with more frequent metastatic recurrence and worse 10-year OS. This data provides further insight for future directives in enhancing healthcare delivery particularly in NET patients with low SES.
Health-related Quality of Life (HRQoL) in Patients With Advanced, Nonfunctional, Well-differentiated Gastrointestinal (GI) or Lung Neuroendocrine Tumors (NET) in the Phase 3 RADIANT-4 Trial
Marianne E. Pavel,1 Jonathan R. Strosberg,2 Lida Bubuteishvili-Pacaud,3 Evgeny Degtyarev,3 Maureen P. Neary,4 Matthias Hunger,5 Jennifer Eriksson,5 Nicola Fazio,6 Matthew Kulke,7 Simron Singh,8 James C. Yao.91Charité Berlin Campus Virchow-Klinikum; 2Moffitt Cancer Centre; 3Novartis Pharma AG; 4Novartis Pharmaceuticals Corporation; 5Mapi; 6Istituto Europeo di Oncologia, IRCCS; 7Dana Farber Cancer Institute; 8Sunnybrook Health Sciences Centre; and 9University of Texas MD Anderson Cancer Center.
Background: In RADIANT-4, everolimus (EVE) + best supportive care (BSC) improved progression-free survival (PFS) vs placebo (PBO) + BSC in 302 patients with advanced, progressive, nonfunctional GI or lung NET (Yao Lancet 2015). We report prespecified and post hoc analyses to assess treatment effect on HRQoL.
Methods: HRQoL was measured with FACT-G, a validated questionnaire with 4 domains: physical (PWB), social/family (SWB), emotional (EWB), and functional wellbeing (FWB). Time to definite deterioration (TDD) of ≥7 points (minimal important difference, MID) in FACT-G total score (range 0–108) was a prespecified secondary trial endpoint analyzed with Cox model to derive the hazard ratio (HR). Post hoc analyses included TDD for FACT-G subscale scores using ≥3 point MID and linear mixed models (LMM) fitted to FACT-G total and subscale scores. In sensitivity analyses, pattern mixture models (PMM) were fitted, assuming missing data were not random.
Results: No statistically significant differences were observed between the treatment arms in TDD of FACT-G total score (HR: 0.81 [95% CI: 0.55, 1.21]), numerically favoring EVE. TDD of PWB, SWB, EWB, and FWB subscale scores were also maintained for EVE vs PBO; HRs 1.01 (95% CI: 0.69, 1.53), 0.72 (95% CI: 0.45, 1.28), 0.57 (95% CI: 0.36, 0.93), and 0.94 (95% CI: 0.60, 1.46), respectively. In LMM, FACT-G total score at week 8 was 79.5 (95% CI: 77.7, 81.3) for EVE and 80.0 (95% CI: 77.6, 82.5) for PBO, declining to 75.7 (95% CI: 73.2, 78.2) and 77.8 (95% CI: 73.5, 82.1) at week 48. PMM confirmed robustness of LMM results.
Conclusion: In addition to PFS benefits, HRQoL is maintained, with no statistically or clinically relevant differences, in patients with advanced, nonfunctional, well-differentiated GI or lung NET receiving EVE vs PBO, despite usual toxicities of active cancer treatment. Analyses of the 4 FACT-G domains showed consistent results.
Health-related Quality of Life (HRQoL) in Patients With Advanced Neuroendocrine Tumors (NET) by Tumor Origin in the Phase 3 RADIANT-4 Trial
Marianne E. Pavel,1 Jonathan R. Strosberg,2 Lida Pacaud,3 Evgeny Degtyarev,3 Maureen P. Neary,4 Matthias Hunger,5 Jennifer Eriksson,5 Jean-François Ricci,6 Nicola Fazio,7 Matthew Kulke,8 Simron Singh,9 James C. Yao.101Charité Berlin Campus Virchow-Klinikum; 2Moffitt Cancer Centre; 3Novartis Pharma AG; 4Novartis Pharmaceuticals Corporation; 5Mapi; 6Wellmera AG; 7Istituto Europeo di Oncologia, IRCCS; 8Dana Farber Cancer Institute; and 9Sunnybrook Health Sciences Centre; 10University of Texas MD Anderson Cancer Center.
Background: In the RADIANT-4 trial, everolimus plus best supportive care (BSC) improved progression-free survival (PFS) compared to placebo plus BSC in 302 patients with advanced progressive nonfunctional NET of gastrointestinal (GI) or lung origin. In addition, HRQoL was maintained with no statistically or clinically relevant differences in patients receiving everolimus compared to placebo. Further post-hoc analyses are presented to assess treatment effect on HRQoL by tumor origin.
Methods: HRQoL was measured with the FACT-G questionnaire (total score range: 0–108 points). FACT-G was completed at baseline and every 8 weeks until month 12, then every 12 weeks until study drug discontinuation. Time to definite deterioration (TDD) of ≥7 points (minimal important difference, MID) in FACT-G total score was a pre-specified secondary endpoint for the overall trial population.
Results: Of 302 patients, 90 had lung NET (n = 63 everolimus and n = 27 placebo) and 211 had GI NET (n = 141 everolimus and n = 70 placebo). GI subgroup included patients with NET of ileum, rectum, jejunum, stomach, duodenum, colon, caecum, appendix, or cancer of unknown primary (CUP; N = 36; generally known as GI origin).
No differences were observed between the treatment arms in TDD of the FACT-G total score in the GI and the Lung subgroup scores, with numerically longer median TTD favoring treatment with everolimus (see Table 1). There are some limitations in analyses in Lung subgroup due to small sample sizes.
