bluuebunny/crossref_metadata_2025 huggingface dataset:
Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Interim analysis of the prospective, observational REFINE trial.
Authors: Lim Ho Yeong , Merle Philippe , Finn Richard S. , Frenette Catherine , Masi Gianluca , Ikeda Masafumi , Zebger-Gong Hong , Fiala-Buskies Sabine , Ozgurdal Kirhan , Kudo Masatoshi , Qin Shukui
Published: February 2020

542

Background: Regorafenib significantly improved overall survival (OS) versus placebo in patients (pts) with uHCC who progressed on prior sorafenib therapy in the phase 3 RESORCE trial. The multicenter, international REFINE trial was designed to evaluate the safety and effectiveness of regorafenib in uHCC in the real-world setting. Methods: This prospective, observational trial aims to recruit 1000 pts with uHCC for whom a decision to treat with regorafenib has been made by the treating physician prior to enrollment according to the local health authority approved label. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints are OS, progression-free survival, time to progression, best overall tumor response, and duration of treatment. Tumor response and progression are assessed per investigator according to local standard. An interim analysis includes the first 500 pts observed for ≥4 months. We report baseline characteristics, starting dose, and treatment duration for the interim analysis. Results: Of 498 pts evaluable for analysis, median age was 67 years (range: 22–91) and 84% were male. 59% were from Asia. Proportions of pts with ECOG performance status 0–1/≥2 were 82%/5% (missing 13%); 67% and 11% of pts had Child–Pugh A and B liver function, respectively (missing/not evaluable 21%). 60% of pts had metastases and 33% had vascular invasion. HCC etiology included hepatitis B 37%, alcohol use 26%, hepatitis C 23%, and NASH 7%. Baseline alpha-fetoprotein levels were < 400/≥400 ng/mL in 44%/26% of pts (missing 31%). The initial regorafenib dose was 160 mg/day (d) in 58% of pts, 120 mg/d in 13%, and 80 mg/d in 28% (8 pts initiated at 40 mg/d). The mean (SD) initial daily dose was 131 mg/d (37). Median duration of treatment was 3.7 months (IQR: 1.9–8.5). Conclusions: In this interim analysis of the observational REFINE study, some differences were observed in the characteristics of pts treated with regorafenib from the phase 3 RESORCE trial, reflecting less stringent inclusion criteria in a real-world study. Efficacy and safety analyses are ongoing. Clinical trial information: NCT03289273.
The efficacy and safety of lenvatinib in patients with intermediate-stage hepatocellular carcinoma: A nationwide multicenter study in Japan.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Sakamoto Azusa , Marusawa Hiroyuki , Ogawa Chikara , Kondo Masahiko , Joko Kouji , Tsuji Keiji , Kimura Hiroyuki , Wada Shuichi , Kobashi Haruhiko , Uchida Yasushi , Furuta Koichiro , Akahane Takehiro , Kusakabe Atsunori , Yoshida Hideo , Matsushita Tomomichi , Abe Takehiko , Sohda Tetsuro , Izumi Namiki
Published: February 2020

548

Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients with intermediate-stage u-HCC. Methods: A total of 240 patients received LEN from March 2018 at 15 sites in Japan was enrolled. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Results: In this study, 88 of 240 (36.7%) patients were BCLC stage B. Among them 76 (86.3%) patients received TACE before LEN and the median number of TACE was 2 (1-10). Only 4 patients were TKI experienced and other 84 (95.5%) patients received LEN as a 1st line therapy. The median pretreatment ALBI score was -2.35 and 75 (85.2%) patients were Child-Pugh A. In this cohort, 73 (83.0%) patients were beyond up-to-seven criteria and the median pretreatment AFP was 38.2 (2-12870) ng/mL. The median observation time was 8.5 months and 16 patients died. The median progression free survival was 8.7 months, and the median overall survival (OS) was not reached. Objective response rate (ORR) and disease control rate (DCR) were 48.5% and 80.3%. AFP decrease ( > 20%) after 1 month was observed in 52 (59.0%) patients. Child-Pugh B patients (n = 13) had significantly shorter OS than Child-Pugh A (p = 0.02) and median OS in Child-Pugh B patients was 8.8 months. The patients received > 6 times TACE before LEN had significantly shorter OS than patients received ≤ 6 times TACE (p = 0.02). Additional TACE was performed in 8 patients and The median time of restarting LEN was 19 days. The median ALBI score before additional TACE, Day 1 after TACE and Day 28 after TACE were -2.38, -2.07, and -2.36.There was no severe adverse event associated with additional TACE. The median duration of LEN in patients treated with LEN and additional TACE was 8.5 months. Conclusions: The ORR and DCR of LEN in Child-Pugh A patients with intermediate-stage HCC were 46.6% and 79.3%. The therapeutic strategies for intermediate-stage HCC should be discussed based on the liver function, tumor states, and treatment course about TACE.
Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma.
Authors: Chon Hongjae , Kim Chang Gon , Yoon Sangeun , Kim Chan , Kang Beodeul , Choi Hye Jin , Lim Ho Yeong
Published: February 2020

