bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical prognostic significance of lymphovascular invasion in gastric cancer.
Authors: Fujikawa Hirohito , Yamada Takanobu , Koumori Keisuke , Watanabe Hayato , Kano Kazuki , Shimoda Yota , Rino Yasushi , Masuda Munetaka , Ogata Takashi , Oshima Takashi
Published: February 2020

428

Background: Lymphovascular invasion (LVI) of malignant tumor is regarded as an initial state of metastasis, including the lymph nodes, and therefore may be a prognostic factor in many malignancies. However, in gastric cancer, according to the current Japanese guidelines, LVI is not clinically useful information, except for in predicting the curability of endoscopic resection, and its clinicopathological characteristics and biological behavior remain unclear. The present study explored the histopathological significance of LVI in gastric cancer and clarified its correlation with the prognosis. Methods: From January 2000 to December 2013, a total of 2090 cases of gastric cancer undergoing radical gastrectomy were enrolled in this study. The correlation of LVI and other histopathological factors with the prognosis was evaluated. Lymphatic vessel invasion (ly) and venous invasion (v) were diagnosed followed the current Japanese classification. LVI positivity (LVIP) and LVI negativity (LVIN) were defined as the presence of lymphatic vessel and/or venous invasion and the absence of LVI, respectively. Results: LVIP was noted in 894 cases (42.8%). The age (p < 0.001), depth of tumor invasion (pT) (p < 0.001), lymph node metastasis (pN) (p < 0.001), and maximum tumor size (p < 0.001) were significantly correlated with the presence of LVI. A multivariate analysis showed that pT (p < 0.001), pN (p < 0.001), and LVI (p = 0.03) were independent risk factors for the prognosis of all patients. On analyzing the significance of every T factor and N factor for the overall survival of LVIP and LVIN cases, no significant difference was recognized in the prognosis among all pT1 patients and pT2-4 patients without nodal metastasis. However, in pT2-4 patients with nodal metastasis, a significant difference was revealed, and the 5-year overall survival rates in LVIP cases were lower than those in LVIN (60.9% [95% confidence interval: 56.3-65.3] vs. 76.7% [95% confidence interval 65.2-84.8], p = 0.005). Conclusions: LVI in gastric cancer is an independent prognostic factor, and its effect tends to be particularly strong in advanced cancer with lymph node metastasis. These patients may therefore require more effective adjuvant therapy.
A clinical scoring system for survival prediction in advanced gastric cancer.
Authors: Kim Jinchul , Yeo Ja Hyun , Hong Jung Yong , Kim Seung Tae , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki , Lee Jeeyun
Published: February 2020

436

Background: We established a scoring system using easily approachable clinical characteristics at the timing of initiating palliative chemotherapy to achieve accurate overall survival prediction to first-line treatment consisting of fluoropyrimidines in patients with advanced gastric cancer. Methods: A total of 1,733 patients were included in the study. The dataset was split into a training (n=1156, 67%) and validation set (n=577, 33%). Top-ranked variables were identified using the Random Forest for Survival algorithm and analyzed into a Cox regression model, thereby constructing the scoring system for predicting overall survival of advanced gastric cancer. Results: Five variables were finally included in the scoring system: serum neutrophil-lymphocyte ratio, alkaline phosphatase, albumin level, performance status, and histologic differentiation. The scoring system determined four distinct risk groups in validation dataset with median overall survival of 17.1 month (95% confidence interval [CI] = 14.9 to 20.5 month), 12.9 month (95% CI = 11.4 to 14.6 month), 8.1 month (95% CI = 5.3 to 12.3 month), and 3.9 month (95% CI = 1.5 to 8.2 month), respectively. AUC to estimate discrimination performance of the scoring system was 66.1 for one-year overall survival. Conclusions: We developed a simple and clinically useful predictive scoring model in a relatively homogenous population who initiate fluoropyrimidine-containing chemotherapy in advanced gastric cancer. Generalized application of the scoring model will require additional independent validation. [Table: see text]
Revisiting the value of drains after low anterior resection for rectal cancer: An analysis of 996 patients.
Authors: Lee Rachel M. , Gamboa Adriana C. , Turgeon Michael K. , Prasad Sanjana , Kwakye Gifty , Hrebinko Katherine , Holder-Murray Jennifer , Abdel-Misih Sherif , Kimbrough Charles , Soda Mosope , Hawkins Alexander , Chapman William C. , Silviera Matthew , Maithel Shishir K. , Balch Glen C.
Published: February 2020

45

Background: Although potentially associated with increased infections, intraoperative pelvic drains are often placed during low anterior resection (LAR) to evacuate postoperative fluid collections and identify/control potential anastomotic leaks. Our aim was to assess the validity of this practice in a large dataset of patients undergoing LAR for rectal cancer. Methods: Patients from the US Rectal Cancer Consortium (2007-17) who underwent curative-intent LAR for a primary rectal cancer were included. Patients were categorized as receiving a closed suction drain intraoperatively or not. Primary outcomes were superficial surgical site infection(SSI), deep SSI, intraabdominal abscess, anastomotic leak, and need for secondary drain placement. Three subgroup analyses were conducted in patients who received neoadjuvant chemoradiation, had a diverting loop ileostomy (DLI), and had low tumors <6cm from the anal verge. Results: Of 996 pts, average age was 58 yrs, 61% were male, and 67% (n=551) received a drain. Drain patients were more likely to be male (64vs54%), have a smoking history (25vs19%), have received neoadjuvant chemoradiation (73vs61%), have low tumors within 6cm of the anal verge (56vs36%), and have received a DLI (80vs71%) (all p<0.05). Drains were associated with an increased anastomotic leak rate (14vs8%, p=0.041), although there was no difference in the need for a secondary drainage procedure to control the leak (82vs88%, p=0.924). These findings persisted in all subset analyses. Drains were not associated with increased superficial SSI, deep SSI, or intraabdominal abscess in the entire cohort or each subset analysis. Reoperation (12vs10%, p=0.478) and readmission rates (28vs31%, p=0.511) were similar. Conclusions: Although not associated with increased infectious complications, intraoperatively-placed pelvic drains after low anterior resection for rectal cancer are associated with an increase in anastomotic leak rate and no reduction in the need for secondary drain placement or reoperation. Routine drainage should be abandoned.
Conversion surgery for advancedgastric cancer with peritoneal metastasis.
Authors: Nakamura Masaki , Nakamori Mikihito , Ojima Toshiyasu , Katsuda Masahiro , Hayata Keiji , Kitadani Junya , Yamaue Hiroki
Published: February 2020