Conclusion: In addition to PFS benefits, HRQoL is maintained in the overall population and GI and Lung sub-groups, with no relevant differences, despite usual toxicities of active cancer treatment. These analyses will support clinical management of NET patients relevant to benefit-risk decision making and may be used in payer evaluations in regions where benefit of everolimus will be assessed separately in patients with NET of GI or Lung origin.
Treatment Patterns, Clinical Outcomes, and Health Care Resource Utilization in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors (mGEP-NETs)
Sonia Pulgar,1 Xiaolong Jiao,2 Beloo Mirakhur,1 Susan Pitman Lowenthal,2 Fadi Braiteh,2 Marley Boyd,2 Patricia Fox,2 Jennifer Frytak,2 David Cox,1 Andrew Paulson.21Ipsen Biopharmaceuticals, Basking Ridge, NJ; and 2US Oncology/McKesson Specialty Health, The Woodlands, TX.
Background: Lanreotide was approved in 2014 by the FDA for mGEP NETs to improve progression free survival. It’s important to understand the recent treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) for patients with mGEP-NETs.
Methods: A retrospective study was conducted using the iKnowMed electronic health record data from the US Oncology Network (USON). Adult patients diagnosed with mGEP-NET from 1/1/2008 to 12/31/2012 were included. Demographic/clinical characteristics, treatment patterns, and HCRU were described. Overall survival (OS) was analyzed using Kaplan-Meier method and Cox regression models.
Results: Of the 229 patients included, median age was 64.0 and primary tumor sites were small bowel (47.6%), pancreas (31.4%), and other (21.0%). Among 192 patients who received treatment, 77%, 12%, and 10.9% of them received somatostatin analogs (SSAs) monotherapy, chemotherapy, and targeted agents as 1st line therapy respectively. Octreotide LAR (OCT) represented 98% (145/148) of SSA usage. 50% (72/144) of patients receiving OCT had a relative dose intensity < 85%, and 16.7% (24/144) received above-label dosing (>30mg/4weeks). Most common adverse events (AEs) of SSAs were diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median OS was 68.0 months (95% CI [57.1, Not Reached]) for the overall cohort. OS was longer in small bowel NETs than in pancreatic (pNETs) or other NETs (median OS 68.0 vs 49.1 vs not reached, P = 0.016). Cox regression analysis suggested that age, BMI, and tumor site were significant prognostic factors. Patients with pancreatic NETs tended to have more hospital or emergency visits (69.4%, 31.9%) than patients with small bowel (61.5%, 22.0%) or other NETs (52.1%, 18.8%) respectively.
Conclusion: SSAs were the main treatment after diagnosis of mGEP-NETs. Dosing variation of OCT suggest an individualized dosing approach is used. OS and AEs were consistent with other studies. Patients with pancreatic NETs appeared to have higher HCRU than other tumor sites.
Incidence and Prevalence of Neuroendocrine Tumors in the United States 1973–2012
Chan Shen, Arvind Dasari, Boc Zhao, Shouhao Zhou, Ya-chen Shih, James Yao. University of Texas MD Anderson Cancer Center.
Background: Neuroendocrine tumors (NETs) have often been considered a group of rare tumors. However, previous literature found that the incidence of NETs has been on the rise in the United States, increasing close to five-fold from 1973 to 2004. In this study, we further examined the recent changes in the incidence and prevalence of NETs as there have been substantial recent advances in epidemiology, molecular biology, diagnostics, and therapeutics.
Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) registries to examine the trend from 1973 to 2012. Associated population data were used for incidence and prevalence analyses.
Results: We identified 64,971 patients diagnosed with NETs from 1973 to 2012. There was a continuing increasing trend in the reported annual age-adjusted incidence of NETs from 2004 (5.44/100,000) to 2012 (6.98/100,000). We found that the increased incidence of NETs is mainly due to increased diagnosis of early stage that now accounts for nearly 2/3 of all incident NETs. Incidence of localized NETs increased from 0.21 per 100,000 in 1973 to 3.15 per 100,000 in 2012; incidence of well-differentiated NETs increased from 0.01 per 100,000 in 1973 to 2.53 per 100,000 in 2012. We estimated the 20-year limited-duration prevalence of NETs to have increased from 6/100,000 in 1993 to 48/100,000 in 2012.
Conclusion: We observed a significant upward trend in reported incidence and prevalence of NETs, most likely due to significant advances in epidemiology, molecular biology, diagnostics, and therapeutics. The increase in incidence and prevalence is most pronounced in localized and well-differentiated NETs.
Functional Status and Costs of Care During the First Year After Diagnosis of Neuroendocrine Tumors Among Elderly Patients
Chan Shen, Arvind Dasari, Yiyi Chu, Shouhao Zhou, Daniel Halperin, James Yao, Ya-chen Shih. University of Texas MD Anderson Cancer Center, Houston, TX.
Background: Functional Neuroendocrine tumors (NETs) secrete hormonal peptides which lead to additional symptom burdens on patients. However, it is largely unknown whether and to what extent the additional symptom burdens translate into higher costs of care. This study aims to examine the cost pattern of elderly NET patients during the first year of diagnosis taking into account of the functional status.
Methods: We used SEER-Medicare data to identify elderly NET patients diagnosed between 1/2003 and 12/2011. Patients who had at least two claims indicative of carcinoid syndrome during the 3 months before and after the NET diagnosis are considered to have functional disease. We conducted separate analyses for patients who were alive throughout the year after diagnosis and patients who died within a year as these patients have very different cost patterns due to the cost of terminal care. We adopted a payer’s perspective and quantified economic outcomes using three measures: total Medicare reimbursement amount, inpatient costs and outpatient costs. We examined the pattern of monthly costs during the first year of diagnosis. We used Wilcoxon two-sample test to compare costs between patients with and without functional NETs.