550

Background: Immune checkpoint blockade with PD-1 inhibitors has shown promising clinical efficacy in patients with hepatocellular carcinoma (HCC). However, emerging evidences show that PD-1 blockade can sometimes lead to a flare-up of tumor growth with rapid clinical deterioration (hyperprogressive disease, HPD). This study aimed to evaluate the incidence and pattern of HPD in a multicenter, real-world cohort of East Asian patients with advanced HCC treated with PD-1 blockade. Methods: We enrolled 148 advanced HCC patients treated with nivolumab between March 2016 and December 2018 in Korea. Clinicopathologic variables, tumor growth dynamic, and treatment outcomes were comprehensively analyzed. Progressive disease was assessed using tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF), and patient with HPD were defined as those who met the criteria of progressive disease by both TGK and TGR. Results: In this large cohort of HCC patients, the median age was 60 years and the majority were male (85%) and HBV-infected (72%). The objective response rate was 17.6% including two complete responders (1.4%). Ongoing responses were seen in 46% of responders at data cut-off. The incidence of HPD after PD-1 blockade was 23%. HCC patients with HPD had dismal prognosis with worse progression-free survival (PFS) and overall survival (OS) (HR, 1.947; 95% CI, 1.226-3.093 and HR, 1.839; 95% CI, 1.108-3.055, respectively) than progressive disease without HPD. Among various baseline clinicopatholgic parameters, elevated neutrophil-to-lymphocyte ratio (NLR) was only significantly associated with HPD. The optimal cut-off value of NLR for HPD prediction was 3.74 determined by ROC curves, and NLR > 3.74 was associated with worse PFS and OS. Conclusions: The real-world efficacy of PD-1 blockade in HCC patients was consistent with previous studies. However, there was also a corresponding risk of HPD as well as a clinical benefit. Therefore, careful patient selection using immunologic biomarkers, such as NLR, could enhance the therapeutic benefit of PD-1 blockade in clinical trials and real-world practice of HCC
A meta-analysis of the accuracy of a neuroendocrine tumor mRNA biomarker (NETest) in the blood.
Authors: Oberg Kjell E. , Califano Andrea , Strosberg Jonathan R. , Ma Steven M. , Pape Ulrich-Frank , Bodei Lisa , Kaltsas Gregory , Toumpanakis Christos , Goldenring James , Frilling Andreja , Paulson Andrew Scott , Modlin Irvin Mark
Published: February 2020

606

Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The inability to effectively assess disease in real-time has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy – liquid biopsy – to facilitate management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD) to assess clinical utility. Methods: A systematic review of the literature using PRISMA guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified 10 original scientific papers, which met inclusion criteria. These were assessed by qualitative analysis, and thereafter meta-analysis. Data were pooled and median (95% CI) diagnostic odds ratio (DOR), positive likelihood ratio (+LR) and negative likelihood ratio (–LR) calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and AUC data. Results: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. Meta-analysis identified the diagnostic accuracy of the NETest to be 94.9-96% with a median DOR of 400, +LR of 164 and–LR of 0.05. The NETest was 85.5-86% accurate in differentiating stable from progressive disease. As a marker of natural history, the accuracy was 90-94%. As an interventional/ response biomarker, the accuracy was 94-97%. The pooled AUC for the NETest was 0.954±0.005, with a z-statistic of 175.06 ( p< 0.001). Conclusions: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of a multianalyte genomic test as a biomarker provides information relevant to NET management consistent with observations regarding the utility of liquid biopsy in other oncological disciplines.
Socioeconomic disparities and outcomes in midgut neuroendocrine tumors.
Authors: Manguso Nicholas , Crystal Jessica , Cox Brian , Paski Shirley C , Hendifar Andrew Eugene , Gong Jun , Gangi Alexandra
Published: February 2020

613

Background: Demographic and socioeconomic disparities have been shown to effect cancer specific outcomes in numerous malignancies but the effect in midgut neuroendocrine tumors (mNETs) is unknown. We sought to investigate whether these factors are associated with survival in mNETs. Methods: The NCDB was queried to identify patients with mNETs between 2004 and 2015. Only patients treated at a single hospital with complete data were included. Overall Survival (OS) was compared based on demographic data, socioeconomic factors, insurance status and place of living. Results: A total of 14,083 patients were identified with a mean age of 72 years (range 18-90). The majority of patients were Caucasian (83.9%) and male (50.9%). Most patients had private insurance (50.5%) or medicare (41.3%). Patients typically lived in larger metropolitan areas (51.5%) and 60.7% lived in zip codes with median household incomes > $48,000. Only 14.7% lived in zip codes where > 20% did not graduate high school (no HSD). The majority were treated at community comprehensive cancer centers (43.8%) or academic/research centers (35.2%). Overall, 3358 (24.5%) presented with metastasis at diagnosis. The 5-year OS for the entire cohort was 78.5%. The 5-year survival was worse in patients with lower median income (73.8% [ < $38,000] vs 81.5% [ > $63,000],p < 0.0001), lower education (74.9% [ > 20% no HSD] vs 80.7% [ < 7% no HSD], p < 0.0001), those not living in proximity to a metro area (73.8% [not metro adjacent] vs 78.7% [metro/adjacent], p = 0.0004) and those treated at a community cancer center (73.6% [community] vs. 80.1% [academic], p < 0.0001). Factors predictive of worse OS were lower income ( < $38,000) (HR 1.16, 95% CI 1.04-1.28), lower education ( > 20% no HSD) (HR 1.14, 95% CI 1.02-1.26), no insurance (HR 1.66, 95% CI 1.33-2.06) and not living in proximity to a metro area (HR 1.27, 95% CI 1.10-1.47). Conclusions: Socioeconomic factors shown to have worse OS in patients with mNETs were lower median income, lower education, treatment at a community cancer center and not living in proximity to a metro area. Patient demographic and socioeconomic factors play an important role in OS for patients with mNETs and access to care must be considered in this subpopulation of cancer patients.
Long-term safety and efficacy of lanreotide treatment in Japanese patients with neuroendocrine tumors: Final analysis of a phase II open-label extension study.
Authors: Ito Tetsuhide , Hisamatsu Seiichi , Nakajima Akihiro , Shimatsu Akira
Published: February 2020