450

Background: Patients with peritoneal metastasis have significantly poor prognosis. We have performed pretherapeutic staging laparoscopy (SL) to diagnose peritoneal metastasis for patients with large type 3, type 4 or serosa-invasive gastric cancer. When peritoneal metastasis disappears by chemotherapy for patients with positive peritoneal cytology (CY1) or peritoneal dissemination (P1), we perform the conversion surgery (CS). Methods: We retrospectively analyzed clinical outcomes of 134 patients with advanced gastric cancer who underwent SL between 2005 from 2016. We examined safety and usefulness of CS for patients with CY1 or P1. Results: CY0P0, CY1P0 and P1 were found in 67, 28 and 39 patients, respectively. The median survival time (MST) of patients with CY0P0, CY1P0 and P1 were 39, 21 and 11 months (CY0P0 vs CY1P0; p = 0.029, CY0P0 vs P1; p<0.001, CY1P0 vs P1; p<0.001). In patients with CY1P0, 20 of 26 patients who received chemotherapy underwent the second look SL, and 14 patients (54%) underwent CS (R0) as peritoneal cytology turned negative. These regimens of chemotherapy were S-1/CDDP (n = 9), Docetaxel/CDDP/S-1 (n = 2), SOX (n = 2) and S-1/Docetaxel (n = 1) and the median number of treatment courses was5courses. The MSTs of patients with or without CS were 40 months and 11 months (p<0.001). Then, there was no difference in overall survival between patients with CS and patients with CY0P0 at the first SL (p = 0.866). All patients with P1received chemotherapy, and 11 of these patients underwent the second look SL. As peritoneal metastasis of 7 patients (18%) disappeared by chemotherapy, they underwent CS (R0). The MSTs of patients with or without CS were 31 months and 9 months (p = 0.026). Regarding complications after CS, surgical-site infection and interstitial pneumonia each occurred in one patient (grade II), and intestinal obstruction (grade IIIa) occurred in one patient. There was no mortality. Conclusions: This study suggests that CS is probably safe and may contribute to improve the survival rate of patients with peritoneal metastasis. Moreover, we developed the NSOX regimen, comprised of a combination nab-paclitaxel, S-1 and oxaliplatin, and have performed a phase I/II trial using the NSOX regimen (UMIN000030909).
Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.
Authors: Yau Thomas , Zagonel Vittorina , Santoro Armando , Acosta-Rivera Mirelis , Choo Su Pin , Matilla Ana , He Aiwu Ruth , Cubillo Gracián Antonio , El-Khoueiry Anthony B. , Sangro Bruno , Eldawy Tarek , Bruix Jordi , Frassineti Giovanni , Vaccaro Gina M. , Tschaika Marina , Scheffold Christian , Shen Yun , Neely Jaclyn , Piscaglia Fabio
Published: February 2020

478

Background: The programmed death-1 inhibitor NIVO had durable responses and a manageable safety profile in pts with aHCC in CheckMate 040 (NCT01658878; El-Khoueiry et al. Lancet 2017) and is approved in the United States, Canada, Australia, and elsewhere for sorafenib (SOR)-treated pts with aHCC. In another CheckMate 040 cohort, NIVO + IPI combination therapy had durable responses in SOR-treated pts with aHCC, with objective response rates (ORRs) > 30% in each dosing arm (Yau et al. J Clin Oncol 2019). CABO is also approved for SOR-treated pts with aHCC; a pivotal phase 3 trial reported median overall survival (OS) of 10.2 mo (Abou-Alfa et al. N Engl J Med 2018). This is the first report of efficacy and safety of NIVO + CABO +/- IPI (doublet and triplet) combinations in pts with aHCC. Methods: SOR-naive or -experienced pts with aHCC were randomized to 2 arms: [1] NIVO 240 mg Q2W + CABO 40 mg daily or [2] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W + CABO 40 mg daily. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included ORR (investigator assessed using RECIST v1.1) and safety/tolerability. Data cutoff was January 2019. Results: 71 pts were randomized to NIVO + CABO (n = 36) or NIVO + IPI + CABO (n = 35). Investigator-assessed ORR was 17% (6 pts with partial response [PR]) in the NIVO + CABO arm and 26% (9 pts with PR) in the NIVO + IPI + CABO arm. Disease control rate was 81% for the NIVO + CABO arm and 83% for the NIVO + IPI + CABO arm; median progression-free survival was 5.5 mo for the NIVO + CABO arm and 6.8 mo for the NIVO + IPI + CABO arm. Median OS was not reached in either arm. Grade 3-4 treatment-related adverse events (TRAEs) were reported in 15 pts (42%) in the NIVO + CABO arm and 25 pts (71%) in the NIVO + IPI + CABO arm and led to discontinuation in 1 (3%) and 7 (20%) pts, respectively. No new safety signals were observed in either arm. Updated data describing the efficacy and safety of the combinations will be shown. Conclusions: In pts with aHCC, NIVO + CABO +/- IPI combination therapy led to clinically meaningful responses. Although the triplet had a higher rate of TRAEs observed than the doublet regimen, the majority of AEs were manageable and reversible. Clinical trial information: NCT01658878.
A real-world application of liquid biopsy (LB) in metastatic colorectal cancer (mCRC).
Authors: Procaccio Letizia , Del Re Marzia , Crucitta Stefania , Gianfilippo Giulia , Daniel Francesca , Di Antonio Veronica , Gallimberti Sara , Munari Giada , Zanella Giulia , Alberti Giulia , Rizzato Mario Domenico , Rasola Cosimo , Maddalena Giulia , Prete Alessandra Anna , Bergamo Francesca , Zagonel Vittorina , Lonardi Sara , Danesi Romano , Fassan Matteo , Loupakis Fotios
Published: February 2020