Results: Our study cohort included 11,914 elderly NET patients. Out of these patients, 7845 (66%) were alive throughout the one year after diagnosis with continuous enrollment, and 4069 (34%) died within one year. Among the patients who lived throughout the year, 2530 (32.25%) had functional disease; while among the patients who died within the year, 1000 (24.58%) had functional disease. Patients with functional NET had higher costs compared to patients without syndrome (Table 1).
Conclusion: This population-based study showed that patients with functional NET incurred higher costs of care.
Association of Disease Progression, Health-related Quality of Life (HRQoL), and Utility in Patients With Advanced, Nonfunctional, Well-differentiated Gastrointestinal (GI) or Lung Neuroendocrine Tumors (NET) in the Phase 3 RADIANT-4 Trial
Simron Singh,1 Marianne E. Pavel,2 Jonathan R. Strosberg,3 Lida Bubuteishvili-Pacaud,4 Evgeny Degtyarev,4 Maureen P. Neary,5 Matthias Hunger,6 Jennifer Eriksson,6 Nicola Fazio,7 Matthew Kulke,8 James C. Yao.91Sunnybrook Health Sciences Centre; 2Charité Berlin Campus Virchow-Klinikum; 3Moffitt Cancer Centre; 4Novartis Pharma AG; 5Novartis Pharmaceuticals Corporation; 6Mapi; 7Istituto Europeo di Oncologia, IRCCS; 8Dana Farber Cancer Institute; 9University of Texas MD Anderson Cancer Center.
Background: Post hoc analyses were performed to determine if disease progression is associated with decline in HRQoL and utility scores using data from RADIANT-4, a phase 3 trial that showed significantly prolonged progression-free survival (PFS) with everolimus + best supportive care (BSC) vs placebo + BSC.
Methods: Pooling data from both arms, 284 patients were analyzed. HRQoL was measured with FACT-G, a validated questionnairewith 4 domains: physical (PWB), social/family (SWB), emotional (EWB), and functional wellbeing (FWB). FACT-G was completed at baseline, every 8 weeks until month 12 after randomization, and every 12 weeks thereafter. Association between disease progression and HRQoL was assessed by fitting linear mixed models. Based on a review of existing mapping functions, 2 mapping algorithms were selected to translate FACT-G scores into EQ-5D utility scores: Young, Med Decis Making 2015 (UK value set); Teckle, Health Qual Life Outcomes 2013 (US value set).
Results: The difference in FACT-G total score pre- vs post progression was significant: 79.7 vs 74.8 (difference: 4.91; 95% CI: 3.71, 6.11) and may be clinically relevant based on published ranges for minimal important difference (Yost & Eton, Eval Health Prof 2005). Differences in subscale scores were: PWB 22.4 vs 20.9 (1.5; 95% CI: 1.05, 1.95); EWB 17.6 vs 16.4 (1.14; 95% CI: 0.78, 1.49); SWB 21.6 vs 20.9 (0.69; 95% CI: 0.24, 1.14); and FWB 18.2 vs 16.9 (1.34; 95% CI: 0.86, 1.82). Mean “Teckle” utility was 0.826 (95% CI: 0.815, 0.836) pre-progression and 0.795 (95% CI: 0.783, 0.807) post-progression; mean “Young” utility was 0.779 (95% CI: 0.763, 0.796) pre-progression and 0.725 (95% CI: 0.706, 0.744) post-progression.
Conclusion: Disease progression in patients with advanced, nonfunctional, well-differentiated GI or lung NET is associated with a significant decline in HRQoL and utility scores. Effective therapy to prolong PFS may delay a decline in HRQoL and utility.
Simulated-Use Study of a Single-Use Delivery Device for Lanreotide Depot in Untrained Health Care Professionals
Daphne Adelman,1 Beloo Mirakhur,2 Alexandria Phan.2,31Feinberg School of Medicine, Northwestern University; 2Ipsen Biopharmaceuticals Inc., Basking Ridge, NJ; 3GI Medical Oncology, Houston Methodist Hospital.
Background: Lanreotide depot is a long-acting somatostatin analog formulation approved in the US for treatment of unresectable, well- or moderately-differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors to improve progression-free survival. The drug is provided in a unique, prefilled, single-use syringe with integrated passive sharps injury prevention feature. Based on the results of a previous simulated use study, additional modifications were made, to enhance the device’s usability. This study evaluated the effects of these changes on the usability of the device in an untrained group of participant health care professionals (HCPs).
Methods: HCPs were given product packaging materials, prefilled device, and IFU; asked to read the IFU; and perform one injection with the device (filled with gel to stimulate injection characteristics of the actual product) using a mannequin. The HCPs were evaluated for understanding of the IFU and correct and safe use of the device.
Results: 100% [16/16] of participant HCPS checked the dose/date in at least 1 location, selected the correct injection site, removed the plunger protector, inserted the needle at 90 degrees, penetrated to the full length of the needle, and compressed the plunger to the bottom in order to inject all the medication, as indicated in the IFU. Most participants (88% [14/16]) correctly maintained pressure on the plunger after delivery of a full dose as indicated, which keeps the needle extended until removed from the patient’s body. Not maintaining pressure after delivery of a full dose results in automatic retraction of the needle but has no measurable clinical impact. All participants successfully allowed the needle to retract, placing the needle in a safe state.
Conclusion: In this simulated-use study, untrained HCPs successfully used the prefilled lanreotide depot injection device with integrated sharps injury prevention feature, thus validating the improvements made to the IFU and the device.