621

Background: Lanreotide autogel 120mg (lanreotide) was approved in Japan in July 2017 for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs) based on the results from an international phase III study (CLARINET study) and a Japanese single-arm phase II study. The CLARINET extension study demonstrated long-term efficacy and safety of lanreotide treatment; however, no Japanese patients were included in the study. To describe the safety and efficacy of long-term lanreotide treatment for NETs in Japanese patients, the final analysis of the Japanese phase II study and its extension study was performed. Methods: This open-label extension study (Study 002, JapicCTI-142698) enrolled patients who completed 48 weeks of treatment with 4-weekly subcutaneous lanreotide in an open-label phase II study in Japanese patients with NETs (Study 001, JapicCTI-132375). Study 002 had the same design as Study 001. Results: Of the 32 patients who started treatment with lanreotide, 17 completed Study 001 and enrolled in Study 002. In the safety analysis set (n = 17), 16 patients (94.1%) developed adverse events (AEs) that were considered drug-related (adverse drug reactions; ADRs), most commonly faeces pale (n = 5; 29.4%), injection site induration (n = 4; 23.5%), flatulence and diabetes mellitus (both n = 3; 17.6% each). No patient permanently discontinued lanreotide or died as a result of an AE. Four patients had a total of eight serious AEs; of these, two events of bile duct stones were considered to be ADRs. In the efficacy analysis set (n = 28), the median lanreotide exposure over Studies 001 and 002 was 52.7 weeks (range: 12–181 weeks). The best overall response was partial response in 2 patients (7.1%; reached at 60 and 108 weeks), stable disease in 20 patients (71.4%) and progressive disease in 6 patients (21.4%). Conclusions: No unexpected serious AEs developed during prolonged use of lanreotide. Lanreotide was effective over long-term treatment in Japanese patients with NETs. Clinical trial information: JapicCTI-132375, JapicCTI-142698.
Treatment outcomes of patients with G3 neuroendocrine neoplasms.
Authors: Jann Henning , Kayser Antonin , Wiedenmann Bertram , Tacke Frank , Roderburg Christoph
Published: February 2020

622

Background: Extra-pulmonary neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) G3 are aggressive neoplasia that are associated with a limited prognosis. Data on this entity is scarce and optimal treatments are only poorly defined. Methods: 105 patients (♀ = 46; 43.8% and ♂ = 59; 56.2%) with histologically confirmed neuroendocrine carcinoma (NEC; n = 83) or neuroendocrine tumor G3 (NET G3; n = 12) or mixed neuroendocrine non-neuroendocrine neoplasms G3 (MiNEN G3; n = 10) were included into this study. Clinical and pathological characteristics at diagnosis, therapies, outcomes and survival data were recorded. Results: Primary tumor localizations included esophagus/stomach (n = 9; 8.7%), pancreas/duodenum (n = 29; 27.9%), appendix/colon/rectum (n = 25; 24.0%), the genitourinary tract (n = 9; 8.7%) and CUP (n = 32; 30.8%). Median Ki-67 across all patients was 70% (range 25-95) with a statistically significant difference in NEC G3 vs. NET G3 (74%, range 25-95 vs. 33.5%, range 25-69; p < .001). Median overall survival (mOS) was 19.2 (±1.6)months and was significantly higher in NET G3 (38 vs. 16.8 months in NEC; p = .012). First-line therapy in most patients was cisplatin or carboplatin in combination with etoposide (n = 64; 61.0%), followed by FOLFOX (n = 29; 27.6%). Twelve Patients (11.4%) received other chemotherapies. Best overall response to first-line chemotherapy was CR (5.7%), PR (52.4%) SD (17.1%) and PD (21%). In patients with Ki-67 < 55% (n = 40) no significant difference between the different regimens was found. In analyzing median PFS (mPFS) in patients with Ki-67 > 55% (n = 65) the combination of cis- or carboplatin with etoposide (mPFS 6.1±0.5 months) was superior to FOLFOX (mPFS 2.8±1.4 months; p = 0.038). Strikingly, in patients with small-cell NEC (n = 28) the combination of cisplatin/etoposide (mPFS 12.3±3months) showed a superior outcome compared to carboplatin/etoposide (mPFS: 6±1.4months; p = .022). Conclusions: Patients with non resectable NEN G3 should be treated with chemotherapy. In cases with proliferative index > 55% the 1st-line regimen of choice should be platinum in combination with etoposide. The difference in efficacy between carboplatin and cisplatin in our data should be evaluated in a prospective setting.
Comprehensive genomic sequencing of high-grade neuroendocrine neoplasms.
Authors: Sun Thomas Yang , Van Hummelen Paul , Martin Brock , Xia Charlie , Lee Hojoon , Zhao Lan , Hornbacker Kathleen , Ji Hanlee , Kunz Pamela L.
Published: February 2020

624

Background: Grade 3 neuroendocrine neoplasms (G3 NENs), if poorly differentiated, have a median survival of only 10-19 months. Little is known regarding their underlying genomics. Methods: We applied multiomics analysis to 46 cases of G3 NEN that included copy number analysis, whole exome, and transcriptomic sequencing. Results: Of the 46 unique cases, 17 were lung, 16 gastroenteropancreatic (GEP), 13 other; 5 well-differentiated, 39 poorly differentiated and 2 mixed. Using a multivariate Cox model, we found histology characteristics (including differentiation, Ki67 and mitotic index) did not correlate with changes in overall survival (OS). The clinical variables that did correlate with OS included: number of lines of treatment (hazard ratio for death [HR], 0.72; p < 0.05), GEP primary site (HR, 5.36; p < 0.005), and non-resected primary tumor (HR, 14.52; p < 0.001). Two copy number changes were associated with worse prognosis: focal deletion 22q13 (HR, 10.23; p < 0.005), and arm amplification 19q (HR, 7.09; p < 0.01). The median OS of the top quartile compared to the rest for 22q13 deletion carriers was 9.9 months vs. 24 months, and for 19q amplification carriers was 8.7 months vs. 36.7 months. We estimated a median tumor mutation burden (TMB) of 3.7 mutations/Mb, with 20% (8/40) of patients showing high TMB ( > 10 mutations/Mb). The top five mutated genes were USH2A, RB1, APC, TP53, and MUC16. We also observed high transcriptomic similarity across all NENs regardless of their site of origin. Conclusions: We identified two copy number changes that can serve as predictive biomarkers in G3 NENs, as they confer an increased risk of death by as high as 10x to the carriers. Further, G3 NENs are characterized by a distinct group of somatic mutations, and a significant number have high tumor mutation burden. Lastly, G3 NENs across different organs were relatively homogeneous in expression profile.
HPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.
Authors: Chauhan Aman , Prieur Alexandre , Kolesar Jill , Arnold Susanne , Cousin Thierry , Payen Lea Francoise , Sands Madison , Napier Dana , Evers Mark , Anthony Lowell Brian
Published: February 2020