48

Background: First-line decision making is the key to the successful management of mCRC patients (pts). RAS/BRAF status is essential to choose the best targeted agent. In hub centers, a not negligible proportion of pts referred from elsewhere may not have standard tissue-based (STB) molecular results available at the time of first oncologic visit (T0). LB may help circumvent these hurdles. Methods: A monoinstitutional prospective head-to-head comparison of LB versus (vs) STB testing was conducted in a real-world setting. Selection criteria included: mCRC with unknown RAS/BRAF status at T0, tissue from primary or metastases archived in external centers, no previous anti- EGFR agents. At T0, pts underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-free (cf) DNA. Primary endpoint was the comparison of time to LB (T1) vs STB (T2) results. Secondary endpoints were the overall percent agreement (OPA), specificity, sensitivity, positive and negative predictive value (PPV and NPV) of LB. Urinary (u) cfDNA testing was also explored. Results: A total of 33 pts were included. Mean T1 was 7 (2-12) days (d) as compared to 22 (7-65) d mean T2. T2 included a mean time for tissue recovery of 17 d. The OPA between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a PPV of 94% and NPV of 69%. In detail, at STB and LB testing, RAS mutation was found in 50% and 43% of pts; BRAF mutation in 17% and 13%, respectively. LB results included 1 false positive and 4 false negative (FN). FN showed a significantly lower tumor burden (i.e. total tumor volume) at basal CT scan. Concordance between STB and ucfDNA testing was 89%, with a sensitivity of 83% and specificity of 100% recorded for ucfDNA analysis. Conclusions: Faster turnaround time, high concordance and accuracy are 3 key-points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.
Survival by line of therapy of older patients with advanced biliary tract cancer (BTC).
Authors: Bobiak Sarah , Danese Mark D. , Lubeck Deborah P. , Gleeson Michelle L.
Published: February 2020

497

Background: Overall survival (OS) in advanced or metastatic BTC has not been adequately described outside the clinical trial setting. Further, real-world descriptions of OS by line of therapy, including in patients who do not receive systemic chemotherapy, are not widely available. In this study, we used data from a recent cohort of US patients available in the SEER-Medicare linked database to examine OS from diagnosis of advanced or metastatic BTC as well as from initiation of first- and second-line treatment. Methods: Patients with advanced or metastatic BTC diagnosed between 2010 and 2013 were identified in SEER-Medicare, with follow-up through 2014. Demographic and clinical characteristics were analyzed. The Kaplan-Meier estimator was used to describe OS from diagnosis among all patients, OS from diagnosis among patients who did not receive systemic treatment, and OS by line of treatment, from date of treatment initiation. The Cox proportional hazards model was used to identify demographic and clinical factors associated with survival. Results: Of the 1,461 eligible patients aged ≥66 years, 39% had gallbladder, 22% had intrahepatic, 22% had extrahepatic, and 9% had ampulla of Vater cancer. More than two-thirds of patients had stage IV disease, and 38% of patients (n = 558) received systemic chemotherapy. Systemic treatment patients were somewhat younger, more likely to be white, have stage IV cancer and less likely to have mobility limitations (24% vs. 38%) than patients who did not receive systemic treatment. Among all patients, unadjusted median OS from diagnosis was 5.6 months (95% CI 5.0-6.1). Among patients who were not treated, unadjusted median survival was 3.3 months (n = 903; 95% CI 2.8-4.0) from diagnosis. When OS was evaluated by line of treatment, median OS was 8.2 months (n = 558; 95% CI 7.6-9.0) from first-line initiation and 5.6 months (n = 220; 95% CI 4.6-6.5) from second-line initiation. Conclusions: Among newly diagnosed, older US patients, less than half receive systemic treatment for their advanced BTC, and outcomes among both treated and untreated patients remain poor. There is an immediate need for better therapies to treat patients with advanced BTC.
Association of socioeconomic disparities with underutilization of palliative care in patients with metastatic foregut cancer.
Authors: Ju Michelle , Porembka Matthew R.
Published: February 2020

