bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of tumor registry reporting and gastrointestinal oncologist determination of intrahepatic cholangiocarcinomas: A quality review analysis.
Authors: Raufi Alexander , Safran Emma , Breakstone Rimini , Almhanna Khaldoun
Published: June 2022

e16113

Background: Diagnosing cholangiocarcinoma (CCA) can be challenging and these tumors are often misclassified as adenocarcinomas of unknown primary (AUP). Accurate identification is critically important to determine the true incidence and to understand the epidemiology of these cancers. Methods: As a quality assessment, gastrointestinal oncologists at our institution reviewed the tumor registry records of all patients diagnosed with intrahepatic CCA, extrahepatic CCA, hepatocellular carcinoma, adenocarcinoma of unknown primary, and adenocarcinoma not otherwise specified. Mixed hepatocellular/cholangiocarcinoma was excluded. Results: Initially the tumor registry reported 37 cases of intrahepatic CCA at the Lifespan Cancer Institute/Rhode Island Hospital between 2017-2020. However, review of the registry records by gastrointestinal oncologists revealed 10 additional cases of intrahepatic cholangiocarcinoma. These cases had been entered into the tumor registry with diagnosis codes of liver adenocarcinoma NOS (n = 8), liver cancer (n = 1) and liver NOS (n = 1). Following review, a total of 47 cases of intrahepatic CCA and 59 cases of extrahepatic CCA were identified at our institution between 2017-2020. The mean age of intrahepatic CCA was 58 and 48% were women. The mean age of extrahepatic CCA was 73 and 42% were women. The updated numbers were reported to the state tumor registry. Conclusions: Difficulties in diagnosis of cholangiocarcinoma may underestimate the true incidence of this disease in the United States. Careful review of tumor registry data across the United States would likely reveal large discrepancies between actual and reported incidence of this disease and further study is warranted.
Immunotherapy with nivolumab after progression on lenvatinib in advanced hepatocellular carcinoma: A real-world Indian experience.
Authors: Rauthan Amit , Patil Poonam , Murthy Nitin Yashas , Somashekhar S.P. , Zaveri Shabber , Aswath Rajashri , V Prathyush , Jomi Chinnu
Published: June 2022

e16117

Background: Firstline treatment of advanced hepatocellular carcinoma (HCC) till recently has been sorafenib or lenvatinib. Lenvatinib, due to its better tolerability and efficacy (in PFS) over sorafenib, is our preferred first line treatment. Nivolumab, with an objective response rate (ORR) of 14.3% and median duration of response of 16.6 months, was approved by FDA on the basis of the CheckMate-040 trial in patients who progressed or were intolerant to sorafenib. There is very limited data of immunotherapy on progression with lenvatinib. Methods: This is a single center, retrospective analysis of patients with advanced HCC who progressed on first line lenvatinib and received treatment with nivolumab. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and toxicity. Results: 15 patients who progressed on lenvatinib, received nivolumab at 3 mg/kg, 2 weekly as second line therapy between July 2019 to July 2021. There were 2 females and 13 males. Median age was 66 years (37-77 years). All patients were BCLC stage C. AFP was elevated in 11 patients. Child Pugh score was A in 10 patients, and B in 5 patients. 7 patients had background of hepatitis B and 1 had hepatitis C. The number of cycles of nivolumab ranged from 2 to 13 cycles. 3 patients (20%) had partial response, 2 had stable disease and 10 (66.6%) had progressive disease by recist criteria. The ORR was 20% and median PFS was 3 months. Median OS was 8 months. The common side effects were hypothyroidism in 7 (46.6%), fatigue in 4 (26.6%) and skin rashes in 3 (20%) patients. Conclusions: Immunotherapy with nivolumab showed limited efficacy in our patients of HCC who have progressed on lenvatinib. There were few patients who showed durable response, but there are no biomarkers to choose these patients. The immune related side effects were manageable. With the first line approval of combination therapy with atezolizumab and bevacizumab, single agent second line immunotherapy with its limited efficacy, may have a reduced role in HCC management.
Efficacy and safety of regorafenib alone or in combinations for advanced hepatocellular carcinoma: A multicenter real-world study.
Authors: Zhu Haidong , Zhu Xiaoli , Song Yusheng , Wang Qi , Wu Jianbing , Xu Hao , Teng Gaojun
Published: June 2022

e16122

Background: The earlier randomized phase III RESORCE trial demonstrated that regorafenib improved overall survival in advanced hepatocellular carcinoma (HCC) patients progressing on sorafenib treatment, with a median survival of 10.6 months and a hazard ratio of 0.63 (95% CI 0.50-0.79, p < 0.0001). Meanwhile, more data were published from retrospective studies evaluating the sequence of single drug sorafenib and regorafenib in advanced HCC patients treated in real-world settings [eg, REFINE study (N = 1000; 100 from China)].We aimed to explore the efficacy and safety of regorafenib alone or in combinations in advanced HCC patients in a real-world setting. Methods: This retrospective multicenter study included pathologically or clinically diagnosed advanced HCC patients who received regorafenib alone or in combinations in first to fourth line settings for at least 28 consecutive days. The primary endpoints were objective response rate (ORR, RECIST 1.1 criteria) and progression-free survival (PFS). The secondary endpoints included overall survival (OS) rate at 6-month and 12-month, disease control rate (DCR) and safety. Kaplan-Meier method was used to calculate survival data. Results: A total of 61 advanced HCC patients (55 male vs. 6 female, 2 first-line recipients vs. 47 second-line recipients vs.11 third-line recipients vs. 1 fourth-line recipients, median age of 53.5 years) from 6 Chinese centers were included between January 2018 and June 2021. Most patients had BCLC stage C (96.7%) and a Child-Pugh A or B score in 23% or 57.4% of cases respectively. 23 (37.7%) patients received single drug regorafenib therapy, the remaining patients (62.3%) received different combination therapies, including regorafenib plus immune checkpoint inhibitors (ICIs) (29.5%), regorafenib combined with TACE (14.8%), and triple therapy (TKI, ICI, TACE) (18.0%). The ORR and DCR of 61 recipients were 71.7% and 83.3%, with a median PFS of 12.67 months (range 7.47-13.97). The 6-month, 12-month OS rates were 80.2% and 68.9%. In second-line recipients, the 6-month, and 12-month OS rates were 85.6% and 76.7%, with a PFS of 12.67 months. 36 recipients had treatment-related adverse events (TRAEs); most frequent TEAEs (≥5%) included fatigue (12.4%), abdominal pain (8.5%), anorexia (7%), rash (7%), diarrhea (6.2%), and hand-foot syndrome (6.2%). Conclusions: Regorafenib alone or in combination is effective and safe in advanced HCC patients, with a high response rate as well as long survival, especially in second-line recipients.
GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy in patients with biliary tract cancers.
Authors: Zhang Wei , Xiang Dong , Lu Chen , Chen Liu , Song Tianqiang , Lu Wei
Published: June 2022