628

Background: Neuroendocrine neoplasms (NENs) are heterogeneous tumors which originate from various organs and are of variable aggressiveness based on grade and morphology. Current biomarkers for NENs lack sensitivity and specificity, especially for high-grade NENs (small and large cell neuroendocrine carcinomas). hPG80, progastrin, is a novel bio-marker which is easily measured in plasma using an ELISA test. Physiologically, hPG80, an 80 amino acid protein, is the precursor of the gastrointestinal hormone gastrin. It is synthetized by gastric antrum G cells, and then processed into gastrin by multiple enzymatic processes. In pathological conditions, the GAST gene, which encodes hPG80, was shown to be over-expressed in human solid tumors from various primary sites. hPG80 is unprocessed and released from the tumor cells and becomes detectable in the blood. This study is the first to explore hPG80 in NENs. Methods: hPG80 was quantified in the plasma from 31 NEN patients using DxPG80 technology (ECS-Progastrin, Switzerland). Progastrin concentrations in 18-70 YO (n = 557) and 18-25 YO (n = 137) healthy blood donors were compared to 31 stage IV NENs patients. The study was IRB approved. Results: Mean age of study cohort at the time of blood collection was 60.9 years. 21 patients had grade 1 and 2 well differentiated NET. 10 patients had high grade NEN (Small cell, large cell and poorly differentiated NEC). High grade sub cohort also included two well differentiated grade 3 NET patients. Mean hPG80 in NENs was 14.17 pM as compared to 2.04 pM and 0.99 pM in 18-70 and 18-25 YO control groups (p < 0.0001), respectively. Subgroup analysis of NENs revealed mean hPG80 of 24.61 pM in high-grade NENs (n = 10) vs 10.88 pM in G1/2 NETs (n = 21). Conclusions: This first-ever study of plasma hPG80 in NENs suggests hPG80 may be a diagnostic and/prognostic blood-based biomarker in both low and high-grade NENs and further study is warranted. A prospective trial is ongoing in high-grade NEN to evaluate its role in monitoring of disease (NCT03958045) and further studies in low-grade NETs are underway. This research was supported by Cancer Center Support Grant (CCSG) from the National Cancer Institute (P30 CA177558) and ECS Progastrin.
Blood neuroendocrine gene transcripts (NETest) as a diagnostic of pancreatic neuroendocrine tumors and to identify the efficacy of surgical resection.
Authors: Partelli Stefano , Muffatti Francesca , Andreasi Valentina , Falconi Massimo , Modlin Irvin Mark
Published: February 2020

631

Background: Surgery is the only treatment for cure of pancreatic neuroendocrine tumours (PNET). There are no effective biomarkers to assess completeness of resection and predict recurrence. The aims of this study were 1) evaluate if blood measurement of neuroendocrine gene transcripts (NETest) were diagnostic of PNET and 2) assess if blood levels correlated with the resection type (R0/ R1/R2). We compared transcript analysis with Chromogranin A (CgA), the current standard of care. Methods: A prospective, longitudinal, single center study (ClinicalTrials.gov ID: NCT03012789) of 30 PNETs. Blood for NETest and CgA were collected preop and on postop day 30 (POD30). Transcript measurement: real-time quantitative reverse transcription PCR and multianalyte algorithmic analysis (NETest) (normal 0-20, > 20 stable and > 40 progressive disease; CgA: (ELISA) (normal < 109mg/ml). Analysis: Student’s t test, Mann-Whitney U test and Fisher’s exact test. Data: mean±SEM. Results: Surgical resections ( n= 30) were: 26 R0, 2 R1, 2 R2. In vitro diagnostic: Preop NETest positive in all 30 (NETest: 38±4) (1005) whereas CgA levels positive (220±66ng/ml) in 9 (30%, p< 0.0001). Surgery R0: ( n= 26): NETest significantly decreased from pre-op of 45±3 to 21±4 ( p< 0.001) at POD30. Post operatively 13 (50%) exhibited an elevated score. One patient (Ki67 18%; extensive nodal involvement) had a score of 80, consistent with residual progressive disease. The remaining 12 had NETest levels of 27 at POD 30. CgA was elevated in 8 (31%) with no decrease at POD30 (154±44ng/ml vs. 109±22ng/ml). R1/R2 ( n= 4): NETest scores unchanged (42±17 vs 46±16) at POD30. CgA levels unchanged (378±332 vs. 753±634ng/ml). Conclusions: The NETest is an accurate in vitro diagnostic biomarker for PNET (100%). After R0 resection NETest decrease indicates the blood test is concordant with tumor removal. Elevated post-resection scores are consistent with residual disease and with reported recurrence rates after pancreatic surgery. CgA exhibited no clinical utility. At 1 month post-surgery, the NETest provides an early indication of high risk recurrence patients who can be stratified for further therapy. Clinical trial information: NCT03012789.
A randomized, multicenter, phase II trial of gemcitabine (G), cisplatin (C) +/- veliparib (V) in patients with pancreas adenocarcinoma (PDAC) and a known germline (g)BRCA/ PALB2 mutation.
Authors: O'Reilly Eileen Mary , Lee Jonathan W. , Zalupski Mark , Capanu Marinela , Park Jennifer , Golan Talia , Tahover Esther , Lowery Maeve Aine , Chou Joanne F. , Sahai Vaibhav , Brenner Robin , Kindler Hedy L. , Yu Kenneth H. , Zervoudakis Alice , Vemuri Shreya , Stadler Zsofia Kinga , Do Richard K. G. , Dhani Neesha C. , Chen Alice P. , Kelsen David Paul
Published: February 2020