502

Background: Metastatic foregut cancers (MFC) are frequently associated with debilitating symptoms that have significant negative impact on patients’ quality of life. Palliative care (PC) is effective in mitigating disease-, psychosocial-, and treatment-related effects. However, PC remains heavily underutilized. The aim of our study was to characterize the rate of PC utilization in MFC and determine the impact of various clinicopathologic and socioeconomic factors associated with the receipt of PC. Methods: We conducted a retrospective review of 277,957 National Cancer Database patients diagnosed with MFC between 2004-2013. Chi-squared tests were used to analyze differences between groups. Logistic regression was performed to assess the impact of factors on the likelihood of receiving PC. Results: PC utilization increased among all groups over time (12.3% 2004-2006 vs. 14.7% 2007-2010 vs. 16.4% 2011-2013 for all cancers). Female sex, Medicaid, median income < $46,000/year, higher education level, higher Charlson/Deyo Score, and pancreatic or biliary cancers were associated with increased likelihood of PC interventions. Additionally, patients treated at an academic center or integrated network cancer program were more likely to receive PC than patients treated in the community setting. When receipt of PC was stratified by race, Hispanics were significantly less likely to have undergone palliative interventions compared to non-Hispanic Whites (OR 0.70, 95% CI 0.66-0.73). Patients with Medicare or private insurance were less likely to receive PC than uninsured patients (OR 0.92, 95% CI 0.87-0.97 and 0.81, 95% CI 0.77-0.89, respectively). Conclusions: Differences in palliative care receipt rates exist with regards to racial/ethnic and socioeconomic factors such as insurance status, median household income, and education level. Patients receiving care in the community setting were also less likely to receive palliative care than those treated at academic or integrated network cancer program centers. Further studies are needed to delineate why these disparities exist with regards to palliative care utilization.
Comparison of the frequency of adverse events requiring interventions determined by telephone follow up in hepatocellular carcinoma patients treated with sorafenib and lenvatinib.
Authors: Morishita Koki , Suzuki Hidetaka , Tauchi Junko , Takeno Misaki K , Hayashi Kohei , Ikeda Masafumi
Published: February 2020

507

Background: The REFLECT trial demonstrated that lenvatinib is non-inferior to sorafenib for first-line treatment of unresectable hepatocellular carcinoma (uHCC). However, no comparison of the frequency of adverse events (AEs) requiring interventions has been reported yet between uHCC patients receiving sorafenib and those receiving lenvatinib. At the National Cancer Center Hospital East, Japan, pharmacists conduct telephone follow-up (TF) during the first month after the start of treatment with sorafenib or lenvatinib in uHCC patients, for the purpose of detecting and treating AEs early. The aim of this study was to reveal the frequency of AEs requiring interventions between patients receiving sorafenib and those receiving lenvatinib, based on TF. Methods: The characteristics, AEs and contents of intervention by TF of 56 uHCC patients who had been started on treatment with sorafenib and lenvatinib were reviewed retrospectively. The study subjects were 33 patients initiated on sorafenib treatment and monitored by TF from March 2017 to March 2018 (Group S) and 23 patients initiated on lenvatinib treatment and monitored by TF from March 2018 to March 2019 (Group L). Results: The total numbers of TFs in Group S and Group L were 91 and 48, respectively. The rate of AEs requiring interventions was significantly higher in Group S as compared to Group L (Group S, 17.6% (16/91); Group L, 4.2% (2/48); p = 0.032). The frequencies of the interventions, including use of supportive treatments (A), withdrawal of sorafenib or lenvatinib (B), and medical examination (C), differed between the two groups (A/B/C: Group S, 8/5/3 times vs. Group L, 2/0/0 times). The most frequently observed AE that necessitated intervention in Group S was the hand-foot syndrome (HFS) (75.0%, 12/16). Conclusions: The frequency of interventions for AEs appears to be higher in uHCC patients receiving sorafenib than in those receiving lenvatinib. Although a great number of patients taking sorafenib had symptomatic AEs, such as HFS, early detection of the symptoms through TF contributed to prevention of treatment withdrawal on account of AEs.
Early experiences with triple immunochemotherapy in young adults with high-risk fibrolamellar carcinoma.
Authors: O'Grady Claire , Gliksberg Ariel , Kent Paul
Published: February 2020

510

Background: Fibrolamellar Carcinoma (FLC) is a rare liver cancer affecting young adults without underlying liver disease. Surgery is the only proven therapy, and recurrence is common. There are no proven systemic treatments, especially for high-risk FLC (unresectable, relapse, progression, metastatic). Research suggests that immunotherapy may work. We share our experience using systemic “triple immunochemotherapy” (TT): 2 week cycles of 7 days continuous infusion 5FU or oral capecitabine, interferon alpha-2b on days 1,3,5,7 or PEG-Interferon and nivolumab on day 1. Methods: Data from all patients who received TT from 5/2018 to 9/2019 was reviewed to assess tolerability, survival and toxicity. Results: 14 patients were treated with TT of which 10 (8F,2M with a median age of 20) were evaluable. They received a median of 13 cycles (6-31). At time of analysis, the median progression free survival was 6 months, 22% longer than prior to TT, with 80% of patients (8) stable or improving, 1 progression, and 1 who died 2 months after initiating TT. For the 4 patients who achieved surgical remission, none have relapsed (PFS 9 months). Overall objective response (CR+PR) and tumor control rate (CR+PR+SD) were 60% and 80%, respectively. There were no withdrawals from treatment due to side effects, though 2 had dose adjustments. All experienced mild adverse effects, most commonly fever and headache, but only 2 patients had grade 3 toxicity. Conclusions: Our early results of TT for high-risk FLC are promising, with good tolerability and treatment response, particularly in patients who have achieved surgical CR. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.