e16133

Background: The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has made great progress recently in advanced biliary tract cancer (BTC). Multi-target TKI lenvatinib or next-generation sequencing (NGS)-guided molecular targeted therapy are also promising. The aim of this study was to explore the anti-tumor effects of combined GemOX plus anti-PD-1 sintilimab and TKI either by lenvatinib or by NGS-guided targeted therapy if there is available target for local advanced or metastatic BTCs. Methods: This is a prospective single arm clinical study. Patients with local advanced or metastatic BTC were given intravenous infusion of standard GemOX (85mg/m2 oxaliplatin on day 1 and gemcitabine 1000mg/m2 on a 1-8-day schedule of a 3-week treatment cycle) plus 200mg q3w of sintilimab and lenvatinib or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR mutation, lenvatinib for PDGFR and KIT mutation, lenvatinib for FGFR/KIT mutation). The primary end point was objective response rate (ORR), and the secondary end points were progression-free survival (PFS) and overall survival (OS). Tumor response was evaluated according to RECIST v1.1 criteria. Results: From November 2020 to December 2021, 22 patients with locally advanced or metastatic BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA) were enrolled in the regimen, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6 %). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. By December 31st, 2021, the median follow-up time was 13.1 months. The most common adverse events were anorexia (68.2%), nausea (68.2%), vomiting (36.36%), hair loss (45.5%) and bone marrow suppression (63.6%). During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeting IDH2, EGFR, FGFR2, PDGFRA/KIT, BRCA2 and resulted in 1 SD and 4 PR with an ORR of 80% and DCR of 100%. The ORR and DCR were both 100% for 4 patients with programmed cell death ligand-1 (PD-L1) expression. While for the 3 patients with supper-progression markers such as RET, MDM2 and FGF14/STK24, there were 2 SD and 1 PD with an ORR of 0% and DCR of only 33%. Conclusions: In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.
The best benefit population treated with lenvatinib plus anti-PD-1 for unresectable hepatocellular carcinoma.
Authors: Chang Xiujuan , Yu Shumin , Pang Jianzhi , Zhang Wei , Kong Huifang , Huang Jiagan , Zhang Guojie , Zhang Huixin , Gu Yueyue , Zhang Jihai , Dong Zheng , Chen Yan , Yang Bin , Liu Jingping , Yang Yongping , Zeng Zhen
Published: June 2022

e16152

Background: To assess the efficacy and safety of lenvatinib plus anti-PD-1 versus lenvatinib alone in patients with unresectable hepatocellular carcinoma (u-HCC) and explore the characteristics of the benefit population for combination therapy. Methods: This retrospective study included 70 u-HCC patients that were treated with lenvatinib plus anti-PD-1 and 140 patients treated with lenvatinib alone in Fifth Medical Center of Chinese PLA General Hospital and Electric Power Hospital of Beijing from November 2017 to February 2021. Clinical features were balanced by stabilized inverse probability of treatment weighting (SIPTW). The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Subpopulation treatment effect pattern plot (STEPP) revealed differential treatment effects. The safety was evaluated by Common Terminology Criteria for AEs version 5.0. Results: During the median follow-up of 21.6 months, 120 (57%) patients died. The combination group showed better OS (21.4 vs. 14 months, p = 0.041), PFS (8.0 vs. 6.3 months, p = 0.015), ORR (38.6% vs. 22.9%, p = 0.026), and DCR (85.7% vs. 69.3%, p = 0.016) than the monotherapy group in unadjusted cohort, which was similar to SIPTW adjusted cohort. The two groups had comparable and manageable AEs. Macrovascular invasion (MVI, HR 2.6, 95%CI 2.18 - 3.92), extrahepatic spread (EHS, HR 2.16, 95%CI 1.49 - 3.13), and Child-Pugh B (CPB, HR 2.08, 95%CI 1.45 - 2.99) were independent factors of OS. Combination therapy improved the 12-month survival rate by 38% for patients with MVI or EHS and CPB, and by up to 18% in the other population. Conclusions: In conclusion, lenvatinib plus anti-PD-1 showed a favorable efficacy and controllable safety for u-HCC patients in real-world practice. The absolute improvement of the 12-month survival rate with combination therapy was more substantial in patients with major vascular invasion or extrahepatic spread and Child-Pugh B.
Lenvatinib combined with hepatic arterial infusion of modified FOLFOX regime as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria.
Authors: Shi Feng , Mai Qicong , Chen Meng , Li Chunlin , Chen Xiaoming
Published: June 2022