639

Background: gBRCA 1,2 mutations occur in 5-8% PDAC. Platinum and poly-ADP ribose polymerase inhibitors (PARPi) effective in BRCA-mut cancers. Phase I GC + V high RR 78%; combination may delay resistance in PDAC (O’Reilly, Cancer, 2018). Herein, we evaluate GC +/- V in a multi-national, randomized phase II trial. Methods: Eligibility: Untreated germline (g)BRCA, PALB2 mut PDAC; measurable stage III/IV; ECOG 0-1. Randomized 1:1 Arm A or B. Treatment: Arm A: G 600 mg/m2 IV, C 25 mg/m2 IV, d3 and 10, V 80 mg PO BID day 1-12, all q 3 weeks or Arm B: GC only. Primary endpoint: RECIST 1.1 response rate (RR). Simon 2-stage per arm: null hypothesis 10% vs promising 28%; type I, II error 10%. Secondary endpoints: progression-free survival (PFS), OS (m), disease control rate (CR+PR+SD), safety and correlative analyses. PFS, OS compared between arms using log-rank test and RR, DCR using Fisher’s exact test between arms. Results: N = 52 enrolled 01/14- 11/18. N = 2 withdrew Arm B. N = 50 for ITT. Male = 22 (44%), Female = 28. Median age = 64 years (range 37-82). BRCA1 N = 12, BRCA2 N = 35, PALB2 N = 3. Stage III N = 8; Stage IV N = 42. Hematologic Toxicity: Arm A vs Arm B: Gd 3-4 neutropenia 13 (48%) vs 7 (30%); Gd 3-4 platelets 15 (55%) vs 2 (9%); Gd 3-4 anemia 14 (52%) vs 8 (35%). Non-hematologic toxicity similar Arm A vs B. Exploratory analyses (combined Arms): Med OS if > 4 m platinum → PARPi: 23 m (95%CI 6.5- 53.9). Med OS by BRCA: BRCA1: 14 m (8.1- 18.5); BRCA2: 20.2 m (12.3- 24.4). Med OS by ECOG: ECOG 0: 23 m (13.8- 24.5); ECOG 1: 14.3 (8.1 vs 16.4). Two-year OS rate for entire cohort: 30.6% and 3-year OS: 17.8%. Conclusions: GC +/- V very active in gBRCA/PALB2 mut PDAC with high RR, PFS, OS with both A, B significantly exceeding threshold RR. Improved DCR arm A vs B, but with greater heme toxicity A vs B. Study confirms GC as reference treatment in gBRCA/PALB2 with durable survival in subset. Funding: National Cancer Institute, CTEP, Lustgarten Foundation, AbbVie. Clinical trial information: NCT01585805 . [Table: see text]
The clinical utility of the 2017 Fukuoka Guidelines and 2015 American Gastroenterological Association Guidelines for the management of intraductal papillary mucinous neoplasms.
Authors: Lanke Gandhi , Campbell Donald , Coronel Emmanuel , Bhutani Manoop S. , Weston Brian , Ross William A. , Kim Michael Paul , Nogueras-Gonzalez Graciela M. , Katz Matthew H. G. , Lee Jeffrey H.
Published: February 2020

640

Background: Mucinous cystadenocarcinoma are malignant and mucinous pancreatic cysts (PC) have malignant potential. The management of PC remains controversial despite consensus guidelines. This study aims to evaluate the clinical utility of the 2017 Fukuoka Guidelines (FG) and 2015 American Gastroenterological Association Guidelines (AGA-G) for the management of PC. Methods: 212 patients who underwent EUS for PC between 2010 and 2017 were identified. The FG and AGA-G were used to define worrisome and high-risk cyst features. Receiver Operating Characteristic (ROC) curve was used to define sensitivity (SN), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV). Results: 141 of 212 patients had IPMNs.EUS-FNA was performed in 76.5% with no reported complications. Median follow-up was 4.2 years. The majority of the IPMNs were in the pancreatic head (44.7%) or body (39.7%) while only 15.6 % were in the tail. Using the FG, 46.1% had at least one worrisome feature (FG-W) and 7.1% had at least one high risk feature (FG-HR). Using the AGA-G, 28.4% had at least one HR feature (AGA-HR1) and 1.4% patients had two or more risk factors (AGA-HR2). A change in cyst character (increase of > 5 mm in 2 years, development of a solid component, or new pancreatic duct dilation) was noted in 43.2% patients. The median time to cyst change was 21 months. For prediction of cyst changes, the FG-W had a SN of 45.8%, SP of 55.4%, PPV 45%, and NPV 56%. FG-HR had a SN of 14.3%, SP of 53.2%, PPV 1.7%, and NPV 91.8%. AGA-HR1 had a SN of 35.3%, SP of 51.5%, PPV 20%, and NPV 69.9%. AGA-HR2 had a SN of 0%, SP of 54.2%, PPV 0%, and NPV 97.3%. No difference was seen in cyst change or development of high risk or worrisome features with CEA > 192 vs. < 192 (p = 0.99). During follow up, 14 patients died, but only one patient died of pancreatic cancer. Conclusions: FG and AGA-G are difficult to validate because malignant cyst transformation is rare. There was no correlation between any cyst characteristics on EUS and cyst changes. FG-W had the best performance in predicting changes. Surgical candidates should be carefully selected, as these guidelines have a limited clinical utility.
Determining when endoscopic ultrasound (EUS) changes management for patients with pancreatic cystic neoplasms.
Authors: Sidhu Hasrit , Maher Khaola , Farnell Dave , Chen Leo , Gan Ian , Segedi Maja
Published: February 2020