[Table: see text]
Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Subgroup analyses from CheckMate 040.
Authors: He Aiwu Ruth , Yau Thomas , Hsu Chiun , Kang Yoon-Koo , Kim Tae-You , Santoro Armando , Sangro Bruno , Melero Ignacio , Kudo Masatoshi , Hou Ming-Mo , Matilla Ana , Tovoli Francesco , Knox Jennifer J. , El-Rayes Bassel F. , Acosta-Rivera Mirelis , Neely Jaclyn , Shen Yun , Tschaika Marina , El-Khoueiry Anthony B.
Published: February 2020

512

Background: NIVO monotherapy is approved in the United States and other countries for pts with HCC treated with sorafenib (SOR) based on CheckMate 040 (NCT01658878) results, which reported 14% objective response rate (ORR) and 16-month median overall survival (mOS; El-Khoueiry et al. Lancet 2017). Primary efficacy and safety of NIVO + IPI in pts with aHCC previously treated with SOR were presented recently (Yau et al. J Clin Oncol 2019). Here, we will present subgroup analyses from this study. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety/tolerability, ORR, and duration of response (DOR; investigator assessment per RECIST v1.1). Key secondary endpoints included disease control rate (DCR), OS, and progression-free survival (blinded independent central review [BICR] per RECIST v1.1); key exploratory endpoints included ORR (BICR per RECIST v1.1). Data cutoff was January 2019. Results: A total of 148 pts were randomized. Minimum OS follow-up from last pt randomization date to data cutoff was 28 months. At baseline, 34% of all pts had vascular invasion; 82% had extrahepatic spread; and 91% had Barcelona Clinic Liver Cancer stage C; 84% discontinued SOR because of disease progression and 14% because of toxicity. For all treated pts, ORR was 31% (7 had complete response), with median DOR of 17 months; DCR was 49%; the 30-month OS rate was 37%. NIVO + IPI was well tolerated; 38% of pts had grade 3–4 treatment-related adverse events (TRAEs; most common any grade: pruritus and rash; most common grade 3–4: aspartate aminotransferase increase and lipase increase); 5% had grade 3–4 TRAEs leading to discontinuation. Subgroup analyses based on duration of prior SOR therapy and other pt characteristics will be presented. Conclusions: NIVO + IPI led to clinically meaningful benefits, with a manageable safety profile in pts previously treated with SOR. NIVO + IPI may provide a new treatment option for these pts. Clinical trial information: NCT01658878.
Sex difference in patients with biliary tract cancer receiving chemotherapy: Post hoc analysis of ABC-01, -02, -03, -04, BILCAP.
Authors: Suzuki Eiichiro , Bridgewater John A. , Valle Juan W. , Primrose John Neil , Wagner Anna Dorothea , Lopes Andre , Fox Richard
Published: February 2020

517

Background: The relationship between toxicity from chemotherapy and clinical outcome in biliary tract cancer (BTC) is uncertain. Aim: This post hoc analysis evaluated differences by sex in the frequency of adverse events (AEs) and overall survival (OS) and its impact on progression-free survival (PFS)/recurrence-free survival (RFS) for BTC patients. Methods: Individual patient data were retrieved from ABC -01, -02, -03, -04, and BILCAP study. AEs were graded according to National Cancer Institute's Common Toxicity Criteria v 4.02 and odds ratios along with 95%CI and p-values derived from logistic regression were used to assess the effect of sex on the risk of AEs. Time to event outcomes were evaluated using Cox regression and plotted using Kaplan-Meier plots. All statistical tests were two-sided. Results: Overall 994 patients-data were examined: 86 in ABC-01, 324 in-02, 124 in -03, 13 in -04 and 447 in BILCAP. A total of 484 (49%) were males (M) and 510 (51%) were females (F). 770 patients were evaluable for AEs because a total of 224 patients in BILCAP study belonged to the observation group. Urinary tract infection (M, 1.6%; F, 5.5%), nausea (M, 50.7%; F, 69.9%), vomiting (M, 29.1%; F, 46.1%), alopecia (M, 11.3%; F, 27.3%), are dominant in F, hyperbilirubinaemia (M, 36.7%; F, 29.1%) and thrombocytopenia (M, 43.1%; F, 34.3%) and hiccups (M, 2.4%; F, 0.5%) are dominant in M at any grade. Vomiting (M, 3.5%; F, 7.0%) and fatigue (M, 4.0%; F, 8.5%) are higher in F than in M for grade 3-5. The median OS (M, 16.2 months (Mo); F, 17.5 Mo), PFS (M, 6.4 Mo; F, 6.5 Mo) and RFS (M, 20.8 Mo; F 19.4 Mo) were similar. Amongst the subgroup of patients with gallbladder, F achieved longer OS (M, 11.5 Mo; F 13.3 Mo, 0.73 (95%CI:0.54,0.99), p = 0.041) and RFS than M (M, 20.8 Mo; median PFS for F not reached, HR:0.52 (95%CI:0.27,1.02), p = 0.057). Conclusions: Females with BTC have tended to have more AEs, especially grade 3+. Although no difference was observed in OS, PFS, and RFS between males and females for the overall cohort of patients, females with gallbladder cancer had an improved OS and RFS compared with males. These findings suggest, in BTC, sex may play a role when designing clinical trials as well as in making treatment decisions.
Initial lenvatinib therapy with no prior TACE in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: A proof-of-concept study.
Authors: Kudo Masatoshi , Ueshima Kazuomi , Chan Stephen Lam , Aoki Tomoko , Hagiwara Satoru , Minami Yasunori , Ida Hiroshi , Takenaka Mamoru , Watanabe Tomohiro , Morita Masahiro , Ogawa Chikara , Wada Yoshiyuki , Ikeda Masafumi , Ishii Hiroshi , Izumi Namiki , Hiraoka Atsushi , Aikata Hiroshi , Nishida Naoshi
Published: February 2020