e16154

Background: Transcatheter arterial chemoembolization (TACE) is not effective for intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria (substage B2) and also impairs the hepatic functional reserve, resulting in poor prognosis. This study aimed to investigate the efficacy and safety of lenvatinib combined transarterial infusion chemotherapy with FOLFOX regimen (FOLFOX-HAIC) for substage B2 HCC. Methods: This study retrospectively enrolled and analyzed 18 patients with substage B2 HCC from Nov. 2019 to Nov. 2021. Patients were orally administered with 8 mg(≤60kg) or 12mg(> 60kg) lenvatinib once daily initially, and FOLFOX-HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2,400 mg/m2 for 46 hours) was performed every 3 weeks and up to 6 sessions. Then patients were treated with lenvatinib alone. Patients with downsizing HCC was allowed for potential curative therapies (surgical resection or ablation). Best response according to the RECIST 1.1 and mRECIST criteria, progression-free survival (PFS) and treatment-related adverse events (TRAE) were evaluated. Results: 18 patients (median age: 63.0 years) underwent a total of 77 cycles of HAIC therapy (mean: 4.3; range: 2-6). All patients were classified as Child-Pugh A class. The ORR were 83.3% (RECIST 1.1) and 94.4% (mRECIST), the disease control rate (DCR) was 100% (RECIST1.1/mRECIST). With a median follow-up period of 12.9 months, the median PFS was 10 months. During the follow-up period, no patient died, and 8 of 18 (44.4%) patients experienced progression. 6-, 9-, and 12-months PFS rates were 94%, 74%, and 55%, respectively. TRAE occurred in 15 of 18 patients (83.3%). Two grade 3 TRAE (hepatic encephalopathy and hypertension) was observed. Conclusions: Lenvatinib combined with FOLFOX-HAIC was well tolerated and had shown promising ORR, PFS rates in patients with intermediate-stage HCC beyond up-to-seven criteria. A prospective large-scale trial is needed to justify these results. [Table: see text]
Adjuvant lenvatinib after radical resection in patients with hepatocellular carcinoma (HCC): Preliminary analysis of a prospective, multi-center, single-arm study.
Authors: Zhou Jian , Sun Hui-Chuan , Huang Zhi-Yong , Liu Lianxin , Wen Tianfu , Zhu Xiao-Dong , SHI Yinghong , Gao Qiang , Qiu Shuang-Jian , Ding Zhenbin , Wang Zheng , Ye Qing-Hai , Huang Xiao-Wu , Huang Cheng , Peng Yuan-Fei , Shi Guoming , Wang Xiao-Ying , Fan Jia
Published: June 2022

e16158

Background: Chinese guidelines recommend surgical resection for patients with China Liver Cancer (CNLC) Stage Ia−IIIa HCC (equal to BCLC stage A/B and selected patients with BCLC stage C). Despite treatment, however, patients with CNLC stage IIb (tumor number > 3) and IIIa (vascular invasion) disease have a high recurrence risk and poor overall survival (OS). Here we assessed the efficacy and safety of adjuvant lenvatinib in patients with high risk of disease recurrence. Methods: In this multi-center, single-arm, prospective clinical trial (NCT04227808), patients underwent radical (R0) resection for CNLC Stage IIb/IIIa HCC within 4-6 weeks were eligible and received treatment of lenvatinib (8 or 12 mg/day for body weight < 60 and ≥60 kg, respectively. Dose modifications were permitted due to adverse reactions) until disease recurrence, intolerable toxicity or death. The primary endpoint was 1-year recurrence-free survival (RFS), and secondary endpoints included OS and safety. The total planned enrollment for this study is 50 patients and here we report our preliminary analysis results. Results: A total of 59 patients were screened from Mar 2020 to Dec 2021 and 50 were enrolled in the study. By the cut of date (Dec 31, 2021), 42 patients had at least one set of follow-up data and were included in the present analysis. The 42 patients were predominantly male (83.3%, n = 35), and the median age was 55.5 years (range: 26–73). 78.6% (n = 33) were HBV-positive and 21.4% (n = 9) of disease were non-viral. Five patients (11.9%) had CNLC Stage IIb and 37 (88.1%) had CNLC Stage IIIa HCC. The median duration of treatment was 8.4 months (range: 1.7-18.7) with a median follow-up of 11.3 months (95% CI: 6.6−15.9). 24% (n = 10) had experienced dose reduction or delay. The 1-year RFS rate was 50.5%, while the median RFS was 16.5 months (95% CI: 11.3–21.7). Two deaths occurred: one secondary to disease recurrence and one from hepatic encephalopathy without recurrence. In total, 90.5% (n = 38) of patients experienced ≥1 treatment-related adverse events (AE) of any grade, and five patients (11.9%) had grade 3 treatment-related AEs (thrombocytopenia in two cases, proteinuria in two cases, and elevated aspartate aminotransferase in one case). There was no treatment-related death. Conclusions: Adjuvant lenvatinib was well-tolerated in patients with CNLC Stage IIb/IIIa HCC after R0 resection. The median RFS was longer than our historical data (mRFS = 9.03 months), and these findings warrant further investigation in a controlled study. Funding: Eisai Co., Ltd. Clinical trial information: NCT04227808.
Hepatic arterial infusion chemotherapy with oxaliplatin plus raltitrexed versus oxaliplatin plus fluorouracil in intermediate and advanced hepatocellular carcinoma: A retrospective study.
Authors: Zang Mengya , Li Qi , Hu Xiaoyun , Yuan Guosheng , Li Rong , Guo Yabing , Chen Jinzhang
Published: June 2022