Addressing Neuroendocrine Tumor Related Emotional Issues
Joy ES Ardill. NET Group, Royal Victoria Hospital, Belfast, United Kingdom.
Background: Patients diagnosed with a NET have many problems that they face at that time and in the months and years after diagnosis. Some of these issues are the same as those faced by anyone with a cancer diagnosis. Some are more specific to patients with NETs.
Methods: In depth interview swith patients in the UK, USA, and Canada reveal these issues and as patients with NETs may survive for many years, issues must be addressed.
Results: Immediate response to diagnosis may be anger, fear or a feeling of isolation. Questions arise, “am I going to die”, “how long have I got” “have I been told the complete truth?” Patients are greatly concerned about best treatment options and where to obtain treatments. Issues surrounding partners, family and friends may be overwhelming. “How will they respond to the news, will they step back, will they be there for me or shall I be alone through the time ahead?” Money issues include “can I keep my job, the mortgage, will I see my kids through their education, if I don’t survive will my family cope financially?”
Embarrassing symptoms, pain, diet, body image and sexual issues are important too. Problems are confounded by confusion surrounding diagnostic tests, and the major ongoing issue surrounding treatment options. As options have increased, the best personal option has become confuses patients. As more informed patients are increasingly common they become the advocate for their own treatment pathway. Information gleaned from the internet may be far from helpful.
Conclusion: Patients need support to cope with the emotional issues and worries that they have relating to their diagnosis.
Evidence of Improved Survival When Patients are Referred on to a Specialist NET Clinic With Multidisciplinary Team Management
Joy Ardill, David McCance, Brian Johnston 1Royal Victoria Hospital Belfast.
Background: European guidelines emphasise the importance of referral to centres of expertise for patients diagnosed with neuroendocrine tumours (NETs). Such clinics (NSC) should function in association with a multidisciplinary team (MDT) that includes surgeons, gastroenterologists, endocrinologists, nuclear physicians oncologists, radiologists, pathologists and specialist NET nurses. NETs of the mid gut are one of the more common NETs, accounting for about 25% of cases. Diagnosis may be delayed. However, when diagnosis is secured many treatment options are available to these patients in recent years.
Our aim was to assess survival outcome in patients diagnosed with midgut NETs treated at a NSC compared to those who were not referred.
Methods: Patients included numbered 254. Male/female ratio was 134/120. Median age (range) at diagnosis was 66.2 (18.2-92.4) years. 172 patients attended the NSC, 82 did not.
Results: Five year survival for those attending the NSC was 67.5% and for those not attending 29.9% (P<0.001). In the NSC group (5.8%) patients died within 6 months, in the non-NSC group (21.95) To remove bias due to the difference in age at diagnosis, patients were age matched at diagnosis (+/- 6M). 69 matched pairs were identified. Those surviving <3M were excluded (to exclude terminally ill patients). Survival was improved in the clinic group, (Log-rank test P=0.012).
Conclusion: Patients with midgut NETs managed at a NSC with a MDT have improved survival.
What Matters Most? An Exploration of Decision Criteria Considered by Patients With GEP-NET and Physicians Using Holistic Multi-Criteria Decision Analysis
Mireille Goetghebeur,1,2 Dima Samaha,2 William M. O’Neil,2 Khoury Eagle,2 Liga Bennetts,2 Louis Lavoie,2 Monika Wagner,2 Danielle Badgley,2 Sylvie Gabriel,3 Anthony Berthon,3 James Dolan,4 Matthew H. Kulke.51University of Montreal; 2LASER Analytica; 3Ipsen Pharma; 4University of Rochester; 5Dana Farber Cancer Institute.
Background: Patient-centered care implies identifying what matters most to patients and physicians through shared decision making on disease management. EVIDEM provides a generic holistic MCDA platform to explore decision criteria and trade-offs. The study aimed to develop a comprehensive decision framework and identify preferences of patients and physicians in the management of unresectable, well- or moderately differentiated non-functioning GEP-NET.
Methods: A decision support framework was designed based on EVIDEM structure, literature reviewand insights from a Chatham-house panel ofUS physicians and patients, representative of different management approaches for GEP-NET. During a second extended panel session (5 patients, 6 physicians), participants provided criteria weights using Hierarchical Point Allocation and Direct Rating Scale (DRS, sensitivity analyses). Insights were collected in writing and through discussions.
Results: The decision support framework included 6 domains pertaining to Outcomes of the intervention (Effectiveness, Patient-Reported Outcomes, autonomy, dignity & convenience, Safety); Type of benefit; Need (Disease severity; Unmet needs; Population size); Costs & constraints (Intervention; Medical and Non-medical [to patients or the healthcare system]); Knowledge (Quality of evidence, Expert consensus) and Feasibility (System capacity). Of the 30 criteria and subcriteria, 26 were considered by more than 90% of participants. Criteria weights were widely distributed reflecting variability in individual perspectives on what matters most. At the group level, highest weights were attributed to Effectiveness (0.18 ± SD 0.12 on a total of 1) and Disease severity (0 .12 ± 0.08), followed by Safety (0.10 ± 0.09), Type of therapeutic benefit (0.10 ± 0.08) and Quality of evidence (0.09 ± 0.06). Most important Effectiveness subcriteria were Overall survival (33% of effectiveness criteria), followed by Progression-free survival (30%). DRS showed similar overall results.
Conclusion: Many aspects are considered by patients and physicians in their decision making processes. Holistic MCDA reveals and structures the complexity and variability of what matters most to patients.