522

Background: Intermediate-stage HCC is a heterogenous population with subgroups of patients that do not benefit from TACE. Hence, we conducted a matched cohort study to compare the efficacy of lenvatinib to TACE in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-7 criteria. Methods: This study first identified 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-7 criteria, without prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected. Propensity score matching was used to adjust for patients’ demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials [1 Phase II and 13 Phase III REFLECT trial], 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The lenvatinib group showed a higher objective response rate (73.3% vs. 33.3%; p < 0.001) and longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Median overall survival was also significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p < 0.01), respectively. Conclusions: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-7 criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib is associated with better outcome than TACE. In particular, leventinib is associated with preservation of hepatic function during treatment while TACE is associated with deterioration of hepatic function.
First-in-human phase I trial of small activating RNA (saRNA) oligonucleotide MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Sarker Debashis , Sodergren Mikael , Plummer Elizabeth Ruth , Basu Bristi , Meyer Tim , Huang Kai-Wen , Evans T.R. Jeffry , Spalding Duncan , Ma Yuk Ting , Palmer Daniel H. , Chee Cheng Ean , Pinato David James , Reebye Vikash , McVeigh Daniel , Raulf Nina , Vasara Jenni , Andrikakou Pinelopi , Habib Robert , Blakey David , Habib Nagy A.
Published: February 2020

554

Background: MTL-CEBPA is the first saRNA to enter clinical trials and targets the transcription factor C/EBPα, a master regulator of myeloid cell differentiation. We have previously reported a favourable safety profile of MTL-CEBPA given as a single agent QWx3 every 28 days, in patients with HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, three out of five patients treated with sorafenib off study have had maintained complete radiological response (CR) of 7-18 months duration; 2 patients demonstrated resolution of lung metastases > 1 year. Here we provide updated data on phase 1 patients treated with sorafenib off study as well as subsequent combination cohorts. Methods: MTL-CEBPA 130mg/m2 QWx3 or BIW and sorafenib 400mg bd were administered to patients with HCC using combination or sequential dosing regimens, in cohorts either tyrosine kinase inhibitor naive or resistant. On treatment liver biopsies evaluated changes in M2 macrophages (CD163). Flow cytometry of peripheral blood determined changes in myeloid cell populations. Results: 12 patients have been treated with MTL-CEBPA co-administered with sorafenib and 14 patients treated with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3) in this group include facial flushing (4/0), raised AST (3/1) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). 1 TKI naïve patient in the co-administration cohort has maintained CR at 7 months and two patients have SD (ongoing at 3 & 4 months both in sequential cohort). IHC in the patient with CR has demonstrated 95% reduction in M2 macrophages with significant decrease in frequency of immature CD10- neutrophils (-85.7%; p = 0.0078), PMN-MDSCs (-49.3%; p = 0.00145) and M-MDSCs (-18.4%; P = 0.0072). All responding patients have underlying HBV or HCV. Conclusions: MTL-CEBPA is a novel saRNA targeting myeloid cells which may result in a significantly enhanced oncological response in HCC of viral aetiology. Updated safety and efficacy data will be presented. Clinical trial information: NCT02716012.
Novel therapeutic avenues for cholangiocarcinoma treatment: A meta-analysis.
Authors: Aljabban Nabeal , Aljabban Jihad , Gurakar Merve , Khorfan Kamal , Syed Saad A. , Gayar Adam , Khan Hajra , Hadley Dexter , Saberi Behnam
Published: February 2020

584

Background: Cholangiocarcinoma (CCA) is a rare cancer of the bile ducts but has been increasing in incidence. The mainstay of treatment of CCA is resection or chemoradiation for more advanced disease, with immunotherapy being an evolving field in treatment. A better understanding of CCA pathogenesis will pave new avenues for treatment. Methods: We employed our STARGEO platform to conduct a meta-analysis of public data from NCBI's Gene Expression Omnibus. We performed meta-analysis with 259 CCA tumor samples against 16 normal intrahepatic duct samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis. Results: Our analysis revealed FXR/RXR and LXR/RXR activation as top canonical pathways. Top upstream regulators identified included HNF1A (with predicted inhibition) and ERBB2 (with predicted activation). The most upregulated genes included several extracellular matrix proteins implicated in cancer including COL1A1, LAMC2 (correlated with poor prognosis in CCA), KRT17 (a keratin implicated in various malignancies but not well described in CCA), and LAMB3 (exerts tumorigenesis through PI3k/Akt signaling). Additionally, we found stark upregulation of the immunophillin FKPBP1A, which is involved in mTOR activation. We also noted upregulation of ubiquitin-associated gene UBASH3B, which inhibits endocytosis in EGFR and has been described in breast cancer but not CCA. From our investigation of immune checkpoint inhibitors, we found upregulation of classically described inhibitors such as CTLA4, TIGIT, and BTLA. In addition, we found upregulation of SIGLEC7, which has been recently shown to suppress immune function by binding to terminal sialic acid on glycans on the surface of immune cells. Conclusions: Our analysis highlights the possible role of ERBB2 and several extracellular genes in the pathogenesis of CCA. We also identify the role of genes not previously described in CCA such as FKBP1A and UBASH3B. Lastly, our results promote the promise of immunotherapy in CCA treatment.
The world-wide incidence of biliary tract cancer (BTC).
Authors: Wang Huifen , Sun Ping , Baria Katherine
Published: February 2020