e16166

Background: Hepatic arterial infusion chemotherapy (HAIC) showed promising outcomes for advanced hepatocellular carcinoma (HCC) and was recommended in patients with advanced HCC in Asia. HAIC with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX) was most commonly used in China. However, Continuous infusion (over 46 hours) with fluorouracil was inconvenient for arterial infusion. Raltitrexed, another antimetabolic drug with long plasma concentrations half-life, could be used in short infusions. HAIC with raltitrexed plus oxaliplatin (RALOX) was reported to be effective and safe in HCC. This study aimed to compare efficacy and safety of HAIC with raltitrexed plus oxaliplatin versus oxaliplatin plus fluorouracil in intermediate and advanced HCC. Methods: Sixty-six patients with intermediated and advanced HCC were included in this retrospective study between March 2019 and November 2020. Thirty-three patients were treated with HAIC of FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracilbolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 46 h, every 3 weeks). Another thirty-three patients received HAIC of RALOX (oxaliplatin 100 mg/m2, raltitrexed3 mg/m2, every 3 weeks). Objective response rate (ORR), diseases control rate (DCR), progression-free survival (PFS) and treatment-related adverse events were analyzed. Results: The ORR was both 33.3% in the FOLFOX group and RALOX group per RECIST 1.1 criteria ( P = 1.00). The DCR was 90.9% and 87.9% in the FOLFOX group and RALOX group, respectively ( P = 1.00). The median PFS was 10.7 months in the FOLFOX group versus 7.9 months in the RALOX group ( P= 0.251). Grade 3/4 treatment-related adverse events were comparable between the two groups, including neutropenia, thrombocytopenia, elevated aminotransferase level and nausea. Conclusions: The efficacy and safety of HAIC with raltitrexed plus oxaliplatin was comparable to HAIC with oxaliplatin plus fluorouracil in intermediate and advanced HCC.
Tremelimumab (day 1 only) and durvalumab in combination with transarterial chemoemobilization (TACE) in patients with hepatocellular carcinoma (HCC).
Authors: Buchalter Jemma , Evans Niamh , Browne Iseult , Mac Eochagain Colm , Flynn Calvin , Carroll Hailey Kathryn , Galligan Marie , Bourke Michele , Lester-Grant Amy , Hoey Katherine , Ryan Ronan , Cantwell Colin P , McCann Jeffrey , McDermott Ray , MacNicholas Ross , Duffy Austin G
Published: June 2022

e16175

Background: TACE induces a peripheral anti-tumor immune response, which may be amplified by immune checkpoint inhibitors (ICI). Combining TACE with dual ICI therapy has been shown to be safe and feasible. Recent data has suggested that Day-1 only anti-CTLA4 dosing, at a higher level of 300mg, could lead to a stronger immune response, and drive a greater expansion than lower dose regimens, whilst maintaining a tolerable safety profile. This novel schedule has not previously been combined with TACE. Methods: Patients with HCC (Childs Pugh A/B7, Barcelona clinic liver cancer stage B/C; ECOG 0/1; sorafenib-naive or experienced) were enrolled in a pilot study of tremelimumab at 2 dose levels (DL1: 75mg IV q4-weekly x 4 and DL2: 300mg IV D1 only) in combination with durvalumab (1500mg IV q-28d) and TACE (D36 +/- 96 hours) until progression of disease (per irRECIST) or off-study criteria. Peripheral immune monitoring was performed and tumor biopsies were obtained at time of TACE. Results: 13 patients enrolled on study; N = 3 at DL1 and N = 10 at DL2. M:F 10:3. Median age 70 (65-74). BCLC B/C 4/9. Extrahepatic disease 6/7. Aetiology: NASH (N = 3), alcohol-related disease (N = 1), HCV (N = 2), hemochromatosis (N = 1), unknown (N = 6). 1 pt discontinued due to G3 colitis. All patients evaluable for response with 2/10 pts on DL2 experiencing PR (at 8 weeks) and overall 7/13 SD and 1/13 PD as best response. Updated PFS and OS data to be presented. Conclusions: Tremelimumab (Day 1 only) and Durvalumab in combination with TACE is safe and feasible in patients with HCC. Follow-up is ongoing and full safety and efficacy data will be presented. Clinical trial information: 2019-002767-98.
Sintilimab combined sorafenib as first-line therapy in patients with advanced hepatocellular carcinoma: A single-arm, single-center, open-label, phase II study.
Authors: Wang Jiabei , Liu Lianxin
Published: June 2022

e16182

Background: Combining a PD-1 inhibitor with tyrosine kinase inhibitor has achieved a high response rate for advanced HCC (aHCC) in first-line settings. Sorafenib remains the approved first-line choice for aHCC and demonstrates survival benefit, manageable toxicity and high accessibility in china. This study aimed to explore the efficacy and safety of sintilimab (anti-PD-1 antibody) combined sorafenib in patients (pts) with aHCC. Methods: This is a single-arm phase II study (CTR2000031242). Eligible pts with aHCC, BCLC stage C or B (unresectable or not applicable for TACE), Child-Pugh scores≤7 and ECOG PS ≤ 1 received first-line treatment of sintilimab (200mg, iv, D1) every 3 weeks plus sorafenib (400mg, po, BID) until disease progression or unacceptable toxicity. Primary endpoints was objective response rate (ORR, per RECIST 1.1), and secondary endpoints included safety, disease control rate (DCR), progression free survival (PFS), duration of response (DOR) and overall survival (OS). Results: As of January 30, 2022, 12 pts were enrolled (males 11; median age 54.5 yrs [range 46-68]; BCLC A/B/C: 1/6/5; Child-Pugh A/B7: 5/7; HBV infection 11). All pts received at least 1 cycles of treatments with median cycles 3.5 [range 1-17]. Median follow-up was 3 months [range 0.7-15]. 12 pts were evaluable for response, with an ORR of 17 % (95%CI, 0.1%-41.4%) and a DCR of 33 % (95%CI, 2%- 64%). The median PFS was 3.2 months and median OS was not reached. All pts were evaluable for toxicity, and 6 (50.0 %) pts had at least one treatment-related AE (TRAE). TRAEs occurring in≥20% of pts were pruritus (25%). 1 pt had grade 3 TRAEs. Conclusions: The combination of sintilimab and sorafenib showed promising clinical activities with manageable toxicity for first-line treatment of aHCC. Clinical trial information: CTR2000031242.
Extrahepatic cholangiocarcinoma versus intrahepatic cholangiocarcinoma: A comparison of survival outcomes and use of palliative care in diagnosed patients.
Authors: Nimish Thakral , Gonzalez Teresita , Nano Olger , Shin Sang Ha , Samuels Shenae , Hussein Atif Mahmoud
Published: June 2022