To Treat or Watch? Identifying Drivers of Decisions for Patients With GEP-NET Using Reflective Multi-Criteria Decision Analysis
Mireille Goetghebeur,1,2 Dima Samaha,2 Hanane Khoury,2 William M. O'Neil,2 Hanane Khoury,2 Liga Bennetts,2 Louis Lavoie,2 Monika Wagner,2 Danielle Badgley,2 Sylvie Gabriel,3 Anthony Berthon,3 James Dolan,4 Matthew H Kulke.51University of Montreal; 2LASER Analytica; 3Ipsen Pharma; 4University of Rochester; 5Dana Farber Cancer Institute.
Background: GEP-NET are slow-growing tumors with heterogeneous presentation. Somatostatin analogs (SSAs) or watchful-waiting are recommended for management of unresectable, well- or moderately-differentiated non-functioning GEP-NET. This study aimed to develop a comprehensive shared-decision making MCDA-framework, and explore drivers of decision.
Methods: A decision support tool was designed using a holistic MCDA-framework (EVIDEM), literature review and insights from a Chatham-house panel of US physicians and patients with GEP-NET. A second extended panel (5 patients, 6 physicians) explored drivers of decision using two scenarios (SSA [reference case lanreotide] versus observation; lanreotide versus octreotide). Evidence was synthesized from a comprehensive literature review. Participants assigned weights through two techniques. For each criterion, participants were prompted to share experiential insights and knowledge, and assign a score (+5 [Much in favor of option 1] to -5 [Much in favor of option 2]). Value contributions (NormWeightXScore) were calculated for each criterion. Sensitivity analyses were performed.
Results: At group level, when exploring treatment over watchful-waiting, Type of therapeutic benefit, Disease severity, Effectiveness (mainly due to Progression-free survival and Disease symptom) and Quality of evidence favored treatment (mean value contribution: 0.08 ± SD 0.06, 0.07 ± 0.09, 0.07 ± 0.09 and 0.06 ± 0.06 respectively) whereas Costs aspects (interventions, medical and non-medical) favored watchful-waiting. When comparing two treatment options, the majority of criteria did not favor one option over another. System capacity (0.02 ± 0.02) and Non-medical costs and constraints (0.02 ± 0.03) tip the scale in favor of lanreotide and Cost of intervention in favor of octreotide (0.08 ± 0.12). Sub-criteria Impact on autonomy and Impact on dignity favored lanreotide. Wide SDs reflect variability of drivers of decision across participants.
Conclusion: Exploration of scenarios identified drivers of decision for GEP-NET management and revealed the diversity of participants perspectives. Holistic MCDA embedded with evidence supports individual reflection and informed shared-decision making.
A Case Series of 27 Primary Ovarian Neuroendocrine Tumors
Marina Heskel, Yahel Weinstein, Angelica Mares, Daniel Tuvin, John Mandeli, Liane Deligdisch. Icahn School of Medicine at Mount Sinai.
Background: Primary ovarian neuroendocrine tumors are rare and are often found incidentally. Differentiation of primary ovarian carcinoids frommetastatic carcinoids is difficult.We examined 27 primary ovarian carcinoids treated over the course of 21 years, one of the largest series in the literature.
Methods: All patients with ovarian neuroendocrine tumors at a single institution between 1994 and 2015 were retrospectively reviewed in this IRB approved analysis. Pathologic review confirmed 27 primary ovarian carcinoids.
Results: The mean age of our cohort was 48.7 years (range 23-75 years). The majority of tumors were found to be benign. Nineteen patients (70.4%) had carcinoids associated with dermoid cysts, of which 9 were associated with thyroid tissue (strumal carcinoids). Seven patients (25.9%) had ovarian mucinous tumors, of which 3 were benign and 4 were malignant. Three of the malignant carcinoids were of the mucinous type, and one malignant tumor was of the insular subtype. Bilateral disease was found in 2 patients. All patients with benign tumors had no evidence of disease at time of review. Of the 4 patients with malignant tumors, one is alive with disease, two have died of disease, and one was lost to follow up. The estimated 5-year overall survival for patients with benign disease was 86%. Immunohistologic stains were positive for both chromogranin and synaptophysin in 16 cases. 6 cases were positive for neuron-specific enolase, 2 were positive for thyroglobin, and 7 were positive for CDX2.
Conclusion: Our case series is one of the largest reported. The average age of our patients was younger than previously reported. Most of the carcinoids were associated with teratomas and the majority of the malignant tumors were of the mucinous variant. In contrast to the existing literature, our cohort had a significant portion of strumal carcinoids.
Retrospective Chart Review of Antidepressant Use in Patients With Carcinoid Tumors
Elie Isenberg-Grzeda,1,2 Meredith MacGregor,3 Afton Bergel,3 Stacy Eagle,4 Fernando Espi-Forcen,5 Reema Mehta,6 Konstantina Matsoukas,3 Jonathan Wills,3 Diane Reidy-Lagunes,3 Yesne Alici.31University of Toronto; 2Sunnybrook Health Sciences Centre; 3Memorial Sloan Kettering Cancer Center;4Stonybrook University Hospital; 5Rush University Medical Center; and 6Jacobi Medical Center.
Background: Patients with carcinoid/neuroendocrine tumors (NET) have higher than expected rates of depression and may require treatment with antidepressans. However serotonergic antidepressants (SA) can theoretically worsen carcinoid syndrome (CS). Some have advised against using SAs in carcinoid/NET patients. Data on antidepressant safety in patients with and without CS (CS+ and CS-, respectively) are limited.