585

Background: Existing epidemiologic research for BTC is limited to certain subtypes, eg gallbladder cancer (GBC), or combines BTC with liver cancer, and only reports regional statistics. Main sources for global BTC epidemiology (particularly anatomic sites) are literature reviews, which can be subject to limitations like inconsistent classification of subtypes, and varying standard population adjustment and comparison timeframes. Given the increasing incidence of BTC, it is critical to monitor global epidemiology to provide insight to public health management and clinical program development. Methods: We evaluated BTC incidence in 15 countries using the Cancer Incidence in Five Continents database Volume XI (CI5 XI) from the International Agency for Research on Cancer. Most CI5 XI registries cover data from 2008-12 with some variations. Incidence was examined by country, region, and anatomic site (extrahepatic cholangiocarcinoma, ECC; intrahepatic cholangiocarcinoma, ICC; GBC; ampulla of Vater cancer, AVC; and unspecified BTCs). Incidence was adjusted to standard world population and reported as age-standardized rate (ASR; per 100,000 person-years) with standard error (SE). Results: The highest incidence of total BTC was in South Korea (SK; ASR = 3.00, SE = 0.02) and lowest in the UK (ASR = 0.66, SE = 0.01). Overall, BTC incidence was higher in Asian countries than Western, and in Asian-Americans than the general US population (ASR = 1.00, SE = 0.02 and 0.77, SE > 0.01, respectively). In Thailand, BTC incidence was higher in the North than South (ASR = 1.93, SE = 0.05 and 1.05, SE = 0.03, respectively). GBC and ECC are the top common subtypes in most countries reported. SK had the highest incidence of all subtypes, with ASR > 2 in GBC, ECC, and ICC. Outside of SK, GBC and ECC were most common in Japan (ASR = 1.93, SE = 0.02 and 2.66, SE = 0.03, respectively); ICC was most common in Thailand (ASR = 1.73, SE = 0.05) and high in France (ASR = 1.01, SE = 0.03). Conclusions: These registry data support past reports of higher BTC incidence in Asian vs Western countries as well as regional variation within countries. Data also suggests that high BTC rates in Asian populations may not be entirely geographical as Asian-Americans suffer a higher BTC incidence than the overall US population.
Increased frequency of PD-1+CD57+Siglec-7- dysfunctional NK cells in patients with nonalcoholic fatty liver disease.
Authors: Sakamoto Yuzuru , Yoshio Sachiyo , Nagatsu Akihisa , Asahi Yoh , Shimada Shingo , Orimo Tatsuya , Kamachi Hirofumi , Kamiyama Toshiya , Kanto Tatsuya , Taketomi Akinobu
Published: February 2020

589

Background: The proportion of non-alcoholic fatty liver disease (NAFLD) has been increasing as a cause of hepatocellular carcinoma (HCC) worldwide. Natural killer (NK) cells are involved in the first line of immune defense against cancer. NK cell function is regulated by activating and inhibitory NK cell receptors. However, the role of NK cells in the pathogenesis of NAFLD and NAFLD-HCC is still largely unknown. In this study, we aimed to clarify the phenotypic and functional features of NK cells in NAFLD and NAFLD-HCC patients. Methods: We performed mass cytometry (CyTOF) and flow cytometry analysis of NK cells in 33 NAFLD patients (22 chronic hepatitis (CH), 8 liver cirrhosis (LC), 3 with HCC (HCC)) and 9 healthy donors (HDs). We compared surface markers on NK cells in cancerous and non-cancerous intrahepatic lymphocytes (IHLs). We also measured NK cell function in the presence of IL-12 and IL-18. Results: The frequency of NK cells was lower in NAFLD patients compared to HDs. PD-1, CD57, ILT2 were highly expressed, and Siglec-7, NKp30, NKp46 were downregulated on NK cells from NAFLD patients, compared with those of HDs. In NAFLD patients, Siglec-7 levels on NK cells were negatively correlated with PD-1 and CD57, and positively correlated with NKp30 and NKp46. The other inhibitory markers (NKG2A, KIR3DL1 and KIRDL2/L3), activating markers (CD69 and NKG2D) and checkpoint markers (Tim-3 and TIGIT) were comparable between NAFLD patients and HDs. PD-1 and CD57 expression levels on NK cells were also significantly upregulated in NAFLD-HCC patients than those in HDs. CD57 was rarely expressed on NK cells in non-cancerous IHLs, on the other hand, highly expressed in cancerous IHLs. The IFNγ production and CD107a expression on NK cells were also decreased in NAFLD patients. PD-1+CD57+Siglec-7− NK cells were observed in NAFLD patients, rarely in HDs. PD-1+CD57+Siglec-7− NK cells were functionally impaired compared to other NK subsets. Conclusions: In patients with NAFLD, NK cells are reduced and functionally impaired, the reason of which may be the increased proportion of dysfunctional PD-1+CD57+Siglec-7− NK subset, and dysfunctional NK cells might be related to impairment of surveillance for HCC.
First results for Australasian Gastrointestinal Trials Group (AGITG) control net study: Phase II study of 177Lu-octreotate peptide receptor radionuclide therapy (LuTate PRRT) +/- capecitabine, temozolomide (CAPTEM) for midgut neuroendocrine tumors (mNETs).
Authors: Pavlakis Nick , Ransom David Turner , Wyld David , Sjoquist Katrin Marie , Asher Rebecca , Gebski Val , Wilson Kate , Kiberu Andrew Ddembe , Burge Matthew E. , Macdonald William , Roach Paul , Pattison David A , Butler Patrick , Price Timothy Jay , Michael Michael , Lawrence Benjamin James , Bailey Dale L. , Leyden John Charles , Zalcberg John Raymond , Turner J. Harvey
Published: February 2020