641

Background: Pancreatic cystic neoplasms (PCNs) are being incidentally detected at an increased rate due to the widespread use of CT and MRI. CT and MRI cannot always differentiate between malignant and benign PCNs. EUS is an emerging tool that provides higher quality descriptions of pancreatic cysts and can be used to differentiate between benign and malignant features. Considering that EUS is a resource dependent tool, we hope to identify the PCN cases in which EUS changes management. Methods: We conducted a retrospective case-control chart review evaluating patients, who were diagnosed with pancreatic cysts and underwent EUS for analysis between January 1, 2010 and December 31, 2017. We determined whether EUS correctly identified high-risk features (HRFs) relative to CT/MRI and whether EUS upstaged or downstaged the CT/MRI diagnosis to change overall patient management. Results: EUS was found to have a high specificity (> 95%) for all high-risk features identified in the AGA and FG guidelines and a low sensitivity ( < 70%) for all high risk features except cyst size > 3cm (82.35%) and mural nodule < 5mm (100%). EUS was found to change management in 29.4% of cases (18.2% upstaged, 11.2% downstaged). EUS screening led to a total of three adenocarcinoma diagnoses, in which two were reported to be invasive. Conclusions: The high specificity of EUS supports its use in the differentiation of high risk PCNs identified on cross-sectional imaging. Its low sensitivity indicates that the reliance on operator experience may be a substantial limitation resulting in inconclusive diagnoses. In conclusion, considering that EUS is successful in changing patient management of PCNs, it should be readily referred when any HRF is identified on cross-sectional imaging.
Pancreatic cancer (PaC)-specific health-related quality of life (HRQoL) with maintenance olaparib (O) in patients (pts) with metastatic (m) PaC and a germline BRCA mutation (gBRCAm): Phase III POLO trial.
Authors: Hall Michael J. , Golan Talia , Hammel Pascal , Reni Michele , Van Cutsem Eric , Macarulla Teresa , Park Joon Oh , Hochhauser Daniel , Arnold Dirk , Oh Do-Youn , Reinacher-Schick Anke C. , Tortora Giampaolo , Algül Hana , O'Reilly Eileen Mary , McGuinness David , Cui Karen , Joo Seongjung , Yoo Hyun Kyoo , Patel Nikunj , Kindler Hedy L.
Published: February 2020

648

Background: In POLO (NCT02184195), maintenance O significantly improved progression-free survival vs placebo (P) in pts with a gBRCAm and mPaC without compromising HRQoL (Hammel Ann Oncol 2019). We report additional predefined exploratory HRQoL data from the PaC-specific EORTC QLQ-PAN26 questionnaire. Methods: Pts were randomized to O (300 mg bid; tablets) or P. QLQ-PAN26 was completed at baseline (BL), after 1, 2, 3 + 4 weeks (wk) of treatment, every 4 wks until progression, at discontinuation, and 30 days after last dose. Scale range = 1–100 (higher score = greater symptoms); a 10-point change was predefined as clinically meaningful. Adjusted mean change from BL (CFBL) was analyzed by mixed model for repeated measures; time to sustained clinically meaningful deterioration (TSCMD) by log-rank test. Results: Analyses included the 89/92 O- and 58/62 P-arm pts with BL data (overall compliance: 97.8% vs 98.3%). Symptom scores were well balanced in both groups at BL and remained low and stable over time (Table). There were no clinically meaningful between-group differences in adjusted mean CFBL symptom scores. TSCMD in symptoms were not significantly different with O vs P. Conclusions: HRQoL was preserved with maintenance O, as shown by a low and stable PaC symptom burden over time, with no difference vs P. These data support the clinical benefit of O in pts with a gBRCAm and mPaC. Clinical trial information: NCT02184195 . [Table: see text]
The impact of primary tumor location (PTL) and age on the risk of developing noncolonic second primary malignancy (SPM) in colon cancer (CC) patients (PTS).
Authors: Chu Charles , Lin Albert Y.
Published: February 2020

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Background: Colon cancer remains one of the leading causes of cancer death worldwide. There has been a renewing interest in the role of PTL (right- or RS vs. left-sided or LS) in CC for their differences in biology, prognostic and predictive features. Given the increasing incidence of early-onset (age 20-49) CC, coupled with their longer life expectancy, we seek to examine the effects of PTL and age in the development of SPM in a population-based cohort. Methods: Surveillance, Epidemiology, and End Results (SEER) Program data were queried to identify CC PTS diagnosed between 1973-2015 with complete follow-up information and available data on SPM. Using SEER*Stat, we calculated standardized incidence ratios (SIRs) -- the ratio of observed to expected cases of SPM based on incidence data in the general US population and compared by PTL (RS vs. LS) and age of diagnosis (20-49 vs. >49). Results: A total of 269,442 (RS/LS=46.4%/53.6%) CC PTS were obtained. Overall RS, compared with LS, CC PTS have a higher likelihood of developing SPM in all sites (OR: 1.09, 95% CI: 1.08- 1.11 vs. 1.03, 1.02-1.04). RS CC PTS and age 20-49 group, compared with other subgroups, has a much greater likelihood of being diagnosed with the following SPM:small intestine, urinary tract, bile duct, gynecologic (GYN), and stomach cancers, as shown in the Table below. Conclusions: Our results show that the increased risk in non-colonic SPMs in CC PTS is associated with RS CC and age less than 49, suggesting the implications on survivorship care and surveillance of SPMs. Furthermore, there may be a possible overlap with Lynch syndrome in these PTS with SPM given the overlap in the presentation of cancer patterns and early-onset of CC, suggesting the indication for MMR testing.