e16192

Background: Cholangiocarcinoma (CCA), a malignancy of the biliary tract epithelium, is of increasing importance due to its rising incidence worldwide. However, it also remains one of the most lethal malignances with a survival rate ranging between 6-16 months. Despite poor outcomes, palliative care remains underutilized in CCA. Determining outcomes, and differences in various CCA types remains crucial in helping patients and clinicians make goal of care decisions with regards to aggressive treatment. Objectives:The objective of this study is to compare survival outcomes between intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA). In addition, it aims to compare the utilization palliative care in either subtype, considering the high morbidity and mortality of the disease. Methods: Pooled cross-sectional observational study of the2004-2017 National Cancer Database (NCDB), which contains almost 400,000 records. The study population included de-identified records of patients with CCA; ages 18-90. Descriptive statistics (frequency, means, and standard deviations) were used. For survival analyses, the Kaplan-Meier method with log-rank test and a multivariate Cox regression model was used. Results: A total of 53,054 patients with CCA were identified. Of which, 63.4% had iCCA and 36.7% of patients had eCCA. There were statistically significant differences between the two cohorts in regard to sex, race/ethnicity, as well as in Charlson Co-Morbidity score. 65.2% of iCCA patients had advanced clinical stages III/IV as compared to 62.5% of eCCA patients. Higher percentage of iCCA patients had bone metastasis (7.8% vs 4.6 %, p < 0.001), pulmonary metastasis (11.5% vs 7.8%; p <0.001) and tumor size greater than 5 cm (62.1% vs 20.7%, p <0.001) compared to eCCA. Regarding treatment, patients with iCCA were more likely to receive multi-agent chemotherapy (35.0% vs 26.2 %, p<0.001). Although statistically significant differences for primary site surgical intervention (25.5% vs 25.0%, p<0.001), as well as for immunotherapy (6% vs 5.4%, p= 0.048), was found, they were not clinically significant. Patients with eCCA had a higher 90-day mortality (11.4% vs 8.2%, p <0.001), with 21% less likelihood of survival compared to iCCA patients (AOR:0.79, CI:0.74-0.84). Palliative care remained underutilized, with a lower utilization in iCCA (15.7% vs 12.5%, p <0.001). Conclusions: Our study demonstrated that iCCA patients have better survival outcomes compared to eCCA patients. This could be due to biological/genomic differences which warrant future investigation. Future clinical trials could also stratify for the location of CCA. Despite CCA’s poor prognosis, palliative care remained underutilized, with lower utilization rates in iCCA compared to eCCA.
Relationship between systemic inflammatory response markers and immune treatment related toxicity (IrAEs) in hepatocellular carcinoma (HCC).
Authors: Dharmapuri Sirish , Ozbek Umut , Saeed Anwaar , Muzaffar Mahvish , Amara Suneetha , Personeni Nicola , Pressiani Tiziana , Nishida Naoshi , Paul Sonal , Bettinger Dominik , Khan Uqba , Fessas Petros , Huang Yi-Hsiang , Kaseb Ahmed Omar , Pillai Anjana , Rimassa Lorenza , Pinato David J. James , Ang Celina
Published: June 2022

e16204

Background: A well-recognized class effect of immune check point inhibitors (ICI) is IrAEs ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Treatment related deaths are reported in ̃5% of patients (pts) treated with ICI. There are, however, no reliable markers to predict the onset & severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) & platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAE (graded ≥2) in HCC pts treated with ICI. Methods: Data was extracted from a large international database from a consortium of 11 tertiary-care referral centers located in the USA, Europe & Asia. NLR=Absolute neutrophil count/ Absolute lymphocyte count (ALC) & PLR=Platelet count/ALC. A cutoff of 5 for was used NLR & 300 for PLR based on literature. We also tested the association between antibiotic & steroid exposure to IrAEs. Results: Clinical data was collected from 361 pts treated between 2016–2020 across the USA (66%), Asia (12%) & Europe (22%) in this multinational database. Most pts received Nivolumab monotherapy (n=318, 74%). 167 (46%) pts developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥2 in 87(52%) pts. Baseline characteristics did not differ significantly between the groups (Table). In a univariable regression model to predict grade ≥2 IrAEs, a PLR >300 was associated with a lower incidence of clinically significant IrAEs (OR = 0.40; p=0.044). NLR >5 was associated with a trend toward lower incidence of clinically significant IrAEs (OR = 0.58; p=0.097). Multivariate analyses confirmed PLR as independent predictive marker of grade ≥2 IrAEs (OR = 0.24; p=0.007). Antibiotics use was not associated with IrAE incidence (OR = 1.02; p=0.954). Steroid use was associated with a >2-fold higher incidence of grade ≥2 IrAEs (OR = 2.74; p<0.001), though it may be noted that 37% of pts received steroids for treatment of IrAEs. Conclusions: Lower NLR & PLR may predict the appearance of IrAEs in HCC treated with ICI, although this conclusion warrants prospective validation. This finding is in keeping with several studies that showed improved survival in pts who develop of IrAEs & have a lower NLR & PLR.[Table: see text]
Immune cell molecular pharmacodynamics of lanreotide in relation to treatment response.
Authors: Alaklabi Sabah , Maguire Orla , Minderman Hans , Iyer Renuka V.
Published: June 2022