604

Background: Single agent 177Lu-octreotate peptide receptor radionuclide therapy is now a standard of care for progressive mNETS. High activity was seen with LuTate and concurrent CAPTEM chemotherapy in a single arm Phase I/II trial. This study was undertaken to determine the relative activity of adding CAPTEM to LuTate PRRT in patients with mNETs. Methods: Non-comparative randomised open label phase II trial of PRRT +/- CAPTEM in patients with mNETs, with 2:1 randomisation: PRRT /CAPTEM (experimental arm) vs. PRRT (control). PRRT /CAPTEM: 7.8GBq LuTate day(D) 10, 8 weekly (wkly) x 4, with b.i.d. oral CAP 750mg/m2 D1-14 & TEM 75mg/m2 D10-14, 8 wkly x 4, vs. PRRT 8 wkly x 4. Primary endpoint: progression free survival (PFS) at 15 months assuming 15 month PFS of 66.4% in the control arm, aiming for PFS rate > 80%; secondary endpoints: objective tumour response rate (complete or partial response) (OTRR), clinical benefit rate (complete or partial response, stable disease) (CBR), toxicity, and QOL. Results: 47 patients enrolled (Dec 2015 - Feb 2018): 33 PRRT/CAPTEM and 14 PRRT. Two patients withdrew prior to treatment. Patient characteristics were balanced except gender (female 58% vs. 14%). Two patients received 2 prior systemic regimens. After a median follow-up of 32 months, the 15 month PFS was 90% (95% CI: 73-97%) v 92% (95% CI: 57-99%); OTRR 25% vs 15%; and CBR 97% vs 92% for PRRT/CAPTEM v PRRT respectively. For treatment related adverse events 22/32 CAPTEM patients experienced one Grade 3 event (69%) vs 5/13 (38%, PRRT); 4/32 pts experienced one Grade 4 event (13%) v 1/13 (8%) respectively. Only one patient failed to complete therapy due to toxicity (PRRT/CAPTEM). Conclusions: This initial planned analysis demonstrates similarly high 15 month PFS for CAPTEM/PRRT relative to PRRT alone. OTRR is numerically higher but at the cost of greater toxicity. Longer follow up is required to determine if the activity of PRRT/CAPTEM is sufficient to warrant Phase III evaluation. Clinical trial information: ACTRN12615000909527.
ENETS single center of excellence experience with the NETest: A real-world assessment of 565 patients.
Authors: Malczewska Anna , Rydel Mateusz , Robek Amanda , Kusnierz Katarzyna , Les-Zielinska Izabela , Czyzewski Damian , Ziora Dariusz , Pilch-Kowalczyk Joanna , Zajecki Wojciech , Kos-Kudla Beata , Modlin Irvin Mark
Published: February 2020

605

Background: There is a substantial clinical unmet need for an accurate and effective blood biomarker of NET disease. We therefore evaluated under real-world conditions the clinical utility of the NETest in a NET Center of Excellence and compare it with the biomarker CgA. Methods: Cohorts: GEP-NET (253), BP-NET (49), colon cancer (37), lung cancers (80), benign lung disease (59) and controls (86). GEP-NETs: 164 (65%) had image-detectable disease or were resection-margin (R1) positive. Grading included G1 [106], G2 [49] and G3 [9]. BP-NETs, 28 of 49 (57%) had evidence of disease. Grading was TC [14], AC [14]. Disease status (stable [SD] or progressive [PD]) determined by RECIST 1.1. Blood sampling: NETest ( n= 565) and NETest/CgA matched samples (135). NETest (PCR) (0-100 score) with positive > 20; progressive > 40. CgA (ELISA). All samples deidentified, and measurement/ analyses blinded. Statistics: Mann-Whitney U-test, McNemar’s test and AUROC. Results: GEPNET: NETest was significantly higher (34.4±1.8, p< 0.0001) in NET disease versus no NET disease (10.5±1, p< 0.0001), non-NET disease (18±4, p= 0.0004) or controls (7±0.5, p< 0.0001). Diagnostic sensitivity was 89%, and specificity 94%. NETest levels were not related to grade (G1: 32±2 vs. G2: 38±3, p= 0.09). BPNET: NETest was significantly higher (30±1.3) vs no NET disease (24.1±1.3, p= 0.0049). Diagnostic sensitivity 100%. Levels were elevated vs controls ( p< 0.0001) and non-NET disease (20±2, p= 0.0001). NETest levels were not related to grade (TC 30±2 vs. AC: 30±2, p= NS). Levels were elevated in PD (55±5.5) vs SD (33.6±2, p= 0.0005). AUCs for detecting disease ranged between 0.89 (GEP-NET) to 1.0 (BE-NET) ( p< 0.0001). Matched GEP-NETS (135): NETest was significantly more accurate for detecting NETS (99%) than CgA (53%, McNemar’s test Chi2= 87, p= 0.0001). sensitivity (99%) and specificity (96%) were better than CgA (37% and 96% respectively). Conclusions: The NETest is an accurate diagnostic test for both GEP- and BP-NEN. It defines clinical status (stable or progressive disease). NETest is significantly more accurate than CgA. The multianalyte genomic blood assessment of NET disease provided clinical information of utility in management.