[Table: see text]
Neoadjuvant therapy (NAT) and its role for pancreatic adenocarcinoma (PC) in the current era: Institutional experience.
Authors: Walzer Emily , Deng Mengying , Handorf Elizabeth A. , Blumenreich Aryeh , Pease Lauren , Dorta Marianna , Sorice Kristen , Lynch Shannon M. , Vijayvergia Namrata , Dotan Efrat
Published: February 2020

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Background: PC affects 57,000 people in the U.S. annually with poor long-term outcomes. NAT for localized disease has increasingly been used but lacks robust prospective data. We investigated the disease course and outcomes for patients (pts) undergoing NAT versus upfront surgery for PC at a high-volume academic center. Methods: Utilizing our IRB-approved retrospective database of metastatic PC pts (year 2000-2017), we identified pts who presented with localized disease and were considered for surgery and present the baseline tumor and treatment characteristics here. Fisher’s exact and Wilcoxon Rank-Sum tests were used for categorical data and Kaplan Meier (KM) curves for survival data when comparing those who had upfront surgery versus surgery following NAT. Results: 352 pts with localized disease at diagnosis were included in our analysis with median age of 65 y (range 38-89) and 45% females. NAT was used in 225 (64%) pts while 109 pts (31%) had upfront surgery and 18 pts (5%) received no treatment. Adjuvant therapy was given to 77% of pts after upfront surgery and 48% of pts after surgery following NAT. NAT regimen consisted of chemotherapy (CTx) and radiation for 48%, CTx alone for 8% and radiotherapy alone for 44% of pts. Of those receiving CTx, 24% received triple agent while 51% and 25% received dual and single agent therapy. Pt factors (age, CCI, gender, BMI, smoking status, race) did not differ between those receiving upfront surgery and surgery following NAT but upfront surgery was associated with a lower stage at diagnosis (p < 0.0001). Surgical resection after NAT occurred in 79 pts (35%) with median overall survival of 26.3m vs 19.7m (p = 0.06) in those who had upfront surgery. Survival rates at year 1, 3, and 5 years were 94%, 34%, and 8% for those with NAT followed by surgery vs 76%, 17%, and 11% for those with upfront surgery (p = 0.06). Conclusions: Use of NAT is prevalent, yet only 35% of pts make it to surgical resection. Survival was improved for pts who underwent resection following NAT versus upfront, although the difference was not statistically significant. Additional research is warranted to define the optimal NAT approach for pts with borderline resectable PC.
First-line drug selection versus sequential treatment in advanced pancreatic cancer: Does it really matter? Multi-institutional Canadian perspective.
Authors: Barrera Ivan , Papneja Neha , Ranger Jill , Papneja Abhishek , Novotny Petr , Ahmed Shahid , Batist Gerald , Kavan Petr
Published: February 2020

673

Background: Folfirinox (FFX) and Gemcitabine with nab-Paclitaxel (GN) are both proven to be superior to Gemcitabine (G) in the first line treatment (1LTx) for advanced pancreatic cancer (APC). Yet, the optimal 1LTx selection nor sequential Tx (ST) has not been fully established. Therefore, the best choice for 1LTx is a matter of debate often influenced by access to drugs. This analysis was conducted to compare outcomes based on 1Ltx selection and ST in APC. Methods: We assessed patients (pts) with APC who received either FFX or GN as 1LTx during 2010-2019 at three Canadian institutions. As well as the ST used. The main objective was to assess survival. Kaplan method and log-rank test were used for survival curves. Results: This retrospective study included 231 pts; 1LTx included 143 pts on FFX and 88 pts on GN. FFX pts were predominantly male; 89(62.2%) vs 46(52.3%) and slightly younger (median age 62 vs 66) than GN. WHO performance status (PS) of 0 were 38 (28.4%) vs 14 (16.5%) and 1 were 90 (67.2%) vs 65 (76.5%) respectively. There were more grade 3-4 toxicity in FFX vs GN group: GI 55 (38.5%) vs 15 (17%) and hematologic 51 (35.4%) vs 20 (22.7%) respectively. Grade 3-4 neutropenia rates were similar in both regimens. The median PFS of FFX was 5.5 months (95% CI: 5.0-6.7) vs 5.1 (95% CI: 3.8-7.1) with GN (p=0.37). The median OS with FFX was 9.3 months (95% CI: 7.5-11.1) vs 10.2 (95% CI: 6.8-11.3) with GN (p=0.81). There were not statically significant. Table shows Tx frequency across 4LTx. 2LTx and beyond regimens included G, GN, FFX, Capecitabine, Irinotecan liposome plus 5-FU, Irinotecan and clinical trials. Conclusions: Our results revealed that pts who received 1LTx FFX or GN had similar PFS and OS even though 1LTx FFX group was younger with better PS, allowing to continue 2-4LTx more frequently when compare with 1LTx GN group. Therefore, 1LTx selection appear to have more impact in our pts rather than ST, whereas GN is less toxic and seems a preferable 1LTx choice for most pts. FFX could be reserved for young high-performance pts. [Table: see text]
Perioperative complication rates following neoadjuvant therapy in pancreatic adenocarcinoma.
Authors: Deig Christopher R. , Beneville Blake , Liu Amy , Kanwar Aasheesh , Grossblatt-Wait Alison , Sheppard Brett C. , Gilbert Erin W. , Lopez Charles D. , Billingsley Kevin G. , Nabavizadeh Nima , Thomas Charles R. , Grossberg Aaron
Published: February 2020