e16213

Background: Lanreotide is clinically effective in advanced neuroendocrine tumors (NETs). The inhibitory effect of lanreotide on tumor cells proliferation is due to binding to somatostatin receptors (SSTR1-5). It has been demonstrated that immune cells express SSTR1-5 differentially. The exact effect of somatostatin analogs (SSAs) on T cells function is not understood. Methods: In vitro and in vivo effects of lanreotide on immune cells were investigated, with regards to clinical response correlates. In vitro, SSTR1-5 expression was measured on CD4+ T helper cells, CD8+ cytotoxic T cells, and CD4+CD25+ T regulatory cells from healthy donors (HD), and lanreotide effect on key functional immune response parameters (NFkB, NFAT, ERK1/2 signaling, IFN, and IL-2 production) were studied. To assess in vivo effects of lanreotide on immune cells of NET pts, peripheral blood mononuclear cells (n = 16) obtained pre and 3 months post treatment were studied for gene and protein expression profiles in sorted T cell subsets using a NanoString immune cell panel. Results: HD T cells had high expression of SSTR2 and low/no expression of the other SSTRs. In vitro, lanreotide had no effect on the functional immune response parameters investigated. For the in vivo study, the patient cohort consisted of 8 responders (no progression by 19 months) and 8 non-responders. Clinicopathological features, see table. Pretreatment immunological competence of responders was greater than non-responders, as indicated by upregulation of TCR signaling (in CD4+) and interferon signaling (in CD8+ and T reg). Irrespective of clinical response, lanreotide had most significant effect on CD8+ T cells, down regulating WNT, TCR, and NF-kB signaling. Compared to non-responders, responders had down regulation of cytokine and chemokine signaling but upregulation of ubiquitination and proteasome degradation associated genes. Several myeloid specific genes were found to be significantly changed in the CD4 T helper population, possibly due to co isolated myeloid cells interacting with T cells during sorting. Conclusions: The in vivo immune effects of lanreotide seen reflect the relevance of parameters in tumor microenvironment such as interactions with myeloid components of the immune system not accounted for under the experimental in vitro conditions.[Table: see text]
Efficacy and safety profile of antivascular endothelial growth factor receptor tyrosine kinase inhibitors (avRTKIs) in patients (Pts) with neuroendocrine tumors(NETs): A systematic review and meta-analysis (SRMA).
Authors: Das Satya , Phillips Sharon E. , Lee Cody L , Laferriere Heather E. , Agarwal Rajiv , Ramirez Robert A. , Berlin Jordan , Dasari Arvind
Published: June 2022

e16216

Background: Vascular endothelial growth factor mediated signaling is central to NETs. As such, multiple avRTKIs have been tested in NETs over the last 2 decades, mostly in small phase II studies. In fact, there have been no randomized phase III trials conducted in United States apart from the one leading to approval of sunitinib in pancreatic (p) NETs. Several other avRTKIs have demonstrated clinical promise including surufatinib in phase III trials conducted in China; this drug is currently under FDA review for potential approval. In the current SRMA, we aim to address this deficiency by benchmarking efficacy and safety profiles of avRTKIs. Methods: A literature search was done to identify all phase II and phase III studies of avRTKIs in pts with NETs published between 1/1/2000–7/31/2021. Data abstraction was performed by one author and validated by another. Efficacy was assessed by aggregating progression-free survival (PFS) and overall response rate (ORR) data. PFS and ORR were assessed using a random effects model separately for pts with pNETs and extra-pancreatic (ep) NETs. Toxicity was assessed by calculating the relative risk (RR) compared to control arm and incidence of adverse events (AEs) of interest. Results: Of 92 identified studies, 17 (with 8 individual avRTKIs) were included in the meta-analysis after excluding redundant studies; baseline study characteristics are listed in the Table.A total of 1611 pts (853 men, 758 women) were available for the analysis; 1194 received avRTKIs. The ORR in pNETs was 18% (95% confidence interval (CI) 13-25%) while the ORR in pts with epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.47, p < .01). The median PFS in pNETs was 13.9 months (95% CI 11.43-16.38 months) while median PFS in epNETs was 12.71 months (95% CI 9.37-16.05 months); test for differences between pNETs and epNETs (x12 = .32, p = .57). The incidence (and RR compared to control) of most common ≥ grade 3/4 AEs were hypertension 22.4% (4.48, p < .001), diarrhea 6.4% (RR 3.03, p = .005), neutropenia 5.2% (20.4, p = .036) and proteinuria 4.6% (27.25, p = .001). Incidence (and RR compared to control) of rare but serious complications included non-central nervous system bleeding 8.7% (2.17, p < .001) and cardiac dysfunction 6.4% (2.52, p = .01). Conclusions: Among pts tx with avRTKIs, pts with pNETs demonstrated improved ORR but not PFS compared to these outcomes in pts with epNETs. In addition, this study also benchmarks the incidence and RR of AEs in pts with NETs treated with avRTKIs who are often on therapy longer than other pts.[Table: see text]
Efficacy and safety of neoadjuvant therapy with stereotactic body radiation therapy followed by nab-paclitaxel/gemcitabine plus camrelizumab for resectable, borderline resectable and locally advanced pancreatic cancer: Preliminary results.
Authors: Xue Jun , Hu Yue , Gou ShanMiao , Yin Tao , Li Xin , Wang Jing , Liu Hongli , Yang Ming , Ma Hong , Hu Jianli , Lin Zhenyu , Li Pindong , Wu Heshui , Zhang Tao
Published: June 2022