Methods: Retrospective chart review of patients with carcinoid tumors at Memorial Sloan Kettering Cancer Center treated with antidepressants from January 1, 2008 through April 1, 2015. Outcome measures included duration of use, reason for starting and stopping antidepressant, dosage range, and whether any instances of serotonin syndrome or carcinoid crisis were documented.
Results: N = 92 (16 CS+ and 76 CS-) and 127 antidepressant prescriptions were identified comprised of various categories except monoamine oxidase inhibitors (MAOIs). Median duration of antidepressant treatment was not significantly different between CS+ and CS- groups (11.5 months vs. 14.3 months, p = .641). No instances of serotonin syndrome or carcinoid crisis were recorded. Of 76 CS- patients, none developed carcinoid syndrome during the study period. The majority of patients did not discontinue antidepressants during the study period. Among CS+ patients who discontinued antidepressants, carcinoid syndrome was never the reported reason for stopping.
Conclusion: This is the largest study of antidepressant safety in carcinoid/NET. Our findings do not support the conclusion of previous authors that antidepressants should be avoided in carcinoid/NET. Several classes of antidepressants appear safe in patients both with and without carcinoid syndrome. Prospective studies are needed to monitor side effects and confirm safety. Future research should also specifically examine the safety profile of non-SAs versus SAs in as well as efficacy of antidepressants in this population.
Antidepressant Use in Patients With Carcinoid Tumors: Results of A Systematic Review
Elie Isenberg-Grzeda,1,2 Meredith MacGregor,3 Konstantina Matsoukas,3 Diane Reidy-Lagunes,3 Yesne Alici.31University of Toronto; 2Sunnybrook Health Sciences Centre; and 3Memorial Sloan Kettering Cancer Center.
Background: Whether or not antidepressants can be safely prescribed to patients with carcinoid/neuroendocrine tumor (NET) is a controversial topic. Some have argued that antidepressant use precipitates carcinoid syndrome and should be avoided in patients with carcinoid/NET. Others have reported long-term antidepressant use with no adverse outcomes. To our knowledge, no systematic reviews of antidepressant use in carcinoid/NET exist. We aim to address this gap.
Methods: We searched five databases: CENTRAL (Wiley Cochrane Library), CINAHL (EBSCO), EMBASE, PsycINFO (OVID), and PubMed. The search strategy was developed using EMBASE’s EMTREE controlled vocabulary which includes an extensive list of drug terms as narrower headings of the concept “antidepressant agent”. The strategy consisted of synonyms for “antidepressive agents” OR synonyms for “depression”, then limited to the concept “carcinoid”. Identified articles were independently reviewed. The project was developed according to PRISMA guidelines. Outcome measures included demographics, antidepressant name, dose, duration, and frequency, as well as frequency of adverse outcomes related to the antidepressants.
Results: The initial search identified 679 articles for possible inclusion. After screening by independent reviewers, 16 articles met inclusion criteria. Three cases reported on adverse outcomes while 9 cases reported no adverse outcomes. At least 25 additional cases were reported to be taking antidepressants though details were not provided.
Conclusion: There is insufficient evidence to recommend completely avoiding the use of antidepressants in patients with carcinoid/NET as previous authors have recommended. Given the uncertainty and overall dearth of literature in this area, we expect that our findings will help guide clinicians in better understanding the issues related to safety and tolerability when considering antidepressant use for patients with carcinoid tumors. We hope that our findings will also help guide future research in this understudied area.
Renal Neuroendocrine Tumors (rNETs): A Single Center Experience
Joseph A. Scales, Johann P. Ingimarsson, Gustavo Westin, Timothy J. Hobday, Thorvardur R. Halfdanarson. 1Mayo Clinic.
Background: The natural history and prognosis of patients with rNETs is not well known. We characterized the presenting features and outcome of therapy in rNETs patients seen from 2000 – 2015.
Methods: Patients were identified using the Cancer Registry. Clinical characteristics were extracted and survival calculated with the Kaplan-Meier method. Fourteen rNETs patients were identified. Median age at diagnosis was 48.5 years (range: 21 – 82). Nine patients were females. Pain was present at diagnosis in 8 patients, flushing and hematuria in 2 patients each.
Results: Four patients had a horseshoe kidney. WHO grade was G1: 36%, G2: 43% and G3: 7%. T stage was T1: 29%, T2: 29%, T3: 36% and mean tumor size 9 cm. Nodal and distant metastasis were present in 8 and 4 patients respectively. Bone metastases were common (2 at diagnosis, 4 at recurrence). Radical or partial nephrectomy performed in 13 patients. Nodal and/or metastatic resection/ablation was done in nine patients. Ten patients had R0 resection. Nine patients had recurrence (median time to recurrence 15.5 months) and eight received systemic therapy upon recurrence. Seven received a somatostatin analog, 4 cytotoxic chemotherapy (platinum + etoposide , 5-FU , irinotecan + cisplatin  and everolimus ). Two patients had a radiographic response, 4 stable disease and 5 progressed. Six patients received second-line therapy with no objective responses. At last follow up (mean follow up: 50 months), 4 patients were free of disease, 5 had stable disease and 3 had progressed. Two patients had died, one from renal NET. The median overall survival from diagnosis was 99.9 months.
Conclusion: rNETs are rare tumors. Most patients had a complete resection but recurrences were common. Despite frequent recurrences, overall survival is long. The role of systemic therapy is uncertain.