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Background: Whether upfront resection or total neoadjuvant therapy is superior for the treatment of potentially resectable pancreatic adenocarcinoma (PDAC) remains controversial. The impact of neoadjuvant treatment on major perioperative complication rates for patients (pts) undergoing resection for PDAC is commonly debated. We hypothesized that rates would be comparable among patients receiving neoadjuvant chemoradiation (neo-CRT), neoadjuvant chemotherapy alone (neo-CHT), or upfront surgery. Methods: This is a retrospective study of 208 pts with PDAC who underwent resection within a multidisciplinary pancreatico-biliary program at an academic tertiary referral center between 2011-2018. Data were abstracted from the medical record, an institutional cancer registry and NSQIP databases. Outcomes were assessed using χ2, Fisher’s exact test and two-tailed Student’s t-tests. Results: 208 pts were identified: 33 locally advanced, borderline or upfront resectable pts underwent neo-CRT, 35 borderline or resectable pts underwent neoadjuvant-CHT, and 140 resectable pts did not undergo neoadjuvant therapy. There were no statistically significant differences in major perioperative complication rates between groups. Overall rates were 36.4%, 34.3%, and 26.4% for pts who underwent neo-CRT, neo-CHT alone, or upfront resection, respectively (p = 0.38). No significant difference were observed in complication rates (35.3% v. 26.4%; p = 0.19) or median hospital length of stay (10 days v. 10 days; p = 0.87) in pts who received any neoadjuvant therapy versus upfront resection. There were two perioperative deaths in the neo-CRT group (6.1%), zero in the neo-CHT group, and four in the upfront resection group (2.9%); p = 0.22. Conclusions: There were no significant differences in major perioperative complication rates, hospital length of stay, or post-operative mortality in pts who underwent neoadjuvant therapy (neo-CRT or neo-CHT alone) versus upfront surgery. Notably, neo-CRT had comparable perioperative complication rates to neo-CHT alone, which suggests neoadjuvant radiation therapy may not pose additional surgical risk.
Rural-urban disparities in colorectal cancer screening: An insight from a statewide database.
Authors: Swaminathan Renugadevi , Morris James D. , Davis Terry C.
Published: February 2020

69

Background: The Healthy People 2020 initiative aims to increase colorectal cancer (CRC) screening. The common CRC screening options are FIT, FOBT, sigmoidoscopy, and colonoscopy. Colonoscopy allows visualization of the entire colon and offers therapeutic benefit whereas stool tests are less invasive, cost-effective and are easily available. Inequities exist in CRC screening among rural residents which may be contributed to a lower level of education, income, health insurance and access to health care. The purpose of the study is to identify the impact of geographic region on the preference of CRC screening modality among Louisiana adults. Methods: We performed a retrospective cohort study among age-eligible Louisiana adults who had CRC screening either with colonoscopy or stool-based tests using the 2016 Behavioral Risk Factor Surveillance System database (n = 1372). We examined demographic characteristics among participants who had CRC screening with colonoscopy versus who had a stool-based test. Multivariable logistic regression analysis evaluated the association of geographic region and the preference of CRC screening. Results: Participants age 65-75 years old were 36% less likely to have a colonoscopy as compared to age 50-64 years (p = 0.0008). African Americans and Hispanic Americans were 34% (p < 0.006) and 55% (p = 0.057) less likely to have a colonoscopy as compared to Caucasian Americans, respectively. Medicaid and Medicare participants were 82% (p < 0.0001) and 52% (p < 0.0001) less likely to have a colonoscopy compared to participants with private insurance, respectively. After adjusting for age, race/ethnicity, education, income, and insurance the odds of screening colonoscopy was 29% lower for rural residents compared to urban residents of Louisiana (OR 0.71 95% CI 0.53 - 0.94). Conclusions: Individuals residing in rural parishes of Louisiana were more likely to have a stool-based test for CRC screening. Health care providers while considering the reliability and feasibility of CRC screening modality should also incorporate patient’s preferences while offering the screening tests to increase the rate of CRC screening.
Effects of early discontinuation of adjuvant chemotherapy (EDAC) and the timing of treatment on outcomes in patients with early-stage pancreatic cancer (ESPC): Result from a population-based retrospective cohort study.
Authors: Muhammadzai Javeria , Moser Michael , Haider Kamal , Shaw John , Chalchal Haji I. , Gardiner Donald , Zaidi Adnan , Ahmed Osama , Luo Yigang , Brunet Bryan , Dorie-Anna Dueck , iqbal mussawar , Beck Gavin , Ahmed Shahid
Published: February 2020

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Background: Although evidence suggests that a delay in initiation of adjuvant chemotherapy (AC) results in inferior outcomes in some cancers, little is known about its detrimental effects in patients with ESPC. Moreover, it is not known if EDAC has been associated with high risk of recurrence and poor survival. The current study aims to determine association between timing and completion of AC and outcomes in ESPC. Methods: Patients with ESPC who were diagnosed from Jan 2007 to Dec 2017 and underwent complete resection in the province of Saskatchewan were examined. Kaplan Meier methods and log rank tests were performed for survival analyses. Cox proportional multivariate analyses were performed for correlation with recurrence and survival. Results: A total 168 patients with ESPC were identified. 97 (57%) patients were excluded as they did not receive AC, were found to have metastatic disease, did not have curative surgery or had received preoperative chemotherapy. Of 71 eligible patients with median age of 69 years (IQR: 57-73), 52% were male, 31% had WHO performance status of 0 and 92% had a comorbid illness. 78% had pancreatic head tumor, 66% had T3 tumor and 63% had node-positive disease. Median time to start of AC from surgery was 73 days (IQR: 59-89). 32% were started AC within 60 days of surgery. 89% received single-agent chemotherapy and 25% received adjuvant radiation. 69% completed planned treatment. Median time to recurrence in group which completed treatment was 22 months (95%CI:15.8-28.2) vs. 9 months (3.3-14.7) if treatment was discontinued early (P < 0.001). Median overall survival of the group that completed treatment was 33 months (17.5-48.5) vs. 16 months (17.5-48.5) if it was stopped early (P < 0.001). On multivariate analysis, EDAC was significantly correlated with recurrent disease (HR = 3.0; 1.6-5.5), P = 0.0001 and inferior survival (HR = 3.2; 1.68-6.12), P < 0.001. No correlation between AC timing and survival was noted. Conclusions: Although timing of AC does not correlate with inferior outcomes, EDAC has been associated with high risk of recurrence and inferior survival in ESPC.