e16227

Background: Neoadjuvant therapy has been attempted to improve local control and prolong survival for pancreatic cancer patients. However, the standard treatment has not been defined. This trial was to evaluate the efficacy and safety of nab-paclitaxel/gemcitabine plus camrelizumab with or without stereotactic body radiation therapy (SBRT) in patients with resectable, borderline-resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This prospective clinical trial was designed to include patients pathologically confirmed and previously untreated resectable pancreatic cancer, BRPC and LAPC. Patients were randomized to receive either SBRT (5 Gy × 5), four courses of nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8 of each 21-day cycle) plus Camrelizumab 200mg (every three weeks) followed by surgery (Arm A) or only four courses of nab-paclitaxel, gemcitabine and Camrelizumab followed by surgery (Arm B). The primary endpoint was objective response rate (ORR), and the second endpoints were disease control rate (DCR), margin-negative (R0) resection rate, progression-free survival (PFS), overall survival (OS) and toxicity. Results: From March 2021 to Jan 2022, 14 eligible patients were enrolled. Eight patients were randomly assigned to Arm A while 6 to Arm B. The median follow-up duration was 33 weeks. Overall, 9 patients completed preoperative therapy and were eligible for response assessment. Among the 9 patients, 4 (44.4%) had partial response (PR), 4 (44.4%) had stable disease (SD), while one had progressive disease (PD). The ORR was 44.4% (4/9), and DCR was 88.9% (8/9). Five of these 9 patients received pancreatectomy with a resection rate of 71.4% (5/7) and the R0 resection rate was 100% (5/5). The reasons why the other 4 patients did not undergo surgery were progression of disease (n = 1), refusal of surgery (n = 1), and still in the interval of neoadjuvant therapy to surgery (n = 2). The most common adverse events of grade 3 or higher were neutropenia (22.2%), neuropathy (11.1%) and thrombocytopenia (11.1%). Median CA 19-9 level was 116U/ml (2 to 12000) in baseline while decreased to 69U/ml (2 to 4832) before surgery. The median OS or PFS has not been reached yet. Conclusions: The neoadjuvant therapy of nab-paclitaxel/gemcitabine plus camrelizumab with or without SBRT had a good safety and efficacy in patients with resectable pancreatic cancer, BRPC and LAPC. Clinical trial information: ChiCTR2100042415. [Table: see text]
Pathologic and clinical outcomes after neoadjuvant modified FOLFIRINOX and gemcitabine and NAB-paclitaxel for pancreatic cancer.
Authors: Markabawi Danny , Ianiro Cora , Burton Jeffrey , Bolton Nathan , Mizrahi Jonathan
Published: June 2022

e16236

Background: Surgical resection is the only potentially curative option for pancreatic cancer (PC). Unfortunately, just 15-20% of patients (pts) have resectable disease at the time of diagnosis. Recently, for a variety of reasons, neoadjuvant chemotherapy (NAC) has been widely adopted in both borderline resectable and resectable tumors. Most guidelines recommend either modified FOLFIRINOX (mFOLFIRINOX) or gemcitabine and NAB-paclitaxel (GnP) in this setting. This is largely based on phase II trials and extrapolations from trials in the metastatic setting. Here we investigate the difference in tumor regression score (TRS) and clinical outcomes between these regimens. Methods: We retrospectively collected data from pts who underwent resection of PC after NAC at Ochsner Health between July 2012 and July 2021. Primary objective was TRS on operative pathology as assessed by the reading pathologist. Secondary objectives were progression free survival (PFS) from the date of surgery and overall survival (OS) from the date of diagnosis. TRSs were dichotomized as complete (0)/moderate (1) responses versus (vs) minimal (2)/poor (3) responses. The dichotomized score was assessed using log-binomial regression. Kaplan-Meier survival analysis was utilized to estimate PFS and OS. Survival curves were compared by the log-rank test. Results: We identified 96 pts with PC who had NAC followed by surgical resection. Mean age at diagnosis was 65.7. 55% had borderline resectable and 45% had clearly resectable disease at diagnosis. 74 pts received mFOLFIRINOX and 22 pts received GnP. Pts receiving GnP were more likely to be older (71 vs 64, P = 0.001) and have a worse Eastern Cooperative Oncology Group performance status (PS) (P = 0.019). TRSs were similar between the 2 groups with 58.1% and 59.1% in each group achieving a TRS of 2. 7 pts in the mFOLFIRINOX group had TRS of 0 (CR) while 0 pts in the GnP group had a TRS of 0. When controlling for age and PS, risk ratio for a lower TRS (0/1 vs 2/3) with mFOLFIRINOX vs GnP was 1.22 (0.27 - 5.47). 40% and 36.4% had disease recurrence after mFOLFIRINOX and GnP, respectively. Median PFS and OS were 15.6 and 23.4 months (m) in the mFOLFIRINOX group and 18.9 and 27.6 m in the GnP group (P = 0.996, P = 0.933, respectively). On multivariate analysis, controlling for age and PS, hazard ratios for OS and PFS with mFOLFIRINOX vs GnP were 0.86 (95% CI 0.38–2.18) and 1.17 (95% CI 0.53–2.84), respectively. Conclusions: Our study showed no difference in TRS between mFOLFIRINOX or GnP as NAC, although the small number of pts who received GnP precluded statistical inference. Differences in survival outcomes between the two NAC regimens were not significantly different, and outcomes were comparable to those reported in the phase II SWOG S1505 trial. Large prospective trials comparing these two regimens in terms of efficacy and toxicity will be required to better answer these questions.
Effect of silencing tumoral carbohydrate sulfotransferase 15 on T cells in a murine model of pancreatic cancer.
Authors: Ye Juanjuan , Suizu Futoshi , Yamakawa Keiko , Kato Motohiko , Tsuchiya Takayoshi , Yoneyama Hiroyuki , Yahagi Naohisa , Matsuda Yoko
Published: June 2022