Identifying and Prioritizing Gaps in Neuroendocrine Tumor Research-results of the Delphi Consensus Project of the Commonwealth Neuroendocrine Tumor Research Collaboration (CommNETS)
Eva Segelov,1 David L Chan,2,3 Ben Lawrence,4 Nick Pavlakis,3 Hagen Kennecke,5 Chris Jackson,6 Calvin Law,7 Simron Singh.71University of New South Wales; 2Sunnybrook Health Sciences Centre; 3Royal North Shore Hospital; 4University of Auckland; 5BC Cancer Agency, University of British Columbia, Vancouver, Canada; 6University of Otago, Dunedin, New Zealand; and 7Odette Cancer Centre.
Background: Australia, Canada and New Zealand share similar challenges in NET research and care provision. We aimed to identify gaps in NET research and develop research priorities to underpin collaborations across the newly formed CommNETS group using the robust Delphi methodology with broad stakeholder engagement.
Methods: A 3 round Delphi: 2 online surveys plus final round at the Inaugural CommNETS meeting; was performed with Wide participation from stakeholders including subject experts (medical, nursing, scientific) and consumers (patients, families, advocates). Round 1 identified gaps in NET research and CommNETs’ strengths compared to USA & Europe; Round 2 identified research priorities; Round 3 ranked priorities after extensive workshops and established project groups.
Results: Round 1 had 203 participants (64% experts; 36% consumers; 52% Canadians, 32% Australians, 17% New Zealanders); of which 132 undertook Round 2. Rankings from experts and consumers were similar except for early diagnosis (mean rank of 17 priorities for experts 9.6, SD = 5.8; consumers = 4.0, SD = 5.2, P = 0.000003). Final priorities (from 147 votes) were: biomarkers (33%); PRRT (16%); new drugs/trials in advanced NET (12%); functional imaging (10%); sequencing therapies for metastatic NET including validated surrogate endpoints (10%); pathological classification (9%); early diagnosis (7%); interventional therapeutics (3%). 6 working groups were founded.
Conclusion: A robust set of CommNETS research priorities was developed by consensus through the Delphi process. Collaborations have commenced to address the research questions.
The Clinicopathologic Characteristics of Primary Presacral Neuroendocrine Tumor: A Single Center Experience
Guoqing Yang,1 Run Yu,2 Nissen Nicholas,2 Andrew Hendifar.21Chinese PLA General Hospital; and 2Cedars-Sinai Medical Center.
Background: Presacral carcinoid tumors are rare entities that are found at the presacral space and have been characterized as both benign or similar to hind-gut tumors. We report our experience in the diagnosis, management, and outcomes of primary presacral neuroendocrine tumors (NETs).
Methods: This was an IRB approved retrospective review of medical records and surgical pathology specimens of patients (pts) with a diagnosis of neuroendocrine tumor at Cedars-Sinai Medical Center between Jan 2000 and Jan 2016.
Results: Ten pts were identified. The median age at presentation was 38 years (20–77 years), and 8 female patients. One patient presented with carcinoid-like symptoms. Two presented without symptoms and were diagnosed incidentally. Seven presented with symptoms related to mass effect. The median size of the tumor was 7.0 cm (3 - 12 cm). Of the 10 cases, 2 were associated with a presacral teratoma. On pathologic review, 6 were grade 1/2 and well differentiated and 2 were grade 3 and poorly- differentiated. 5 cases were metastatic on presentation with liver, lung or skeletal metastasis. CT, MRI, PET-CT and Scintigraphic imaging were used routinely for all cases. 7/8 cases were detectable using Octreoscan. 9 pts were treated with a somatostatin analog. 6 patients were treated surgically.
Conclusion: Presacral neuroendocrine tumors are clinically and histologically similar to GEPs and infrequently present with flushing or diarrhea. Octreoscan imaging and somatostatin analog therapy were frequently applied. Further biologic characterization of this rare subtype is needed.
Cisplatin and Etoposide or Temozolomide and Capecitabine in Treating Patients With Neuroendocrine Carcinoma of the Gastrointestinal Tract or Pancreas That Is Metastatic or Cannot Be Removed by Surgery
Jennifer R. Eads,1,2 Paul Catalano,3,4 George A. Fisher,5 David Klimstra,6 Zheng Zhang,7 Daniel Rubin,5 Andrei Iagaru,5 Terence Z. Wong,8,9 Peter O’Dwyer.10,111University Hospitals Seidman Cancer Center; 2Case Comprehensive Cancer Center; 3Dana Farber Cancer Institute; 4ECOG-ACRIN Biostatistics Center; 5Stanford University; 6Memorial Sloan Kettering Cancer Center; 7Brown University; 8University of North Carolina; 9Lineberger Comprehensive Cancer Center; 10University of Pennsylvania; 11Abramson Cancer Center.
Background: Poorly differentiated (G3) GEPNECs are rare tumors for which little prospective data are available. Historically these tumors have been treated akin to small cell lung cancer with platinum and etoposide based on histologic similarities. Emerging pathologic and clinical data suggest heterogeneity amongst G3 GEPNECs based on histology (small cell vs. non-small cell), Ki-67, response to therapy (platinum based vs. temozolomide based) and survival. Temozolomide based therapy appears the most promising alternative option. The proposed study will provide the first prospective data regarding the role of cisplatin and etoposide vs. temozolomide and capecitabine for G3 GEPNECs and their correlation with clinical parameters.