e16241

Background: Limited T cell infiltration within immunosuppressive microenvironment is still a hurdle for immune checkpoint inhibition therapies in pancreatic cancer. Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan biosynthetic enzyme and responsible for tumor matrix remodeling. To investigate the role of CHST15 on tumor immune microenvironment, we evaluated the changes in tumor immune cell profiling in a syngeneic mouse model by implanting pancreatic cancer cells with silencing of CHST15 gene. Methods: We constructed CHST15 shRNA-transfected mouse pancreatic cancer cell line KPC, confirmed repression of CHST15 protein then used as tumor-specific CHST15 knocked-down KPC (CHST15 KD). Wild-type KPC (WT) or CHST15 KD cells were implanted subcutaneously to left hind footpad of syngeneic C57BL/6J mice and the tumor growth was monitored. Kinetics of immune cell components were analyzed by immunohistochemical staining for both tumor microenvironment and tumor draining lymph node (TDLN) at weeks 1, 2, 3 and 4 after inoculation (n = 5-6 at each time point). Results: In the WT group, tumor growth was accelerated from week 2 to week 4, while the growth was almost completely inhibited in the CHST15 KD group. Quantitative analyses for immune-stained tissues at week 4 showed the significant repression of CHST15 in the CHST15 KD group. This was associated with the significant increase of CD3+, CD4+ and CD8+ T cells in tumor microenvironment, while T cells were barely detected in the WT group. A significant number of EdU+ proliferating T cells and Granzyme+ CD8+ T cells were found in the CHST15 KD group compared to the WT group. In the TDLN, EdU+ CD4+ and CD8+ T cells were diminished at week 2 from week 1 in the WT group, suggesting active T cell suppression occurred at week 2, which was prior to rapid tumor expansion. In strikingly contrast, massive proliferation of CD4+ and CD8+ T cells was observed in the CHST15 KD group from week 2. RNA expression analysis revealed that anti-tumor T cell activity-related genes including recognition of cancer cells by T cells, cancer antigen presentation, killing of cancer cells, were significantly up-regulated in both tumor and TDLN in the CHST15 KD group. These results suggest that tumoral CHST15 remotely provides T cell suppressive signal to TDLN and blockade of CHST15 reactivates T cell immunity, leading to accelerated tumor-infiltrating T cells. Conclusions: The present study demonstrated that blockade of tumoral CHST15 augments the number of activated tumor-infiltrating T cells and inhibits tumor growth in mouse pancreatic cancer. The effect of tumoral T cell accumulation is followed by boosted T cell priming in immune suppressive TDLN. These findings suggest the possibility of a new immunotherapy by enhancing T cell infiltration in refractory pancreatic cancer.
Effect of obesity on time to progression in patients with resectable and potentially resectable pancreatic cancer.
Authors: Asawa Palash , Vusqa Urwat Til , Karna Rahul , Attah Abraham Attah , Sweeney Ryan , Shah Shivani , Jayakrishnan Thejus , Srinivasamaharaj Srividya , Samhouri Yazan , Monga Dulabh K.
Published: June 2022

e16246

Background: Obesity has been identified as a risk factor for pancreatic cancer. The prevalence of obesity has been on a rise in the last two decades. Obesity is defined by the world health organization (WHO) as body mass index (BMI) > 30.0 kg/m2. Studies have shown obese patients to have worse survival than non-obese patients with pancreatic cancer. However, there is limited data on effect of obesity on disease progression. We sought to identify the relationship between obesity and time to progression in patients with resectable and potentially resectable pancreatic ductal adenocarcinoma (PDAC). Methods: We performed a retrospective review of charts of all patients diagnosed with PDAC from 2017-2019 at Allegheny Health Network. Demographics (including age, sex, and race), treatment details, and time to progression date of diagnosis (rounded off in months) were obtained. Two-sided Mann-Whitney U test and Fischer’s exact test were used to evaluate differences between groups with continuous and categorical variables respectively. Furthermore, paired t test was used to compare mean time to progression between the patients in the obese and non-obese groups. A p-value of < 0.05 was considered as level of significance. Results: Out of the 121 patients who received treatment at our institution, 40 patients who had resectable or potentially resectable disease and had progression of disease were included in the analysis. The median age of patients was 68. The majority were females (60%), Caucasians (90%), had Stage I (65%) and potentially resectable disease (55%). Around 70% of patients were treated surgically, 80% received chemotherapy and 26% received radiation therapy. Twelve out of 42 patients were obese (27.5%). No difference in patient characteristics including demographics, staging, and treatment characteristics (proportion of patients who received surgery, chemotherapy, and radiotherapy) was identified between obese and non-obese group patients. The mean time to progression was 11.9 months in obese group as compared to 13.7 months in non-obese group (p = 0.63). Conclusions: Our study showed no significant difference in time to progression of disease between obese and non-obese patients with resectable/potentially resectable pancreatic cancer. Our study is limited by its small sample size, retrospective nature, and unidentifiable confounding factors that could potentially affect outcomes. Larger scale studies are needed to investigate the effect of obesity as a prognostic factor for disease progression in patients with pancreatic cancer.