Methods: This is a multi-center, randomized phase II trial. Pts with locally advanced/unresectable or metastatic G3 GEPNEC are randomized to receive capecitabine 750 mg/m2 PO every 12 hours days 1–14 and temozolomide 200 mg/m2 PO daily days 10–14 (Arm A) or cisplatin 25 mg/m2 IV daily days 1–3 and etoposide 100 mg/m2 IV daily days 1–3 (Arm B). Cycle length: 28 days (Arm A), 21 days (Arm B). Eligibility criteria include G3 non-small cell histology, Ki-67 proliferative index 20-100%, ≥ 10 mitotic figures per 10 high powered fields, measurable disease, no prior chemotherapy. Primary endpoint is progression free survival (PFS); secondary endpoints include response rate (RR), overall survival (OS) and toxicity. Tissue specimens will be collected for central pathology review with assessment of Ki-67 and its correlation with PFS, OS and response. CT, PET and octreoscan images will be banked. A total of 126 pts will be needed to accrue 120 eligible cases to detect an improvement in PFS from 6 months in the control arm (Arm B) to 10 months in the experimental arm (Arm A) with 90% power and a one-sided significance level of 0.10 using a log-rank test. Planned accrual is 4 pts per month over 30 months with an additional 12 months of follow-up. The trial was activated in November 2015. Clinical trial information: NCT02595424.
A Phase II Trial of LEE011 in Combination With Everolimus in the Treatment of Advanced Well Differentiated Neuroendocrine Tumors of Foregut Origin
Nitya Raj,1 Jennifer Chan,2 Arvind Dasari,3 Marinela Capanu,1 Laura Tang,1 Diane Reidy-Lagunes.11Memorial Sloan Kettering Cancer Center; 2Dana Farber Cancer Institute; 3The University of Texas MD Anderson Cancer Center.
Background: Changes in the retinoblastoma tumor suppressor pathway are believed to contribute to the development of well differentiated neuroendocrine tumors (WDNETs). Specifically, the downregulation of proteins that normally inhibit the cyclin dependent kinases Cdk4 and Cdk6 have been demonstrated to contribute to NET development. Separately, rigorous investigation of everolimus in WDNETs has unequivocally demonstrated a survival benefit in this patient population.
Pre-clinical data suggests that LEE011 (Cdk4/Cdk6 inhibitor) is synergistically active with everolimus. The aim of this study is to evaluate the antitumor efficacy of the combination of LEE011 and everolimus in subjects with advanced WDNETs of foregut origin (thymic, bronchopulmonary, gastric, duodenal, and pancreatic).
Methods: This is a multicenter, non-randomized, phase II clinical trial using a Simon two stage optimal design. Main inclusion criteria include: adult patients with well/moderately differentiated WDNET of foregut origin, low/intermediate grade, unresectable and/or metastatic, documented evidence of disease progression with measurable disease, ECOG PS 0–1. Between 15 and 43 patients will be enrolled from three sites. All subjects will receive the oral combination LEE011 (300 mg daily, 3 weeks on/1 week off) and everolimus (2.5 mg daily). Patients will receive therapy until progressive disease/death or unacceptable toxicity. All enrolled patients will be followed by telephone contact for overall survival until death/withdrawal consent. The primary endpoint, progression free survival (time from therapy initiation to progressive disease/death), will be assessed based on radiographic review using RECIST v1.1. Secondary endpoints include safety, objective response rate, clinical benefit rate, and overall survival. Correlative objectives include exploring the effect of this drug combination on biomarkers related to the retinoblastoma pathway and/or the pathogenesis of WDNETs. This trial is scheduled to begin enrollment in the summer of 2016.
SPINET: A Randomized, Double-blind, Placebo-controlled Phase III Study of Lanreotide Autogel/Depot (LAN) in Patients with Advanced Lung Neuroendocrine Tumors
Diane Reidy-Lagunes,1 Matthew Kulke,2 Edward Wolin,3 Simron Singh,4 Diego Ferone,5 Beloo Mirakhur,6 Philipp Hoffmanns,6 Aude Houchard,6 Martyn Caplin,7 Eric Baudin.81Memorial Sloan Kettering Cancer Center; 2Dana-Farber Cancer Institute; 3Markey Cancer Center; 4Sunnybrook Health Sciences Centre; 5IRCCS AOU San Martino-IST; 6Ipsen; 7Royal Free Hospital; 8Gustave-Roussy Cancer Campus.
Background: The large phase III CLARINET study demonstrated antitumor efficacy LAN 120 mg vs placebo (PBO) for metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of grade 1 or 2 (Ki-67 <10%). Surgery remains the mainstay for localized lung NETs; other approved treatment options for advanced lung NETs are limited. The aim of the SPINET study is to evaluate the safety and antitumor efficacy of LAN 120 mg in patients with advanced lung NETs.
Methods: SPINET is a large multinational, multicenter, randomized, double-blind, PBO-controlled phase III study (NCT02683941; EudraCT: 2015-004992-62). Main inclusion criteria: adult patients with well-differentiated typical or atypical, metastatic and/or unresectable lung NETs, positive somatostatin-receptor imaging, ≤1 course of chemotherapy, ECOG PS 0–1. A total of 216 patients will be enrolled from 80 sites across the USA, Canada, and Europe. Patients will be randomized 2:1 to receive either LAN (120 mg every 28 days) or PBO both alongside best supportive care, until progressive disease (PD)/death or unacceptable toxicity. Patients receiving placebo who experienced PD may opt to receive LAN 120 mg in an open-label extension phase. All patients who experience PD will be followed to document survival, quality of life (QoL), and subsequent anticancer treatments.
Results: The primary endpoint is progression-free survival (PFS, time from randomization to progressive disease [PD]/death), and will be assessed based on central review using RECIST v1.1. Main secondary endpoints include PFS according to local review, objective response rates, overall survival, changes in plasma chromogranin levels, LAN pharmacokinetics, QoL, and safety.
Conclusion: The ongoing SPINET trial is the first prospective, placebo-controlled, randomized study designed to assess the effect of LAN 120 mg on typical and atypical carcinoid lung NETs.